Basic Endocrinology

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 Basic Endocrinology
for Students of Pharmacy and Allied Health
Sciences

Andrew Constanti (The School of Pharmacy, University of

London, London, UK)
and
Andrzej Bartke (Department of Physiology, Southern Illinois
University, School of Medicine, Carbondale, IL, USA)

with clinical contributions and case studies by

Romesh Khardori (Division of Endocrinology, Department of

Internal Medicine, Southern Illinois University, School of Medicine
Springfield, IL, USA)

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To Heather, Lisa and Sophia
 Table of Contents

Preface xi

Chapter 1: Introduction and General Principles 1

The Mode of Action of Hormones on Cells 2
Control of Hormone Secretion: The Concept of Feedback Mechanisms 3
Direct Negative Feedback 4
Indirect Negative Feedback 6
Positive Feedback 6
Review Questions 7
References 8
Chapter 2: The Hypothalamus and Pituitary 9
Structure and Histology 9
Histology 10
The Hypothalamic-Hypophyseal Portal System 11
Hypothalamic Releasing and Inhibiting Hormones that Influence the Anterior 11
Pituitary
Gonadotrophin Releasing Hormone 12
Corticotrophin Releasing Hormone 12
Thyrotrophin Releasing Hormone 13
Prolactin-Releasing/Inhibiting Factors 13
Growth Hormone Releasing Hormone 13
Hormones of the Anterior Pituitary 14
Gonadotrophins 14
Thyrotrophin (Thyroid Stimulating Hormone, TSH) 15
Corticotrophin (Adrenocorticotrophic Hormone, ACTH) 16
 vii

Prolactin 19
Growth Hormone 20
Hormones of the Posterior Pituitary 23
Vasopressin 23
Oxytocin 25
Review Questions 26
Clinical Case Studies 26
References 29
Chapter 3: The Adrenal Gland 32
Structure and Histology 32
Histology 32
Biosynthesis and Release of Adrenocortical Hormones 34
Control of Release 34
Glucocorticoids 34
Carbohydrate Metabolism 35
Protein Metabolism 35
Fat (Lipid) Metabolism 35
Anti-inflammatory and Immunosuppressive Actions 35
Response to Stress 39
Mechanism of Action 39
Clinical Disorders 40
Mineralocorticoids 44
Mechanism of Action 44
Clinical Disorders 46
Review Questions 47
Clinical Case Studies 48
References 52
Chapter 4: The Thyroid Gland 55
Structure and Histology 55
Histology 55
viii

Biosynthesis and Release of Thyroid Hormones 55

Control of Release 58
Thyroid Hormones 59
Calorigenesis 59
Influence on Metabolism 59
Maturation of the Central Nervous System (CNS) 60
Skeletal Growth and Maturation 60
Mechanism of Action of Thyroid Hormones 60
Clinical Disorders 61
Thyroid Hyposecretion 62
Thyroid Hypersecretion 63
‘Sick Euthyroid’ Syndrome 67
Review Questions 67
Clinical Case Studies 68
References 70
Chapter 5: Endocrine Secretions of the Pancreas 72
Structure and Histology 72
Histology 72
Pancreatic Hormones 73
Insulin 73
Glucagon 79
Other Islet β-cell Peptides 81
Clinical Disorders 82
Glucagon Hyposecretion 82
Insulin Deficiency 83
Secondary Diabetes 84
Primary Diabetes Mellitus 85
Gestational Diabetes 87
Some Late Clinical Features of Diabetes 87
Insulin Excess 88
 ix

Diagnosis and Monitoring of Diabetes 88

Treatment of Diabetes 91
Acute Complications of Diabetic Therapy 96
Review Questions 97
Clinical Case Studies 98
References 102
Chapter 6: The Gonads and Reproduction 105
The Male Reproductive System 105
Structure and Histology 105
Control of Spermatogenesis and Hormone Release 107
Androgens: Testosterone 108
Clinical Disorders 110
Some Clinical Uses of Androgens 110
The Female Reproductive System 112
Structure and Histology 112
The Ovarian Cycle and Hormone Release 112
The Uterine Cycle 113
Hormonal Regulation of Menstrual Cycle 114
Hormonal Changes during Pregnancy 115
The Menopause 118
Female Sex Hormones 119
Clinical Disorders 120
Some Clinical Uses of Oestrogens and Progestogens 121
Intrauterine Devices (IUDs) 129
Pregnancy Testing 130
Review Questions 130
Clinical Case Studies 132
References 135
Chapter 7: The Parathyroid Glands, Vitamin D and Hormonal Control of Calcium 137
Metabolism
The Parathyroid Glands 138
x

Structure and Histology 138

Parathyroid Hormone 138
Principal Actions 138
Bone Cells Affected by Parathyroid Hormone 140
Mechanism of Action 140
Clinical Disorders 141
Calcitonin 143
Principal Actions 144
Clinical Disorders 144
Therapeutic Uses 144
Vitamin D 145
Principal Actions 146
Clinical Disorders 147
Keratinocyte Differentiation 150
Other Hormones Affecting Calcium Homeostasis 150
Gonadal Steroids 150
Glucocorticoids 151
Growth Hormone 151
Osteoporosis 151
Risk Factors 152
Bone Density Measurements 152
Prevention and Treatment 153
Review Questions 154
Clinical Case Studies 155
References 157

Abbreviations list 160

UK/USA spelling 164
Index 165
 Preface

This textbook is primarily intended to provide undergraduate students of pharmacy with a clear and concise
account of basic endocrine function and dysfunction, at a level sufficient to meet the requirements of first- or
second year qualifying examinations. It is not intended to replace standard texts, but merely to serve as an
accompaniment and convenient revision guide.
The text is based on a series of endocrinology lectures delivered to Pharmacy and Toxicology/
pharmacology students at The School of Pharmacy, University of London, and is presented in an original
stylised format to allow for easier reading/learning; this approach has received a highly favourable response
from students and colleagues here over the past ten years, and was the main impetus for undertaking this
new book endeavour.
Basic Endocrinology for Students of Pharmacy and Allied Health Sciences is arranged into seven
chapters: the first provides a basic introduction to the organization of the endocrine system and the concept
of feedback regulation of hormone release. Subsequent sections deal, in turn, with the hormone secretions
of each major endocrine gland, covering the mechanisms that control hormone release, the principal actions
of the hormones in the body, the most commonly recognised clinical disorders that can arise when
hormones are under or oversecreted, and how these disorders may be diagnosed and managed
therapeutically. Where effects of hormones or major signs/symptoms of endocrine diseases are described,
the text is separated into distinct sections for easier identification.
This chosen format is especially intended to assist students in learning information in a logical ordered
sequence. Review questions and clinical case studies (fictitious) dealing with common endocrine diseases
(prepared with the consultation and kind collaboration of Dr. Romesh Khardori) are included at the end of
every main chapter as a further aid to learning and revision. Drug names and doses (appropriate at the time
of writing) of currently available pharmaceutical preparations with an endocrine basis, and those used to
treat endocrine diseases, are also included throughout, based on current information provided in the British
National Formulary (BNF; September 1996) and the Monthly Index of Medical Specialities (MIMS; June
1997); [equivalent preparations used in the USA are listed for the convenience of overseas readers, based on
the Physicians Desk Reference, 1996]. Since drug information may be subject to updates (with some
preparations being modified or withdrawn), readers are recommended to check with more current editions
of MIMS, BNF or Desk Reference for descriptions of currently available formulations and their usage.
Although the text presented has been based on information from recent articles, reviews and book
chapters, it is not meant to provide a comprehensive coverage of the literature, and more advanced readers are
advised to consult the original references quoted at the end of each chapter for further source of
information.
The field of human endocrinology is a vast and rapidly expanding area, and to achieve our goal of brevity
and a clear focus on key concepts (essential for examinations), it was necessary to sacrifice much detailed
xii

physiological and molecular detail on the synthesis, release, transport and mechanism of hormone action. We
hope that the resultant simplified, logical presentation style we have adopted in dealing with the subject (not
easily found in other endocrine texts) will make the learning of endocrinology a more interesting and
pleasurable experience!
We would like to thank Mr. Derek King (Department of Pharmacology, The School of Pharmacy) for useful
assistance and advice in the preparation of the original illustrations.

Andrew Constanti Andrzej Bartke

London, UK Carbondale, Illinois, USA
Romesh Khardori
Springfield, Illinois, USA
 1
Introduction and General Principles

Effective communication between different parts of the body is absolutely essential for the functioning of
any multicellular organism. In vertebrates, including humans, this communication is maintained by nerve
fibres and hormones; endocrinology is concerned with the nature of these hormones and with hormonal
communication.
Hormones are specialized chemical substances that are produced by particular ductless internal glands of
the body (or groups of secretory cells), and then discharged directly into the bloodstream (in response to a
stimulus) by a process of endocrine secretion. They are then carried via the circulation to other parts of the
body where, in extremely small quantities (10−7–10−12 mol/l), they exert specific regulatory effects on their
selected ‘target’ cells, which possess particular recognition features (hormone receptors). Some hormones
however, act more generally in the body, rather than on a specific target tissue. By contrast, exocrine glands
discharge their secretions via ducts, to the external surface of the body (e.g. milk, sweat) or into the
intestinal lumen (e.g. digestive enzymes).
Modern research in endocrinology also includes studies of locally-produced growth factors, and other
substances that are involved in communication between different cell types within an organ (so-called
paracrine hormones); these substances would not therefore fit into the ‘classical’ concept of hormones and
endocrine control.
The four principal physiological areas of hormonal function include the control of reproduction, the
general growth and development of the body, the regulation of electrolyte composition of bodily fluids and
the control of energy metabolism.
Chemically, hormones may be classified into three main groups: amino acid (tyrosine) derivatives (from
the adrenal medulla and thyroid gland), steroids, structurally related to cholesterol (from the sex glands and
the adrenal cortex) and proteins/polypeptides (from the pancreas and pituitary gland). Many polypeptide
hormones are synthesized and stored by the endocrine cell as inactive longer chain ‘pro-hormones’, from
which the hormone itself is eventually released by enzymatic cleavage.
As a means of communication between cells, the endocrine hormonal system may be contrasted with the
nervous system, where cells communicate electrically by means of precisely defined nerve fibres, releasing
specific neurotransmitters onto other effector cells that they innervate (e.g. nerve, muscle or gland cells).
Nervous communication becomes important when a fast, rapidly modulated message is required e.g. that
involved in skeletal muscle movement (operating within milliseconds), whereas hormonal communication
would seem better suited for providing a more slowly developing (from seconds to several days),
widespread, and longer-term regulatory action. There are also occasions where the two systems can be seen
to interact: i.e. the nervous system may influence endocrine secretion and vice versa. The sources and chief
physiological actions of the major endocrine hormones, and the location of the principal endocrine organs
of the body are given in Table 1.1 and Figure 1.1 respectively.
2 BASIC ENDOCRINOLOGY—CHAPTER 1

The Mode of Action of Hormones on Cells

The mechanisms by which hormones exert their specific effects on target cells can be varied. Protein and
polypeptide hormones do not generally penetrate into the cell interior, but react externally with a specific
receptor located in the cell membrane. This may result in direct membrane effects (e.g. a change in ionic
permeability or solute transport characteristics) or intracellular effects mediated by second messenger
systems within the cell (e.g. the action of the pancreatic hormone glucagon on liver cell membranes to
stimulate glycogenolysis, is mediated by adenylate cyclase and the production of cAMP (cyclic 3′,5′-
adenosine monophosphate; Figure 1.2)). In the case of the pancreatic hormone insulin, the peptide is
believed to interact initially with surface insulin receptors, followed by an internalization of the insulin-
receptor complex and a direct modulation of key enzymatic processes (see Chapter 5).
Steroid hormones on the other hand (e.g. the sex hormones oestradiol, progesterone, testosterone; the
adrenal corticosteroids cortisol, aldosterone and also vitamin D), being lipophilic, enter cells directly to
combine with highly specific receptor proteins in the cytoplasm or the nucleus. This hormone-receptor
complex then acts within the cell nucleus where it binds to special acceptor sites (hormone

Table 1.1. Major endocrine glands and the principal hormones they produce.
Endocrine gland Hormone released Abbr. Main actions
Hypothalamus Gonadotrophin releasing GnRH Stimulation of LH and FSH
hormone release
Thyrotrophin releasing TRH Stimulation of TSH release
hormone
Corticotrophin releasing CRH Stimulation of ACTH
hormone release
Growth hormone releasing GHRH Stimulation of GH release
hormone
Somatostatin SS GH-release inhibiting
factor
Dopamine Prolactin-release inhibiting
factor
Anterior pituitary Luteinizing hormone LH Development of corpus
luteum; stimulation of sex
hormone production
Follicle stimulating FSH Growth of ovarian follicles/
hormone spermatogenesis
Thyrotrophin TSH Release of thyroid hormone
Corticotrophin ACTH Release of adrenocortical
steroids
Growth hormone GH Bone and muscle growth
Prolactin PRL Milk production
Posterior pituitary* Oxytocin Milk ejection
Vasopressin AVP Exerts antidiuretic action
Thyroid (follicles) Thyroxine and tri- T4, T3 Increase in basal metabolic
iodothyronine rate (BMR)
(C-cells) Calcitonin Control of Ca metabolism
 INTRODUCTION AND GENERAL PRINCIPLES 3

Endocrine gland Hormone released Abbr. Main actions

Parathyroid Parathyroid hormone PTH Control of Ca metabolism
Adrenal cortex Cortisol Influences carbohydrate/
protein/fat metabolism
Aldosterone Influences Na+/H2O
balance
Adrenal medulla Adrenaline Noradrenaline Influences blood pressure/
blood sugar level
Ovary (follicle) Oestrogen Stimulates development of
female reproductive tract
(corpus luteum) Progesterone Maintains pregnancy;
stimulates development of
uterus/mammary gland
Testes Testosterone Anabolism; stimulates
development of male
reproductive tract;
spermatogenesis; libido
Pancreas (islets of Insulin Glucagon Control of carbohydrate
Langerhans) metabolism
* Note: oxytocin and vasopressin are really hypothalamic hormones produced in the neurosecretory cells of the
paraventricular (PVN) and supraoptic (SO) nuclei, and transported through the axons of their neurosecretory
cells to the posterior pituitary, where they are stored and eventually released (see Chapter 2).

response elements) on the nuclear DNA, leading ultimately to a change in the rate of transcription of
specific genes. Thyroid hormones are also able to penetrate the cell membrane (mainly by diffusion), but
unlike steroids, they bind directly with high affinity receptor proteins associated with the nuclear DNA to
influence mRNA transcription and protein synthesis (see Figures 3.5 and 4.4 respectively).

cAMP is not the only second messenger that may be involved in mediating hormone actions.
Other signal transduction mechanisms involving, for example, the stimulation of guanylate cyclase (to
produce cGMP, cyclic 3′,5′-guanosine monophosphate), or activation of protein kinase C (via
stimulation of phospholipase C and hydrolysis of membrane polyphosphoinositides to yield inositol-1,
4,5-trisphosphate (IP3) and diacylglycerol (DAG)) may also function to control certain hormone
responses.

Some hormone receptors can also mediate the breakdown of membrane phospholipids via the activation of
the enzyme phospholipase A2, resulting in the production of arachidonic acid and a range of ‘eicosanoid’
metabolites (e.g. prostaglandins, thromboxanes, leukotrienes and plateletactivating factor (PAF)) involved
in allergic responses and inflammation. Arachidonic acid itself may also function as an intracellular
messenger to regulate the activity of certain enzymes (e.g. protein kinase C) and membrane ion channels.

Control of Hormone Secretion: The Concept of Feedback Mechanisms

In order to maintain the correct regulatory function of a hormone, the endocrine gland should receive
constant feedback information about the state of the system being regulated, so that hormone release can be
finely adjusted (closed-loop system).
4 BASIC ENDOCRINOLOGY—CHAPTER 1

Figure 1.1. The location of principal endocrine organs in the body.

The secretory activity of most endocrine target organs is controlled by the anterior pituitary, which is in
turn, under the influence of hypothalamic releasing hormones/factor’s released by hypothalamic nerve
fibres into the pituitary blood supply.

Modulatory feedback loops also exist, that do not involve the hypothalamus and anterior pituitary
e.g. in the control of insulin or parathyroid hormone release.

The principal endocrine feedback mechanisms are as follows:

Direct Negative Feedback

This is the most common ‘closed-loop’ control mechanism, in which an increase in the level of a circulating
hormone, decreases the secretory activity of the cells producing it. The loop is illustrated schematically in
Figure 1.3. In this typical hierarchical arrangement, specialized groups of nerve cells in the hypothalamus
synthesize specific peptides (releasing hormones) that are secreted into the capillary network feeding the
anterior pituitary gland, and then stimulate the pituitary cells to release specific trophic hormones. These
peptides, in turn, stimulate their particular target gland cells to release a target gland hormone into the
 INTRODUCTION AND GENERAL PRINCIPLES 5

Figure 1.2. Schematic diagram showing basic mechanism by which certain hormones can influence target cell activity
by stimulating the production of an intracellular second messenger (cyclic AMP). The binding of hormone to an external
receptor site (R) activates an intermediate stimulatory guanine nucleotide regulatory protein (G protein: Gs) leading to
dissociation of bound GDP (guanosine diphosphate) and association of GTP (guanosine triphosphate). The G protein α-
subunit (+GTP) then dissociates to activate adenylate cyclase (AC) leading to formation of cAMP and activation of
protein kinase A. Subsequent phosphorylation of specific enzymes/cellular proteins causes changes in their activity,
resulting in the hormone effect. cAMP is metabolized to 5′-AMP by the enzyme phosphodiesterase. Note: some
hormone receptors linked to an inhibitory G protein (Gi) can produce a reduction in cAMP formation.

general circulation. The latter then exerts a negative feedback effect on the anterior pituitary, to regulate the
level of trophic hormone release.

Example
The secretion of thyroxine by the thyroid gland is directly controlled by the pituitary trophic hormone
TSH (thyroid stimulating hormone). A high blood level of thyroxine diminishes the output of TSH, so
6 BASIC ENDOCRINOLOGY—CHAPTER 1

Figure 1.3. Schematic representation of a simple endocrine, direct negative feedback loop. Secretion of a specific
releasing hormone by hypothalamic nerve cells, stimulates cells of the anterior pituitary to release a trophic hormone.
This, in turn, initiates release of target hormone from the selected target gland. Circulating levels of target gland
hormone exert a negative (inhibitory) effect on the anterior pituitary to control trophic hormone release.
that the activity of the thyroid gland decreases (and vice versa). Similar feedback mechanisms govern the
secretory activity of other target organs e.g. the adrenal cortex, ovaries and testes.

Indirect Negative Feedback

Here, the target gland hormone inhibits the release of pituitary trophic hormone indirectly, by inhibiting the
secretion of hypothalamic releasing hormone. This type of mechanism appears particularly important in
regulating adrenal and gonadal (testicular and ovarian) hormone secretions.

Example
The corticosteroid hormones secreted by the adrenal gland may indirectly inhibit the release of
corticotrophin (adrenocorticotrophic hormone, ACTH) from the anterior pituitary, by inhibiting the
release of hypothalamic corticotrophin releasing hormone (CRH). In addition, the trophic hormone itself
(ACTH) may act back directly on the hypothalamic neurones to ultimately inhibit its own release (‘short-
loop’ feedback) (Figure 1.4).

Positive Feedback
Such a mechanism is less common, and tends to be intrinsically unstable, as it attempts to increase rather
than stabilize the level of a circulating hormone. A hormone may either facilitate its own release directly, by
acting on the anterior pituitary, or indirectly by stimulating hypothalamic hormone release.

Example
 INTRODUCTION AND GENERAL PRINCIPLES 7

Figure 1.4. Endocrine feedback loops involving direct, indirect and ‘short-loop’ negative feedback mechanisms. The
hypothalamic-pituitary control of corticosteroid hormone production by the adrenal gland is used here as an example
(see Chapter 3). Hypothalamic corticotrophin releasing hormone (CRH) stimulates the anterior pituitary to release
corticotrophin (ACTH), responsible for releasing cortisol from the adrenal cortex. Cortisol inhibits ACTH release by
direct negative feedback on the pituitary, and indirectly by modulating secretion of hypothalamic CRH. The trophic
hormone ACTH also exerts an inhibitory effect on CRH release by a ‘short-loop’ feedback mechanism.

During the female menstrual cycle, a positive feedback loop is activated when the blood level of
oestrogen, released from the ovaries, attains a certain high threshold level. At this point, oestrogen
stimulates (rather than inhibits) the pulsatile release of the gonadotrophic hormones, luteinizing hormone
(LH) and follicle stimulating hormone (FSH) from the pituitary, and also the hypothalamic
gonadotrophin releasing hormone, (GnRH). The resultant surge in gonadotrophin secretion (particularly
LH) leads to ovulation and abrupt termination of the positive feedback loop (see Chapter 6).

Review Questions
Question 1: Define the terms exocrine, endocrine, paracrine and hormone.
Question 2: State the three main chemical groups of hormones.
Question 3: Outline the basic mechanisms by which hormones exert their effects on target cells.
Question 4: Give examples of some signal transduction mechanisms that may be involved in
mediating hormone actions.
Question 5: Explain the principle of hormonal feedback.
8 BASIC ENDOCRINOLOGY—CHAPTER 1

Question 6: Explain the functional relation between the hypothalamus and anterior pituitary in
controlling hormone release.
Question 7: Describe (giving examples) the various types of hormonal feedback mechanism.
Question 8: Draw a diagram showing the location of the principal endocrine organs in the body.

References

• Goodman HM. (1988). Introduction. In Basic Medical Endocrinology, Raven Press, New York, pp. 1–25
• Hedge GA, Colb HD, Goodman RL. (1987). General principles of endocrinology. In Clinical Endocrine Physiology,
WB Saunders Co., Philadelphia, pp. 3–33
• Guyton AC, Hall JE. (1996). Introduction to endocrinology. In Textbook of Medical Physiology, 9th ed. WB
Saunders Company, USA, pp. 925–932
• Thibodeau GA, Patton KT. (1993). The endocrine system. In Anatomy & Physiology, 2nd ed. Mosby-Year Book,
Inc., USA, pp. 402–439
 2
The Hypothalamus and Pituitary

Structure and Histology

The secretions of the hypothalamus and anterior pituitary play a major role in the control of hormone
release from other endocrine glands.
The hypothalamus is situated in part of the forebrain known as the diencephalon, located between the
cerebrum (telencephalon) and the midbrain (mesencephalon); it lies immediately beneath the thalamus,
forming the floor and lower lateral walls of the third ventricle. Although it is a relatively small area of the
brain, it performs many important functions e.g. controlling eating, drinking and sexual drives/behaviour, as
well as essential autonomic nervous activities (regulation of blood pressure and heart rate). It is also
involved in the maintenance of body temperature, controlling the sleep-wake cycle and for setting
emotional states such as fear, pain, anger and pleasure.
Specialized clusters of neurones within the supraoptic and paraventricular nuclei of the hypothalamus
have a vital neuroendocrine function in synthesizing the peptide hormones vasopressin and oxytocin,
which are transported down their axons and released from the posterior pituitary to affect water balance and
uterine contractility/breast milk ejection respectively. Other hypothalamic neurones secrete releasing or
inhibiting hormones into the blood, which influence the secretion of trophic hormones by the anterior
pituitary gland (discussed below); the hypothalamus thus represents a major link between the nervous and
endocrine systems.
The pituitary gland is a dual organ (about 1 cm in diameter), located in a bony hollow at the base of the
brain (just below the hypothalamus), to which it is linked by the pituitary (infundibular) stalk. It is formed
embryologically from oral (epithelial) and neural (hypothalamic) ectoderm fusing to form the anterior lobe
(pars distalis; ca. 75% of the pituitary mass) and posterior lobe (neurohypophysis or pars nervosa)
respectively (Figure 2.1); these two parts function as independent endocrine glands. In some vertebrate species
(e.g. fish, reptiles and amphibians) a distinct intermediate lobe of endocrine tissue (pars intermedia) is
present as part of the adenohypophysis; this portion of the pituitary secretes the peptide hormone
melanocyte stimulating hormone (MSH), important in controlling skin pigmentation changes (see below).
In adult humans, the intermediate lobe is not well developed, and exists only in vestigial form.
The anterior pituitary secretes six principal peptides, known as trophic hormones. With the exception of
growth hormone (GH) and prolactin (PRL), all have their major effects restricted to specific target
organs.
10 BASIC ENDOCRINOLOGY—CHAPTER 2

Figure 2.1. Diagram showing basic anatomical features of the pituitary gland, divided into functionally-independent
anterior (adenohypophysis) and posterior (neurophysis) portions and connected to the hypothalamus by the infundibular
stalk. The pars intermedia (intermediate lobe) is not well developed in man.

Hormone Target Organs(s)

FSH, LH (Gonadotrophins) Gonads (Ovaries/testes)
ACTH (Corticotrophin) Adrenal gland
TSH (Thyrotrophin) Thyroid gland
PRL (Prolactin) Mammary gland
GH (Somatotrophin) Bone, Soft tissue, Viscera
Mnemonic: “F—L—A—T—PRo—G”

Histology
The secretory cells of the anterior pituitary may be classified according to the trophic hormone they release,
and their cytoplasmic staining characteristics; different cells may also be identified by more specific
immunocytochemical methods, using selective hormone antisera, or by in situ hybridization techniques,
which detect the expression of the corresponding hormone genes. The various cell-types and the hormones
they release may be summarized as follows:

1. Somatotrophs Secrete Growth Hormone (GH)

2. Mammotrophs Secrete Prolactin (PRL)
3. Corticotrophs Secrete Corticotrophin (ACTH)
4. Thyrotrophs Secrete Thyrotrophin (TSH)
5. Gonadotrophs Secrete Gonadotrophins (LH/FSH)
Some gonadotroph cells may secrete both LH and FSH.
 THE HYPOTHALAMUS AND PITUITARY 11

The Hypothalamic-Hypophyseal Portal System

Synthesis and release of these trophic hormones is determined partly by direct feedback effects exerted by
the target gland hormones (Chapter 1), and partly by specific hypothalamic releasing or inhibiting
hormones. These agents are secreted by specialized hypothalamic (peptidergic) neurones with nerve
endings in the region of the median eminence. The hypothalamic-hypophyseal portal system of veins, takes
blood from a primary capillary bed in the median eminence, along the pituitary stalk, and enters the anterior
pituitary to form a secondary bed of capillaries; the released hypothalamic hormones readily enter the portal
capillaries and are then transported via the portal veins to the anterior lobe, where they exert their effects
(Figure 2.2).

Hypothalamic Releasing and Inhibiting Hormones that Influence the Anterior

Pituitary
The actions of the principal hypothalamic hormones, and their current therapeutic uses may be summarized
as follows:

Figure 2.2. The hypothalamic-hypophyseal portal system. Hypothalamic peptidergic neurones secrete releasing
hormones that are transported by small hypophyseal portal blood vessels in the median eminence and pituitary stalk, to
affect target cells of the anterior pituitary. These respond by releasing trophic hormones that enter into the pituitary
venous blood supply and are carried to target tissues via the general circulation.
12 BASIC ENDOCRINOLOGY—CHAPTER 2

Gonadotrophin Releasing Hormone

Gonadotrophin releasing hormone (GnRH), (also known as luteinizing hormone releasing hormone (LHRH)
or gonadorelin) is a linear decapeptide, that is released in a pulsatile fashion from hypothalamic GnRH
neurones. Although other hypothalamic and/or gonadal peptides may be involved, both luteinizing hormone
(LH) and follicle stimulating hormone (FSH) release is most likely promoted by a single releasing hormone
(GnRH), whose production can be inhibited by circulating oestrogens (indirect negative feedback). This
phenomenon may largely underlie the effectiveness of the ‘combined’ oral contraceptive pill (see
Chapter 6).
Synthetic gonadorelin (Fertiral) is available in the form of an injection (500 µg/ml) given intravenously
or by pulsatile subcutaneous injection for the treatment of infertility and amenorrhoea (cessation of
menstruation) in women, induction of puberty or for assessment of pituitary function.

Because of the very short half-life of GnRH in the circulation, there has been considerable
interest in modifying the GnRH molecule to produce stable analogues that may be more suitable for
clinical applications. A number of synthetic analogues such as buserelin, goserelin, leuprorelin or
nafarelin, with potent GnRH activity (agonistic analogues) have been developed, but their clinical
testing revealed unexpected inhibitory rather than stimulatory effects on the pituitary-gonadal axis,
when given continuously. Thus, after initial stimulation of gonadotrophin release, the prolonged (2–4
week) administration of these agents (by subcutaneous injection or nasal spray), ultimately causes a
down-regulation and loss of GnRH receptors from the pituitary gonadotrophs, a reduced
responsiveness to further stimulation by GnRH (or agonistic GnRH analogues) and a decrease in
gonadotrophin (and gonadal steroid) release. GnRH analogues have found clinical application mainly
in the treatment of advanced, androgen-dependent prostatic cancer, endometriosis (see Chapter 6),
precocious puberty and other conditions where suppression of gonadotrophin release is desirable.

Analogues of GnRH which bind competitively to GnRH receptors but do not exhibit GnRH agonist activity
(GnRH antagonists) have also been developed; their early clinical usage was however, complicated by local
skin reactions (reddening, oedema) at the site of injection, due to a histamine-releasing action. Some of the
recently synthesized GnRH antagonist analogues are devoid of these untoward side effects, and show
considerable promise for future use in the control of fertility and for other clinical applications where
pituitary suppression of GnRH action is required.

Corticotrophin Releasing Hormone

Corticotrophin releasing hormone (corticoliberin, CRH) (also referred to as corticotrophin releasing factor,
CRF) is a 41 amino acid peptide, responsible for controlling the secretion of corticotrophin (ACTH). This
action can be influenced by several other substances: in particular, glucocorticoid hormones (Chapter 3),
that inhibit the releasing effect of CRH on the pituitary corticotrophs (may be important in negative
feedback control), and vasopressin, oxytocin (see p. 16–17), or adrenaline which potentiate it. Various
endogenous neurotransmitters are also involved in the regulation of hypothalamic CRH release: e.g.
acetylcholine and serotonin (5-hydroxytryptamine; 5-HT) directly facilitate its release, whereas the
inhibitory amino acid G ABA (γ-aminobutyric acid), dopamine and noradrenaline have release-inhibitory
effects. Glucocorticoids may also inhibit the release of CRH at the hypothalamic level (indirect negative
feedback). The CRH receptor on the pituitary cells appears to be linked to the adenylate cyclase second
messenger system.
 THE HYPOTHALAMUS AND PITUITARY 13

Thyrotrophin Releasing Hormone

Thyrotrophin releasing hormone (TRH) was the first hypothalamic factor to be isolated and characterized. It
is a simple tripeptide (pyroGlu-His-Pro-NH2), and is particularly potent in promoting the release of
thyrotrophin (TSH) (picogram quantities are effective). TRH also promotes the secretion of pituitary
prolactin. Interestingly, TRH may be found elsewhere throughout the brain and spinal cord (where it may
act as a neuromodulator or transmitter) and also in the gastrointestinal tract and pancreas, although its
functions here are uncertain. Synthetic TRH (Protirelin) is available for clinical use (by intravenous
injection) in thyroid function tests.

Prolactin-Releasing/Inhibiting Factors
Although TRH is believed to be an important hypothalamic prolactin-releasing factor, prolactin can also be
released by several other endogenous peptides e.g. oxytocin, vasoactive intestinal polypeptide (VIP),
angiotensin-II, substance P, galanin and neurotensin. The prolactin release-inhibiting factor however, is a
simple non-peptide, dopamine, that is released into the portal blood supply by specific dopaminergic
neurones originating in the hypothalamus. This tonic inhibitory action of dopamine, effectively maintains
prolactin secretion at a minimal level, until required during lactation, or release in response to stress.

About 70% of hypothalamic prolactin release-inhibiting activity can be attributed to dopamine,

while the remaining 30% can be accounted for by other factors including GnRH-associated peptide
(GAP). GAP is a 56 amino acid peptide derived from the GnRH precursor protein (proGnRH), that is
believed to be co-produced with GnRH in the same population of hypothalamic neurones and co-
secreted into the pituitary portal blood to affect prolactin release.

Growth Hormone Releasing Hormone

Growth hormone releasing hormone (GHRH) (somatocrinin) is a 44 amino acid peptide (derived from a
larger precursor molecule) that is responsible for stimulating (specifically) the synthesis and release of
pituitary growth hormone (GH). It is the 1–21 N terminal fragment of the molecule that appears to be
necessary for biological activity. Although GHRH bears a strong structural resemblance to the pancreatic
hormone glucagon, and is also known to be present in the pancreas and upper intestinal tract, its
physiological functions outside the brain remain uncertain. A synthetic analogue of GHRH, sermorelin
(Geref 50) (administered by intravenous injection) is now available for use as a diagnostic test for normal
pituitary secretion of GH (see also below: the insulin tolerance test). Other small peptide and non-peptide
derivatives have also recently been developed which show potent G H-releasing properties (GH
secretagogues, e.g. hexarelin) and may eventually prove useful for the treatment of short-stature children with
abnormal G H secretion. Interestingly, these agents appear to stimulate the pituitary in synergy with GHRH,
although they interact with a different type of receptor.
A hypothalamic GH-release inhibiting hormone, somatostatin (SS) (often referred to as somatotrophin
release inhibiting hormone, SRIH) has also been characterized and synthesized. It is a cyclic 14 amino
acid peptide, with a powerful, receptor mediated (non-competitive), inhibitory effect on the action of GHRH
on anterior pituitary somatotrophs; it is also capable of inhibiting the basal secretion of TSH and prolactin
from the pituitary gland. SS can be found elsewhere in the brain and spinal cord, the gastrointestinal tract
(myenteric plexus), and in the pancreas, where it suppresses the release of both insulin and glucagon. A stable,
long-acting analogue of SS, octreotide (Sandostatin), is available as a therapeutic agent (given by
14 BASIC ENDOCRINOLOGY—CHAPTER 2

subcutaneous injection) in the short-term treatment of acromegaly (see p. 15), and some hypersecretory
endocrine tumours (e.g. insulinomas, glucagonomas and VIPomas).

VIP (vasoactive intestinal polypeptide; 28 amino acid residues), is a member of the secretin-
glucagon family of peptides, found throughout the gastrointestinal tract (mainly the pancreas and
neurones of the duodenum) and also in the brain (hypothalamus and cerebral cortex). Patients with
abnormally high plasma levels of VIP arising from VIP-secreting tumours, can suffer from severe
watery diarrhoea and electrolyte imbalance.

Hormones of the Anterior Pituitary

Gonadotrophins
Gonadotrophins are complex glycoprotein (carbohydratecontaining) hormones of around 28 kDa molecular
weight. They each consist of two glycoprotein subunits α and β, with the β sequence being different for LH
and FSH respectively. The common a subunit appears to be necessary for the interaction of the gonadotrophins
with their target gland receptors.

LUTEINIZING HORMONE (LH)

In females, a surge of LH (in co-operation with FSH) at midcycle, induces ovulation, then maintains the
corpus luteum after ovulation; (this secretes progesterone). In males, it stimulates the interstitial (Leydig)
cells in the testes to produce testosterone.
Control of release is primarily via hypothalamic GnRH (pulsatile), and modulated by feedback loops
involving the ovarian or testicular steroids. The human chorionic gonadotrophin (hCG), produced by the
placenta during pregnancy, has a similar structure to LH, and exhibits LH-like activity.

FOLLICLE STIMULATING HORMONE (FSH)

This hormone (along with LH) promotes the development of the ovarian follicle (and consequent oestrogen
production) and stimulates spermatogenesis in males.
Recombinant FSH (Puregon) is now available for treatment of anovulatory infertility in women
undergoing assisted conception.
Control of release: is principally via GnRH, and also shows a pulsatile pattern (less marked than that of
LH). In the male, FSH also stimulates the Sertoli cells of the testes to produce a peptide, inhibin which
provides the main direct negative feedback control of FSH biosynthesis and release from the anterior
pituitary. It has little or no effect on LH release. In the female, a similar peptide released by granulosa cells
of the developing ovarian follicle, appears to serve a similar inhibitory function on FSH secretion. Inhibin
may also have an important intragonadal (paracrine) function in enhancing the LH-stimulated production of
testicular and ovarian steroids (see Chapter 6) (Figure 2.3).
Hyposecretion of gonadotrophins leads to amenorrhoea, sterility and loss of sexual potency. In the
young, the sex organs and secondary sexual characteristics fail to develop (delayed puberty).
Hypersecretion of FSH and LH is extremely rare, but in children it could lead to sexual precocity
(excessive premature development).
 THE HYPOTHALAMUS AND PITUITARY 15

Figure 2.3. Control of gonadotrophin (LH, FSH) and gonadal steroid secretion by the hypothalamus and anterior pituitary.
Pulsatile release of GnRH by the hypothalamus induces release of LH and FSH from the pituitary, that stimulate the
ovaries (in the female) to produce oestradiol and progesterone, and the testes (in the male) to produce testosterone; these
steroids exert negative feedback control of GnRH and LH release at the hypothalamic and pituitary levels. Secretion of
FSH is controlled mainly by feedback loops involving the gonadal peptides inhibin and activin.

Thyrotrophin (Thyroid Stimulating Hormone, TSH)

Like the gonadotrophins, this glycoprotein hormone consists of two polypeptide chains, α and β, with the α
chain being identical to that found in LH, FSH and hCG. Its primary action is to stimulate the thyroid gland
to secrete the thyroid hormones tri-iodothyronine (T3) and thyroxine (T4). This is achieved by:

1. Stimulation of thyroid iodide uptake;

2. Increased synthesis of the thyroidal storage protein, thyroglobulin;
3. Stimulation of T3/T4 synthesis and release, and
4. An increase in the thickness of the follicular epithelium and vascularity of the thyroid gland. Excess
TSH can result in an enlarged thyroid (goitre).

Control of release is via hypothalamic TRH. TSH release is also influenced by circulating thyroid
hormones at the pituitary level (direct negative feedback) and by some other circulating endocrine
hormones e.g. cortisol, growth hormone and oestrogens. The hypothalamic factors somatostatin and
dopamine exert some tonic inhibitory influence on TSH secretion (Figure 2.4). The normal plasma level of
TSH is within the range 0.5–5 µU/ml (about 10 pM).
Hyposecretion produces a clinical picture similar to primary thyroid deficiency.
Hypersecretion gives the symptoms of hyperthyroidism similar to Graves’ disease (see Chapter 4).
16 BASIC ENDOCRINOLOGY—CHAPTER 2

Figure 2.4. Regulation of pituitary thyrotrophin (TSH) secretion via release of hypothalamic TRH and by direct
negative feedback effects of the thyroid gland hormones T3 and T4 on the anterior pituitary. Dopamine (DA) and
somatostatin (SS) released by specific hypothalamic neurones, also exert a tonic inhibitory action on pituitary TSH
release.

Corticotrophin (Adrenocorticotrophic Hormone, ACTH)

This single-chain peptide hormone consists of 39 amino acids and is derived from a larger precursor molecule,
preproopiomelanocortin (POMC). It stimulates the adrenal cortex to secrete glucocorticoids (mainly
cortisol) and also small amounts of sex hormones (androgens and oestrogens); this action is mediated by
specific high affinity ACTH receptors present on the adrenal cell membrane, linked to intracellular
production of cAMP. The synthetic preparation tetracosactrin (Syncatheri) containing the first 24 amino
acid sequence of ACTH, may be given by intramuscular or intravenous injection to test adrenocortical
function.

Several other peptide fragments derived from the POMC prohormone are also released from the
pituitary along with ACTH during stress; in particular, β-lipotrophin (β-LPH) and β-endorphin
(Figure 2.5). Beta-endorphin belongs to the class of endogenous opioid compounds that are normally
produced by the brain and other tissues, and bind to the same receptors which interact with morphine,
heroin and other opioid drugs. Endogenous opioids produced in the CNS are believed to exert anti-
nociceptive and pain-reducing effects. However, the hormonal role (if any) of these peptides produced
in the pituitary, has not been fully established. In reptiles and amphibia, further processing of ACTH
or γ-lipotrophin within the intermediate lobe of the pituitary (pars intermedia; not well developed in
humans) can occur to yield α- or β- forms of the melanocyte stimulating hormone (MSH). This
peptide acts on the skin melanocytes to disperse melanin pigment, and therefore to induce darkening
of the skin (important for camouflage). In view of the structural overlap between ACTH and MSH,
the former can, in excess amounts, exert MSH-like activity. Interestingly, POMC and POMC-derived
 THE HYPOTHALAMUS AND PITUITARY 17

Figure 2.5. Peptide hormone fragments derived from the sequential proteolysis of the precursor molecule (prohormone)
preproopiomelanocortin (POMC) in the anterior pituitary gland. In certain reptiles and amphibians, corticotrophin
(ACTH) can be further processed by cells of the pars intermedia to produce α-MSH (comprising the first 13 amino
acids of ACTH) and γ-lipotrophin can be cleaved to yield β-MSH (melanocyte stimulating hormones). CLIP is a
corticotrophin-like intermediate lobe peptide. Numbers in brackets indicate length of amino acid chains.

peptides are also produced locally in the skin by melanocytes and keratinocytes, and may therefore be
important for maintaining normal skin functions.

Control of release is mainly via hypothalamic CRH, and regulated by circulating cortisol (direct and
indirect negative feedback) (Figure 2.6). Pharmacological inhibition of release can also be produced by
administration of synthetic corticosteroid analogues. ACTH secretion shows a characteristic circadian
rhythm (low level around midnight-peak at around 6 a.m.). Release of ACTH (and POMC cleavage
products) is promoted by stress e.g. trauma, pain, fear or hypoglycaemia (low blood sugar level) and also by
the posterior pituitary peptide vasopressin. The latter may, in fact, act synergistically with CRH to regulate
ACTH release from pituitary cells.
Hyposecretion of ACTH (rare) causes failure of cortisol secretion, a general lack of health and well
being, a reduced response to stress and skin depigmentation.
Hypersecretion (due to a pituitary microadenoma, or ‘ectopic’ non-endocrine tumour) will result in
Cushing’s syndrome (Chapter 3). When Cushing’s syndrome arises due to a pituitary tumour, it is called
Cushing’s disease, which nowadays is treated either by surgical (trans-sphenoidal) removal of the adenoma
(where possible), or by external pituitary irradiation therapy. Alternatively, where surgery is inappropriate,
patients may be treated with aminoglutethimide (Orimeten) an aromatase enzyme inhibitor which also
interferes with adrenal steroid synthesis; maintenance doses of a glucocorticoid (e.g. hydrocortisone;
Chapter 3) may also need to be given in this case. [The use of aromatase inhibitors in the treatment of
advanced breast or prostate cancer is discussed in Chapter 6].
18 BASIC ENDOCRINOLOGY—CHAPTER 2

Figure 2.6. Control of pituitary corticotrophin (ACTH) release by hypothalamic releasing hormone (CRH) and negative
feedback loops involving the adrenal corticosteroid cortisol, acting back on the anterior pituitary and hypothalamus. The
secretion of CRH by the hypothalamus is primarily influenced by various stressful stimuli (e.g. acute trauma, pain, fear,
or hypoglycaemia), by the sleep-wake cycle, and also by endogenous neurotransmitters (5-HT and acetylcholine
facilitate CRH release, whereas GABA, dopamine and noradrenaline have an inhibitory effect). Arginine-vasopressin
(AVP) secreted by the hypothalamus, is a powerful stimulus of pituitary ACTH release. ACTH itself can inhibit CRH
release by a negative feedback effect on the hypothalamus (‘short-loop’ feedback). Various cytokines, including
interleukins (IL-1, IL-6) and tumour necrosis factor-α (TNF-α) released by macrophages, monocytes, endothelial cells
and lymphocytes during inflammatory/immune responses, have a direct stimulatory effect on hypothalamic CRH and
pituitary ACTH release (see Chapter 3).

Under certain circumstances, treatment may involve bilateral adrenalectomy (removal of the adrenal
glands). However, following this, the negative feedback effect of cortisol on the pituitary tumour is lost,
allowing it to grow further and secrete more ACTH, resulting in excess skin pigmentation (a symptom of
Nelson’s syndrome).

A patient that has undergone total adrenalectomy will require lifelong supplements of adrenal
steroids (glucocorticoids and mineralocorticoids; Chapter 3) to remain alive and healthy.
 THE HYPOTHALAMUS AND PITUITARY 19

Prolactin
Prolactin (PRL) is a single chain peptide (198 amino acids) with a chemical structure very similar to that of
growth hormone (GH). It is principally involved (in co-operation with other hormones) in the development
of the female breast, and in the initiation and maintenance of lactation (milk production) shortly after
childbirth. It is released from pituitary mammotroph cells in increasing amounts during pregnancy (under
the influence of circulating oestrogen), and acutely in response to suckling, by means of a sensory neural
reflex arising in the nipple. The suckling reflex also depends on a prior ‘sensitization’ of the secretory
alveoli of the breast by oestrogen. Although its function in human males is unknown, excess prolactin levels
can exert powerful inhibitory effects on both male and female gonadal function and libido (sexual drive),
primarily via actions on the CNS and by suppression of GnRH release.
Control of release is via (non-specific) hypothalamic inhibiting and releasing factors. The dominant
tonic influence is inhibitory via release of hypothalamic dopamine, from dopaminergic neurones, into the
portal circulation. The dopamine receptor agonist bromocriptine can thus be effective in controlling
excessive prolactin secretion. Release is promoted by various substances including TRH, VIP and also by
various stresses e.g. fear, hypoglycaemia, or anaesthesia/surgery. The posterior pituitary peptide oxytocin is
also a powerful releasing agent, and may be involved in the suckling-induced response. Prolactin exerts a
stimulatory short-loop feedback effect on the hypothalamic dopamine-secreting neurones, thereby inhibiting
its own release (Figure 2.7). Like ACTH, plasma levels of prolactin show a distinct circadian rhythm
(highest level at night) in both males and non-pregnant females; this rhythm disappears during pregnancy
and lactation, when prolactin release is at its highest.
Hyposecretion of prolactin leads to failure of lactation in women.
Hypersecretion of prolactin (hyperprolactinaemia) may result from a pituitary tumour (prolactinoma;
one of the most common type of pituitary tumour) or hypothalamic disease. Infertility and menstrual
complaints are the principal symptoms; in men, this manifests as a decreased libido, inadequate sperm
production and impotence, whereas in women, there may be a complete lack of menstruation.
Overproduction of prolactin may also lead to inappropriate (non-pregnant) milk production
(galactorrhoea). The latter condition may also occur when hypothalamic dopamine action is antagonized by
therapeutic administration of certain antidepressants and tranquillizers such as the phenothiazine
trifluoperazine (Stelazine) or the butyrophenone haloperidol (Serenace) prescribed for psychiatric
disorders.
The effects of excess prolactin secretion on gonadal function is believed to result from (a) an indirect
inhibition of LH/FSH release by blocking the synthesis and release of hypothalamic GnRH and (b) a direct
inhibition of LH/ FSH action on the ovaries and testes.

There is a tendency for ovulation to be inhibited during the period of breast feeding, although this
inhibition is by no means reliable.

Treatment. This may be directed at the underlying tumour (surgical removal or radiotherapy) or by oral
administration of the dopamine D2 receptor agonist bromocriptine (Parlodel) (1–10 mg daily), which
should reduce the plasma prolactin concentration and tumour size, and eventually restore gonadal function
back to normal. This drug is also used to suppress unwanted lactation after childbirth and in the treatment of
acromegaly (see below) and cyclical benign breast disorders.
Two other more selective and longer-acting dopamine D2 agonists, cabergoline (Dostinex) and
quinagolide (Norprolac) have recently been introduced, with actions and uses similar to those of
bromocriptine. A sustained-release injectable form of bromocriptine (Parlodel-LAR; given by intramuscular
20 BASIC ENDOCRINOLOGY—CHAPTER 2

Figure 2.7. Control of prolactin secretion by hypothalamic releasing/inhibiting factors. The principal prolactin-releasing
hormones are TRH (thyrotrophin releasing hormone) and oxytocin (released during the infant suckling response);
release is also promoted by various stress factors. Secretion of dopamine (DA) by specific hypothalamic neurones,
exerts a tonic inhibitory influence on pituitary prolactin release. Prolactin itself can inhibit its own release by
stimulating hypothalamic dopamine production (positive short-loop feedback). Excessively high levels of prolactin can
inhibit gonadal function.

injection) is also currently under clinical investigation for the medical treatment of large (>10 mm)
prolactin-secreting macroprolactinomas (associated with severe visual impairment) and also
microprolactinomas (<10 mm size).

Growth Hormone
Growth hormone (GH; somatotrophin) is the most abundant of the pituitary trophic hormones, but unlike
them, it can influence a variety of target tissues. It is a single chain peptide containing 191 amino acids and
2 disulphide bridges. GH promotes linear growth of bone (particularly long bones) by stimulating the
growth and calcification of the epiphyseal cartilage cells; it also influences the growth of the visceral organs,
adipose and connective tissue, endocrine glands and striated muscle. GH levels are at their highest during
early childhood and particularly at puberty (it is essential for normal gonadal development), then levels
steadily decline throughout life, implying that G H may not be essential for normal adult health. However,
some recent findings suggest that GH deficiency may be responsible for some symptoms of ageing, and
treatment of elderly individuals with G H has been reported to exert beneficial effects on body composition
and bone density. Overproduction of G H in the young results in abnormal body growth (gigantism). G H
also antagonizes the peripheral action of insulin (increases blood glucose levels) and is therefore generally
 THE HYPOTHALAMUS AND PITUITARY 21

considered to be a diabetogenic hormone; (patients suffering from GH excess can thus show a mild
hyperglycaemia and insulin resistance).
The principal effects of GH on protein, carbohydrate and lipid metabolism are:

1. Stimulation of cellular amino acid uptake and protein synthesis (particularly in skeletal muscle and
liver).
2. Stimulation of lipolysis within adipose tissue, and consequent increase in plasma free fatty acid levels.
3. Decreased glucose uptake by muscle and adipose tissue.
4. Increased gluconeogenesis (glucose output) within the liver.

Many of the actions of GH on bone and peripheral soft tissue growth are mediated indirectly by the G H-
induced production of growth-promoting peptides known as insulin-like growth factors (IGFs), derived
mainly from the liver and kidney, (or produced locally) and transported in the plasma in association with
specific binding proteins. The principal IGF (IGF-1 or somatomedin-C) is a highly conserved 70 amino
acid peptide with a close structural resemblance to the insulin precursor molecule proinsulin (Chapter 5).
Specific receptors for IGF-1 (similar to the insulin receptor) are known to be present on skeletal muscle,
liver, adipose and cartilage (chondrocyte) cells, and ultimately mediate an increase in DNA synthesis and
cell division in these tissues. GH can also act directly on some tissues (e.g. skeletal muscle and adipose
tissue) to modulate cell growth, by interacting with specific G H receptors in the target cell membrane.
Control of release (pulsatile) is via the hypothalamic releasing hormone GHRH and the release
inhibiting hormone somatostatin (SS) (see p. 10). Release is also promoted by stress (e.g. hypoglycaemia,
cold, surgery or severe exercise), during the onset of deep sleep, and following a rise in blood levels of
certain amino acids, particularly arginine or leucine. The response to exercise is greater in women than in men,
most likely due to an enhancing effect of circulating oestrogens on GH secretion. Since GH has no specific
target gland, there is no feedback control by a target gland hormone as such; GH may, however, affect its
own release my means of short-loop feedback on the hypothalamus to stimulate SS secretion (see
Chapter 1). Somatomedins can also affect GH release by inhibiting the action of GHRH at the pituitary
level, and also indirectly, by promoting the synthesis and release of SS from the hypothalamus (Figure 2.8).

In the insulin tolerance test of normal pituitary function, an intravenous injection of soluble
insulin (0.1 U/kg) is given (under close medical supervision) to lower blood glucose to ≤40 mg/dl, and
therefore to stimulate GH release. This response is reduced or lacking in patients with pronounced
pituitary disorders. Measurement of serum IGF-1 levels is also a good marker of overall GH
secretion. The hypoglycaemic stress test can also be used to assess the normal pituitary release of
ACTH. A general insufficiency of the anterior pituitary gland is referred to as panhypopituitarism.

Hyposecretion
In childhood (caused by hypothalamic or pituitary dysfunction) this leads to impairment of growth
(dwarfism), characterized by a short stature, obesity and hypoglycaemia.
Treatment. Dwarfism may be treated by initiating human GH replacement therapy (very expensive!); the
authentic human hormone somatropin is nowadays prepared biosynthetically in bacteria by recombinant
DNA technology (Humatrope) and administered on a body weight basis (0.5– 0.7 i.u./kg) by regular
subcutaneous injection over a few years. The use of GH derived from human cadaver pituitaries has
therefore been discontinued (also due to risk of prion particle transmission of Creutzfeldt-Jakob disease, a
form of presenile dementia). In some rare cases, dwarfism (Larontype) can also result from an inadequate
22 BASIC ENDOCRINOLOGY—CHAPTER 2

Figure 2.8. Regulation of growth hormone (GH) release. The two main hypothalamic hormones involved in the control
of GH secretion are GHRH (stimulatory) and somatostatin (SS; inhibitory). GH release is also promoted by stress
(particularly hypoglycaemia or exercise), deep sleep, and by some dietary amino acids. Somatomedins produced by the
action of GH on liver and kidney cells, inhibit GH release via negative feedback on the pituitary and via stimulation of
SS release from the hypothalamus. GH can also decrease its own production by stimulating hypothalamic SS release
(positive short-loop feedback). Some actions of GH on cell growth are mediated directly via specific GH receptors in
the target tissues.

production of the IGF polypeptides in response to normal plasma levels of GH (a form of GH resistance);
such individuals would not be expected to respond to exogenous GH administration, but could be treated by
giving intravenous or subcutaneous doses of IGF-1.

Hypersecretion
This usually results from a benign pituitary tumour (adenoma); (ectopic release of GH or GHRH from
other neuroendocrine tumours can also occur in some rare instances). In young patients, this leads to
gigantism, due to excessive growth in the long bones (highest recorded giant — 8′ 11″ at 22 years). Such
children tend to be tall with long arms and legs, but are physically weak.
In adults, the long bones do not grow in length; however, abnormal bone and soft tissue growth leads to
coarse facial features (prominent brow, large nose, protruding jaw, enlarged lips and tongue), enlarged
fleshy ‘spade-like’ hands and feet, and overgrowth of the soft internal organs (particularly the heart and
kidneys): such patients may also be diabetic. The condition is referred to as acromegaly, and can develop
slowly over a period of years; gradual enlargement of the pituitary tumour may also eventually lead to
headaches and visual field disturbances. Plasma IGF-1 is clearly elevated in most patients.
 THE HYPOTHALAMUS AND PITUITARY 23

In the glucose suppression test for acromegaly, the patient is given 50–100 g of glucose syrup
after an overnight fast, and the plasma GH level measured after 60 min. In a normally-responding
individual, the increased glucose load would decrease the GH level to ≤5 ng/ml; a maintained high
level (≥10 ng/ml) would however, be diagnostic of GH hypersecretion.

Treatment. This includes surgical (trans-sphenoidal or transfrontal) removal of the pituitary tumour and/or
radiotherapy (less preferred). For mild cases, the dopamine receptor agonist bromocriptine (Parlodel)
given orally (10– 20 mg daily, for life; see p. 13) may be effective in lowering GH levels; nausea,
constipation and nasal congestion are, however, common side effects with this drug, which may limit its
long-term tolerability. Bromocriptine may also be used to treat persistent symptoms following irradiation
therapy.
Treatment (expensive!) of acromegalic patients with the synthetic somatostatin analogue octreotide
(Sandostatin; 0.1–0.2 mg given subcutaneously, 3–4 times daily) to reduce GH hypersecretion and tumour
size, can be useful prior to surgical intervention. The development of long-acting depot preparations of
somatostatin in the near future, should hopefully improve the medical management of this condition.

Hormones of the Posterior Pituitary

The posterior pituitary (neurohypophysis) does not synthesize hormones, but it contains a large number of
unmyelinated nerve fibres originating from neuronal cell bodies located within the supraoptic (SON) and
paraventricular (PVN) nuclei of the hypothalamus. These fibres form the hypothalamo-hypophyseal tract
within the pituitary stalk. These neurones synthesize (predominantly) two nonapeptide (nine amino acid)
hormones, vasopressin and oxytocin respectively, which are then transported as protein (neurophysin)-
bound secretory granules down the nerve fibres, to collect at the nerve terminals within the posterior
pituitary. The hormones are released by exocytosis into the capillary bloodstream running close to the nerve
terminal swellings (Figure 2.9). The posterior pituitary gland also contains numerous non-secretory
neuroglial cells (pituicytes) scattered among the nerve fibres.

Vasopressin
The principal action of vasopressin (also called arginine vasopressin, AVP) is to stimulate the reabsorption
of water from the distal convoluted tubules and collecting ducts of the kidney, thereby reducing urine volume
and conserving body fluid; AVP is therefore also referred to as the antidiuretic hormone (ADH). This
effect is mediated by specific AVP (V2-type) receptors on the tubular cell surface, linked to a rise in
intracellular cAMP. In large quantities, AVP has a direct vasoconstrictor action on blood vessels, and can
increase the systemic blood pressure; the latter effect (mediated by AVP V1a-type receptors, linked to IP3
production) may be of significance in maintaining vascular tone in cases of severe haemorrhage: [selective
V1a receptor antagonists are currently being used to evaluate the possible pathophysiological role of AVP in
the development of hypertension]. AVP can also facilitate the release of ACTH from the anterior pituitary
in response to hypothalamic CRH (mediated via V1b type receptors; see page 13).
Control of release of AVP is primarily influenced by:

1. Plasma osmolarity (mainly due to changes in plasma Na+ level), sensed by specialized hypothalamic
osmoreceptor neurones connected with the SON. A relatively small increase in osmolarity (ca. 1–2%),
increases the release of AVP so that less water is cleared and vice versa*.
24 BASIC ENDOCRINOLOGY—CHAPTER 2

Figure 2.9. Mechanism of oxytocin and vasopressin release by the posterior pituitary. The peptide hormones are
synthesized by neurosecretory cells of the paraventricular and supraoptic nuclei in the hypothalamus, and transported in
the form of secretory granules, down nerve axons in the pituitary stalk, to be stored in nerve terminals (close to blood
capillaries) in the posterior pituitary lobe. Release occurs in response to suckling (oxytocin) or changes in blood volume/
osmolarity (vasopressin).

2. Blood volume/arterial pressure: sensory stimuli arising from systemic arterial, venous and atrial
baroreceptors (stretch-sensitive) normally inhibit AVP secretion, via afferent autonomic nerve
projections to the SON; a low plasma volume or pressure (more than 10–15% reduction, e.g. in
response to haemorrhage) thus decreases baroreceptor stimulation resulting in an increase in circulating
AVP.

An increase in AVP release also occurs in response to:

severe pain, fear, nausea, general anaesthesia or certain drugs/neurotransmitters e.g. nicotine,
morphine (and other opiates), angiotensin II, prostaglandin E2 and noradrenaline. Alcohol, however,
inhibits AVP release (alcohol-induced diuresis).

An increase in blood volume can also evoke the release of a 28 amino acid peptide from atrial
muscle fibres, termed atrial natriuretic peptide (ANP) that causes an increase in the excretion of Na
+ and water by the kidneys (natriuresis) and vasodilatation. The heart itself can therefore behave as an

important endocrine organ! Accordingly, ANP inhibits the secretion of AVP by the posterior
pituitary, and may therefore contribute to the volume control of AVP release.
 THE HYPOTHALAMUS AND PITUITARY 25

Hyposecretion of AVP, caused by damage or dysfunction (e.g. tumours) of the hypothalamus, can lead to
diabetes insipidus, a condition in which excessively large amounts of dilute urine (10–15 litres/day) are
produced by the kidneys. Patients experience frequent urination (polyuria) and excessive thirst and drinking
(polydipsia).
Treatment. This involves the administration of synthetic vasopressin (Pitressin) by subcutaneous or
intramuscular injection, or by intranasal administration of the vasopressin analogues lypressin
(Syntopressin) or desmopressin (Desmospray) in the form of nasal spray solutions. Common side-effects
associated with their use include nausea, nasal congestion and the desire to defaecate.
Hypersecretion of AVP: the rare condition of inappropriate AVP production is known as Schwartz-
Bartter syndrome (or SIADH: syndrome of inappropriate ADH) in which excessive water retention (low
serum osmolarity), a severe loss of plasma sodium (hyponatraemia), and a reduced ability to excrete diluted
urine (high urine osmolarity) occur. Symptoms include weakness, lethargy, headache, weight gain, anorexia,
and in extreme cases, confusion, seizures, and possible coma/death due to cerebral oedema; the excess AVP
levels can arise from an ectopic AVP-secreting tumour (malignant bronchial neoplasm), certain pulmonary
disorders (e.g. severe pneumonia, acute bronchitis), brain lesions affecting osmoreceptor function (minor
head injury), or as a consequence of antidepressant/antipsychotic drug therapy (e.g. fluoxetine, sertraline,
imipramine, amitryptyline, haloperidol).
Treatment. This involves prompt removal of the tumour where possible, or treatment of the underlying
malignant disease; alternatively, water restriction, hypertonic (3%) saline infusion (together with a loop
diuretic: frusemide) or oral administration of the AVP antagonist demeclocycline (Ledermycin) may be
used.

Oxytocin
Although oxytocin has a similar structure to AVP, it has distinctly different physiological functions,
mediated via specific oxytocin receptors on target cells (linked to IP3 second messenger system). It is
present in both sexes, but its effects are well understood only in females. Oxytocin stimulates the rhythmic
contractions of uterine smooth muscle during parturition (childbirth), and also stimulates milk ejection from
the lactating breast in response to infant suckling (milk let-down) by contracting the myoepithelial cells
present in the alveolar secretory epithelium. Oxytocin contributes to, but is not essential for initiation or
maintenance of labour.
Control of release: Activation of sensory nerve endings in the nipple during suckling, and the uterus
during childbirth, ultimately stimulate release of oxytocin from the posterior pituitary; these reflexes
(relayed to the hypothalamus via the spinothalamic tract) represent good examples of neurogenic feedback
control mechanisms.
Disorders of oxytocin secretion are rarely encountered. Synthetic oxytocin (Syntocinon) is available for
clinical use in the form of an injection, given by slow intravenous infusion for the induction of labour,
where the uterine effort is inadequate, and also to stimulate uterine contractions after childbirth and delivery
of the placenta, thereby lessening the danger of uterine haemorrhage.

* Changes in blood volume and pressure can influence the threshold value (set-point) of the osmoreceptors to fluid
osmolarity, so that a fall in volume/pressure results in an enhancement of osmoreceptor sensitivity and vice versa.
26 BASIC ENDOCRINOLOGY—CHAPTER 2

Review Questions
Question 1: State the location of the pituitary gland and outline its anatomical arrangement.
Question 2: List the main trophic hormones secreted by the anterior pituitary, describe their major
target organ effects, and outline the mechanisms controlling their release.
Question 3: List the main hypothalamic releasing/inhibiting hormones and describe how they
influence the anterior pituitary.
Question 4: Describe the effects of hypothalamic GnRH, CRH, TRH, dopamine, GHRH and
somatostatin (SS).
Question 5: What is GnRH-associated peptide (GAP); how does it affect prolactin release?
Question 6: Describe (giving examples) the clinical uses of (a) GnRH analogues (b) octreotide
(SS analogue).
Question 7: What is the significance of melanocyte stimulating hormone (MSH) in man? What is
the structural relationship between MSH and corticotrophin (ACTH)?
Question 8: What type of drug is aminoglutethimide? Under what conditions may it be used
therapeutically?
Question 9: Describe the consequences of excessive prolactin secretion and how this may be
treated.
Question 10: Describe the consequences of under- or oversecretion of GH in early life and in
adulthood. Give the appropriate treatments for each condition.
Question 11: List the major symptoms of acromegaly.
Question 12: What is the glucose suppression test? How may it be used in the diagnosis of GH
hypersecretion?
Question 13: Explain briefly, the morphology of the posterior pituitary gland.
Question 14: Name the two hormones secreted by the posterior pituitary and state from which
hypothalamic nuclei they originate.
Question 15: Describe the principal actions of vasopressin (AVP) and explain the mechanisms
controlling its release. By what other name is this hormone usually referred to?
Question 16: What are the factors that control the release of atrial natriuretic peptide (ANP)?
Describe the main effects of this peptide in the body.
Question 17: Describe the cause, symptoms and treatment of diabetes insipidus.
Question 18: What are the causes of Schwartz-Bartter syndrome (or SIADH: syndrome of
inappropriate ADH)? Describe the main symptoms and treatment of this condition.
Question 19: Describe the main actions of oxytocin and explain the mechanisms controlling its
release.
Question 20: Give the clinical uses for synthetic oxytocin.

Clinical Case Studies

Patient 1
A 17 year old girl was referred for evaluation of primary amenorrhoea. The patient was totally
asymptomatic and denied use of the oral contraceptive pill or any other medications. She had no previous
illnesses. A pregnancy test was negative. Clinical examination was normal. She had no galactorrhoea, and
external genitalia were normal.
 THE HYPOTHALAMUS AND PITUITARY 27

Laboratory investigation showed that her full blood count (FBC), urinalysis and serum electrolytes were
normal. Blood chemistry, plasma cortisol and thyroid function tests were also normal. Her plasma
oestradiol level was 50 pg/ml (normal >25 pg/ml), luteinizing hormone (LH) was 4.7 mU/ml (normal 4–30
mU/ml) and follicle stimulating hormone (FSH) was 5 mU/ml (normal 4–30 mU/ml). However, serum
prolactin was elevated at 231 ng/ml (normal <20 ng/ml). An MRI (magnetic resonance image) of the head
revealed a 6 mm pituitary microadenoma.
Question 1: What are the causes of hyperprolactinaemia?
Question 2: What impact does hyperprolactinaemia have on reproductive functions?
Question 3: What is the treatment for microprolactinoma?
Answer 1: Hyperprolactinaemia may result from physiological conditions (stress, pregnancy,
infant suckling); pharmacological factors (drugs: dopamine receptor antagonists [e.g
phenothiazines, butyrophenones, metoclopramide], reserpine or methyldopa [depletors of
hypothalamic dopamine], oestrogens, opiates, monoamine oxidase (MAO) inhibitors, cimetidine,
verapamil) or pathological factors (pituitary tumours, pituitary stalk lesion, primary
hypothyroidism, chronic renal failure or severe liver disease).
Answer 2: Hyperprolactinaemia decreases the activity of the hypothalamic GnRH pulse
generator, leading to reduced gonadotrophin production/secretion and consequent low sex steroid
levels. The LH/FSH and oestradiol levels were however, normal in this patient. Excess prolactin
may also directly interfere with gonadotrophin action on the gonads, resulting in a functional
hypogonadism; the outcome will be menstrual dysfunction (amenorrhoea) and infertility;
(decreased libido, impotence and infertility in men). There is growing evidence that when
hypogonadism develops, the risk of osteopenia (low bone mass) also increases.
Answer 3: Treatment with a dopamine D2 receptor agonist such as bromocriptine is the initial choice
for management of microprolactinomas (tumours <10 mm in size). This agent mimics the normal
inhibitory ‘tone’ exerted by hypothalamic dopamine-secreting neurones on pituitary prolactin
secretion, and may reduce serum prolactin concentration and tumour size without the need for
surgical removal; [bromocriptine can also be used to treat larger (>10 mm) prolactin-secreting
tumours (macroprolactinomas) prior to surgery; these are often associated with severe visual field
defects].
The patient was started on bromocriptine (2.5 mg daily, at bed time) and the dose increased to 5
mg daily over a period of 6 weeks. By the 10th week, the prolactin level had been completely
normalized (19 ng/ml), and the patient had her first menstrual period. An MRI of the head at 6
months, showed a normal pituitary gland. The patient is currently euprolactinaemic on a
maintenance dose of bromocriptine (2.5 mg daily).

Patient 2
A 45 year old man presented at the emergency clinic complaining of increasing headache and double vision
over the past two days. Past medical history included a ten year history of decreased sexual drive,
impotence, tiredness, cold intolerance and arthritic pain in the hands and feet. He had also noticed that he
shaved less frequently than before, his wedding ring no longer fitted him, and that his shoe size had
progressively increased over the years. His facial features had also changed, particularly his nose and jaw.
Clinical examination revealed a blood pressure of 105/65 mmHg (supine) with postural hypotension, lack of
underarm and pubic hair, pale, dry, thickened skin, and prominent enlargement of the nose, lips tongue, ears
and lower jaw. The hands and feet were also enlarged and ‘doughy’. Deep tendon reflexes showed a
28 BASIC ENDOCRINOLOGY—CHAPTER 2

delayed relaxation phase. A visual field test revealed a bitemporal hemianopia. The patient was admitted for
further evaluation.
An MRI (magnetic resonance image) of the head showed an enlarged pituitary, with some suprasellar
extension. Laboratory investigation indicated that FBC and blood chemistry were normal, although plasma
glucose was 10 mmol/l (normal 3.6–6.4 mmol/ l) and phosphate 5.1 mg/dl (normal 2.5–4.8 mg/dl). Serum
electrolytes were: Na+ 129 mmol/l (normal 135–145 mmol/l), K+ 4.6 mmol/l (normal 3.5–5 mmol/l. Plasma
cortisol at 8 a.m. was 4 µg/dl (normal 5–20 µg/dl), ACTH 20 pg/ml (normal 40–100 pg/ml), thyroxine (T4)
1.8 µg/dl (normal 4–12 µg/dl), TSH <0.5 µU/ml (normal 0.5–5 µU/ml), LH 2 mU/ml (normal 4–30 mU/ml),
testosterone 168 ng/dl (normal male 300–1110 ng/ dl), GH 62 ng/ml (normal <5 ng/ml) and IGF-1 560 ng/ml
(normal male adult 40–180 ng/ml). Serum prolactin was normal.
Question 1: What is this patient most likely suffering from? What is causing his chronic and acute
symptoms?
Question 2: What is the explanation of the laboratory findings?
Question 3: How would this condition be treated?
Answer 1: This patient is showing classic signs of chronic acromegaly with multiple endocrine
deficits (hypopituitarism) due to progressive growth of a pituitary tumour, secreting excess amounts
of growth hormone (GH); [ectopic production of GHRH may also lead to pituitary GH
oversecretion]. The patient also shows acute symptoms of optic compression (revealed by the
visual field disturbances) that occurs when the pituitary tumour enlarges sufficiently to compress
the central part of the optic chiasm. The main features of acromegaly include a gradual change in
facial features (prominent brow, large nose, lips, tongue and protruding jaw) and overgrowth of
the hands and feet, developing over a period of years; such patients can also show symptoms of
glucose intolerance (diabetes), and arthritic pain in the extremities.
Answer 2: The condition is characterized by an elevated plasma levels of GH and IGF-1 (insulin-
like growth factor-1), although this in itself may not be diagnostic; both serum calcium and
phosphate levels may also be increased in acromegalics. The associated hypopituitarism is caused
through interruption of normal pituitary function by the expanding tumour; it is indicated by the
low serum levels of testosterone, cortisol and thyroxine, with concomitant low levels of LH and
ACTH and TSH. The resulting condition is a mixed clinical picture of hypogonadism (decreased
libido and facial, axillary/pubic hair growth), hypothyroidism (dry, coarse skin, fatigue cold
intolerance, delayed tendon reflexes) and hypoadrenalism (pale skin, mild hypotension).
Answer 3: One day after admission, the patient’s headache and visual disturbances became more
acute, and a decision to remove the pituitary tumour by open transfrontal surgery was made, with
abrupt improvement in visual field abnormalities the next day. The patient was then placed on
oral replacement therapy (hydrocortisone, testosterone and thyroxine) to correct for endocrine
deficiencies. The serum GH, and blood glucose/ phosphate levels normalized after three days.
Recession of soft tissue overgrowth was observed over several months, although there was no
indication of a recovery of pituitary function. A repeat MRI scan one year post-operatively
showed no recurrence of the tumour; the patient was maintained on replacement therapy.

Removal of pituitary tumours by trans-sphenoidal or open transfrontal surgery is used when the tumour
size has expanded sufficiently to cause compression of the optic chiasm; with smaller tumours producing no
pressure symptoms and not associated with significant hypopituitarism, the excess GH secretion (with some
tumour shrinkage) can be achieved by administration of the dopamine receptor agonist bromocriptine (10–
 THE HYPOTHALAMUS AND PITUITARY 29

20 mg daily) or the long-acting somatostatin analogue octreotide (0.1–0.2 mg, 3–4 times daily;
subcutaneous).

UK/USA Drugs—Trade names

UK USA
Hypothalamic hormones
Gonadotrophin releasing hormone (GnRH) Feritral Factrel Lutrepulse
GnRH agonists Buserelin Supprelin
Goserelin Lupron
Leuprorelin Synarel
Nafarelin
Thyrotrophin releasing hormone (TRH) Protirelin Relefact TRH
GHRH analogue (Sermorelin) Geref
Somatostatin analogue (Octreotide) Sandostatin Sandostatin
Pituitary hormones
Adrenocorticotrophic hormone (ACTH) Acthar
ACTH analogue (Tetracosactrin) Syncathen Cortrosyn
Human growth hormone (GH) Humatrope Humatrope Protropin/Nutropin
Vasopressin (AVP) Pitressin Pitressin
Vasopressin analogues:
Lypressin Syntopressin Diapid
Desmopressin DDAVP DDAVP*
Desmospray
Oxytocin Syntocinon Syntocinon
Pitocin
Dopamine agonists
Bromocriptine Parlodel Parlodel
Cabergoline Dostinex
Quinagolide Norprolac
Dopamine antagonists
Haloperidol Serenace Haldol
Trifluoperazine Stelazine Stelazine
* DDAVP: 1-desamino-8-D-arginine vasopressin

References

Books

• Ascoli M, Segaloff DL. (1996). Adenohypophyseal hormones and their hypothalamic releasing factors. In Goodman
& Gilman’s The Pharmacological Basis of Therapeutics, edited by JG Hardman, LE Limbird, A Goodman,
Gilman et al., 9th ed. McGraw-Hill, USA, pp. 1363–1382
30 BASIC ENDOCRINOLOGY—CHAPTER 2

• Carola R, Harley JP, Noback CR. (1990). The endocrine system. In Human Anatomy at Physiology, McGraw-Hill,
Inc, USA, pp. 474–504
• Chandrasoma P, Taylor CR. (1991). The pituitary gland. In Concise Pathology, 1st ed. Prentice-Hall, USA,
pp. 833–838
• Fitzgerald PA. (1992). Pituitary disorders. In Handbook of Clinical Endocrinology, 2nd ed. Prentice-Hall, USA,
pp. 1–72
• Genuth SM. (1993). The hypothalamus and pituitary gland. In Physiology, edited by RM Berne, MN Levy, 3rd ed.
Mosby-Year Book Inc, USA, pp. 897–931
• Goodman HM. (1988). Pituitary gland. In Basic Medical Endocrinology, Raven Press, New York, pp. 27–44
• Guyton AC, Hall JE. (1996). The pituitary hormones and their control by the hypothalamus. In Textbook of Medical
Physiology, 9th ed. WB Saunders Company, USA, pp. 933–944
• Hassan T. (1985). The pituitary gland. In A Guide to Medical Endocrinology, Macmillan Publishers Ltd, pp. 22–43
• Hedge GA, Colby HD, Goodman RL. (1987). The brain-pituitary interface. In Clinical Endocrine Physiology, WB
Saunders Co, Philadelphia, Chapters 3–5, pp. 53–98
• Junqueira LC, Carneiro J, Long JA. (1986). Pituitary & Hypothalamus. In Basic Histology, 5th ed. Lange Medical
Publications, Connecticut, pp. 435–445
• McCann SM. (1988). The anterior pituitary and hypothalamus. In Textbook of Endocrine Physiology, edited by JE
Griffin, SR Ojeda. Oxford University Press, New York, pp. 70–99
• Samson WK. (1988). The posterior pituitary and water metabolism. In Texbook of Endocrine Physiology, edited by JE
Griffin, SR Ojeda. Oxford University Press, New York, pp. 100–111
• Thibodeau GA, Patton KT. (1993). The endocrine system. In Anatomy & Physiology, 2nd ed. Mosby-Year Book
Inc, USA, pp. 402–439
• Tyrrell JB, Findling JW, Aron DC. (1994). Hypothalamus and pituitary. In Basic & Clinical Endocrinology, edited
by FS Greenspan, JD Baxter, 4th ed. Appleton & Lange, Connecticut, pp. 64–127

General

• ABPI Data Sheet Compendium 1994–1995. (1994). Datapharm Publications Ltd, London
• British National Formulary. (1996). Drugs used in the treatment of disorders of the endocrine system, British
Medical Association and Royal Pharmaceutical Society of Great Britain, Chapter 6, pp. 285–327
• Baird JD, Irvine WJ, Edwards CRW. (1987). Endocrine and metabolic diseases. In Davidson’s Principles &
Practice of Medicine, edited by J Macleod, C Edwards, I Bouchier, 15th ed. Churchill Livingstone, pp. 423–492
• Ellsworth AJ, Bray RF, Bray SB, Geyman JP. (1991). The Family Practice Drug Handbook, Mosby-Year Book
Inc, USA
• Greenstein B. (1994). Endocrinology at a glance, Blackwell Science, Oxford
• Hillson RM. (1994). The drug therapy of endocrine and metabolic disorders. In Oxford Texbook of Clinical
Pharmacology and Drug Therapy, edited by DG Grahame-Smith, JK Aronson, 2nd ed. Oxford University Press,
pp. 365–378
• Kumar PJ, Clark ML. (1990). Endocrinology. In Clinical Medicine, 2nd ed. Bailliere Tindall, pp. 764–831
• Monthly Index of Medical Specialities (MIMS), June 1997. Haymarket Medical Ltd, London
• Plowman PN. (1987). Endocrinology and Metabolic Diseases, John Wiley & Sons Ltd
• Rang HP, Dale MM, Ritter JM. (1995). The endocrine system. In Pharmacology, 3rd ed. Churchill Livingstone,
pp. 417–426
• Rees PJ, Williams DG. (1995). Endocine disorders. In Principles of Clinical Medicine, Edward Arnold, pp. 517–554
• Wilson JD, Foster DW. (1992). Williams Textbook of Endocrinology, WB Saunders Co, Philadelphia
 THE HYPOTHALAMUS AND PITUITARY 31

Journal Articles

• Adams SP. (1987). Structure and biologic properties of the atrial natriuretic peptides. Endocrinol Metab Clin N Am,
16, 1–17
• Beckers A. (1993). Presurgical octreotide treatment in acromegaly. Acta Endocrinol, 129, suppl. 1, 18–20
• Chen C-LC. (1993). Inhibin and activin as paracrine/autocrine factors. Endocrinology, 132, 4
• Conn PM, Crowley WF Jr. (1991). Gonadotrophin-releasing hormone and its analogues. New Engl J Med, 324,
93–103
• Conn PM. et al. (1986). Mechanism of action of gonadotrophin releasing hormone. Annu Rev Physiol, 48, 495–513
• Frohman LA, Downs TR, Chomczynski P. (1992). Regulation of growth hormone secretion. Frontiers in
Neuroendocrinology, 13, 344–405
• Gelato MC, Merriam GR. (1986). Growth hormone releasing hormone. Annu Rev Physiol, 48, 569–591
• Hsueh AJW, et al. (1987). Heterodimers and homodimers of inhibin subunits have different paracrine action in the
modulation of luteinizing hormone-stimulated androgen biosynthesis. Proc Natl Acad Sci USA, 84, 5082–5086
• Jaffe CA, Barkan AL. (1994). Acromegaly: recognition and treatment. Drugs, 47, 425–445
• Laron Z. (1993). Somatomedin-1 (insulin-like growth factor-1) in clinical use. Drugs, 45, 1–8
• Laron Z. (1995). Growth hormone secretagogues. Drugs, 50, 595–601
• Marcus R, et al. (1990). Effects of short term administration of recombinant human growth hormone to elderly
people. J Clin Endocrinol Metab, 70, 519–527
• Patel YC, Srikanat CB. (1986). Somatostatin mediation of adenohypophysial secretion. Annu Rev Physiol, 48,
551–567
• Rivier CL, Plotsky PM. (1986). Mediation by corticotrophin releasing factor (CRF) of adenohypophysial hormone
secretion. Annu Rev Physiol, 48, 475–494
• Rivier JP, et al. (1992). GnRH antagonists: a synopsis. Contraception, 46, 109–112
• Ruberg M, et al. (1987). Stimulation of prolactin release by vasoactive intestinal peptide (VIP). EurJ Pharmacol, 51,
319–320.
• Rudman D, et al. (1990). Effects of human growth hormone in men over 60 years old. New Engl J Med, 323, 1–6
• Strobl JS, Thomas MJ. (1994). Human growth hormone. Pharmacol Rev, 46, 1–34
• Wintzen M, Gilchrest BA. (1996). Proopiomelanocortin, its derived peptides, and the skin . J Invest Dermatol, 106,
3–10
• Woodruff TK, Mayo KE. (1990). Regulation of inhibin synthesis in the rat ovary. Annu Rev Physiol, 52, 807–821
• Zeidel ML. (1990). Renal actions of atrial natriuretic peptide: regulation of collecting duct sodium and water
transport. Annu Rev Physiol, 52, 747–759
 3
The Adrenal Gland

Structure and Histology

The adrenal glands are situated above the upper pole of each kidney, embedded in fatty tissue, and receive a
copious arterial blood supply from the aorta and renal arteries. Each gland (weighing 6–10 g) consists of an
outer cortex and an inner medulla which secrete quite different types of hormones (steroids and
catecholamines respectively). An extensive sympathetic (preganglionic) nerve supply runs to the medulla,
which secretes adrenaline (80%) and noradrenaline (20%). Unlike the latter, the adrenal cortex is
essential to life, and consists of three separate epithelial cell layers arranged into three zones (Figure 3.1):

The outer layer: (zona glomerulosa): secretes

mineralocorticoids; involved in Na+/H2O balance
The middle layer: (zona fasciculata): secretes
glucocorticoids: involved in regulating protein/carbohydrate metabolism; also
secretes some sex steroids
The inner layer: (zona reticularis): secretes
glucocorticoids and some sex steroids

The adrenal secretion of sex steroids (testosterone, dehydroepiandrosterone, oestradiol, and

progesterone) is normally small and physiologically insignificant, compared with the testicular and
ovarian secretion of these hormones (see Chapter 6). In females, the growth of underarm (axillary)
and pubic hair is dependent on adrenal androgen secretion.

Histology
The zona glomerulosa forms a very narrow zone immediately beneath the thick outer connective tissue
capsule that surrounds the gland. The cells are small, ovoid in shape and arranged into small ovoid clusters
or ‘arches’: these cells produce the mineralocorticoid hormone aldosterone, involved in regulating Na+, K+
and water balance in the body.
The zona fasciculata is the widest of the three cortical zones, and consists of larger cells arranged radially
into long columns, with blood capillaries running in between. The cytoplasm of the cells contains numerous
lipid droplets, which represent a precursor store for the synthesis of glucocorticoid steroids: these are
important in maintaining life and regulating protein and carbohydrate metabolism.
 THE ADRENAL GLAND 33

Figure 3.1. Schematic cross-section of an adrenal gland, showing the different functional zones. The cortex and
medulla are functionally distinct types of endocrine tissue.

Figure 3.2. The basic C17 cyclopentanoperhydrophenanthrene steroid nucleus, with numbers indicating the position of
carbon atoms and possible side chains.

The innermost zona reticularis is composed of irregular columns of smaller epithelial cells with capillary
spaces in between. The cells are smaller and contain fewer lipid droplets.
The adrenal medulla (derived embryologically from neural crest tissue) consists of clusters of large
roundish chromaffin cells which produce catecholamines, surrounded by a network of reticular fibres, blood
vessels and autonomic nerve fibres; the cells are of two types, storing either adrenaline or noradrenaline,
and may be considered as modified sympathetic ganglion cells (devoid of axons and dendrites). Indeed,
small numbers of sympathetic ganglionic neurones, occurring singly or in small groups, may also be found
within the medullary tissue. Chromaffin cells are so called because they exhibit numerous brown chromaffin
granules (100–300 nm diameter) when stained with chromium salts (chromaffin reaction). Secretion of
catecholamines into the bloodstream occurs in direct response to stimulation of preganglionic (cholinergic)
sympathetic nerve fibres as part of the so-called “fight-or-flight” response to stress.
34 BASIC ENDOCRINOLOGY—CHAPTER 3

Biosynthesis and Release of Adrenocortical Hormones

All the adrenalcortical hormones are polycyclic steroids, derived initially from plasma cholesterol, and bear
the same basic 17-carbon steroid cyclopentanoperhydrophenanthrene nucleus (Figure 3.2). Some
cholesterol is also formed intrinsically from acetate and acetylcoenzyme A. The initial biosynthetic steps
occurring within the adrenal cells are common; however, the hormone end-products may vary according to
the type of carbon side chain or groupings attached at position C17.
Generally,
C21 compounds can possess either glucocorticoid, mineralocorticoid, or progestogenic activity;
C19 compounds usually possess androgenic (masculinizing) activity, whereas,
C18 compounds can have oestrogenic (feminizing) activity.
A double bond between C4–C5 (written as 5) and a ketone group at C3 appear to be essential for normal
adrenocorticoid activity; potent glucocorticoids generally also require hydroxyl groups at positions 11 and
21, whereas active mineralocorticoids require an aldehyde group at position 18 (Figure 3.3.).

Steroid hormones are not ‘flat’ molecules, but have a complex three-dimensional shape.

Control of Release
Adrenal steroids are not stored within the adrenocortical cells in significant amounts, but are liberated as
soon as they are synthesized. The rate of glucocorticoid synthesis and secretion (principally cortisol) is
controlled exclusively by the anterior pituitary hormone corticotrophin (ACTH) under negative feedback
control (see Chapter 1). The effects of ACTH on the adrenal cells are believed to be mediated by specific
membrane receptors linked to intracellular cyclic AMP production. ACTH is also necessary for the normal
growth and maintenance of the adrenal cortex (trophic effect), which may undergo atrophy (gradual wasting
away) after surgical removal of the pituitary. Cortisol secretion, like that of ACTH shows a circadian rhythm
(24 hour periodicity), with the highest blood levels being exhibited in the morning, before waking; the
physiological significance of this variation however, remains uncertain.
By contrast, the regulation of mineralocorticoid (mainly aldosterone) secretion, is largely mediated by
the reninangiotensin system involving the kidney (see p. 34). Both glucocorticoids and mineralocorticoids
are bound to plasma proteins in the circulation (mainly transcortin— an α2-globulin, and albumin) leaving
only about 10% free and metabolically active; aldosterone also has a specific binding globulin, although its
degree of binding to protein is relatively less. The free plasma cortisol concentration (about 100–700 nmol/l
at 9.00 a.m.) is about 2000 times greater than the plasma aldosterone concentration (50–300 pmol/l).

Glucocorticoids
Cortisol (also known as hydrocortisone) is the principal glucocorticoid secreted in man, although some
corticosterone is also produced.
The main actions of the glucocorticoids are:

1. Control of carbohydrate, protein and fat metabolism.

2. Suppression of tissue inflammation in response to injury.
3. Suppression of immune response to foreign antigens.
4. Increase in capacity of the body to withstand various noxious stimuli (stresses).
 THE ADRENAL GLAND 35

The anti-inflammatory and immunosuppressant actions only become apparent at high or

therapeutic concentrations of glucocorticoids.

Carbohydrate Metabolism
Cortisol increases blood glucose levels by stimulating glucose formation in the liver (gluconeogenesis) from
circulating amino acid precursors, and promotes the storage of liver glycogen; the effects are accomplished
by the induced production of additional metabolic enzymes involved in gluconeogenesis and glycogen
synthesis. Cortisol also antagonizes the action of insulin on glucose uptake into muscle and adipose tissue;
a prolonged action of cortisol may therefore lead to a high blood sugar level (hyperglycaemia).

Protein Metabolism
Cortisol inhibits amino acid uptake and protein synthesis in peripheral tissues. It also promotes protein
breakdown in muscle, skin and bone, with consequent release of amino acids into the blood (utilized for
gluconeogenesis). The synthesis of glucose thus occurs at the expense of protein catabolism. Excess cortisol
can therefore lead to muscle wasting as well as loss of protein (collagen) from the skin and capillary walls
(increased tendency to bruise) and bone matrix.

Fat (Lipid) Metabolism

Cortisol stimulates fat breakdown (lipolysis) in adipose tissue, with release of fatty acids and glycerol (for
gluconeogenesis), while inhibiting fat synthesis. Excess cortisol may cause an unusual redistribution of
body fat with increased deposition in the face and trunk, and between the shoulders (symptoms of Cushing’s
syndrome; see below). The principal metabolic actions of the glucocorticoids are summarized in Figure 3.4.

Anti-Inflammatory and Immunosuppressive Actions

Cortisol (and other glucocorticoids) when administered at relatively high pharmacologic doses, inhibit the
normal inflammatory process which occurs when tissue is damaged. This action underlies the therapeutic
use of corticosteroids in the treatment of certain severe chronic inflammatory conditions e.g. rheumatic
diseases (rheumatic fever, rheumatoid arthritis), allergic rhinitis and eczematous skin disorders. A wide
range of synthetic glucocorticoids are now available for systemic and topical use.
Some commonly used glucocorticoid preparations include:

1. Prednisolone (Prednesol, Deltastab, Precortisyl)

2. Betamethasone (Betnelan, Betnovate [as valerate])
3. Dexamethasone (Decadron)
4. Triamcinolone (Adcortyl)
5. Beclomethasone (Propaderm)
6. Fluocinolone (Synalar)

The introduction of a 9α-fluoro group into the steroid ring (as in betamethasone, dexamethasone
or triamcinolone) greatly enhances the anti-inflammatory activity of the molecule, as does the
36 BASIC ENDOCRINOLOGY—CHAPTER 3

Figure 3.3. Pathways for synthesis of adrenocortical steroids from cholestrol: (numbers in brackets indicate
intermediate stynthesis steps omitted for clarity). Note that the conversion of corticosterone to aldosterone occurs only
within the zona glomerulosa which lacks 17α-hydroxylase enzyme activity, and is thus unable to produce cortisol or
androgens; also the enzyme aromatase (oestrogen synthetase) catalyses the conversion of testosterone to oestradiol, as
well as the direct conversion of androstenedione to oestrone.
substitution of a valerate group at position C17, or the insertion of a double bond between C1 and C2
(as in prednisolone).
 THE ADRENAL GLAND 37

Figure 3.4. Principal metabolic actions of cortisol. Protein and fat breakdown are promoted with a resultant release of
amino acids and glycerol substrates, utilized by the liver for glucose and glycogen synthesis. The insulin-sensitive
uptake of glucose by fat and muscle cells is also inhibited.

ANTI-INFLAMMATORY EFFECT
The mechanisms underlying the anti-inflammatory actions of glucocorticoids are varied and complex, as are
the sequence of reactions involved in the inflammatory response itself. The latter may be regarded as a primary
defensive reaction of tissues to trauma, harmful invading organisms or chemical substances and other
antigenic agents, and is intended to protect the host tissue from further damage.
Inflammation is characterized by a reddening, warmth, swelling and pain at the site of injury, reflecting a
localized vasodilatation, leak of protein and fluid from microcapillaries and venules, and release of
chemical pain mediators; the increased blood flow facilitates the delivery of phagocytic leucocytes (e.g.
neutrophils) and serum factors to the injured area. These defensive processes are initiated primarily by the
production of prostaglandins, thromboxanes, platelet activating factor (PAF) and leukotrienes derived
from the metabolism of the fatty acid arachidonic acid.
Glucocorticoids are known to inhibit the synthesis and release of these important inflammatory mediators
by suppressing the activity of the enzyme phospholipase A2 (PLA2), involved in the formation of
arachidonic acid from cell membrane phospholipid (phosphatidyl choline). This effect is mediated indirectly
via the induction of a phosphoprotein lipocortin-1, that inhibits PLA2 activity, and also directly by
inhibition of inducible PLA2 synthesis. Inhibition of the production of cyclo-oxygenase-2 (COX-2), an
inducible form of the enzyme responsible for conversion of arachidonic acid to pro-inflammatory-
prostaglandins has also been recently demonstrated.
Other factors that contribute towards the anti-inflammatory effect include:

1. Stabilization of intracellular lysosomal membranes, thereby preventing release of proteolytic lysosomal

enzymes in inflamed tissue.
2. Decrease in recruitment and phagocytic activity of blood leucocytes at specific sites of tissue
inflammation, [due to decreased release of chemoattractants and endothelial cell activators].
3. Decrease in the proliferation and deposition of collagen fibrils by fibroblasts at the site of injury.
38 BASIC ENDOCRINOLOGY—CHAPTER 3

4. Decrease in the synthesis of a number of epithelial cellderived peptide mediators (cytokines) e.g. GM-CSF
(granulocyte macrophage colony stimulating factor), tumour necrosis factor-α (TNF-α) and
interleukins-1, 6 and 8 (IL-1, IL-6, IL-8), involved in the initiation and enhancement of inflammation.

Cyclo-oxygenase (COX) is known to exist in at least two distinct isoforms, COX-1 and COX-2.
COX-1 is expressed in most tissues and has important physiological functions including provision of
small amounts of prostaglandins necessary for gastroprotection, platelet aggregation and the control
of renal blood flow, whereas COX-2 is only present at low levels in normal tissue, but is induced
locally by proinflammatory stimuli (e.g. cytokines, growth factors, bacterial endotoxins).
Corticosteroids preferentially inhibit the activity of COX-2 (and subsequent prostaglandin
production), thereby producing a potent anti-inflammatory effect.
The recently developed nonsteroidal anti-inflammatory drug (NSAID) meloxicam (Mobic) also
shows selective effects towards COX-2 and is intended for treatment of rheumatoid arthritis and other
inflammatory conditions, while minimizing the risk of gastric or renal side effects (resulting from
COX-1 inhibition).

In large doses, glucocorticoids can also have anti-allergic effects due partly, to an inhibition of mast cell
development and migration, and the formation and release of histamine from mast cell granules. This
property, although delayed in onset, can be useful in the adjunctive treatment (along with adrenaline) of
emergency cases of severe asthma and anaphylactic shock. In these cases, hydrocortisone (Hydrocortistab)
would be given by slow intravenous injection.

IMMUNOSUPPRESSIVE EFFECT
Therapeutic doses of glucocorticoids have major effects on the circulating cells (lymphocytes) involved in
the immune response; principally, they inhibit the synthesis and action of essential peptide factors required
for triggering the proliferation and maturation of T-lymphocyte cells (thymus-derived) within lymphoid
tissue, following antigen presentation. These factors include interleukin-1 (IL-1), interleukin-6 (IL-6) and
tumour necrosis factor-α (TNF-α) (cytokines released from antigen-presenting macrophages) and
interleukin-2 (IL-2) (a lymphokine released from T-cells). This ultimately leads to a reduced number of
circulating T-cells, and also B-lymphocytes (bone-marrow derived) therefore resulting in a decreased
antibody production (immunosuppression). A direct inhibition of antibody formation and a killing of B- and
T-cells may occur at high glucocorticoid concentrations; a reduction in size of the thymus gland (and other
lymphoid tissue) can also result following sustained high therapeutic doses.
Glucocorticoids also interfere with the interaction of other important lymphokine mediators (produced by
T-lymphocytes) with their target cells (e.g. macrophage activation and migration factors, B-cell helper
factors and immune interferon-γ, an important anti-viral molecule).
The immunosuppressive action of glucocorticoids can be useful therapeutically:

1. For the treatment of various autoimmune diseases;

2. In the prevention of tissue rejection following transplant or graft operations; however, since the
resistance to infection will also be reduced, antibiotics must also be given concurrently.
 THE ADRENAL GLAND 39

Response to Stress
Unfavourable stresses such as acute trauma, major surgery, severe infection, pain, haemorrhage,
hypoglycaemia, cold, fever or emotional stimuli can (via the release of negative feedback inhibition of the
hypothalamic-pituitary axis; see Chapter 2) dramatically increase plasma cortisol levels, which appears to
‘protect’ the body against these stressful circumstances. In adrenalectomized patients, even relatively mild
stress can prove fatal, unless replacement glucocorticoids are given. Apart from increasing blood levels of
glucose and free fatty acids for energy sources, the nature of this protective action of cortisol towards stress
is still largely unclear. Recent evidence however suggests that the pronounced inhibition of production of
cytokines and other inflammatory/immune mediators by glucocorticoids, may be an important component
of the ‘stress protection’ response, by preventing stress-induced defence reactions from ‘overshooting’ and
becoming potentially damaging to the host. Accordingly, peripherally-produced cytokines like IL-1, IL-6
and TNF-α have been shown to directly stimulate release of CRH and ACTH from the
hypothalamicpituitary axis during inflammatory/immune stress, indicating an important regulatory link
between the immune and central nervous systems under such conditions.

Abrupt stopping of prolonged glucocorticoid therapy may (due to negative feedback effects on
the anterior pituitary and hypothalamus; Chapter 1) result in adrenal insufficiency, and therefore an
inability to withstand stressful stimuli. A gradual reduction of dosage over a period of weeks or
months is therefore advisable, along with the carrying of steroid treatment cards to warn patients of
possible complications.

Mechanism of Action
Cortisol permeates readily through target cell membranes and interacts with the C-terminal portion of a
specific glucocorticoid receptor protein (GR) present predominantly in the cytosol. A change in
conformation in the middle (DNA-binding) domain of the protein then allows it translocate into the nucleus
and to bind reversibly with specific regulatory sites (glucocorticoid response elements; GREs) on target
DNA molecules (close to promoter region of target genes), with a resultant induction or repression of gene
transcription (Figure 3.5). Dimerization of the hormone-receptor complex is apparently necessary for correct
interaction with the regulatory elements.
In the absence of glucocorticoid, inactive GR is associated with a blocking protein (Hsp-90, a so-called
heat shock protein), that may also be important for maintaining the normal steroid binding activity of the
receptor. The ability of the hormone to affect target cells is thus dependent on the presence of GR and its
degree of inhibition by blocking proteins. In view of the complex intracellular mechanism of action of
cortisol, its pharmacological effects may not be evident for hours or even days. A similar basic mode of
action also applies to other steroid and thyroid hormones, for vitamin D and for retinoic acid (vitamin A
acid); the GR protein is thus one member of a general steroid/thyroid hormone receptor superfamily.
Recent biochemical observations indicate that the GR (like other steroid hormone receptors) is in a
partially phosphorylated state in the absence of ligand, and becomes hyperphosphorylated (by intracellular
kinases) in the presence of hormone; this induced change is now regarded as an important step governing
the subsequent transcriptional activity of the receptor.

A decrease in the activity of the gene-transcription factor AP-1 (activator protein-1), activated
during chronic inflammation has been proposed to be an important mechanism underlying the anti-
inflammatory and immunosuppressive action of glucocorticoids; the activated glucocorticoid receptor
40 BASIC ENDOCRINOLOGY—CHAPTER 3

forms a protein-protein complex with AP-1 within the nucleus, thereby counteracting the activating
effects of AP-1 on gene transcription.

Clinical Disorders

Hyposecretion of Glucocorticoids
Adrenalcortical insufficiency (hypoadrenalism), although rather uncommon, may either be primary, due
to autoimmune adrenal disease affecting both adrenal cortices (Addison’s disease) or secondary due to low
ACTH levels (e.g. due to negative feedback on the hypothalamic-pituitary axis during prolonged
corticosteroid therapy, or due to hypofunction of the pituitary per se). In the former, there is a deficiency in
both cortisol and aldosterone production (see below).
Primary adrenal insufficiency may also arise as a consequence of metastatic infiltration, granulomatous
disease involving the adrenal gland (tuberculosis, histoplasmosis, sarcoidosis), acute adrenal haemorrhage
caused by meningococcal septicaemia or anticoagulant drug therapy, adrenalitis occurring in acquired
immune deficiency syndrome (AIDS), or a congenital unresponsiveness to ACTH.

A rare defect in the adrenal ACTH receptor protein has been suggested as one possible cause of
familial glucocorticoid deficiency (FGD), an inherited syndrome characterized by an insensitivity of
the adrenal gland to ACTH.

Clinical features of Addison’s disease include:

1. Muscle weakness, postural hypotension and dehydration (due to aldosterone deficiency); salt craving;
hypoglycaemia.
2. Anorexia and decrease in body weight.
3. Nausea, vomiting, diarrhoea; fever; abdominal pain.
4. Tiredness and malaise.
5. Low levels of plasma cortisol, associated with high levels of ACTH. Adrenal autoantibodies may also
be present in the serum.
6. Increased skin pigmentation (lack of cortisol leads to an increase in plasma ACTH levels due to release
from negative feedback; note that ACTH has MSH-like activity: see p. 11); the pigmentation is
particularly prominent around scars, skin creases, elbows, knees and buttocks, the nipple area and the
gums.

Low plasma cortisol levels with low levels of ACTH would be expected in patients with
secondary hypoadrenalism; low cortisol/high ACTH levels are also seen in cases of congenital
adrenal hyperplasia, where enzyme defects occur in cortisol biosynthesis (see below).

Treatment. In patients with chronic adrenal insufficiency, combination replacement therapy with both
glucocorticoid and mineralocorticoid compounds is necessary. A combination of hydrocortisone and
fludrocortisone (a synthetic mineralocorticoid: Florinef) administered by mouth, is nowadays
recommended. Alternatively, cortisone acetate (Cortisyl), which possesses virtually equal glucocorticoid
and mineralocorticoid activity, may be used. Acute cases of adrenal insufficiency (adrenal crisis), as may
 THE ADRENAL GLAND 41

Figure 3.5. Intracellular mechanism of action of cortisol. The glucocorticoid penetrates the target cell membrane and
combines with a specific glucocorticoid receptor (GR) present in the cytoplasm, to form a steroid/receptor complex. The
interaction induces a conformational change in the receptor and dissociation of an associated heat shock protein
(Hsp-90) before translocation into the nucleus to combine with target sites (glucocorticoid response elements) on DNA
molecules, in a dimeric form. The induction (or repression) of target genes leads to stimulation (or inhibition) in
synthesis of specific proteins that mediate the ‘steroid response’.

occur in Addison’s disease patients subjected to excessive stress, require an immediate intravenous infusion
of hydrocortisone together with saline, to correct for low blood volume.

In the short ACTH stimulation test of adrenocortical insufficiency, plasma cortisol levels are
measured at 30 and 60 min following administration of a synthetic ACTH analogue (tetracosactrin;
42 BASIC ENDOCRINOLOGY—CHAPTER 3

Synacthen; p. 11) by intramuscular or intravenous injection. In patients with primary adrenocortical

failure, the expected rise in plasma cortisol level is not observed; (normally, a peak cortisol level of
≥18 µg/dl would be expected following administration of 250 µg tetracosactrin).

In congenital (virilizing) adrenal hyperplasia, there are inherited enzymatic defects in cortisol biosynthesis;
any of the steroidogenic enzymes may be affected. Deficiency of 21β-hydroxylase, one of the key enzymes
in the cortisol (and aldosterone) synthetic pathway, leads to a reduction in cortisol secretion (with a
compensatory rise in plasma ACTH) and a build up of adrenal androgenic steroid precursors (17-hydroxy-
progesterone, androstenedione and ultimately testosterone; see Chapter 6). Aldosterone synthesis may also,
occasionally be affected. The excess production of ACTH leads to an excessive growth (hyperplasia) of the
adrenal cortex.
Apart from general symptoms of glucocorticoid/mineralo-corticoid deficiency, female infants may show
symptoms of masculinization at birth (abnormal sexual organs, clitoral enlargement) or later in life
(precocious puberty, acne, hirsutism or amenorrhoea in adulthood). Affected male infants may go
undetected at birth, unless significant salt-loss or shock under stress occurs.
Treatment involves carefully-dosed glucocorticoid (and if necessary, mineralocorticoid) replacement
therapy to suppress excess ACTH (and therefore inappropriate steroid) secretion.

Hypersecretion of Glucocorticoids
Excess production of cortisol may result either from over-production of ACTH (due to pituitary disease:
80% of cases, or by an ectopic ACTH-secreting tumour) or from an ACTH-independent adrenal cortical
tumour (adenoma, micro- or macronodular adrenal hyperplasia or carcinoma). The majority of ectopic
tumours secreting high levels of ACTH are thoracic in origin (bronchial, thymic, pancreatic or medullary
thyroid tumours), some of which may be difficult to locate (‘occult’) using conventional X-ray or other
modern radiographic imaging methods. In rare cases, an ectopic CRH-secreting tumour may be present.
The resultant condition of hypercortisolism (more prevalent in women) is called Cushing’s syndrome. Its
symptoms may also be induced after long-term therapy with glucocorticoids (e.g. for asthma, rheumatoid
arthritis or inflammatory bowel disease).

The condition of excess pituitary ACTH secretion is traditionally referred to as Cushing’s disease.

The classical features of Cushing’s syndrome are:

1. Muscle weakness and wasting; thin arms and legs—due to increased protein breakdown.
2. Back pain (due to osteoporosis); osteoporotic fractures of the hip, ribs or vertebrae may occur in the
elderly.

Excess cortisol (or glucocorticoid treatment) interferes with bone metabolism primarily by
reducing the absorption of Ca2+ from the gastrointestinal tract (due to reduced formation of an
active vitamin D metabolite; see Chapter 7), increasing renal Ca2+ excretion, inhibiting bone cell
(osteoblast) function and also by enhancing (indirectly) the rate of bone resorption. Inhibition of
protein synthesis leads to loss of vital collagen from the bone matrix.
3. Tendency to bruise easily, and development of purple striae within the skin (particularly on the thighs
and abdomen) —due to defective protein synthesis.
 THE ADRENAL GLAND 43

4. Redistribution of body fat tissue, so that patient develops a rounded (moon) face, prominent abdomen
(trunk obesity), ‘buffalo’ hump and thin legs; the reasons for this fat redistribution remain uncertain.
5. Virilization of females (hair growth on face/body, amenorrhoea, acne) due to synthesis of abnormally
high levels of adrenal androgens. The androgen precursors dehydroepiandrosterone (DHEA), DHEA
sulphate (DHEAS) and androstenedione are subsequently converted to testosterone in peripheral tissues.

A similar excess in adrenal androgen production can occur in the condition of congenital
adrenal hyperplasia (see above).
6. Hyperglycaemia, polyuria (excessive urination), polydipsia (excessive thirst), tendency towards
diabetes mellitus (see Chapter 5).
7. Psychological disturbances, particularly in patients with a previous history of mental disorder; excess
cortisol can lead to euphoria, hallucinations, paranoia or suicidal depression. The threshold for inducing
seizure activity may also be reduced.
8. High levels of plasma and urinary free cortisol (with loss of diurnal variation), and low (or
undetectable) levels of plasma ACTH (due to negative feedback inhibition by cortisol).

Treatment. This is usually by removal of the pituitary, ectopic (usually in lung) or adrenal tumour if
possible, coupled with corticosteroid replacement therapy. When tumours are not easily located or
inoperable, patients may undergo therapy with the steroid synthesis inhibitor aminoglutethimide
(Orimeten; 250 mg–1 g daily; see also Chapter 6) together with supplementary corticosteroids if necessary.
Dizziness, nausea, severe drowsiness and skin rashes may however occur as side effects of
aminoglutethimide therapy.
Prolonged therapeutic use of synthetic glucocorticoids for their anti-inflammatory or immunosuppressive
properties may also induce symptoms of Cushing’s syndrome as detailed above; their gradual
discontinuation should, however, lead to a resolution of the Cushingoid symptoms.
Metyrapone (Metopirone) is a competitive inhibitor of the 11β-hydroxylase enzyme involved in the final
step of cortisol synthesis in the adrenal cortex; this drug may also be used in the treatment of Cushing’s
syndrome arising from an ectopic ACTH-secreting tumour (bronchial carcinoma), and also for controlling
symptoms in patients prior to pituitary or adrenal surgery.

In the overnight dexamethasone suppression test of suspected Cushing’s syndrome, a patient is

given a single 1 mg dose of dexamethasone at midnight, and the plasma cortisol level measured the
next morning (8 a.m.). In a normal individual, the plasma cortisol would be reduced to a low level
(<5µg/dl), due to the negative feedback effects of dexamethasone; however, in a Cushing’s syndrome
patient, where the hypothalamic-pituitary axis would be under continual feedback suppression from
cortisol, no lowering of the plasma cortisol level would be observed. Such patients would also fail to
show the normal circadian rhythm of glucocorticoid secretion.

The overnight dexamethasone test would confirm the presence or absence of Cushing’s syndrome but not
readily distinguish between pituitary-dependent Cushing’s syndrome and hypercortisolism due to ectopic
ACTH secretion. In alternative low and high dose dexamethasone suppression tests, a 0.5 mg dose of
dexamethasone is given initially every six hours for two days, followed by a 2 mg dose six hourly for
another two days; plasma cortisol levels are measured at 8 am on days zero and two. Following the low
dose test, a failure to suppress the excess cortisol production would confirm the presence of Cushing’s
syndrome; after the high dose test however, suppression of cortisol levels would be expected if the
44 BASIC ENDOCRINOLOGY—CHAPTER 3

condition is pituitary-dependent (Cushing’s disease), but not if it arises from ectopic ACTH/CRH secretion
or an adrenal tumour.
In the CRH stimulation test, synthetic ovine CRH (oCRH) is given by intravenous bolus (1 µg/kg body
weight), and plasma ACTH levels measured at regular intervals thereafter. In patients with pituitary
Cushing’s disease, a significant rise in ACTH would be expected, whereas patients with ectopic ACTH
production would not generally show such a response.

Mineralocorticoids
Aldosterone is the principal potent mineralocorticoid secreted in man, although some deoxycorticosterone
is also produced. Many other steroids can exert a similar (usually weaker) mineralo-corticoid action.
Mineralocorticoids can also possess some glucocorticoid activity (and vice versa). Aldosterone is a very
powerful mineralocorticoid, the active free concentration in the plasma being in the order of 100 pmol/l.
The main actions of aldosterone are:

1. Conservation of body sodium and excretion of potassium; aldosterone increases Na+ reabsorption while
promoting excretion of K+ and H+ across epithelial cell walls in the distal convoluted tubule and
collecting ducts of the kidney. The resultant decrease in Water excretion (by passive tubular
reabsorption), increases blood volume.
2. Decrease in the ratio of sodium to potassium ion concentrations in sweat and in saliva; the increased
inward transport of Na+ (with passive efflux of K+) occurs across the epithelial cell membranes of
sweat and salivary gland ducts. In a hot climate, Where excessive sweating may occur, the action of
aldosterone would be important in preventing excessive Na+ loss via this route.
3. Increase in the reabsorption of Na+ from the colon, and increased excretion of K+ in the faeces.

Although only about 2% of the Na+ filtered by tne kidney is reabsorbed under the control of
aldosterone, inhibitors of aldosterone action e.g. spironolactone (Aldactone) or potassium
canrenoate (Spirocton-M) will act as powerful diuretics, useful in the treatment of oedema. These
drugs competitively antagonize the action of aldosterone on kidney tubule Na+ reabsorption, so that
more water is excreted in the urine.

Mechanism of Action
The effects of aldosterone on epithelial Na+ reabsorption have a delayed (1–2 hour) onset, and are mediated
intracellularly by interaction with a high affinity cytosolic (type I) mineralocorticoid receptor (highly
homologous with the glucocorticoid receptor) which then binds with regulatory elements of nuclear DNA to
induce the synthesis of a Na+ transport protein (channel) (c.f. the genomic action of glucocorticoids;
Figure 3.5). An increased synthesis of Na+/ K+-ATPase molecules that pump Na+ out of the tubular cells
into the interstitial fluid, may also be initiated. The mechanisms underlying the K+ and H+ excretion effects
however, are less well understood: the movement of K+ into the tubular fluid is most likely a passive
response to the increased intracellular Na+ load, whereas the tubular secretion of H+ in exchange for Na+ is
thought to occur via the rapid (within 1–2 min) stimulation of a Na+-H+ antiporter in these cells. Recent
evidence indicates that this latter effect may be non-genomically mediated following the interaction of
aldosterone with specific surface membrane receptors (insensitive to spironolactone or canrenoate). The
 THE ADRENAL GLAND 45

involvement of intracellular inositol 1,4,5-trisphosphate (IP3) in mediating these effects has also been
suggested.
The principal steps involved in the action of mineralocorticoids are summarized in Figure 3.6.

The presence of the local enzyme 11-β-hydroxysteroid dehydrogenase (11-HSD) in aldosterone-

sensitive tissues ensures mineralocorticoid specificity of the intracellular type 1 mineralocorticoid
receptor, by catalysing the conversion of circulating cortisol and corticosterone to their receptor-
inactive analogues cortisone and 11-dehydrocorticosterone respectively (aldosterone itself is a poor
substrate for 11-HSD). This effectively prevents glucocorticoids from reaching mineralocorticoid
receptors and thus confers aldosterone specificity. In patients that lack 11-HSD, or where the activity
of the enzyme has been compromised (due to excess ingestion of liquorice!), ‘protection’ of the
mineralocorticoid receptors is lost, allowing cortisol to exert mineralocorticoid effects in the kidney.
Such individuals show symptoms of mineralocorticoid excess (see below) such as Na+ retention,
hypertension and a low plasma K+ level (hypokalaemia) that may be treated by administration of
spironolactone.

Control of Release of Aldosterone

Although ACTH does transiently stimulate some aldosterone release, and is important in the tonic
maintenance of the zona glomerulosa, it is not considered a major factor in the long-term control of
aldosterone production and secretion. The release is, instead mainly influenced by the reninangiotensin
system and the plasma sodium and potassium concentrations.
Renin-Angiotensin System. Renin is a proteolytic enzyme released by specialized juxtaglomerular cells
(situated within the afferent arteriolar walls of the kidney) when there is a fall in renal blood pressure and an
excessive reduction in circulating blood volume (e.g. during haemorrhage, salt or water loss). Circulating
renin promotes the production of an inactive decapeptide angiotensin I from an α2-globulin precursor
angiotensinogen (derived from the liver). Angiotensin I is rapidly converted in the lung and plasma (via the
angiotensin-converting enzyme; ACE) to the active octapeptide angiotensin II, which directly stimulates
the synthesis and release of aldosterone from the zona glomerulosa of the adrenal cortex. Angiotensin II
also has a potent, direct vasoconstrictor action that helps to maintain the blood pressure of the arterial
circulation under extreme conditions, and a further important central effect (via the subfornical organ) to
control water intake (dipsogenic effect); [ACE inhibitor compounds such as captopril (Capoten) and
enalapril maleate (Innovace) are currently being used in the treatment of hypertension and heart failure].
Circulating angiotensin II is degraded by angiotensinase enzymes (e.g. glutamyl aminopeptidise A) to
angiotensin III (heptapeptide) [and ultimately to angiotensin IV (hexapeptide)], which has less potent,
though similar vasoconstrictor and aldosterone-releasing actions to angiotensin II.

Two main types of specific cell surface angiotensin II receptor have been described, termed AT1
and AT2, with two subtypes of AT, (AT1A and AT1B); the angiotensin II receptors of the adrenal
cortex are mainly of the AT1B subtype, linked through activation of phospholipase C to the
intracellular generation of IP3, release of Ca2+ from internal stores, and consequent stimulation of
aldosterone synthesis (involving inner mitochondrial transport of cholesterol). AT1A receptors are the
predominant type found in the kidney, blood vessel walls and the brain; AT2 receptors are also
present in the brain and other peripheral tissues, but their functional role has not been clearly defined.
Highly selective AT1 receptor antagonists losartan potassium (Cozaar) and Valsartan (Diovan)
have recently been introduced for the treatment of hypertension.
46 BASIC ENDOCRINOLOGY—CHAPTER 3

Figure 3.6. Mechanism of action of aldosterone on renal tubular Na+ reabsorption and K+/H+ excretion. Binding of
aldosterone to an intracellular mineralocorticoid receptor protein (MR), followed by translocation of the complex to the
nucleus and binding with nuclear DNA, induces the de novo synthesis of Na+ channel proteins that facilitate the transfer
of Na+ across the luminal membrane and also Na+/K+-ATPase molecules that pump Na+ into the interstitial fluid. K+
efflux may occur passively in exchange for Na+, whereas secretion of H+ (via the Na+-H+ antiporter) may be stimulated
by a rapid non-genomic mechanism involving a surface membrane minerlocorticoid receptor (linked to intercellular IP3
[inositol 1,4,5-triphospate] generation).

Angiotensin IV has been shown to bind to a pharmacologically distinct type of angiotensin receptor
(termed AT4), particularly concentrated on aortic and coronary vessel endothelial cells, as well as
mammalian heart, adrenal gland and brain; the physiological role of angiotensin IV in these tissues
however, is unknown.

Plasma Na+ and K+ Concentrations. Either a large decrease (>20 mEq/l) in plasma Na+ or a small increase
(ca. 1 mEq/ l) in plasma K+ concentration stimulates the synthesis and release of aldosterone by a direct
action on the biosynthetic enzymes in the adrenal cortex.

Clinical Disorders

Mineralocorticoid Hyposecretion
 THE ADRENAL GLAND 47

Isolated deficiency in aldosterone production (hypoaldosteronism) due to adrenal enzyme defects is very
rare, but it may occur for example, as a consequence of renal disease due to diabetes mellitus (see
Chapter 5) or in patients with AIDS. The general symptoms of mineralocorticoid deficiency i.e. increased Na
+/H O excretion, hyperkalaemia (high plasma K+), hypotension and metabolic acidosis would also be seen
2
in conjunction with those of glucocorticoid lack in cases of adrenal insufficiency (e.g. Addison’s disease),
treated by replacement therapy.

Mineralocorticoid Hypersecretion
Aldosterone excess (hyperaldosteronism) may be divided into two types:
Primary Aldosteronism (Conn’s Syndrome). This is usually caused by a bilateral adrenal hyperplasia
(abnormal enlargement) or small tumour (adenoma) of the adrenal zona glomerulosa. Patients exhibit
hypertension (due to Na+ and H2O retention, without peripheral oedema) and a low plasma K+ level
(hypokalaemia); muscle weakness, fatigue and cardiac dysrhythmias; a mild metabolic alkalosis may also
be present;
Plasma renin levels are characteristically low in this condition.
Diagnosis is made by demonstration of a high plasma or urine aldosterone level, in conjunction with a
low level of plasma renin; blood volume expansion by saline loading, would fail to suppress the high
aldosterone level.
Treatment would involve the surgical removal of the tumour responsible for the disorder, or long-term
administration of an aldosterone receptor antagonist e.g. spironolactone. The latter would also be used in
the control of patients prior to surgery.
Secondary Aldosteronism. This is caused by an abnormally increased renin release, and therefore raised
levels of angiotensin II. Patients may have peripheral oedema.
Some possible causes include:

– Poor renal perfusion e.g. in renal artery stenosis;

– Malignant hypertension (i.e. hypertension associated with progressive renal failure due to renal arteriolar
necrosis);
– Renal tumour of the juxtaglomerular cells;
– Excessive Na+ and H2O loss during diuretic therapy (most common cause) or dietary Na+ deprivation;
– Congestive heart failure or liver cirrhosis.

Treatment of the underlying cause of the abnormal reninangiotensin system activation should be attempted,
coupled with administration of spironolactone for long-term management.

Review Questions
Question 1: State the location of the adrenal glands and explain briefly, the morphology of the
medulla and outer cortex regions.
Question 2: List the major secretions of each cortical area.
Question 3: Define the terms glucocorticoid and mineralocorticoid and name the naturally
secreted hormones of each group.
Question 4: Name the plasma precursor from which all steroids are derived.
48 BASIC ENDOCRINOLOGY—CHAPTER 3

Question 5: Under what conditions may the secretion of sex steroids from the adrenal cortex
become physiologically significant?
Question 6: Describe the mechanisms controlling cortisol release; what do understand by the
circadian rhythm of ACTH/cortisol secretion?
Question 7: Describe the main effects of cortisol on:
(a) carbohydrate metabolism
(b) protein metabolism
(c) fat (lipid) metabolism.
Question 8: Describe how cortisol protects the body from unfavourable stresses.
Question 9: Explain how glucocorticoids at therapeutic doses, produce antiinflammatory and
immunosuppressive effects.
Question 10: Give examples of some commonly used synthetic glucocorticoids.
Question 11: Outline how glucocorticoids and mineralocorticoids exert their effects via
intracellular receptors.
Question 12: Describe the causes, symptoms and treatment of Addison’s disease.
Question 13: Explain why prolonged corticosteroid therapy can also lead to hyposecretion of
cortisol.
Question 14: Describe the causes, symptoms and treatment of Cushing’s syndrome.
Question 15: What is the overnight dexamethasone suppression test? How may this test be useful
in the diagnosis of Cushing’s syndrome? Would this test be able to distinguish between pituitary-
dependent Cushing’s disease and hypercortisolism due to ectopic ACTH secretion?
Question 16: Describe the main effects of aldosterone on Na+/H2O excretion.
Question 17: Give examples of a clinically useful mineralocorticoid and an aldosterone
antagonist.
Question 18: Describe the mechanisms controlling aldosterone release, mentioning:
(a) the renin angiotensin system
(b) the effects of plasma Na+/K+ concentration.
Question 19: What are ACE inhibitors? Give examples of some currently available compounds,
and their therapeutic uses.
Question 20: Describe the causes, symptoms and treatment of Conn’s syndrome.

Clinical Case Studies

Patient 1
A 28 year old female was referred to a hospital Endocrinology Department with amenorrhoea of six months
duration, weight gain, an increase in facial hair growth and muscle weakness, with occasional calf cramps.
Clinical examination revealed a weight of 17 stone (238 lb; 108 kg) with a blood pressure of 160/90 mmHg.
She had a rounded face with marked hirsutism (prominent soft hair growth on the upper lip and chin area);
she also had several bruise patches (ecchymoses) over her extremities, particularly her legs. The abdomen was
protuberant and supraclavicular and dorsal fat pads were enlarged. Examination of her heart and chest was
normal. Neurological examination was also normal. She had no visual symptoms.
Laboratory tests revealed that her full blood count (FBC), urinalysis and electrolytes were normal; blood
chemistry however, showed a blood glucose of 8.3 mmol/l (150 mg/ dl). An oral glucose tolerance test (see
Chapter 5) indicated a mild diabetes. In the overnight dexamethasone suppression test, plasma cortisol
 THE ADRENAL GLAND 49

measured at 8 a.m., following oral administration of 1 mg dexamethasone at 12 p.m. the previous night, was
23 µg/dl (normal <5µg/dl). Urinary free cortisol was 230µg/24 hours (normal 20–100 µg/24 h), and the
plasma ACTH level at 8 a.m. was 150 pg/ml (normal 40–100 pg/ml). The patient then underwent a standard
low dose (2 mg/day for 2 days) oral dexamethasone suppression test which failed to alter the plasma
cortisol level; a high dose (8 mg/day for 2 days) dexamethasone test however, resulted in a >60% reduction
in plasma cortisol from the basal pre-test level, indicating a high set-point but intact negative feedback
inhibitory mechanism.
An adrenal CT scan appeared normal, but an MRI (magnetic resonance image) of the head revealed an 8
mm pituitary microadenoma.
Question 1: What is the most likely diagnosis in this patient?
Question 2: What is the basis of the laboratory screening tests ordered for the patient, and what
results would you expect if the diagnosis is correct?
Question 3: What treatment would you recommend for this condition?
Answer 1: The patient’s symptoms of rounded ‘moon’ face, increased facial hair and lack of
menstruation (virilization by adrenal androgens), trunk obesity, ‘buffalo hump’, bruises, mild
hypertension and impaired glucose tolerance are characteristic of chronic excess glucocorticoid
secretion (Cushing’s syndrome).
The latter may arise as a consequence of an ACTH-secreting pituitary adenoma, an adrenal
cortical adenoma, or ectopic secretion of ACTH or CRH. Long-term treatment with exogenous
glucocorticoids may also lead to Cushing’s syndrome, and remains the most common cause of
this condition in clinical practice.
Answer 2: Measurement of 24 hour urinary free cortisol, or an overnight dexamethasone
suppression test remain the two most often used initial screening tests for Cushing’s syndrome.
Twenty-four hour urinary samples are useful in providing an ‘average’ of a day’s hormone
secretion; random cortisol measurements are of little value. In the alternative low dose
dexamethasone suppression test, administration of dexamethasone (0.5 mg q.d.s. for 2 days) will
suppress adrenal cortisol production in normal individuals but not in subjects with Cushing’s
syndrome. Following a high dose dexamethasone suppression test (2 mg q.d.s. for 2 days), cortisol
secretion would be suppressed if the Cushing’s syndrome is pituitary-dependent (termed
Cushing’s disease), [as in the above case], but not if it arises from excess ectopic ACTH or CRH,
or an adrenal tumour. For this patient, a CT scan confirmed the presence of a pituitary (ACTH-
secreting) adenoma. Note that the plasma level of ACTH was correspondingly high; a low (or
undetectable) ACTH level (<0.01 pg/ml) would have been indicative of non-ACTH dependent
disease.
Answer 3: Transsphenoidal surgery is the treatment of choice for pituitary-dependent Cushing’s
disease. When surgery is inappropriate, the aromatase enzyme inhibitor aminoglutethimide (250
mg-1 g daily), may be used to block adrenal steroid synthesis. In children, external irradiation
therapy is equally effective as surgery or even superior.
The patient underwent transsphenoidal adenomectomy with total amelioration of her Cushingoid
symptoms, and normalization of blood pressure, menstrual periods and blood glucose within four
months following surgery. She remained asymptomatic with normal plasma cortisol and blood
glucose thereafter.
50 BASIC ENDOCRINOLOGY—CHAPTER 3

Patient 2
A 39 year old female presented at the hospital outpatient’s clinic with a history of dizziness (particularly on
standing), increasing fatigue and muscle cramps and some loss of scalp and body hair (underarm, pubic).
The symptoms had worsened in the last 4 months, during which she had lost about 1 stone (14 lb; 6.4 kg) in
weight. She had no prior medical history. Clinical examination revealed a supine (lying down) blood
pressure of 110/65 mmHg, with a marked postural hypotension (30 mmHg on standing); there was
distinctive freckling of the face and increased pigmentation skin creases around the palms, elbows and
knees, and over the buccal mucosa in the mouth. There were also three small areas of vitiligo over her back.
Laboratory investigation revealed a normal full blood count (FBC) and urinalysis. Blood chemistry
however, gave a serum Na+ of 129 mmol/l (normal 135–145 mmol/l), K+ 5.8 mmol/l (normal 3.5–5.0 mmol/
l) and blood glucose of 3.2 mM (normal 3.6–6.4 mmol/l). Chest X-ray and thyroid function tests were
normal. Deep tendon reflexes were also normal. The plasma cortisol level measured at 8 a.m. was 2.1 µg/dl
(normal 5– 20 µg/dl) with a concomitant ACTH level of 1200 pg/ml (normal 40–100 pg/ml). Plasma
aldosterone at 8 a.m. was 1.8 ng/dl (normal 6–30 ng/dl, upright). After a short ACTH stimulation test, the
plasma cortisol level remained unchanged one hour post-test.
Question 1: What is the most likely cause of the patients’s symptoms?
Question 2: What are the diagnostic criteria for the condition?
Question 3: How is the disorder treated?
Answer 1: This is a classical presentation of primary hypoadrenalism (Addison’s disease),
confirmed by the low plasma cortisol and aldosterone levels along with a high level of ACTH.
The condition is most commonly caused by autoimmune damage to both adrenal glands;
however, adrenal damage arising from infections, sarcoidal or tubercular infiltrations or acute
haemorrhage may also lead to adrenal insufficiency. Use of drugs interfering with steroid
synthesis (aminoglutethimide) or action will also result in a clinical picture of hypoadrenalism.
The symptoms of dizziness, fatigue, weight loss and muscle cramps result from a combined lack
of cortisol and aldosterone action on brain and muscle cells. Aldosterone deficiency causes loss of
total body Na+/H2O, a reduction in blood volume and postural hypotension; this is accompanied
by a decreased K+ excretion, leading to hyperkalaemia. Scalp alopecia (hair loss) and vitiligo
(skin depigmentation) most likely result from an associated autoimmune attack of hair follicles
and skin melanocytes respectively; loss of axillary and pubic hair is due to lack of adrenal
androgens, normally important for growth of body hair in females. The increased skin
pigmentation and face freckling are caused by the melanocyte stimulating (MSH-like) action of
excess ACTH.
Answer 2: Diagnosis of Addison’s disease is made by documentation of low plasma cortisol and
aldosterone levels with concurrent high ACTH levels; the titre of anti-adrenal antibodies in the
serum would also be expected to be high. The lack of adrenal response to ACTH was confirmed
by the short ACTH stimulation test in which 250 µg of synthetic ACTH (tetracosactrin) is
administered intravenously over 2 min, and plasma cortisol levels measured at 30 and 60 mins
following the injection. Normally a peak level of 18 µg/dl or more is seen during the test. Patients
with adrenal failure are unable to achieve this level.
Answer 3: Treatment of Addison’s disease involves combined replacement doses of a
glucocorticoid and a mineralocorticoid taken for life. On diagnosis of primary hypoadrenalism,
the patient was started on hydrocortisone (25 µg/ day) and fludrocortisone (0.1 mg/day)
replacement therapy. The patient became totally asymptomatic within ten days, but was advised to
 THE ADRENAL GLAND 51

double her glucocorticoid dose during any period of stress (in an attempt to mimic the normal
physiological response).

Patient 3
A 52 year old man was admitted to the hospital Endocrinology Division for evaluation of hypertension of
four years duration, with progressive muscular weakness and muscle cramps. The patient had been treated
with various antihypertensive medications without significant improvement. His history was negative for
any other medical illness, and there was no family background of hypertension or neuromuscular disease.
He had been placed on potassium supplements about two years ago, but he did not know why. Lately, he
had stopped taking potassium. He was not taking any other medications. Clinical examination revealed
hypertension (195/105 mmHg; supine) and an early systolic ejection murmur in the aortic area. There was
no peripheral oedema.
Laboratory investigation revealed a normal FBC and urinalysis; blood chemistry gave a serum Na+ of 149
mmol/l (normal 135–145 mmol/l) and a serum K+ of 2.6 mmol/l (normal 3.5–5.0 mmol/l). Further
investigation showed normal 24 hour levels of urinary free catecholamines, metadrenaline and
vanillylmandelic acid (VMA). His 8 a.m. plasma cortisol and 24 hour urinary free cortisol levels were
normal; however, he showed a plasma aldosterone of 35 ng/dl (normal 6–30 ng/dl, upright) with a
concurrent plasma renin activity of 0.6 ng/ml/hour (normal 1.3–4.0 ng/ml/hour). The renin activity did not
increase after slow intravenous administration of frusemide (40 mg) and 4 hours of ambulation (upright
posture). A CT scan of the abdomen showed a round and solitary tumour (2.5 cm diameter) in the left
adrenal gland.
Question 1: What are the common causes of endocrine hypertension?
Question 2: What is the most likely diagnosis in this patient, and how may the condition be
treated?
Answer 1: The main causes of endocrine hypertension include an adrenal medullary tumour
(phaeochromocytoma), Cushing’s syndrome, mineralocorticoid excess (primary aldosteronism,
congenital adrenal hyperplasia), hyperthyroidism, acromegaly and hypercalcaemia. Urinary
excretion of the adrenaline/noradrenaline metabolites, metadrenaline/normetadrenaline and VMA
would be markedly increased in patients with phaeochromocytoma.
Answer 2: A combination of chronic Na+ retention (resulting in hypertension) and an unprovoked
hypokalaemia (typically resistant to potassium supplementation—causing muscle weakness and
cramps) suggests a possible hyperaldosteronism. A characteristic of primary hyperaldosteronism
(Conn’s syndrome) is the combination of a high plasm aldosterone level with suppressed plasma
renin activity. An increase in renin secretion by the kidney juxtaglomerular cells would normally
be expected following a stimulus that reduces renal perfusion pressure, decreases plasma
volume or causes Na+ depletion (e.g. a diuretic). In the present case, the ongoing hypertension and
Na+ retention caused by excess (non-suppressible) aldosterone secretion continues to depress
normal renin activity, despite a diuretic challenge by the ‘loop’ diuretic frusemide.
Treatment depends upon the type of underlying pathology. In this patient, the diagnosis of an
aldosterone producing adenoma (aldosteronoma) was confirmed, and he underwent a left
adrenalectomy with resolution of his hypokalaemia and hypertension [the aldosterone antagonist
spironolactone may also be used to manage patients prior to surgery]. He remains asymptomatic
at three years post-surgery.
52 BASIC ENDOCRINOLOGY—CHAPTER 3

UK/USA Drugs—Trade names

UK USA
ACTH/ACTH analogue
ACTH Acthar/Cortrosyn
Tetracosactrin Syncathen
Glucocorticoids
Beclomethasone Propaderm Beclovent/Beconase
Betamethasone Betnelan Celestone
Betnovate Lotrisone
Dexamethasone Decadron Decadron/Hexadrol
Fluocinolone Synalar Synalar/Fluonid
Hydrocortisone Hydrocortistab Cortef/Hydrocortone
Prednisolone Prednesol Delta-cortef
Deltastab Blephamide
Precortisyl Prelone
Triamcinolone Adcortyl Aristocort
Glucocorticoid-mineralocorticoid
Cortisone Cortisyl Cortone
Mineralocorticoid
Fludrocortisone Florinef Florinef
Aldosterone antagonist
Spironolactone Aldactone Aldactone
Steroid synthesis inhibitor
Aminoglutethimide Orimeten Cytadren

References

Books

• Aron DC, Tyrrell JB. (1994). Glucocorticoids & adrenal androgens. In Basic & Clinical Endocrinology, edited by FS
Greenspan, JD Baxter, 4th ed. Appleton & Lange, Connecticut, pp. 307–346
• Chandrasoma P, Taylor CR. (1991). The adrenal cortex & medulla. In Concise Pathology, 1st ed. Prentice-Hall,
USA, pp. 864–876
• Fitzgerald PA, Copeland PM. (1992). Adrenal disorders. In Handbook of Clinical Endocrinology, edited by PA
Fitzgerald, 2nd ed. Prentice-Hall, USA, pp. 227–287
• Fletcher RF. (1987). Adrenal. In Lecture Notes on Endocrinology, 4th ed, Blackwell Scientific Publications, Oxford,
pp. 144–168
• Ganong WF. (1995). The adrenal medulla & adrenal cortex. In Review of Medical Physiology, 17th ed, Appleton &
Lange, Connecticut, pp. 327–351
 THE ADRENAL GLAND 53

• Genuth SM. (1993). The adrenal glands. In Physiology, edited by RM Berne, MN Levy, 3rd ed. Mosby-Year Book,
Inc, USA, pp. 949–979
• Goodman HM. (1988). Adrenal glands. In Basic Medical Endocrinology, Raven Press, New York, pp. 71–113
• Guyton AC, Hall JE. (1996). The adrenocortical hormones. In Textbook of Medical Physiology, 9th ed. WB Saunders
Company, USA, pp. 957–970
• Hedge GA, Colby HD, Goodman RL. (1987). Adrenal cortex. In Clinical Endocrine Physiology, WB. Saunders Co,
Philadelphia, pp. 127–159
• Junqueira LC, Carneiro J, Long JA. (1986). Adrenals & other endocrine glands. In Basic Histology, 5th ed, Lange
Medical Publications, Connecticut, pp. 446–467
• Kaplan NM. (1988). The adrenal glands. In Textbook of Endocrine Physiology, edited by JE. Griffin, SR Ojeda.
Oxford University Press, New York, pp. 245–272
• Laurence DR, Bennett PN. (1992). Endocrinology I: adrenal corticosteroids, antagonists, corticotrophin. In Clinical
Pharmacology, Churchill Livingstone, pp. 549–563
• Magiakou M-A, Chrousos GP. (1994). Diagnosis and treatment of Cushing’s disease. In The Pituitary Gland, edited
by H Imura, 2nd ed. Raven Press Ltd, New York, pp. 491–508
• Playfair JHL. (1990). Cell-mediated immune responses. In Immunology at a glance, 4th ed, Blackwell Scientific
Publications, Oxford, Chapters 6 and 19
• Rang HP, Dale MM, Ritter JM. (1995). Pharmacology, 3rd ed, Churchill Livingstone, Chapters 11 and 21
• Schimmer BP, Parker KL. (1996). Adrenocorticotrophic hormone; adrenocortical steroids and their synthetic
analogs. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics, edited by JG Hardman, LE
Limbird. A Goodman, Gilman et al, 9th ed. McGraw-Hill, USA, pp. 1459–1485
• Whitby LG, Percy-Robb IW, Smith AF. (1984). Steroid hormones. In Lecture Notes on Clinical Chemistry, 3rd ed,
Blackwell Scientific Publications, Oxford, pp. 354–386

Journal Articles

• Barnes PJ, Adcock I. (1993). Anti-inflammatory actions of steroids: molecular mechanisms. Trends in Pharmacol
Sci, 14, 436–441
• Capponi AM, Python CP, Rossier MF. (1994). Molecular basis of angiotensin II action on mineralocorticoid
synthesis. Endocrine, 2, 579–586
• Cato ACB, Wade E. (1996). Molecular mechanisms of anti-inflammatory action of glucocorticoids. BioEssays, 18,
371–378
• Edwards CRW, et al. (1988). 11β-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid
receptor. Lancet ii, 986–989
• Funder JW. (1993). Aldosterone action. Annu Rev Physiol, 55, 115–130
• Funder JW, et al. (1988). Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated.
Science, 242, 583–585
• Kakouris H, Eddie LW, Summers RJ. (1993). Aldosterone-specific membrane receptors and related rapid, non-
genomic effects. Trends in Pharmacol Sci, 14, 1–6
• Müller J. (1995). Aldosterone: The minority hormone of the adrenal cortex. Steroids, 60, 2–9
• Munck, A, Naray Fejes Toth A. (1994). Glucocorticoids and stress: Permissive and suppressive actions. Ann NY
Acad Sci, 746, 115–130
• O’Banion MK, Winn VD, Young DA. (1992). cDNA cloning and functional activity of a glucocorticoid-regulated
inflammatory cyclooxygenase. Proc Natl Acad Sci USA, 89, 4888–4892
• Orti E, Bodwell JE, Munck A. (1992). Phosphorylation of steroid hormone receptors. Endocrine Rev, 13, 105–128
• Power RF, Conneely OM, O’Malley BW. (1992). New insights into activation of the steroid hormone receptor
superfamily. Trends in Pharmacol Sci, 13, 318–323
54 BASIC ENDOCRINOLOGY—CHAPTER 3

• Pratt WB. (1993). The role of heat shock proteins in regulating the function, folding and trafficking of the
glucocorticoid receptor. J Biol Chem, 268, 21455–21458
• Schleimer RP. (1993). An overview of glucocorticoid anti-inflammatory actions. Eur J Clin Pharmacol, 45, S3–S7
• Smith DF, Toft DO. (1993). Steroid receptors and their associated proteins. Molec Endocrinol, 7, 4–11
• Stewart PM, Wallace AM, et al. (1987). Mineralocorticoid activity of liquorice: 11β-hydroxysteroid dehydrogenase
deficiency comes of age. Lancet, 2, 821–824
• Wehling M. (1994). Nongenomic actions of steroid hormones. Trends Endocrinol Metab, 5, 347–353
• Wehling M. (1997). Specific, nongenomic actions of steroid hormones. Annu Rev Physiol, 59, 365–393
• Wehling M, Eisen C, Christ M. (1993). Membrane receptors for aldosterone: a new concept of nongenomic
mineralocorticoid action. News in Physiol Sci, 8, 241–244
• Weinberger C, Bradley DJ. (1990). Gene regulation by receptors binding lipid-soluble substances . Annu Rev Physiol,
52, 823–840
 4
The Thyroid Gland

Structure and Histology

The thyroid gland develops embryologically as an epithelial invagination from the base of the foetal tongue.
It consists of two large lobes (normally weighing ca. 15–20 g) lying on both sides of the trachea, just
beneath the larynx (voice box), connected by a narrow strand of thyroid tissue called the isthmus
(Figure 4.1A); a small pyramidal extension of tissue upwards from the isthmus is also sometimes present.
The gland receives a profuse blood supply through the thyroid arteries, and is also richly innervated by
fibres of the autonomic nervous system, although the role played by these nerves in the control of thyroid
blood flow and function seems minimal. The whole gland is enveloped by a capsule of fibrous connective
tissue.

Histology
Thyroid tissue is composed of numerous closed spherical follicles (ca. 200–300 µm in diameter), each
comprising of a rim of simple cuboidal epithelial cells surrounding a mass of colloidal storage protein called
thyroglobulin (a 670 kDa glycoprotein). The height of the cuboidal epithelium can vary according to the
functional state of the gland: thus, when the gland is relatively inactive, the colloidal mass is large and the
surrounding follicular cells are flattened, whereas under hyperactive conditions, the follicular lumen
decreases in size, and the endocrine cells become columnar in appearance. Fingers of loose connective
tissue, containing blood vessels, lymphatics and nerve fibres, separate the follicles into several functional
lobules. Lying in between the thyroid follicles are groups of separate larger epithelial cells, the
parafollicular C cells, responsible for the secretion of a peptide hormone calcitonin, involved in the control
of calcium metabolism (see Chapter 7). C-cells may also be present in the follicular epithelium, but never
border the follicular lumen (Figure 4.1B).

Biosynthesis and Release of Thyroid Hormones

The two active hormones secreted by the thyroid, are iodinated derivatives of the amino acid tyrosine; these
are thyroxine (T4; about 90% of output) containing four iodine atoms, and triiodothyronine (T3; about
10% of output) containing three iodine atoms. The term ‘thyroid hormone’ thus encompasses both T3 and
T4.
Inorganic iodine is concentrated within the thyroid follicular cells by a highly efficient, active iodide pump
mechanism that removes it from the thyroid blood supply. A wide range of anions can compete with iodide
56 BASIC ENDOCRINOLOGY—CHAPTER 4

Figure 4.1(A). Anterior view of the human thyroid gland.

for the carrier system, and can thereby inhibit the activity of the iodide pump e.g. perchlorate ,
thiocyanate (SCN-) or pertechnetate (Tc=Technetium).

Radioactive pertechnetate administered in the form of an isotonic injection solution (sodium

pertechnetate [99mTc] injection BP) is widely used clinically as a radioactive label in thyroid (and also
brain) diagnostic scanning procedures. Tc-99m is a metastable radionuclide formed by the radioactive
decay of molybdenum-99.

The processes involved in thyroid hormone synthesis and release may be summarized as follows:

1. Accumulated iodide is rapidly oxidized to free iodine by a thyroid peroxidase enzyme at the apical
surface of the follicular cell, and is then immediately incorporated into the 3- and 5-ring positions of the
tyrosine molecules to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) respectively.
2. Coupling of MIT and DIT via an ether linkage then occurs (involving the same thyroid peroxidase
enzyme) to form the active hormones T3 (3,5,3′-triiodothyronine) and T4 (3,5,3′,5′-
tetraiodothyronine or thyroxine). Small amounts (<1%) of the 3,3′,5′-triiodothyronine derivative
 THE THYROID GLAND 57

Figure 4.1(B). Histological appearance of a transverse section of the thyroid gland. Each thyroid follicle (lined with
simple cuboidal epithelial cells) is filled with thyroglobulin storage protein (colloid); note the variable size of the
follicles. Calcitonin-producing parafollicular cells are present in between the follicles (magnification×40).
(reverse T3 or rT3) are also synthesized, but this has no significant biological activity (Figure 4.2).
Under conditions of starvation or severe illness, larger amounts of rT3 may be produced relative to T3.
3. During iodination and coupling, the tyrosyl residues remain covalently linked to thyroglobulin
molecules at the apical border; (the large thyroglobulin precursor polypeptide is produced continuously
as secretory vesicles by the follicular cells, and exocytosed into the colloid through the apical
membrane). The thyroid hormones remain in this stored form within the colloid, until they are secreted.
4. Under the influence of the thyroid stimulating hormone thyrotrophin (TSH), resorption and
proteolysis of the stored thyroglobulin-hormone complex within the follicular cells leads to the release
of active hormones (ca. 20:1, T4:T3) by diffusion from the basal surface into the local capillary blood
supply. Thyroxine is then deiodinated in peripheral tissues (e.g. liver and kidney) to yield the more
active T3 (ca. 10 times more potent); MIT, DIT and released iodide are re-utilized for hormone
synthesis by the gland (Figure 4.3). Only minimal amounts of the free thyroglobulin normally escape
from the fol licles to reach the blood stream.

The presence of iodine atoms in the thyroid hormone molecule does not appear to be essential for
biological activity, since these can be replaced by other bulky/hydrophobic groupings to yield equally
(or more) active analogues.
In the bloodstream, T3 and T4 are extensively bound (>99%) to plasma proteins (principally
thyroxine binding globulin [TBG], thyroxine binding prealbumin and albumin); it should however be
noted, that only the free unbound hormones are biologically active on their target cells. T3 is less
avidly bound by plasma proteins than T4.
58 BASIC ENDOCRINOLOGY—CHAPTER 4

Figure 4.2. Chemical structure of the thyroid hormones and their intermediate precursors. Numbers indicate
positions of iodine atoms in the molecule.
Control of Release
Synthesis and release of thyroid hormone is controlled by pituitary thyrotrophin (TSH), which interacts
with specific receptors on the basal membrane of the follicular cells to cause an increase in intracellular
cAMP and subsequent activation of protein kinase A (see Figure 1.2). TSH also stimulates the active iodide
pump process by inducing the synthesis and insertion of new carrier molecules in the basal membrane.
Release of TSH is, in turn, stimulated by hypothalamic TRH and regulated by negative feedback effects
exerted by free circulating thyroid hormones (principally T3) on the anterior pituitary gland (see Figure 2.4).
 THE THYROID GLAND 59

Figure 4.3. Synthesis and release of thyroid hormones (T3 and T4) by the thyroid follicular cell. Dietary iodide, pumped
actively through the basal membrane, is oxidized and attached to thyroglobulin tyrosyl residues at the apical surface.
Internal coupling of iodotyrosines leads to T3/T4 production. Endocytosis and proteolysis of thyroglobulin releases
thyroid hormones into the circulating blood. MIT, DIT and tyrosine are re-utilized for synthesis.

Thyroid Hormones
Thyroid hormones increase the basal metabolic rate (BMR) (a measure of O2 consumption) in virtually all
tissues of the body. They stimulate the synthesis of specific proteins involved in calorigenesis (heat
production) and also influence protein, carbohydrate and fat metabolism.

Calorigenesis
Thyroid hormones increase O2 consumption in all tissues except the brain, testes, anterior pituitary and
spleen, which results in increased heat production (through the splitting of ATP molecules) and is therefore
important in the process of thermoregulation in a cold environment. It is now believed that this effect
(which has a typically long latent period of 4–5 days) may be mediated partly through the synthesis of new
Na+, K+-ATPase (sodium pump) molecules in the cell membranes, and partly via a direct (nongenomic)
activation of oxidative phosphorylation in liver mitochondria.

Influence on Metabolism
Carbohydrate metabolism is stimulated both directly (via an increase in gastrointestinal glucose absorption
and the synthesis of specific metabolic enzymes) and indirectly by an increase in tissue sensitivity to
catecholamines, insulin and growth hormone. The net result is an increase in gluconeogenesis and
60 BASIC ENDOCRINOLOGY—CHAPTER 4

glycogenolysis in the liver, and glucose utilization by fat, liver and muscle cells. Enhanced glycogenolysis
is particularly evident in patients with hyperthyroidism (see below).
Protein metabolism (both resynthesis and degradation) is stimulated when thyroid hormone levels are low;
however, at abnormally high levels, protein breakdown predominates (particularly marked in muscle),
leading to significant weight loss and elevation in plasma amino acid levels.
Fat metabolism is generally stimulated, but lipolysis is favoured, along with an increased oxidation of
free fatty acids. Part of this lipolytic effect is due to potentiation of catecholamine activity on adipose tissue
(a β-adrenoceptor effect). Plasma cholesterol is lowered by thyroid hormones, through an indirect
facilitation of liver cholesterol uptake from the blood (increased synthesis of low-density lipoprotein (LDL)
receptors in the liver cell membranes).

Maturation of the Central Nervous System (CNS)

Thyroid hormones are essential for normal CNS development during late foetal and early postnatal life; the
optimal growth of cortical and cerebellar neurones, and the adequate myelination of nerve fibres is vitally
dependent on their presence. Their absence or deficiency in utero or at birth, if not diagnosed early and
promptly treated with thyroid hormone replacement, invariably causes irreversible mental retardation
(cretinism).

Skeletal Growth and Maturation

The actions of thyroid hormone are generally synergistic with those of growth hormone (GH); thyroid
hormone is thus essential for normal bone growth and maturation, and the eventual development of normal
adult stature. Normal amounts of thyroid hormone are also necessary for proper functioning of the nervous
and cardiovascular systems, the gastrointestinal tract, as well as for regular development of the teeth, skin
and hair follicles.

Mechanism of Action of Thyroid Hormones

Being lipophilic molecules, free (unbound) T3 or T4 are able to enter target cells freely by passive diffusion;
in addition, active transport of T3 and T4 into some cells can also occur via specific carrier proteins. Upon
cell entry, T4 is immediately monodeiodinated to form the more active T3, or the inactive rT3 derivatives; (T4
is therefore regarded as a prohormone in this respect). Like the steroid hormones, the effects of T3 are
mediated by an interaction with specific high affinity thyroid hormone receptors (TRs) located in the cell
nucleus with a resultant stimulation (or repression) of target gene expression. Translocation of T3 into the
nucleus also involves a direct active uptake mechanism, together with an additional process involving a low
affinity cytosolic thyroid hormone binding protein (CTBP) (Figure 4.4; see also Chapter 3, p. 30). In
contrast with steroids however, the formation of the T3-receptor complex occurs directly at the nuclear
level, since the unliganded TRs are already bound to regulatory thyroid hormone response elements (TREs)
on the target DNA even in the absence of thyroid hormone. After synthesis, TRs are not, therefore, retained
in the cytoplasm in combination with heat shock proteins; a thyroid hormone receptor auxiliary protein
(TRAP) however, appears to be important for stabilization of TR binding to the nuclear DNA within the cell.
Several isoforms of the TR protein (TRα1–3, β1–2) have been identified, with characteristically different tissue
distributions (e.g. TRβ2 is only expressed in the pituitary); the biological functions of all these variants have
 THE THYROID GLAND 61

Figure 4.4. Proposed intracellular mechanism of action of the thyroid hormones. Both T3 and T4 enter the target cell
membrane by passive diffusion (and also by active uptake), but T4 is immediately converted to the more active T3 and
inactive reverse T3 forms. Unlike the steroid hormones (c.f. Figure 3.5), T3 enters the cell nucleus directly via a nuclear
transport process (and an additional process involving a cytosolic thyroid hormone binding protein [CTBP]), and reacts
with specific thyroid hormone receptors (TRs), already bound to target DNA regulatory elements; a nuclear protein
TRAP (thyroid hormone receptor auxiliary protein) is required for efficient binding of TRs to DNA. The consequent
increase (or decrease) in synthesis of specific proteins, mediates the thyroid hormone ‘response’ of the target cell. T3
can also interact directly with mitochondria to increase energy production.

not, however, been clearly established. Some evidence for more rapid non-nuclear effects of thyroid
hormones, mediated by surface membrane receptors has also been adduced.

Clinical Disorders
Apart from diabetes mellitus, thyroid dysfunction is one of the most common endocrine disorders
encountered in adults, affecting up to 10% of the UK population (females are generally more prone to
thyroid disorders than males). The two most common thyroid diseases are inadequate thyroid function,
hypothyroidism, and excessive thyroid function, hyperthyroidism (thyrotoxicosis).
62 BASIC ENDOCRINOLOGY—CHAPTER 4

Thyroid Hyposecretion

ADULT HYPOTHYROIDISM
Hypothyroidism can develop as a result of a functional defect in the thyroid itself (primary hypothyroidism)
or as a consequence of reduced stimulatory input from the pituitary (secondary hypothyroidism). Primary
hypothyroidism is most commonly caused by an autoimmune destruction of the thyroid gland, leading to a
deficiency in the amounts of circulating thyroid hormones (Hashimoto’s thyroditis). The condition is
typically slow to develop, has a strong familial tendency and is most prevalent in middle-aged women,
although it may also occur in men at any age. It is characterized by the appearance of destructive serum
antibodies to thyroglobulin and to cytoplasmic components of the thyroid follicular cells (microsomal
peroxidase enzyme), and a progressive infiltration of the gland by lymphocytes and plasma cells. A painful
diffuse swelling of the gland (goitre) may be present in the early stages of the disease.

Goitre is the name given to any enlargement of the thyroid that may be associated with decreased,
normal or increased thyroid activity. Any substance (natural or otherwise) that can induce one is
called a goitrogen (e.g. goitrin, present in cabbages, turnips or cauliflower). Lithium carbonate, used
in the treatment of manic depression, is a potential goitrogen due to its ability to interfere with thyroid
hormone release.

The main symptoms of primary hypothyroidism include:

1. Low BMR—a general slow-down of bodily processes, slow movements and reflexes, muscle cramps.
2. Weight gain and cold intolerance (impaired calorigenesis), decreased sweating, constipation. men-
(heavy periods).
3. Myxoedema—characteristic skin changes; the skin of both the hands and face thickens and becomes
coarse, dry and puffy, due to subcutaneous depositon of semifluid mucopolysaccharide material; hair
loss.
4. Tiredness/lethargy—weakness, slowness of thought, memory impairment, depression, slow, hoarse
speech, bradycardia.
5. Increase in plasma carotene concentration, producing a yellowish, jaundice-like tinge to the skin [the
low levels of thyroid hormone impede the normal synthesis of vitamin A from carotenes in the liver,
which then accumulate in the blood]
6. Serum T3/T4, levels are low, but TSH levels are high due to a lack of negative feedback effects.
Abnormally high levels of plasma cholesterol may also be present.

Total (bound+free) circulating T3 and T4 in the serum can be measured by sensitive

radioimmunoassay (RIA). procedures. These values can be influenced by changes in the concentration
of thyroid hormone binding proteins (e.g. during pregnancy, oestrogen therapy or severe accurate
immunoradiometric assay (IRMA) for serum TSH, utilising highly specific monoclonal TSH antio
available. Measurements of free T3/T4 can also be made using RIA kits or more cumbersome
equilibrium dialysis methods.

Treatment. Thyroid hormone replacement therapy is necessary for life; this is administered in the form of
thyroxine sodium tablets (Eltroxin; 50 µg daily initially, rising to 100– 200 µg daily), or liothyronine
 THE THYROID GLAND 63

sodium (T3) (Tertroxin; 20 µg tablets every 8 hours or by slow intravenous injection), which has a more
rapid onset of action, useful in cases of severe hypothyroidism (myxoedema coma with hypothermia).
Frequent measurements of serum TSH are made to check for adequacy of the replacement therapy; patients
also need to be advised on the importance of taking the thyroid hormone replacements on a regular basis.
Maintenance doses of thyroid hormone may need to be increased during pregnancy.

CHILDHOOD (CONGENITAL) HYPOTHYROIDISM

Uncorrected hypothyroidism at birth (usually due to ectopic location or failure of proper development of the
thyroid) leads to cretinism; infant subjects are dwarfed, with a protruding tongue and abdomen, mentally
retarded, and have coarse scanty hair and dry, yellowish skin. Early diagnosis is essential (based on TSH
assay of a heel-prick blood sample absorbed onto filter paper), followed by thyroxine replacement therapy
(10 µg/kg up to 50 µg daily).
Development of primary hypothyroidism in early childhood, (juvenile hypothyroidism), is usually
characterized by stunted growth, delayed sexual development and mental slowness, usually reflected by
poor performance at school. The replacement dose of thyroxine (25–200 µg daily) needs to be carefully
adjusted to ensure that catch-up growth progresses at a normal rate.
Some other important causes of hypothyroidism include:

1. Surgical removal (partial thyroidectomy) or radioactive iodine (131I) treatment of thyroid tissue for the
relief of hyperthyroidism.
2. Inadequate TSH production due to pituitary or hypothalamic disease; this rare secondary condition is
not normally accompanied by a goitre or myxoedema, but is associated with deficiencies in the other
pituitary trophic hormones, and is therefore treated with a combination of glucocorticoid/sex steroid
and (later) thyroid hormone replacement therapy.
3. Iodine deficiency: endemic goitre may result from a low dietary intake of iodide (e.g. from seafood);
this is pretty rare in Western countries where iodized table salt is generally available, but may still
occur in certain parts of the world that are distant from the sea, or in mountainous regions.
4. Amiodarone administration: the iodine-containing cardiac anti-arrhythmic agent amiodarone
(Cordarone X) can interfere with the peripheral conversion of T4 to T3, leading to an increase in serum
T4 (and inactive rT3) levels; significant clinical symptoms of hypothyroidism (or even hyperthyroidism:
see below) may develop in some patients taking this drug, that usually reverse within a few weeks
following drug withdrawal. The drug is not therefore recommended for use in patients with a history of
thyroid disease.

Thyroid Hypersecretion
Hyperthyroidism (thyrotoxicosis) is most commonly caused by an overactivity of the thyroid gland itself
resulting from an autoimmune condition known as Graves’ disease. The serum of such patients contains
specific thyroid-stimulating immunoglobulins (TSIs) that bind to the TSH receptors on the follicular cells,
and like natural TSH, stimulate the cells to produce thyroid hormone. Antithyroglobulin and
antimicrosomal autoantibodies may also be present. The disease is 5–8 times more prevalent in 40–50 year
old females than in males, and is commonly associated with other autoimmune disorders such as myasthenia
gravis, Addison’s disease, and pernicious anaemia.
The major symptoms of Graves’ disease are:
64 BASIC ENDOCRINOLOGY—CHAPTER 4

1. High BMR—a general acceleration of body metabolism; increased heat production leading to heat
intolerance, excessive sweating and warm skin.
2. Weight loss (despite a good appetite), due to muscle wasting (thyrotoxic myopathy); diarrhoea;
menstrual disturbances.
3. Rapid pulse, tremor, palpitations and other tachycardias (atrial fibrillation in the elderly), hypertension:
[the increased thyroid hormone secretion generally exaggerates responses of the sympathetic nervous
system due to an increase in the number and affinity of β-adrenoceptors].
4. Restlessness, overanxiety, nervousness, irritability, hyperexcitability and emotional instability.
5. Eye changes*—possible eyelid retraction and protrusion of the eyeballs (exophthalmos or proptosis) in
about 50% of patients, due to thickening of the extraocular muscles caused by lymphocyte infiltration
and deposition of mucopolysaccharide and oedema around the orbital soft tissues.
6. Diffuse toxic goitre (symmetrical swelling of the thyroid).
7. Serum T3/T4 levels are raised, but the serum TSH level is low (undetectable) due to excessive negative
feedback effects of the elevated T3/T4 hormones on the anterior pituitary.

The development of Graves’ ophthalmopathy cannot be directly attributed to the excess levels of
T3/T4, and may even occur in patients in the absence of other hyperthyroid symptoms. In extreme
cases, ocular pain with blurring or loss of vision, and corneal ulceration may occur. Like Graves’
disease, it is thought to be due to an autoimmune process directed against the orbital connective tissue
or muscle cells, although the nature of the autoantibodies involved and the factors involved in their
induction are not known. Achievement of normal hormone levels by therapy of hyperthyroidism is
important in reducing the long-term persistence of the condition. Systemic administration of
glucocorticoids, surgical therapy or orbital irradiation (sparing the lens and retina) can also be
effective in the treatment of local eye symptoms in severe cases.

TREATMENT
There are three methods currently available for the treatment of Graves’ hyperthyroidism: antithyroid
drugs, radioactive iodine (131I) or surgery.
Antithyroid Drugs.

1. Thiourea derivatives (thionamides): Carbimazole (NeoMercazole) or propylthiouracil. These agents

are accumulated by the thyroid, and reduce thyroid hormone secretion by diverting oxidized iodide
away from the thyroid peroxidase enzyme involved in the production and coupling of iodotyrosines
within the gland. Carbimazole may also have some specific immunosuppressant effects on the thyroid.
They are used mainly for the long-term treatment of hyperthyroid patients and also for the preparation
of patients prior to radioiodine treatment or subtotal thyroidectomy. Carbimazole is rapidly converted
to an active metabolite methimazole in the body (only the latter drug is used in the USA). Unlike
Carbimazole, propylthiouracil can inhibit the de-iodination of T4 to T3 in peripheral tissues. In an
attempt to induce a lasting remission, carbimazole/methimazole therapy is usually started with a
relatively large daily dose (20–60 mg) for 4–8 weeks, then progressively reduced to a maintenance
dosage continued for up to 12–18 months, followed by gradual withdrawal. Retreatment may, however,
be necessary 1–2 years after stopping therapy (a major disadvantage of these drugs). Although T3/T4
synthesis is rapidly inhibited, the clinical response to carbimazole or propylthiouracil can be delayed
 THE THYROID GLAND 65

for 1–2 weeks until the endogenous stores of thyroid hormone become depleted. Overtreatment with
antithyroid drugs may even lead to symptoms of hypothyroidism developing in some patients.
A recently introduced ‘block-and-replace’ treatment protocol using daily doses of carbimazole (40–
60 mg) together with replacement doses of thyroxine (50–150 µg daily) for up to 18 months, has been
found to produce significantly lower relapse rates in thyrotoxic patients.
Side effects associated with carbimazole or propylthiouracil include severe skin rashes, nausea,
vomiting and (rarely) agranulocytosis (a low white blood cell count), heralded by a severe sore throat,
mouth ulcerations and fever requiring immediate withdrawal of the drug and treatment with antibiotics.
Propylthiouracil (at tenfold higher dosage; 300–600 mg daily) may then be substituted in patients
unable to tolerate carbimazole and vice versa. Carbimazole and propylthiouracil may be given during
pregnancy and breast-feeding, provided the smallest possible effective doses are used and foetal
development is closely monitored throughout.
2. Aqueous iodine solution BP (Lugol’s iodine): A solution of 5% iodine dissolved in 10% potassium
iodide in purified water, is usually given orally (5–10 drops diluted with milk or water, three times
daily) to hyperthyroid patients for about 10–14 days prior to thyroid surgery, in order to reduce the size
and vascularity of the gland. Under such conditions excess iodine (converted to iodide in the liver)
transiently inhibits thyroid hormone production by an unknown mechanism (this effect is usually
absent in normal, euthyroid individuals); Lugol’s solution is of no use in the long-term control of
hyperthyroidism, since the antithyroid effects of the iodine do not persist for more than a few weeks,
but it can be of value in the emergency treatment of thyrotoxic crisis (see below) where a rapid relief of
symptoms is required.

Potassium iodide tablets (60 mg twice daily) may also be given for 7–10 days prior to
operation, and contain sufficient iodine to suppress thyroid function.
3. β-Adrenoceptor blockers: Non-cardioselective beta-blockers such as propranolol (Inderal), nadolol
(Corgard) or sotalol (Beta-cardone) may be administered initially along with antithyroid medication to
rapidly ameliorate the tachycardia, palpitations, agitation and tremor symptoms of hyperthyroidism.
They have no effect on thyroid hormone secretion, and are therefore of little use in long-term management
of thyrotoxicosis.

Radioactive Iodine. Iodine-131 (131I), given as a tasteless solution of Na131I is often the treatment of choice
for thyrotoxic patients over 40 years and for the elderly. It is absolutely contraindicated for use in pregnant
women (due to risk of foetal hypothyroidism) or in very young children. Radioactive iodine acts by
accumulating in the thyroid and selectively destroying the overactive thyroid tissue by local irradiation
(mainly β, with some γ emission) over a period of 1–6 months. During this lag period, symptoms may be
treated with carbimazole or propranolol. Patients must be adequately controlled into a ‘euthyroid’ state with
antithyroid drugs prior to giving 131I. Drugs are usually stopped two days before and following radiotherapy
to permit optimal thyroidal 131I uptake.
Side effects: initial discomfort in the neck and transient worsening of symptoms may occur for a few days
after treatment (radiation thyroditis). Undertreatment may allow the condition to persist, and even adequate
therapy may eventually result in the development of hypothyroidism over several years. Regular
measurements of serum TSH levels are therefore essential during the post-treatment period. Repeated
treatment may be necessary in some persistently hyperthyroid patients after 6–9 months.
Surgery. Partial thyroidectomy offers prompt and effective control (particularly in patients with recurrent
hyperthyroidism after drugs), but is a technically demanding procedure even for a skilled surgeon, since the
66 BASIC ENDOCRINOLOGY—CHAPTER 4

parathyroid glands and recurrent laryngeal nerves may also be inadvertently damaged (resulting in
hypoparathyroidism and voice changes respectively). As with radioiodine treatment, problems may arise
later from resultant hypothyroidism. Prior to surgery, it is common practice to give antithyroid drug (and β-
adrenoceptor blocker) therapy in order to restore the patient to a ‘euthyroid’ metabolic state, followed by
aqueous iodine solution to reduce the vascularity of the gland (making it easier and safer to operate).

In recent years, there has been a significant shift in therapeutic preference towards radioactive
iodine therapy (rather than antithyroid drugs or surgery) for the treatment of hyperthyroidism.

OTHER COMMON CAUSES OF HYPERTHYROIDISM

Toxic Multinodular Goitre. This is quite common in elderly patients, and is due to the development of
multiple hyperactive thyroid nodules. The patient may have normal thyroid hormone levels initially, but
eventually the nodules function independently, and mild hyperthyroidism develops, without exophthalmos.
Usual treatment is with surgery or radioactive iodine since relapses are common after a course of antithyroid
drugs. The underlying cause of the condition is unknown.
Solitary Toxic Nodule. This can occur in patients at any age, due to the development of a single
overactive thyroid nodule (e.g. a benign autonomous follicular adenoma, not under pituitary control), that
secretes excess thyroid hormones. Patients present with mild symptoms of hyperthyroidism and may be
treated with radioiodine or partial thyroidectomy.
Subacute (De Quervain’s) Thyroiditis. This is a rather uncommon, self-limiting inflammatory condition of
the thyroid, most likely of viral origin, that can follow an upper respiratory tract infection. Swelling and
tenderness of the thyroid may be present, with pain on swallowing, depending on the severity of the
inflammation. Some symptoms of hyperthyroidism e.g. weight loss, excessive sweating, irritability,
tachycardia and tremor may also occur due to inflammatory release of preformed thyroid hormone.
Treatment is with oral analgesics and corticosteroids for thyroid pain and inflammation, and propranolol for
hyperthyroid cardiac effects. A transient phase of mild hypothyroidism, may follow the condition.
Thyrotoxic Crisis (‘Thyroid Storm’). This is a rare, though serious medical emergency that can occur due
to a sudden release of large amounts of thyroid hormone in an otherwise controlled hyperthyroid patient
following sudden stress or infection, or after surgery/radioiodine therapy in unprepared patients. Extreme
restlessness, confusion, abdominal pain, tachycardia (with possible heart failure) and fever are present.
Immediate treatment is begun with propranolol (slow intravenous infusion), antithyroid drugs and aqueous
iodine (orally or by nasogastric tube if necessary) together with corticosteroids, antibiotics and intravenous
maintenance fluids/electrolytes. The hyperthermia may be treated with ice packs.
Secondary hyperthyroidism may also arise from the following:

1. Surreptitious (secret) ingestion of excessive amounts of thyroid hormone in an attempt to lose weight
(Thyrotoxicosis factitia).
2. TSH-producing pituitary adenoma (rare).
3. Ovarian teratoma with thyroid elements (Struma ovarii).
4. Metastatic thyroid carcinoma (follicular type).
5. Treatment with the cardiac anti-arrhythmic drug amiodarone (Cordarone X).

The TRH test can be useful in the diagnosis of hyperthyroidism. A 400 µg dose of TRH is injected
intravenously and plasma levels of TSH are measured before and 20–30 minutes after injection, to
 THE THYROID GLAND 67

test for an adequate anterior pituitary response. In primary hyperthyroid patients, the expected rise in
plasma TSH (generally between 5–30 mU/l) is suppressed due to the ongoing negative feedback
inhibition of the pituitary by the high thyroid hormone levels. In some patients, TRH injection can
cause a brief rise in blood pressure, tachycardia or bronchospasm.

‘Sick Euthyroid’ Syndrome

In addition to the conditions of hypo- and hyperthyroidism described above, abnormal results of the thyroid
function tests can be encountered in patients suffering from various acute or chronic illnesses or stresses.
These conditions include: myocardial infarction, renal failure, cirrhosis, serious burns, sepsis, surgical
trauma, anorexia, and malnutrition. Abnormally low serum T3/T4, with high levels of reverse T3 levels can
result from altered rates of peripheral conversion of T4 to T3 and/or reverse T3, or from changes in TBG
levels. Basal serum TSH levels are generally normal in these patients, which may serve as an important
diagnostic feature of the ‘sick euthyroid’ syndrome. Treatment of the underlying disorders eventually leads
to a normalization of the affected indices of thyroid function.

Review Questions
Question 1: State the location of the thyroid gland and explain briefly, its histological structure.
Question 2: Name the hormones secreted by the thyroid and describe how they are stored within
the gland.
Question 3: What is the function of the parafollicular C cells?
Question 4: Name the amino acid from which thyroid hormones are derived.
Question 5: Describe how thyroid follicular cells are capable of accumulating iodide from the
blood.
Question 6: Outline the use of radioactive pertechnetate in diagnostic scanning.
Question 7: Describe the mechanisms controlling thyroid hormone release.
Question 8: Explain how thyroid hormones are transported in the bloodstream.
Question 9: What do the abbreviations T3 T4 and rT3 represent? Which is the more active
hormone?
Question 10: Summarize the main effects of thyroid hormone on:
(a) calorigenesis
(b) carbohydrate/fat/protein metabolism
(c) maturation of the CNS
(d) skeletal growth and maturation.
Question 11: Outline how T3 and T4 exert their biological effects via intracellular receptors.
Question 12: Describe the causes, symptoms and treatment of:
(a) adult hypothyroidism
(b) congenital and juvenile hypothyroidism.
Question 13: Define the meaning of the term goitre; what is a goitrogen.
Question 14: What type of drug is amiodarone? Why is this agent not recommended for use in
patients with a history of thyroid disease?
Question 15: List the major symptoms of hyperthyroidism (thyrotoxicosis: Graves’ disease,).
68 BASIC ENDOCRINOLOGY—CHAPTER 4

Question 16: Explain the three methods used for treating Graves’ hyperthyroidism and state their
limitations.
Question 17: Explain the rationale for use of Lugol’s iodine and β-adrenoceptor blockers in the
treatment of thyrotoxicosis.
Question 18: Describe some other common causes of hyperthyroidism.
Question 19: What is the TRH test? How may it be used in the diagnosis of hyperthyroidism?
Question 20: Explain the causes of ‘sick euthyroid’ syndrome.

Clinical Case Studies

Patient 1
A 33 year old female was seen by her GP, complaining of nervousness, increased sweating, palpitations,
weakness, weight loss (despite a good appetite) and amenorrhoea of three month duration. She had lost
about eight kg (18 lb) weight since the appearance of symptoms about one year ago. The patient had no prior
medical history, but there was a strong family history of thyroid disease. She was referred to a hospital
Endocrinology Department for further investigation. Clinical examination revealed a very anxious, restless
young female of slender build. She had fine tremors, and her palms were warm and moist. Despite it being
winter, she was wearing only light clothing, and claimed that she did not feel cold. Her heart rate was 116
beats/min and blood pressure was 140/80 mmHg. The thyroid gland was diffusely enlarged, and there was a
mild protrusion of her eyes. Cardiac examination showed a soft systolic murmur, best heard in the
pulmonary area. Pulmonary examination was unremarkable, as was the rest of the examination.
Thyroid function tests revealed an elevated serum T4 of 16.8 µg/dl (normal: 4–12 µg/ dl) and TSH < 0.05
µU/ml (normal 0.5–5 µU/ml). Total serum T3 was 369 ng/dl (normal 80–180 ng/dl) and TSH receptor
antibodies were strongly positive.
Question 1: What is the patient most likely to be suffering from?
Question 2: What is the recommended treatment for her condition?
Question 3: What other possible treatments are there, and what are their side effects?
Answer 1: This patient has classic signs of autoimmune thyroid disease (Graves’ disease) with
hyperthyroidism. It is the most common cause of hyperthyroidism, more commonly seen in
females than in males, and often associated with other autoimmune disorders. The diagnosis is
verified by the laboratory findings showing elevated levels of serum T3/T4 with a very low level
of TSH (due to negative feedback effects of excessive thyroid hormone). The presence of TSH
receptor antibodies (thyroidstimulating immunoglobulins (TSIs)) that continuously stimulate
thyroid hormogenesis, confirms the autoimmune nature of the disease. The major symptoms of
Graves’ disease include: excessive sweating, warm skin and weight loss, due to a general
acceleration of body metabolism with increased heat production, and tachycardia, tremor and
palpitations, due to general overactivity of the sympathetic nervous system. Cardiac murmur,
commonly found in hyperthyroidism, can be attributed to an increased cardiac output. Protrusion
of the eyeballs (exophthalmos) is also seen in ca. 50% of hyperthyroid patients, due to lymphocyte
infiltration and fluid deposition around the orbital soft tissues.
Answer 2: Following diagnosis of Graves’ disease, the patient was treated with an antithyroid
drug (propylthiouracil, 450 mg daily) and a β-adrenoceptor blocker (propranolol, 80 mg daily),
 THE THYROID GLAND 69

becoming asymptomatic in 3 weeks. She refused to be treated with radioactive iodine, and was
therefore continued on propylthiouracil; her thyroid indices normalized in 16 weeks.
Answer 3: Treatment for Graves’ disease includes medical therapy with antithyroid drugs
(thionamides) (together with beta-blockers), radioactive iodine (131I) thyroid ablation, or surgical
subtotal thyroidectomy. Beta-blockers are useful for the short-term treatment of the tachycardia,
palpitations, nervousness and tremor symptoms, while long-term (12–18 month) treatment with
thionamides is aimed at controlling the excessive hormone secretion. Side effects associated with
propylthiouracil include skin rashes, nausea and agranulocytosis. With medical treatment alone,
about 50% of patients remain in remission after completion of treatment. The recovery from
exophthalmos is unpredictable. Use of radioactive iodine is based on its selective accumulation in
the thyroid gland, and consequent destruction of overactive thyroid tissue by local irradiation. A
possible side-effect of such radiotherapy is the higher risk of developing hypothyroidism (ca. 50%
over 10 years) compared to medical or surgical treatments. Radioactive iodine cannot be used in
patients who are pregnant or in very young children.

Patient 2
A 77 year old woman was admitted to hospital for evaluation of rectal bleeding. The patient was noticed to
be lethargic and complained about the hospital air conditioning being too cold. She was unable to elaborate
on any previous medical illnesses, and had not seen a doctor for several years.
Clinical examination revealed a puffy face with some periorbital oedema, cool dry yellowish skin, slow
heart rate (58 beats/min), loss of eyebrows and non-pitting oedema. Her temperature was 35°C, blood
pressure was 150/90 mmHg, and deep tendon reflexes showed a delayed relaxation phase. Her thyroid gland
was firm and non-tender. She also complained of some weight-gain over the past year, difficulty in
‘remembering things’, always feeling tired (particularly in the evenings) and being constipated.
Laboratory tests revealed a normal full blood count (FBC) and urinalysis, but blood chemistry showed an
elevated cholesterol level of 13.8 mmol/l (268 mg/dl). Thyroid function tests showed a serum TSH of 102
µU/ml and a total T4 of 0.9 µg/dl.
Question 1: What is the likely diagnosis and cause of this patient’s condition?
Question 2: How would her condition be treated, and what special considerations need to be
applied in her case?
Answer 1: This is a typical case of primary hypothyroidism, where symptoms have been neglected
for a long time (commonly mistaken for normal aging). Major manifestations of hypothyroidism
include: easy fatigability, mental slowness and memory impairment, weight gain, constipation,
cold intolerance (due to impaired heat production), muscle cramps, slow heart rate (bradycardia),
hair loss, dry skin, puffy face (due to myxoedema), husky voice and slow relaxation of deep
tendon reflexes. Reduced conversion of plasma carotenes to vitamin A in the liver may give a
yellowish colour to the skin. A rise in blood cholesterol level may also occur due to a decrease in
its rate of degradation. Hypothyroidism is diagnosed by documentation of low serum thyroxine (T4)
levels with high levels of TSH in suspected individuals.
Idiopathic atrophie thyroid disease is the most common cause of hypothyroidism in the elderly,
and is presumably the end stage of a destructive autoimmune thyroid disease, causing a deficiency
in circulating thyroid hormone. When the thyroid gland itself is dysfunctional, the term primary
hypothyroidism is used, whereupon low serum T3/T4 levels and high TSH levels would be
expected (due to lack of negative feedback effect). The condition is typically slow to develop, as
70 BASIC ENDOCRINOLOGY—CHAPTER 4

in this patient. When the defect lies in the pituitary or hypothalamus, the condition is known as
secondary hypothyroidism, and would be characterized by low serum levels of both TSH and T3/
T4.
Answer 2: On diagnosis of primary hypothyroidism, the patient was started on liothyronine
sodium (T3), 20 µg daily, with 20 µg dose increments made every five weeks, till TSH and
thyroxine levels stabilized. Starting replacement treatment with small doses is important in the
elderly, to avoid precipitating ischaemic cardiac episodes (anginal pain). Drugs that interfere with
the absorption of liothyronine from the gut (e.g. diphenylhydantoin, activated charcoal or
cholestyramine [anion-exchange resin]) are also to be avoided. This patient became completely
asymptomatic in six months, and was able to take daily walks and watch late night television—
something she could never do before.

UK/USA Drugs—Trade names

UK USA
Thyroid hormones
L-thyroxine sodium Eltroxin Levothroid/Levoxine
Levoxyl/Synthroid
Liothyronine sodium Tertroxin Cytomel
Triostat
Antithyroid drugs
Carbimazole Neo-Mercazole
Methimazole* Tapazole
Propylthiouracil Propylthiouracil
β-adrenoceptor blockers
Propranolol Inderal Inderal
Inderide
Nadolol Corgard Corgard
Corzide
Sotalol Beta-cardone Beta pace
* Methimazole is an active metabolite of carbimazole. Carbimazole is converted to methimazole in vivo.

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 THE THYROID GLAND 71

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• Edmonds C. (1991). Thyroid disease: diagnosis and treatment options. Prescriber, (39), 33–36
• Evans RM. (1988). The steroid and thyroid hormone receptor superfamily. Science, 240, 889–895
• Ichikawa K, Hashizume K. (1995). Thyroid hormone action in the cell. Endocrine J, 42, 131–140
• Lazar MA. (1993). Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocrine Rev, 14, 184–193
• Lazarus JH. (1997). Hyperthyroidism. Lancet, 349, 339–343
• Nemere I, Zhou L-X, Norman AW. (1993). Nontranscriptional effects of steroid hormones. Receptor, 3, 277–291
• Wartofsky L. (1993). Has the use of antithyroid drugs for Graves’ disease become obsolete? Thyroid, 3, 335–344
 5
Endocrine Secretions of the Pancreas

Structure and Histology

The pancreas has both exocrine and endocrine functions, carried out by distinctly different groups of cells.
The endocrine portion is limited to small rounded clusters of glandular tissue, the islets of Langerhans, ca.
300 µm in diameter, that form <2% of the mostly exocrine (acinar) pancreatic mass, but nevertheless secrete
two crucially important peptide hormones involved in blood glucose regulation, insulin and glucagon.
There are about 106 islets scattered throughout the human pancreas, each constituting an independent
secretory unit receiving a copious capillary blood supply via the gastroduodenal and superior mesenteric
arteries, and draining ultimately through the splenic and superior mesenteric veins into the portal vein.

Histology
Each pancreatic islet consists of ca. 2,500 specialized epithelial cells embedded within the exocrine tissue;
four principal types of cell have been identified using immunohistochemical or other specialized staining
methods:

1. α-cells (ca. 20% of islet population) are the largest cell type, localized towards the outer margins of the
islet, produce glucagon;
2. β-cells are smaller and more numerous (ca. 70%), occupying the central area of the islet, produce
insulin;
3. δ-(D) cells (ca. 10%), distributed along the islet periphery, produce somatostatin (which is a
hypothalamic G H release-inhibiting hormone; see Chapter 2) that may exert a localized paracrine
action on other islet cells to influence both insulin and glucagon secretion.
4. The so-called PP (or F) cells constitute a minor proportion of the islet cells, and secrete pancreatic
polypeptide; the functional role of this peptide in the release of other pancreatic hormones is not,
however, fully understood.

Neighbouring islet cells are metabolically and electrically linked via gap junctions, perhaps ensuring a
synchronized mode of hormone secretion. Sympathetic and parasympathetic nerve fibres terminate close to
all types of islet cell.
 ENDOCRINE SECRETIONS OF THE PANCREAS 73

Figure 5.1. The proposed structure of the insulin precursor molecule, proinsulin. Before secretion, the C-peptide
fragment connecting the A and B peptide chains of the insulin molecule is enzymatically cleaved to yield insulin. Note
the two disulphide bridges connecting the peptide chains and the third intrachain link within the A chain.

Pancreatic Hormones

Insulin

BIOSYNTHESIS, STORAGE AND RELEASE

Insulin is a 51 amino acid polypeptide synthesized in the β-cells as a precursor molecule, proinsulin
(derived from a larger insulin gene product, preproinsulin); the folded proinsulin structure consists of an A-
chain and a B-chain, linked by two disulphide bridges, together with a 31 amino acid intermediate
connecting peptide (C-peptide). An additional disulphide link is also present within the A-chain portion
(Figure 5.1).
Following synthesis, the proinsulin is stored within cytoplasmic secretory granules (located close to the
cell membrane), where the C-peptide is slowly cleaved by peptidase enzymes to yield insulin and C-peptide
molecules. The insulin is retained in the core of the granule in the form of a polymeric complex in
association with zinc.
Release of insulin (together with equimolar amounts of inactive C-peptide and some proinsulin) occurs
by exocytosis in a Ca2+-dependent manner; once released into the portal circulation, the insulin is rapidly
metabolized by the liver (and kidneys) with a plasma half-life of ca. 5–10 min. The detection of C-peptide
in the blood (by radioimmunoassay) may be used as a measure of β-cell activity in diabetic patients (see
below).
Control of Release. Insulin release is regulated by a number of stimulatory and inhibitory factors,
although a basal level of secretion is normally maintained. Release is principally influenced by:

1. The blood glucose concentration: One of the major physiological determinants of insulin secretion by
the β-cells, is the level circulating glucose in the blood; an increase in blood glucose level (above ca. 4.
74 BASIC ENDOCRINOLOGY—CHAPTER 5

5 mmol/l) stimulates both synthesis and release of insulin by a direct feedback mechanism. Insulin
release occurs in a characteristically biphasic manner (early and late phases) in response to continuous
glucose stimulation, suggesting the existence of at least two storage pools for insulin within the cells.

This stimulatory effect of glucose depends on its initial facilitated transport into the β-cell
(via the GLUT2 carrier protein), and subsequent metabolism to yield an increase in intracellular
levels of ATP. The high level of ATP then inhibits the activity of a special class of ATP-sensitive
K+ channels (KATP) present in the β-cell membrane, with a resultant cell depolarization, influx of
Ca2+ and triggering of hormone release. With normal levels of intracellular ATP, these channels
remain open, and thereby maintain the β-cell in a hyperpolarized (non-secreting) state.
2. Other islet hormones: Glucagon and somatostatin may also influence insulin release indirectly
(stimulation or inhibition respectively) by modulating the levels of intracellular cAMP; a rise in cAMP
and subsequent activation of protein kinase A, generally promotes exocytosis of insulin and vice versa
(Figure 5.2).
3. Gastrointestinal hormones: Several hormones released from the gastrointestinal tract (see below p. 66)
e.g. gastrin, secretin, cholecystokinin and particularly gastric inhibitory peptide (GIP) (from mucosal
endocrine K-cells) stimulate insulin release directly. These humoral effects may be physiologically
important in dealing with a sudden surge in blood glucose following a meal. It is well known that an
orally-administered dose of glucose releases more insulin than an intravenously administered one,
indicating the important role of gastrointestinal factors (released during food ingestion) in enhancing
insulin secretion.

A truncated glucagon-like peptide (tGLP-1 or incretin), derived from a preproglucagon

precursor molecule (see below) is secreted by endocrine L cells of the lower intestine following a
meal or glucose ingestion. tGLP-1 is a potent stimulator of insulin secretion from pancreatic β-
cells (insulinotropic action); the antidiabetogenic effects of tGLP-1 are currently being
investigated for use in the treatment of patients with diabetes mellitus (see below).
4. Amino acids and fatty acids: Arginine, leucine and some other amino acids derived from protein
digestion are potent stimulators of insulin release; these effects are generally synergistic (mutually-
enhancing) with those of glucose. An increase in free fatty acid levels also promotes the secretion of
insulin.
5. Some other hormones: Growth hormone (GH), glucocorticoids and thyroid hormone may stimulate
insulin release indirectly by increasing the blood glucose level.
6. The autonomic nervous system: Parasympathetic (vagal) nerve stimulation increases insulin secretion
while the dominant effect of sympathetic nerve stimulation is to inhibit release; the latter is due to
activation of α-adrenoceptors on the β-cell membrane, leading to a decrease in intracellular levels of
cAMP (Figure 5.2) (activation of β-adrenoceptors by adrenergic agonists has the opposite effect).

PRINCIPAL ACTIONS OF INSULIN

Insulin is the only hormone with the ability to directly lower the blood glucose level. It may generally be
regarded as an anabolic hormone, promoting the storage of chemical energy derived from food in the form
of glycogen, proteins and lipids (triglycerides), while suppressing the mobilization (catabolism) of stored
nutrients; the major target organs for insulin action are consequently the liver, muscles and adipose tissue,
 ENDOCRINE SECRETIONS OF THE PANCREAS 75

i.e. organs that are specialized for energy storage. Some tissues of the body such as kidney, brain, or red
blood cells are less sensitive or unresponsive to this hormone.
The two principal types of effect of insulin on target cells may be summarized as follows:

Figure 5.2. Mechanisms involved in the control of insulin release by the pancreatic β-cell. External glucose is
transported into the cell via a specific carrier protein (GLUT2) and metabolised to produce a rise in intracellular ATP. The
increased level of ATP then closes ATP-sensitive K+ channels with a resultant depolarization of the cell, influx of Ca2+
through voltage-sensitive Ca2+ channels and release of insulin from secretory granules. Release is also modulated by
other factors operating via surface receptors linked to adenylate cyclase (AC) and cAMP production.
Note: specific block of ATP-sensitive K+ channels by antidiabetic sulphonylurea drugs, may also induce release.

1. Effects on solute transport: an increase in the cellular transport of glucose, amino acids and fatty acids;
2. Modulation of key intracellular metabolic pathways: an increase in the synthesis of glycogen, proteins
and fats and an increase in the synthesis of nucleic acids by direct stimulation of DNA and RNA
formation.
76 BASIC ENDOCRINOLOGY—CHAPTER 5

Carbohydrate Metabolism: Effects on Glucose Transport. Plasma glucose is normally maintained within the
range of 3.6–6.4 mmol/l (65–115 mg/dl); however, for tissues such as skeletal and cardiac muscle and
adipose cells, glucose cannot penetrate the cell membrane by simple (or facilitated) diffusion down its
concentration gradient, and intracellular glucose is consequently very low. In the presence of insulin,
glucose uptake by these tissues is rapidly increased, due to the selective mobilization (and activation) of
preformed glucose transporter molecules (GLUT4) from intracellular vesicles to the cell membrane. This
process is believed to be mediated by an insulin-dependent phosphorylation of proteins involved in vesicle
translocation (Table 5.1).

Table 5.1. Major metabolic effects of insulin.

↑ in glucose transport in muscles and fat
↑ in muscle amino acid uptake
↑ in protein synthesis ↓ in muscle protein breakdown
↑ in fat synthesis in liver and adipose tissue (lipogenesis) ↓ in fat breakdown in adipose tissue (lipolysis)
↑ in conversion of glucose to glucose-6-P in liver ↓ in liver gluconeogenesis (synthesis of glucose from non-
carbohydrate sources e.g. amino acids, lactate and
glycerol)
↑ in glucose metabolism (glycolysis)
↑ in glycogen synthesis in liver and muscle ↓ in glycogen breakdown (glycogenolysis)
(glycogenesis)

Some tissues (e.g. liver, red blood cells and particularly brain cells) depend on facilitated diffusion only
(via specific glucose transporter proteins) for glucose entry, therefore an adequate blood glucose level is
essential for their normal function. Proximal tubule cells of the kidney and luminal epithelial cells of the
small intestine also possess an active Na+-dependent glucose transporter (SGLT1) that is independent of
insulin.

At least five structurally related, facilitative glucose transporter proteins (termed GLUT1–5) have
so far been identified, each with a characteristic tissue distribution; only the GLUT4 isoform however
(uniquely expressed in skeletal muscle, cardiac muscle and fat cells), is regulatable by insulin.

Carbohydrate Metabolism: Effects on Metabolic Pathways. Insulin also has numerous and complex effects
on the intracellular pathways involved in glucose and glycogen metabolism.
The principal effects of insulin are:

1. Stimulation of glycogen synthesis in skeletal muscle, liver and adipose tissue by a direct increase in
glycogen synthase and a decrease in glycogen phosphorylase activity.
2. Increase in hepatic glucose phosphorylation (due to stimulation of glucokinase activity), and a decrease
in glucose dephosphorylation (due to inhibition of glucose-6-phosphatase activity).
3. Increase in glucose metabolism (glycolysis) with a simultaneous decrease in liver gluconeogenesis.
Key enzymes involved in glycolysis (conversion of glucose into pyruvate and lactate) including 6-
phosphofructokinase and pyruvate kinase are stimulated by insulin, whereas those required for
gluconeogenesis (formation of glucose from amino acids, lactate and glycerol) including pyruvate
carboxylase and phosphoenolpyruvate carboxykinase are inhibited.
 ENDOCRINE SECRETIONS OF THE PANCREAS 77

The general decrease of glucose entry into the blood from hepatic glycogen stores, along with the increase
in cellular glucose uptake, accounts for the unique blood glucose-lowering effect of insulin in the body. The
major pathways for glucose and glycogen metabolism affected by insulin are summarized in Figure 5.3.
Protein Metabolism. Insulin stimulates the cellular active transport of plasma amino acids into muscle
(thereby lowering blood amino acid levels) and also stimulates muscle protein synthesis directly, (anabolic
action) while depressing protein breakdown. The lower levels of circulating amino acids contribute towards
the overall decrease in liver gluconeogenesis.
Fat Metabolism. Insulin stimulates uptake of glucose into adipose cells and promotes the synthesis
(lipogenesis) and storage of fatty acids in the form of triglycerides in both adipose and hepatic tissues (the
activity of the blood capillary enzyme lipoprotein lipase, that facilitates the clearance of dietary fat from the
plasma, is increased by insulin). It also prevents fat breakdown (lipolysis) by inhibiting hormone-sensitive
lipase activity in adipose cells; the levels of circulating free fatty acids are therefore reduced (an important
feature that prevents the generation of plasma ketone bodies (see below)). The major effects of insulin on
carbohydrate, protein and fat metabolism are listed in Table 5.1.

MECHANISM OF ACTION OF INSULIN

Insulin has a complex catalogue of effects on many tissues. These effects are now known to be mediated via
an interaction with specific insulin receptors on the target cell surface. The insulin receptor is a large
transmembrane glycoprotein (molecular mass ca. 400 kDa) composed of two identical α-subunits, each
coupled to each other and to two identical β-subunits by disulphide bridges (Figure 5.4). The α-subunits,
containing the high affinity insulin binding sites, are located externally, whereas the β-subunits span the cell
membrane and possess an intrinsic tyrosine-specific protein kinase activity that is regulated by insulin
binding. This kinase activity appears essential for mediating most of the metabolic actions of insulin. Some
rare genetic disorders characterized by a cellular resistance to insulin (see below) are believed to result from
a fault in insulin receptor structure and function.

Protein kinase enzymes catalyse the transfer of phosphate groupings from ATP to amino acid
residues on proteins, whereas phosphatase enzymes catalyse the hydrolytic removal of phosphate
groups and therefore effectively reverse the regulatory effects of the kinases.

Following binding of insulin to one of the α-subunits, the internal β-subunit domain of the adjacent αβ
dimer becomes rapidly phosphorylated (autophosphorylation via ATP) which in turn stimulates the intrinsic
tyrosine kinase activity of the receptor. The principal intermediate cytoplasmic protein substrate for the insulin
receptor kinase is termed the insulin receptor substrate-1 (IRS-1), a 185 kDa peptide containing multiple
potential tyrosine phosphorylation sites within its molecule. The phosphorylated sites in IRS-1 associate
with high affinity with distinct cellular signalling proteins (e.g. phosphatidylinositol-3′ -kinase) containing
Src homology 2 domains (SH2 proteins) that ultimately mediate the multi-faceted insulin response
(Figure 5.4). IRS-1 itself has no intrinsic catalytic function, but it acts as a multisite ‘docking’ protein that
interacts with various regulatory elements during insulin signal transmission. Some key enzymes and
proteins that undergo phosphorylation (via kinases) or dephosphorylation (via phosphatases) in response to
insulin are listed in Table 5.2.

The receptor for the insulin-like growth factor (IGF-1; see Chapter 2) shares many structural
similarities with the insulin receptor, and also utilizes the IRS-1 signalling pathway.
78 BASIC ENDOCRINOLOGY—CHAPTER 5

Figure 5.3. Effects of insulin on glucose, glycogen and fatty acid metabolism in the liver. Some key enzymes that are
either stimulated (+) or inhibited (−) by insulin action are indicated. Insulin generally facilitates glucose oxidation (to
pyruvate) and the reactions leading to glycogen and fatty acid synthesis, while inhibiting the production of glucose from
amino acids, lactate and glycerol (gluconeogenesis). (Some intermediate reaction steps have been omitted for clarity.)
Prolonged stimulation of the insulin receptor leads to internalization (endocytosis) of the insulin-receptor
complex and insulin degradation, that may serve to terminate the insulin signal; (various phosphatases may
also be involved in the reversal of insulin effects). Some of the internalized receptors are degraded, while
most are recycled to the plasma membrane. The internalized insulin receptor can still function as a tyrosine
kinase, suggesting a supplementary role in the signal transduction process. Many features of the insulin
action pathway however e.g. the mechanism by which insulin influences DNA and RNA synthesis, are still
relatively unclear.
 ENDOCRINE SECRETIONS OF THE PANCREAS 79

Figure 5.4. Cellular mechanism of action of insulin. Binding of the hormone to one external α subunit of the insulin
receptor causes a conformational change, leading to autophosphorylation of three tyrosine residues on the adjacent β
subunit and stimulation of intrinsic tyrosine kinase activity. Tyrosine phosphorylation of the principal insulin receptor
substrate (IRS-1) enables it to act as an intermediate signalling molecule leading ultimately to activation/deactivation of
key metabolic enzymes involved in mediating the insulin ‘response’.

Glucagon
Glucagon is a simple, 29 amino acid unbranched peptide that is synthesized in pancreatic islet α-cells from a
larger
80 BASIC ENDOCRINOLOGY—CHAPTER 5

Table 5.2. Some key enzymes that are dephosphorylated (via protein phosphatases) or phosphorylated (via kinases) in
response to insulin.
Enzymes undergoing dephosphorylation Effect on enzyme active
Glycogen synthase Activation
Pyruvate dehydrogenase Activation
*Acetyl-CoA carboxylase Activation
Glycogen phosphorylase Inactivation
Phosphorylase kinase Inactivation
Hormone-sensitive lipase Inactivation

Enzymes and protiens undergoing phosphorylation Effect

cAMP phosphodiasterase Activation
ATP-citrate lyase Activation
Protein phosphatase-1G (PP1G) Activation
Proteins controlling intracellular translocation of glucose Transfer of glucose transporters (GLUT4) from
transporter molecules intracellular stores to plasma membrane
* The involvement of insulin in the dephosphorylation/ phosphorylation of this enzyme is still controversial.
Insulin is known to activate protein phosphatase-1G (PP1G), involved in the dephosphorylation of glycogen
synthase (and phosphorylase kinase), by means of a phosphorylation reaction on the G-subunit (site 1); this is
mediated by an insulinstimulated protein kinase (ISPK).

preproglucagon precursor molecule and stored in the form of cytoplasmic granules. Unlike insulin, its
structure is identical in different mammalian species. It is released from the islet cells (into the portal
circulation) by a process of Ca2+-dependent exocytosis, mediated by a rise in the level of intracellular cAMP
(c.f. mechanism of insulin secretion; Figure 5.2). Once released, it is rapidly metabolized by the liver and
kidney (plasma half-life ca. 3–5 min). Gut glucagon is also secreted by specialized α-like cells in the
mucosa of the stomach and duodenum, and has the same actions as the pancreatic hormone.

CONTROL OF RELEASE
Glucagon release is affected by the following factors:

1. The blood glucose concentration: In contrast to insulin, an increase in blood glucose level (e.g.
following a meal) inhibits glucagon release and vice versa.

The sensitivity of islet α-cells to glucose is dependent on an adequate level of insulin. Thus,
under conditions of insulin deficiency (i.e. diabetes mellitus; see below), the normal secretion of
glucagon in response to a lowered blood glucose may be impaired.
2. Other islet hormones: Glucagon release is inhibited by both somatostatin and by insulin; (note that insulin
release is directly stimulated by glucagon).
3. Gastrointestinal hormones: cholecystokinin, gastrin and gastric inhibitory peptide (GIP) stimulate
glucagon release.
4. Amino acids and fatty acids: Certain amino acids, particularly arginine and alanine stimulate glucagon
secretion, whereas increased levels of free fatty acids cause an inhibition of its release (cf. opposite
 ENDOCRINE SECRETIONS OF THE PANCREAS 81

effect of fatty acids on insulin release). The increased secretion of glucagon in response to a protein-
rich meal enables the liver to dispose of the excess plasma amino acids by gluconeogenesis.
5. The autonomic nervous system: Both sympathetic and parasympathetic nerve stimulation increase the
secretion of glucagon. Secretion is also enhanced by stressful stimuli (e.g. vigorous exercise) most
likely acting via the sympathetic nervous system.

ACTIONS OF GLUCAGON
The main actions of glucagon are generally opposite to those of insulin, and tend to protect the body from
hypoglycaemia (blood glucose <2.8 mmol/l). It is a catabolic hormone that raises the blood glucose
concentration by affecting carbohydrate, protein and fat metabolism in the liver, its major target organ.
These effects are mediated by specific membrane glucagon receptors (coupled to adenylate cyclase) that
generate an increase in intracellular cAMP levels in the target cells.
The principal actions of glucagon may be summarized as follows:

1. Increase in hepatic glycogenoly and gluconeogenesis, leading to an increase in production and release
of glucose into the blood.
2. Increase in lipolysis and mobilization of fatty acids (from triglycerides), resulting in increased levels of
circulating ketoacids, acetoacetate and β-hydroxybntyrate (ketogenesis: see below). This effect is
mediated by an increase in hormonic-sensitive lipase activity (via elevation of cAMP).

INSULIN-GLUCAGON MOLAR RATIO

Compared to insulin, the basal level of glucagon secretion is relatively high; the intake of food however,
induces a greater relative change in the level of plasma insulin than plasma glucagon. The so-called insulin-
glucagon ratio (normally around 2.0) may thus vary considerably in response to the availability of nutrients
and the immediate energy requirements of the body: e.g. the ratio may be decreased to < 0.5 during periods
of fasting or after a prolonged period of exercise (due to preferential release of glucagon); under these
conditions, glycogenolysis and gluconeogenesis are promoted in order to provide an adequate blood glucose
level (particularly for the central nervous system) and lipolysis is facilitated to provide fatty acids and
ketones as energy sources for oxidation by muscle and liver. When nutrients are abundant (e.g. after a
mixed meal), the ratio can rise to ca. 10 or more due to increased insulin release, thereby promoting the
deposition of glycogen, proteins and fat.

Other Islet β-cell Peptides

AMYLIN
Amylin (or islet amyloid polypeptide: IAPP) is a 37 amino acid peptide produced by the pancreatic β-cells
and normally co-secreted along with insulin at very low levels (ca. 1:100 molar ratio), following nutrient
stimuli. Structurally, it belongs to the calcitonin family of peptides, which includes calcitonin itself and the
calcitonin gene-related peptides (CGRPα and CGRPβ) (ca. 50% homology), considered to be important
regulatory neuropeptides, both in the central and peripheral nervous systems. Not surprisingly, amylin has
similar (though less potent) hypocalcaemic and vasodilator effects to those of calcitonin or CGRP
respectively, mediated via a specific type of G-protein coupled cell membrane receptor. Amylin can also
82 BASIC ENDOCRINOLOGY—CHAPTER 5

influence carbohydrate metabolism by reducing the synthesis of glycogen from glucose in skeletal muscle,
while increasing muscle glycogen breakdown to lactate (opposite actions to insulin), thereby increasing
plasma lactate (and subsequently glucose) concentration; it may also exert an autocrine inhibitory effect on
islet insulin secretion.
The main interest in amylin centres on its recently proposed role in the aetiology of type II, non-insulin-
dependent diabetes mellitus (NIDDM; see below): plasma amylin levels are generally found to be high in
patients with chronic NIDDM, and low or deficient in type I, insulin-dependent diabetics (IDDM). When
present in excess, amylin can aggregate to form insoluble pancreatic amyloid fibrils which are deposited
within the islet cells, and may be a critical factor contributing to their eventual degeneration; [this effect of
pancreatic amylin is reminiscent of that of the amyloid β-peptide (Aβ) which forms neurotoxic amyloid
fibrils in the brains of subjects with Alzheimer’s disease]. Since amylin functionally opposes the metabolic
effects of insulin on skeletal muscle, its excess production has also been suggested as a possible cause of
insulin resistance, glucose intolerance and obesity associated with type II diabetes. Therapeutic strategies
aimed at inhibiting pancreatic amyloid production or blocking peripheral amylin action are currently being
investigated for possible use in the treatment of NIDDM.

PANCREASTATIN
Pancreastatin (PST) is a 49 amino acid peptide, derived from chromogranin A (CgA), an acidic glycoprotein
that is co-secreted with catecholamines from sympathetic nerve terminals and adrenal chromaffin cells.
Since CgA is processed to PST in the plasma, it has been suggested that the blood levels of this peptide may
reflect excessive sympathetic nerve activity in essential hypertension. Circulating plasma PST-like
immunoreactivity may also be used as a useful clinical marker of certain tumours of the sympathetic nervous
system (neuroblastomas, ganglioneuromas) and also the pituitary (adenomas), pancreas and gut, which are
known to release significant amounts of this (and other) regulatory peptides*. Within the pancreas, PST is
co-released with insulin, and can inhibit both insulin and glucagon secretion, as well as exocrine pancreatic
secretions. PST is also present in the gut (stomach, duodenum, small intestine and colon) and is stored and
co-secreted along with parathyroid hormone (PTH) in the parathyroid gland (see Chapter 7); its functional
role at these sites, however is unclear.

Clinical Disorders

Glucagon Hyposecretion
Clinical conditions of glucagon undersecretion are not well known, although some cases of neonatal
hypoglycaemia have been attributed to glucagon deficiency. On rare occasions, excess secretion of glucagon
by pancreatic glucagonsecreting tumours (glucagonomas) may be encountered, and may lead to mild
diabetic symptoms (e.g. hyperglycaemia and weight loss); treatment is usually by surgical removal of the
tumour. Glucagon hydrochloride (1 mg, by intramuscular, intravenous or subcutaneous injection) may be
used clinically in the emergency treatment of severe hypoglycaemia.
 ENDOCRINE SECRETIONS OF THE PANCREAS 83

Insulin Deficiency
Hyposecretion of insulin by the pancreas results in the common condition of diabetes mellitus, which affects
ca. 2% of the UK population at any age. The overall prevalence of diabetes in the US is similar, with
considerable ethnic differences, including a greater than 40% incidence in the Pima Indians of Arizona. It is
a serious condition in which the normal conversion of glucose into energy by the body is disrupted, along
with a severe reduction in the ability to store glycogen, fat and proteins; this may result in:

1. Chronic hyperglycaemia and glycosuria (high blood and urine glucose levels respectively),
2. Polyuria (increased urine production) with dehydration and excessive thirst (polydipsia),
3. Polyphagia (increased appetite) due to inadequate transport of glucose into cells and consequent
triggering of the hunger sensation and,

*Endocrine secretions of the gastrointestinal tract

A large variety of peptide hormones are also secreted by specialized enteroendocrine cells of the gastrointestinal
mucosa to affect gastrointestinal secretion and motility [the entire study of endocrinology is, in fact, founded on the
discovery of the first gut hormone—secretin, by Bayliss & Starling in 1902]. These gut peptides have common
structural and functional characteristics and can be grouped into hormone ‘families’, each group presumably arising
from a common ancestral gene; not all these substances however, have a known physiological function.
Some principal examples include:
The gastrin family: gastrin, cholecystokinin (CCK)
The secretin family: secretin, glucagon, vasointestinal polypeptide (VIP), gastric inhibitory peptide (GIP)
The pancreatic polypeptide family: pancreatic polypeptide (PP). peptide YY (PYY), neuropeptide Y (NPY)
The tachykinin family: substance P, gastrin-releasing peptide (GRP)
Orphan peptide family: motilin. neurotensin. somatostatin, galanin, pancreastatin
Some of the peptides, derived from the gut (and pancreas) circulate in the bloodstream to affect distant organs, and may
therefore be regarded as true hormones in the classical endocrine sense (e.g. gastrin, CCK, GIP, secretin); others serve a
paracrine or autocrine role, being secreted in a more localized manner to affect nearby (or the same) cells within the
gastrointestinal system (regulatory peptides). Some serve a peptidergic neurotransmitter role within the enteric nervous
system of the gut (e.g. VIP).
A large number of gut peptides are also localized in the central nervous system (and vice versa), where they are believed
to act as neurotransmitters or neuromodulators (neurocrine role) (e.g. somatostatin, substance P, CCK). Apart from
somatostatin and its analogue octreotide however, (see Chapter 2), the use of gastrointestinal peptide hormones or
their antagonists in treating clinical disorders is not firmly established at present. [For a detailed description of the
properties and known functions of the major regulatory peptides of the gut, see Mulvihill & Debas (1994).
Nevertheless, certain gastrointestinal hormones have pathophysiological significance:
Some recognised clinical implications involving gastrointestinal peptides include:
The Zollinger-Ellison syndrome, a rare condition in which unregulated ectopic secretion of gastrin occurs from a
gastrin-producing tumour (gastrinomo—usually in the endocrine pancreas or duodenum) resulting in
hypergastrinaemia, occurrence of severe recurrent peptic ulcers (nonresponsive to therapy) and unexplained diarrhoea;
treatment usually consists of surgical tumour resection (where possible) or long-term therapy with a proton pump
inhibitor (omeprazole, lansoprazole) or histamine H2 receptor antagonist (cimetidine, ranitidine, famotidine).
Gastrin is secreted by endocrine G-cells of the gastric antral mucosa and also by cells of the duodenum; it is mainly
responsible for stimulating acid (HCl) secretion from the gastric parietal cells, and also promoting their growth (trophic
effect), it exists in three active forms with different peptide chain lengths (17, 34 and 14 amino acid residues). Gastrin
has also been found to stimulate the growth of gastric and colorectal cancer cells; gastrin receptor antagonists are
therefore being evaluated for possible therapeutic use in treating gastrin-responsive gastrointestinal cancers as well as
preventing gastric ulcer formation.
84 BASIC ENDOCRINOLOGY—CHAPTER 5

4. Wasting of muscle and fat, with an increase in ketoacid metabolites in the blood (ketosis).

MAJOR CONSEQUENCES OF INSULIN DEFICIENCY

Hyperglycaemia and Glycosuria. In the absence of insulin, the blood glucose concentration (normally
between 3.6– 6.7 mmol/l after fasting) can rise above 35 mmol/l. Normally, glucose is filtered by the renal
glomeruli, then completely reabsorbed in the kidney tubules by carrier mechanisms. However, when the
filtered load exceeds the renal threshold of ca. 10 mmol/l (180 mg/dl), glucose appears in the urine and acts
as an osmotic diuretic (retaining water in the tubules), leading to polyuria, dehydration and polydipsia. The
renal threshold for glucose generally tends to increase with age. In severe cases, a profound fall in blood
volume with eventual coma/death may result.
Ketosis. In the absence of insulin, lipolysis is stimulated, and free fatty acid levels in the blood increase.
Fatty acids are normally converted in the liver to their intermediate acyl CoA derivatives, and then oxidized
in the mitochondria to acetyl CoA; the latter enters the citric acid cycle to undergo further oxidation,
yielding CO2 and energy (Figure 5.5). Lack of insulin causes excess acetyl CoA to accumulate in the liver,
where it condenses to form ketone bodies: acetoacetate, 3-hydroxybutyrate and acetone, which then appear
in the blood (ketonaemia) and urine (ketonuria) of uncontrolled insulin-dependent diabetics; the acetone
imparts a characteristic sweet smell to the breath of such patients. High concentration of ketone bodies in
the circulation also induces nausea, vomiting, metabolic acidosis (abnormally low blood pH) and ultimately
a diabetic coma.
Muscle Wasting. Insulin deficiency will tend to reduce all anabolic processes and facilitate catabolic
processes; protein breakdown will therefore be increased, and blood amino acid levels will rise. This protein
depletion (together with the enhanced fat breakdown) contributes to the severe muscle wasting, weakness
and loss of weight found in chronic diabetics.

Secondary Diabetes
Hyperglycaemia may also be caused by an excess secretion of various hormones including cortisol,
adrenaline, growth hormone, glucagon and thyroxine, all of which may therefore induce a secondary
diabetes. The condition may also be caused by administration of certain drugs that reduce glucose tolerance

Likewise, the gastrin-releasing peptide (GRP) is thought to act as an autocrine growth factor involved in the initiation
and progression of some human breast cancers; synthetic antagonists acting at the GRP receptor may then have a
possible therapeutic use in inhibiting the growth of such tumours. The measurement of certain gastrointestinal peptides
in the blood by radioimmunoassay (e.g. gastrin, VIP, glucagon, somatostatin, neurotensin) may have a more general
diagnostic value in the early detection of neuroendocrine gastrointestinal and pancreatic tumours.
The Verner-Morrison Syndrome is a condition in which ectopic secretion of vasointestinal peptide (VIP) occurs from a
pancreatic islet cell tumour (‘VIPoma’; see also Chapter 2) causing a characteristic voluminous watery diarrhoea (due to
overstimulation of the intestinal epithelium), hypokalaemia and metabolic acidosis (due to faecal loss of K+ and
); specific VIP receptor antagonists may thus prove useful in the management of this condition (usually treated by
surgical excision of the tumour, or subtotal pancreatectomy). It has been suggested that VIP or its analogues could also
be effective, in the treatment of bronchial asthma.
VIP is a basic 28 amino acid peptide secreted mainly by enteric peptidergic nerve cells (and also pancreatic D cells) but
not gut endocrine cells; its main function is to stimulate intestinal electrolyte (and water) secretion and also to relax
intestinal sphincters.
 ENDOCRINE SECRETIONS OF THE PANCREAS 85

Figure 5.5. Summary of reactions involved in fatty acid metabolism (lipolysis). In the absence of insulin (as in diabetes
mellitus), the inhibitory effect on the hormonesensitive lipase activity is removed, allowing fat breakdown to predominate
and free fatty acid levels in the blood to increase. Under such conditions, accumulation of acetyl CoA in the liver leads
to formation of ketone bodies.

(e.g. thiazide diuretics) or influence carbohydrate metabolism (e.g. oestrogen-containing oral

contraceptives and corticosteroids).

Primary Diabetes Mellitus

This may be classified into two types, based on the patient’s requirement for insulin therapy:
86 BASIC ENDOCRINOLOGY—CHAPTER 5

INSULIN-DEPENDENT DIABETES MELLITUS (IDDM; TYPE I)

This accounts for ca. 10–20% of all diabetic cases. It is usually acute in onset, and occurs mainly in young
non-obese individuals during childhood or at puberty (although adults at any age may also be affected). The
condition is characterized by a selective destruction of the pancreatic islet β-cells, such that very little or no
insulin production is present; such patients therefore require regular insulin injections for treatment.
Subjects with IDDM also commonly possess serum antibodies directed against their islet β-cells (islet cell
antibodies; ICAs), or much less frequently, against insulin itself or the insulin receptors. These autoimmune
antibodies can be detected months or even several years before main clinical features develop, and may
therefore be useful as a diagnostic marker in susceptible individuals (i.e. first degree relatives of known type
I diabetics).

The incidence of other autoimmune diseases e.g. Addison’s disease, thyroid disease and
pernicious anaemia is markedly increased in patients with IDDM. Although IDDM is not directly
inheritable, patients that possess certain human leucocyte antigen (HLA) types carry an increased risk
of developing this disease that may be inherited. The HLA antigens are cell-surface glycoproteins that
are present on all cell-types except red blood cells and sperm; they form part of a set of cell-surface
molecules determined by the so-called major histocompatibility complex (MHC) of genes present on
the short arm of human chromosome 6. The six important HLA gene loci (termed A, B, C, DP, DQ
and DR) code for over 100 possible known types of HLA antigen, with each individual possessing a
fixed combination of these molecules. The particular antigens that predispose a person towards IDDM
are HLA-DR3, DR4 (or both) and DQw8 (w indicates a provisional identification); (interestingly, the
presence of HLA-DR2 somehow protects against the development of diabetes). Some other
autoimmune diseases have also been linked to particular HLA groupings (e.g. Graves’ disease and
HLA-B8).
It has been suggested that the development of certain specific HLA antigens may increase the
susceptibility of islet β-cells to viral attack (e.g. by mumps, rubella or coxsackie B4 virus) or to
damage by environmental toxins, so that an abnormal autoimmune response ultimately develops
against altered self-antigens presented on the β-cell membrane.

NON-INSULIN-DEPENDENT DIABETES MELLITUS (NIDDM; TYPE II)

This type of diabetes (formerly called maturity-onset diabetes) is the more common (80–90% of all cases)
and is normally slower to develop, usually in older (over 40 years) more obese individuals; it is claimed to
affect ca. 5% of the world population. Such patients continue to secrete some insulin, therefore insulin
therapy is usually not required; however the amount secreted is generally not sufficient to maintain a
normal blood glucose level. Some patients may, in fact, show a characteristic insulin resistance (coupled
with a high blood insulin level or hyperinsulinaemia, leading eventually to β-cell exhaustion) suggesting a
defect in the action of insulin (particularly in stimulating muscle glucose uptake) at the receptor or
postreceptor levels. The insulin resistance leads to an increase in the rate of lipolysis and elevation in free fatty
acid levels; this, coupled with an increased liver glucose production and reduced glucose uptake, results in a
significant hyperglycaemia. Despite the above abnormalities, the development of ketosis in type II diabetes
is relatively rare.

The exact origin of this insulin resistance in NIDDM remains controversial, although it is clear
that a direct relationship exists between the degree of obesity of an individual and the resistance to
 ENDOCRINE SECRETIONS OF THE PANCREAS 87

insulin action. A defect in insulin receptor function due to a genetic mutation of the insulin receptor
gene, may be one principal mechanism involved. Other possibilities include the synthesis of
structurally abnormal insulins, the presence of a defect in the glucokinase enzyme gene, or a specific
down-regulation of the insulinsensitive glucose transporter protein (GLUT4) in target tissues,
following sustained hyperglycaemia.

Unlike type I diabetes, there is no HLA link or presence of autoimmune ICAs, however a very strong genetic
component exists in the development of NIDDM (more significant than with type I); this means there is a
significant probability of inheriting the disease from a type II diabetic parent. Moreover, if one identical
twin develops type II diabetes, there is an increased probability that the other twin will also develop it.
A missense mutation in the glucagon receptor gene has recently been shown to be highly associated with
the development of type II diabetes.

Gestational Diabetes
This condition may develop during pregnancy (2–3% of cases) and resolve after delivery. It can however,
recur during subsequent pregnancies, or develop later in life, into type II diabetes unrelated to pregnancy
(ca. 50% risk). Good control of maternal blood glucose during pregnancy is important, as it improves the
general outcome for the foetus (reducing risk of major congenital abnormalities or foetal death); the babies
of diabetic mothers however, still tend to be larger than normal for their gestational age (macrosomia), and
may suffer from the respiratory distress syndrome (due to lack of lung phospholipid surfactant). Gestational
diabetes may be treated by controlled diet alone, or by administration of insulin (the insulin requirement
may progressively increase during the pregnancy); oral hypoglycaemic drugs (see below) are not generally
recommended to be taken while pregnant, due to an increased risk of congenital abnormalities or
development of neonatal hypoglycaemia. Established type II diabetics may need to switch to insulin therapy
during pregnancy.

Some Late Clinical Features of Diabetes

MACROVASCULAR COMPLICATIONS
All chronic diabetics (i.e those that have had the condition for 20 years or more) have a high risk of
developing serious cardiovascular disease (atherosclerosis) at an earlier age than other people; this is partly
due to the derangement of lipid and cholesterol metabolism (causing hyperlipidaemia, and
hypercholesterolaemia). The larger blood vessels e.g. coronary and cerebral arteries, as well as peripheral
vessels become more prone to occlusion (thrombosis), leading to possible ischaemic heart disease (myocardial
infarction), or stroke. Limb ischaemia, ultimately requiring amputation of a foot or a leg for gangrene is also
more likely.

MICROVASCULAR COMPLICATIONS
Long-term diabetic patients (particularly those with a poor history of glycaemic control) also have an
increased risk of developing damage to small blood vessels (microangiopathy). This involves a thickening
of the basement membrane (associated with an increased protein glycosylation) and increased permeability
of the fine capillaries, particularly in the eye and kidney, resulting in retinal damage (retinopathy) and
88 BASIC ENDOCRINOLOGY—CHAPTER 5

defective kidney filtration (nephropathy) with appearance of protein in the urine (proteinurea). Diabetes
still remains the most common cause of blindness in middleaged adults; cataract formation (increased lens
opacity), particularly in young diabetics, and refractive changes in the lens are also common. Frequent
ophthalmic observation of diabetics is therefore considered essential.
Microvascular damage to blood vessels in the skin may cause skin lesions (dermopathy), particularly in
the feet, where poor circulation (coupled with a general delay of tissue healing and increased susceptibility
to infection) can result in foot ulceration and even gangrene of the toes. Diabetics (particularly the elderly)
are thus advised to wear comfortable shoes, to avoid cutting their own toe-nails and to undergo regular foot
examination by a chiropodist.

PERIPHERAL NEUROPATHY
Peripheral nervous tissue (mainly sensory nerves), can become progressively damaged, leading to pain and
eventual numbness in the feet; foot ulceration and infection may therefore occur without the patient being
aware of the problem. Common early signs of diabetic neuropathy include the loss of deep tendon reflexes
and vibration sense in the lower limbs. Damage to sympathetic and parasympathetic nerves (autonomic
neuropathy) may also result in the loss of cardiovascular reflexes.

Both neuropathy and cataract formation in diabetics has been associated with the intracellular
accumulation of sorbitol within the peripheral nerve or lens tissue; this nondiffusible sugar is formed
in excess when glucose levels are high (catalysed by the enzyme aldose reductase), and may then
induce osmotic swelling and damage in certain vulnerable cells.

Insulin Excess
Hypersecretion of insulin (hyperinsulinism) can either result from a rare insulin-secreting (usually benign)
tumour of the pancreatic islets (insulinoma) or very rarely from a diffuse proliferation of endocrine cells
within the pancreas (islet β-cell hyperplasia; more common in children). The excess insulin action leads to a
chronic intractable hypoglycaemia (associated with fasting or exercise), manifested mainly as episodic
neurologic symptoms (neuroglycopenia) e.g. lack of concentration, confusion, disorientation, amnesia,
abnormal behaviour (often misdiagnosed as psychiatric illness), and possible seizures or coma.
Treatment of insulinomas is usually by surgical removal of the tumour(s), although these may be very
small and difficult to locate. Alternative medical therapy involves longterm oral administration of diazoxide
(Eudemine), a potent inhibitor of pancreatic insulin secretion. Diazoxide is used to normalize blood glucose
levels prior to tumour surgery, and in the management of β-cell hyperplasia; it is also a powerful directly-
acting vasodilator, and may be given by rapid intravenous bolus (300 mg) to lower blood pressure quickly
in cases of acute hypertensive emergency. Blind subtotal resection of the pancreas (pancreatectomy) is less
favoured as a mode of treatment.

Diagnosis and Monitoring of Diabetes

URINE GLUCOSE TESTS

An initial simple test for monitoring of urinary glucose (not necessarily diagnostic of diabetes) may be
made using plastic, glucose-sensitive reagent strips (e.g. Clinistix, DiaburTest or Diastix; Tes-Tape in the
 ENDOCRINE SECRETIONS OF THE PANCREAS 89

USA); these provide a colour reaction proportional to the urine glucose concentration, which may be compared
visually with a colour chart. Alternatively, diagnostic reagent tablets (Clinitest; poisonous: not to be
taken!), which rely on the standard reduction by glucose, of an alkaline copper solution, may also be used
for simple screening purposes (less popular). Urinalysis is a less accurate method of assessing diabetic
control than direct blood glucose monitoring.

Diagnostic tablets (Acetest) or ketone-sensitive reagent strips (Ketostix or Ketur Test) for ketone
(mainly acetone and acetoacetic acid) detection in the urine, are also available, as are tests for urinary
proteins (albumin) (using Albustix or Albym-Test reagent strips); the latter test is considered useful for
the early detection of diabetic nephropathy (see below).

BLOOD GLUCOSE TESTS

Self measurement of glucose in a blood drop (usually obtained by pricking the side of a finger) may also be
made using specific glucose-sensitive colour test strips (containing glucose oxidase) that are either read
visually against a colour chart (e.g. Dextrostix; Glucose VT) or used in conjunction with a portable reflectance
meter (e.g. the pocket Accutrend Mini or Accutrend Alpha with BM-Accutest strips or Reflolux S meter, with
BM-Test 1–44 strips: Boehringer Mannheim Diagnostics) (Figure 5.6). In the USA, the One Touch
(Lifescan) blood glucose monitoring system is widely used.
Although somewhat expensive, such meters can provide a rapid and reliable measurement of blood
glucose within the range of ca. 0.5–30 mmol/l and are therefore ideally suited for the maintenance of
accurate home monitoring records. Patients, however, need to be carefully advised on the correct methods
for obtaining the blood (several springloaded lancet pens are available; e.g. Softclix; Boehringer Mannheim)
and for recording and interpreting the results.
A postprandial (after food) blood glucose level of between 4–10 mmol/l is considered as an optimal
target for a controlled diabetic.

GLYCOSYLATED HAEMOGLOBIN (HbA1C)

Dipstick tests are useful for providing immediate information about a patient’s degree of diabetic control;
however, in order to obtain an assessment of more long-term glycaemic control over a preceding period of
about four weeks, a laboratory measurement of glycosylated haemoglobin levels (also called glycated
haemoglobin or HbA1C) in the blood, can be made using chromatographic, electrophoretic or
radioimmunoassay techniques. The slow chemical (nonenzymatic) reaction between glucose and
haemoglobin yields a small glycosylated fraction (termed HbA1C), normally comprising ca. 4–6% of the
total blood haemoglobin. Other circulatory proteins (e.g. albumin, fructosamine) or structural proteins (e.g.
collagen, myelin and lens crystallins) can also become glycosylated. A close linear correlation exists
between the %HbA1C level and the mean blood glucose concentration measured over a previous 2–3 month
period in both diabetic and non-diabetic individuals, thereby enabling an estimate of chronic glucose
homeostasis to be made. A glycosylation level of ca. 8.4% is to be expected for a moderately well
controlled type I diabetic patient, whereas a level exceeding 10% would indicate a more strict control
regimen is required. The glycosylation of lens crystallins has been implicated in the formation of diabetes-
related cataracts.
90 BASIC ENDOCRINOLOGY—CHAPTER 5

Figure 5.6. Measurement of blood glucose by means of a glucose-sensitive test strip and portable reflectance meter. A.
Example of a commercially available ‘pocket’ glucose meter (Accutrend ‘mini’) that can provide a rapid digital reading
of the blood glucose level (sensitivity range 1.67–22.2 mmol/l). The meter is used in conjunction with glucose oxidose-
impregnated test strips (BM-Accutest). B. The recommended procedure for obtaining a measurement involves (1)
washing hands thoroughly, then obtaining a blood drop from a side finger prick; (2) the blood is soaked onto the pad of
a reagent strip and placed into the meter; (3) after 12 seconds, the meter displays the blood glucose level; (4) a rough
visual check can also be made against a colour scale. (Photographs kindly provided by Boehringer Mannheim UK Ltd.)

In the oral glucose tolerance test (OGTT) for diabetes, a 75 g glucose drink (usually Lucozade) is
given to an overnight fasted patient, and estimations of venous plasma glucose are obtained at zero
time and then at half-hourly intervals for 2–3 hours (while still fasting). Normally, plasma glucose
 ENDOCRINE SECRETIONS OF THE PANCREAS 91

Figure 5.7. Disposable preloaded pen injector containing a pre-mixed biphasic insulin formulation (Human Mixtard 30
Pen). (Photographs kindly provided by Novo Nordisk Ltd, UK.)

should not exceed 8.5 mmol/l at any time during the test, and should return to the fasting level of ca.
4–6 mmol/l after 2 hours. In cases of impaired glucose tolerance (IGT), the fasting plasma glucose
level is usually normal, but remains elevated (between 7.8–11.1 mmol/l) at 2 hours after the glucose
load. A diagnosis of diabetes is made if the fasting plasma glucose is above 7.8 mmol/l, a high plasma
glucose level (>11.1 mmol/l) is attained at 2 hours and the rise is more prolonged.

Plasma (or serum) glucose concentrations tend to be ca. 10% higher than whole blood glucose
levels.

Treatment of Diabetes
Education and counselling of the patient about their condition and treatment is all important. It is also
necessary to advise on the self-monitoring of blood/urinary glucose or ketones and the correct injection
techniques for insulin administration.
The major aims of treatment are:

1. To keep blood glucose near to normal (between 4 and 10 mmol/l) over 24 hours (particularly avoiding
hypoglycaemia), thereby minimising the risk of long-term complications. Very strict control in more
elderly patients may be difficult to achieve.
2. To ensure that the patient has sufficient energy for normal work and recreation (and for steady growth
in young patients).
3. To ensure the patient ‘feels well’, and maintains a normal body weight (obesity should be avoided).

This control may be achieved using a combination of three methods: diet, insulin or oral hypoglycaemic
(antidiabetic) drugs, according to the type and severity of diabetes, and the body weight and occupation of
the person.

TYPE I
DIABETES
Insulin replacement therapy is required for life, coupled with frequent self-monitoring of blood/urine
glucose and ketones. Insulin doses are given on an individual basis by subcutaneous injection, once or twice
a day (before breakfast and/or before the evening meal), or more often as governed by a patient’s needs (5–
20 units/dose is usually sufficient). Small adjustments in dose (in 0.5–2 unit increments) can be made
throughout the day, based on the pattern of the glycaemic response following each administration. If a meal
is missed, an appropriate reduction in insulin dose would be required.
Insulin pens. Nowadays the use of insulin injection ‘pens’ (Figure 5.7) that can deliver metered doses of
insulin from a preloaded disposable pen (Lilly Humaject; Novo Nordisk Human Mixtard pen) or replaceable
92 BASIC ENDOCRINOLOGY—CHAPTER 5

cartridge (e.g. NovoPens, for use with Novo Nordisk Penfill cartridges; [Novolin Pen in the USA]) offers a
reliable and more convenient alternative to the injection of insulin via a conventional plastic syringe; such
pens (although more costly) are particularly advantageous for use by partially sighted or more elderly
diabetic patients that would normally experience some difficulty in drawing up their daily doses.
It is recommended that injection sites are rotated frequently (outer thighs, upper arms, lower abdomen or
buttocks) in order to avoid skin hardening or development of local skin reactions e.g. fat atrophy
(lipodystrophy; now less common with human or highly purified animal insulins) or fat hypertrophy.

Formulations of insulin combined with absorption enhancers (e.g. deoxycholate or laureth 9) for
intranasal administration, are currently being investigated.

Insulin Pumps. Systems for delivery of a continuous subcutaneous infusion of soluble insulin (CSII) via a
portable battery-operated pump have also been developed; these consist of a small external infusion pump with
an insulin reservoir (ca. 3 ml), which can be programmed to provide various ‘basal’ rates of insulin delivery
throughout the day (via an in-dwelling subcutaneous catheter), in accordance with patient self-monitoring
of blood glucose levels. The pumps can also provide small bolus doses prior to each meal as needed, in an
attempt to simulate the normal pattern of insulin secretion. Such ‘open loop’ pump therapy is most suitable
for improving glycaemic control in selected type I patients with a particularly unstable diabetes; close
medical follow-up is however necessary to avoid the risk of hypoglycaemia. Common complications of
CSII include inflammation at the injection site, pump malfunction, catheter obstruction and systemic
infection (rare). Some examples of available pumps (expensive!) include the MiniMed 506 (MiniMed
Technologies, USA) and the HTron V100 (Disetronic Medical Systems, Switzerland).
Implantable programmable insulin infusion pump systems (very expensive!) are currently undergoing
intensive clinical trials throughout Europe; these small radiocontrolled units (ca. 5 year life) are introduced
subcutaneously within a skin pocket in the abdomen, with a catheter placed peritoneally. They are
particularly useful in the management of type I diabetics with resistance to conventional subcutaneous or
intramuscular insulin. Apart from mechanical failure of the system, pump movement and possible
development of infection at the implantation site, blockage of peritoneal catheters due to insulin aggregation
and precipitation at body heat can be a major problem.
So-called ‘closed loop’ pump systems (artificial pancreas) consist of an external infusion pump, an
automatic blood glucose sensor and a microprocessor for analysis of blood glucose data and for adjusting
the rate of insulin delivery; these systems are more suitable for hospital, research or ‘intensive care’
environments, where critical blood glucose control is essential (e.g. during surgery or emergency treatment
of diabetic ketoacidosis; see below). Several types of miniaturized glucose sensor suitable for long-term
subcutaneous implantation are presently being evaluated; these mainly utilize a glucose oxidase/hydrogen
peroxide amperometric detection system, designed to transmit sensor data to a remoter reservoir.
Development of a local inflammatory tissue reaction to the implanted devices may however, limit their
glucose sensitivity.
A novel non-invasive glucose monitoring system based on ‘reverse iontophoresis’ of glucose across the
skin has also been described recently, but this will require further development and evaluation before
becoming generally accepted.
Pancreatic islet cell transplantation. This also offers a potentially useful approach for the future treatment
of diabetes. Numerous research studies conducted over the past decade have reported significant clinical
improvement in glucose control in type I diabetics that received islet cells isolated from human cadavers
(injected into the liver, via the portal vein) or cultured pancreatic tissue from aborted human embryos
 ENDOCRINE SECRETIONS OF THE PANCREAS 93

(transplanted intracerebrally). A major problem however, has been the immune rejection of the transplanted
islets, which necessitates the use of ongoing (possibly damaging) immunosuppressive therapy. New methods
aimed at ‘hiding’ islets from the host’s immune system by encapsulating them within biocompatible
semipermeable plastic fibres (implanted subcutaneously) are currently under investigation.
Types of Insulin Preparation. Human insulin (Humulin; Novolin in the USA; Insulin lispro) may be
obtained either by modifying a precursor molecule formed by yeast cells using recombinant DNA
technology (pyr) or biosynthetically from bacteria using recombinant DNA techniques (prb); [it can also be
prepared by enzyme modification of pork insulin (emp) (B30 alanine is converted to threonine); Human
Velosulin]. Genetically engineered human insulin is currently the treatment of choice for the majority of
diabetic patients using insulin therapy. Insulins derived from porcine or bovine pancreas (the molecules
vary only slightly from human insulin) are also available, but their use is progressively declining with each
year. The animal insulins are prepared in highly purified form to minimize contamination by insulin
derivatives and other pancreatic peptides which may be antigenic (e.g. proinsulin, C-peptide or glucagon).
The use of bovine insulin is less popular, in view of its greater antigenic properties.
Solutions of soluble insulin are rapidly absorbed; therefore, to prolong their action, various insulin
formulations are available in which insulin is complexed with protamine (a polyamine) or combined with
zinc to form particle or crystalline suspensions which are more slowly absorbed. Mixtures of the different
insulin preparations may also be used to achieve different patterns of activity. The four main types of insulin
formulation used (classed according to their duration of action) along with some examples of currently
available preparations are summarized in Table 5.3.

Insulin in solution in pharmaceutical preparations tends to self-associate into dimers which, in the
presence of zinc ions, form a stable hexameric assembly. Dimers can also exist in the plasma
following insulin administration and limit the biological availability of the insulin molecule
(monomer). Current research is aimed at development of ‘monomeric’ human insulin analogues with
less tendency to self-associate in solution, which would therefore be more rapidly absorbed following
subcutaneous injection (giving an earlier postprandial hypoglycaemic response).

Unopened vials, cartridges or preloaded ‘pens’ containing insulin preparations should always be refrigerated
(2– 8°C) but never frozen. Vials containing a standard strength

Table 5.3. Four main types of insulin formulation [BNF: Sept. 1996; MIMS: June 1997].
Insulin type Type of action Example Description
Short acting Rapid onset (1/2–1 h); Neutral insulin injection (B.P.) Clear buffered neutral solution
peak effect at 2–4 h; (Soluble Insulin)
duration up to ca. 8 h; Human Velosulin
useful for diabetic emergencies Human Actrapid
(i.v.) Humulin S
Humalog (Insulin Lispro)
Intermediate Slow onset (1–2 h); Isophane insulin injection (B.P.) Cloudy suspension of insulin-
peak effect at 4–12 h; Human Insulatard protamine complex
duration ca. 12–24 h
Insulin zinc suspension Cloudy suspension of insulin-
(amorphous) (B.P.) Semitard zinc complex.
MC (porcine)
94 BASIC ENDOCRINOLOGY—CHAPTER 5

Insulin type Type of action Example Description

Insulin zinc suspension (mixed) Mixture of amorphous Zn and
Humulin Lente crystalline insulins (30/70%)
Long-acting Delayed onset (2–4 h); Insulin zinc suspension Cloudy suspension of larger
peak effect at 6–12 h; (crystalline) (B.P.) insulin-zinc crystalline particles
duration up to ca. 36 h Human Ultratard
Mixtures Biphasic action provides both Biphasic insulin injection B.P. Suspension of soluble and
rapid and prolonged effects; Rapitard MC crystalline insulin (25/75%)
speed of onset depends on % of
soluble insulin in mixture;
duration up to ca. 24 h
Biphasic Isophane insulin B.P. Suspension of soluble and
Human Mixtard 30 isophane insulin (variable

of 100 units/ml are currently available in the UK and in the USA (1 unit of insulin is equivalent to 0.035 mg
of anhydrous insulin), along with disposable syringes calibrated in units. Insulin vials, cartridges or
preloaded ‘pens’ in use can be kept at room temperature (up to 25°C) for up to 1 month.

TYPE II
DIABETES
Since there is still some pancreatic β-cell activity in such patients, control may be possible by diet alone, or
by use of oral hypoglycaemic drugs or other antidiabetic agents. However, in some type II diabetics (e.g.
those showing a continued weight loss), insulin may also be required for adequate control.
Patients are advised to avoid all forms of refined sugar in their diets (e.g. jams, sweets, cakes, chocolate or
sugary drinks), to restrict their intake of saturated fats or refined carbohydrates, and to increase intake of
foods that have a high dietary fibre content (e.g. wholemeal bread, bran cereals and beans), since this can
improve postprandial blood glucose control. Alcohol may be taken in moderation (except in sweet wines or
liqueurs), preferably followed soon after by food; it should be emphasized that alcohol itself may induce
hypoglycaemia. Artificial sweeteners are also permitted. Ideally, obese patients should aim to reduce and to
maintain their body weight at a more normal level; regular physical exercise is also recommended.
If an initial trial period (ca. 1–3 months) of dietary treatment alone fails to produce adequate glycaemic
control, then oral hypoglycaemic drugs may be taken in addition. There are two types of drug that are
currently used in the UK, sulphonylureas and biguanides, taken in tablet form. In the USA, the biguanide
metformin has recently been approved for treatment of type II diabetes.
Sulphonylureas. These agents act initially to stimulate any residual capacity of the pancreatic β-cell to
produce insulin owing to their specific ability to close ATP-regulated potassium channels in the β-cell
membrane (see p. 60 and Figure 5.2). In the long term, they may also potentiate the action of endogenous
circulating insulin on target tissues by increasing the number of insulin receptors.
Some currently used sulphonylureas include:

Tolbutamide (Rastinon)
Chlorpropamide (Diabinese)
Glibenclamide (Daonil, Euglucon)
Glipizide (Glibenese, Minodiab)
 ENDOCRINE SECRETIONS OF THE PANCREAS 95

Gliclazide (Diamicron)
Gliquidone (Glurenorm)
Tolazamide (Tolanase)

Side effects: these are very rare, but may include skin rashes, blood disorders, fever and jaundice.
Glibenclamide appears to be the most popular, taken as a 2.5 or 5 mg tablet daily at breakfast time.
Gliclazide and tolbutamide are preferred in elderly patients or those with renal impairment, because of
their relatively short duration of action. Chlorpropamide is now rarely used in view of its particularly
prolonged half-life in the body and its unusual tendency to produce facial flushing in some patients after
drinking alcohol. Sulphonylureas may cause slight weight gain in some patients.
Biguanides. The only biguanide in current use is metformin (Glucophage), taken alone or more commonly
in combination with a sulphonylurea. This drug acts primarily by stimulating muscle glucose uptake and by
inhibiting both hepatic gluconeogenesis and glucose absorption from the gut. It also has some appetite-
suppressant action which may be useful for the more obese type II diabetic.
Side effects are more common with this class of drug and include gastrointestinal disorders, nausea,
vomiting, diarrhoea, anorexia, malaise, development of an unpleasant metallic taste and a risk of lactic
acidosis (phenformin was withdrawn from use for this reason); metformin is not therefore recommended
for elderly patients or those with hepatic or renal failure.
Oral hypoglycaemics are generally not advised to be taken during pregnancy or while breast feeding.

OTHER ANTIDIABETIC AGENTS

Acarbose (Glucobay) is a relatively new form of oral antidiabetic treatment. It acts as a competitive
inhibitor of the α-glucosidase group of enzymes in the small intestine, which are normally responsible for
the conversion of complex dietary carbohydrates like sucrose into their component monosaccharides
(mainly glucose). The rise in blood glucose that follows a meal is therefore reduced. Acarbose may be taken
alone with diet (50 mg tablets, three times a day before or with food) or in combination with other
conventional hypoglycaemic agents. It is contraindicated for use in patients with chronic intestinal disorders
or those with hepatic/renal impairment; it is also not recommended for pregnant or nursing mothers or for
children.
Side effects: these are principally gastrointestinal. The increased levels of unabsorbed carbohydrate in the
bowel leads to increased production of intestinal gases, giving rise to flatulence, abdominal distension and
pain, softer stools and diarrhoea.
Guar Gum (Guarem) is a non-absorbable complex carbohydrate bulking agent obtained from the seeds of
the Indian cluster bean. When mixed with water, it forms a viscous gel that slows gastric emptying and
retards intestinal carbohydrate absorption following a meal; the blood glucose level is therefore reduced. In
general, consuming a relatively high proportion of dietary carbohydrate as polysaccharides has been found
to improve glycaemic control in diabetics. Guar gum is available in the form of dispersable granules that are
stirred into liquid and taken immediately before a main meal. It is only intended to be used as an adjunct to
diet or oral hypoglycaemic therapy.
Side effects: apart from being somewhat unpalatable, guar gum preparations may cause flatulence,
abdominal distension and a feeling of ‘fullness’. It is not recommended for children.
Thiazolidinediones: These are a new class of drugs designed to facilitate insulin action. They act
intracellularly beyond the insulin receptor. Troglitazone, representing this class, has now been approved
96 BASIC ENDOCRINOLOGY—CHAPTER 5

for use in the UK and USA (marketed as Romozin and Rezulin respectively). The drug is primarily designed
to break insulin resistance, and can be safely used in patients with renal failure. Food enhances its
bioavailability. Treatment is initiated at 200 mg once a day, up to a maximum of 600 mg a day.

Acute Complications of Diabetic Therapy

HYPOGLYCAEMIA
A major adverse effect of the oral hypoglycaemics (particularly sulphonylureas), or injecting too much
insulin, is the development of hypoglycaemia (blood glucose below 3 mmol/l). Patients should be warned
about hypoglycaemic symptoms and advised to carry glucose tablets (Dextrosol) or sugar with them at all
times, together with a diabetic identity card.
Drug interactions with the oral hypoglycaemics can also occur due to displacement of the hypoglycaemic
agent from plasma protein binding by other drugs (e.g. tolbutamide with aspirin or sulphonamides) resulting
in a sudden increase in hypoglycaemic effect. Corticosteroids, oral contraceptives and thiazide diuretics
would have an opposing, i.e. hyperglycaemic action. Alcohol may enhance the action of insulin by exerting
its own hypoglycaemic effect.
The usual autonomic (adrenergic) symptoms of acute hypoglycaemia are: nervousness, sweating,
tremor, palpitations (this may be masked in patients taking β-adrenoceptor blockers); intense hunger,
tingling of the lips and tongue; confusion and ultimately loss of consciousness; (some of these symptoms
may be missed due to autonomic neuropathy).

Since human insulin has a slightly more rapid onset of action and a shorter-lasting effect, some
patients may experience unexpected hypoglycaemia (with less pronounced warning symptoms) on
transfer from animal source to human insulin preparations.

Treatment. The immediate remedy is to take 2–4 small lumps of sugar or 3 glucose tablets with a little
water at the first signs of a reaction and to lie down for 10–15 min to allow the symptoms to gradually
disappear. Oral glucose should be used rather than sugar, when taking acarbose. If the patient is unconscious,
an intramuscular injection of glucagon (1 mg) may be given to raise the blood glucose level, followed by
oral glucose when the patient responds. If no response is obtained, then an intravenous infusion of 20–50 ml
glucose (50%) should be administered.

KETOACIDOSIS AND DIABETIC COMA

Ketoacidosis develops more gradually (over a period of days) and only in type I diabetics. It can be caused
by injecting too little (or no) insulin, or brought on by an acute infection, illness or sudden stress, all of
which tend to increase the blood glucose level. Therefore, for insulin-dependent diabetics, it is important to
continue to inject their normal, or a slightly increased insulin dose during an illness.
The usual symptoms of diabetic ketoacidosis are: excessive thirst, frequent urination (leading to
dehydration); drowsiness, abdominal pain; loss of appetite; nausea, vomiting, hyperventilation, and a
strong smell of acetone on the breath.
If untreated, the condition may lead to diabetic coma and death. It is therefore considered as a medical
emergency and requires immediate intravenous infusion with soluble insulin (1 unit/ml; 0.2 units/kg body
weight as a bolus, followed by 0.1 unit/kg continuous infusion) and correction fluids (sodium chloride,
 ENDOCRINE SECRETIONS OF THE PANCREAS 97

potassium chloride and sodium bicarbonate [when acidosis is severe]) until the blood glucose level has
fallen to <10 mmol/l, blood ketones have disappeared and the patient is well enough to take food.
Treatment of any underlying infection should also be ongoing.

Review Questions
Question 1: State from which cells of the pancreas insulin is secreted.
Question 2: State what other principal peptides are secreted by the pancreatic islet cells.
Question 3: Describe the basic molecular structure of insulin and outline its synthesis from
precursor peptides.
Question 4: Describe the control of insulin release by (a) the blood glucose concentration, (b) other
islet hormones, (c) gastro-intestinal hormones, (d) dietary amino acids.
Question 5: State the major action of insulin on the blood glucose level.
Question 6: State the major target organs for insulin action.
Question 7: What is the normal range of plasma glucose concentration?
Question 8: Describe the effects of insulin on glucose transport.
Question 9: State what tissues are independent of insulin for glucose transport.
Question 10: Describe the effects of insulin on:
(a) glycogen metabolism,
(b) hepatic glucose phosphorylation,
(c) liver glucose metabolism,
(d) muscle protein metabolism,
(e) fat metabolism in adipose tissue.
Question 11: State from which islet cells glucagon is secreted.
Question 12: Describe the control of glucagon release by:
(a) the blood glucose concentration,
(b) other islet hormones,
(c) gastrointestinal hormones,
(d) amino acids.
Question 13: State the major action of glucagon on the blood glucose level.
Question 14: State the major target organ for glucagon action.
Question 15: Describe the effects of glucagon action on:
(a) glycogen metabolism,
(b) fat metabolism.
Question 16: Name the condition characterized by hyposecretion of insulin.
Question 17: List the major consequences of insulin deficiency.
Question 18: Name some other hormones that may cause hyperglycaemia when secreted in
excess.
Question 19: List the principal features of type I diabetes.
Question 20: List the principal features of type II diabetes.
Question 21: What is amylin? From where is it secreted, and what is its proposed role in the
aetiology of type II diabetes?
Question 22: Explain the condition of gestational diabetes and how it can arise.
98 BASIC ENDOCRINOLOGY—CHAPTER 5

Question 23: Describe some common tests for monitoring urinary/blood glucose concentration
and give their underlying principles of use.
Question 24: Explain the significance of glycosylated Hb as a measure of diabetic control.
Question 25: Describe the glucose tolerance test and explain the expected result for a normal or
diabetic subject.
Question 26: Describe the macrovascular and microvascular complications that can arise in long-
term diabetic patients.
Question 27: Describe some other chronic complications of diabetes.
Question 28: Outline the major aims of diabetic treatment.
Question 29: State the three current methods available for diabetic treatment.
Question 30: Give examples of possible treatment regimes for type I diabetes.
Question 31: Describe the use of insulin pump systems in the treatment of diabetes. What do you
understand by the terms ‘open loop’ and ‘closed loop’ pump therapy?
Question 32: Discuss the use of pancreatic islet cell transplantation as a possible approach for
the treatment of diabetes.
Question 33: Give examples of some currently available types of insulin preparation.
Question 34: Outline possible treatment regimens for type II diabetes.
Question 35: Give examples of some currently used oral hypoglycaemic drugs, explain their
mechanism of action and give their side effects.
Question 36: Give examples of other commonly used antidiabetic agents, and explain their
mechanism of action.
Question 37: Describe some possible drug interactions that can occur while taking oral
hypoglycaemic drugs.
Question 38: Describe the possible causes, symptoms and treatment of hypoglycaemia.
Question 39: Describe the causes, symptoms and treatment of diabetic ketoacidosis and diabetic
coma.
Question 40: What are the causes of hyperinsulinism? List the main symptoms that may arise from
this condition, and how it may be treated.

Clinical Case Studies

Patient 1
A 14 year old girl was brought to her GP’s office, complaining of weight loss, dry mouth, lethargy, easy
fatigability and difficulty in catching the breath; some nausea and abdominal pain was also experienced.
The symptoms were noticed by the parents about 10 days before the visit. However, the patient herself had
noted an increased frequency of urination (polyuria) and increased thirst (polydipsia) about 8–10 weeks
prior.
A urine analysis using the Clinitest method and Ketostix reagent strips revealed positive glucose and
ketones respectively. Her temperature was 39°C and a chest examination revealed some congestion. The
patient was immediately admitted to hospital for management. Clinical examination revealed a dehydration,
fruity odour to the breath, tachycardia (120 beats/min) and dry mouth, lips and tongue. The respiratory rate
was 30/min and her blood pressure was 110/70 mmHg.
Laboratory data indicated that her plasma glucose level was 26.1 mmol/l, serum acetone was positive (at
a dilution of 1:8), arterial blood pH was 7.18 with a bicarbonate level of 17 mmol/l. Other serum values
 ENDOCRINE SECRETIONS OF THE PANCREAS 99

determined at this time were (mmol/l): Na+ 130, K+ 5.8, Cl– 92, and glycosylated haemoglobin 13.1%;
blood islet cell antibodies were positive, and the HLA genotype was DR3/DR4.
Question 1: What is the most likely diagnosis in this patient? What are the causes of her observed
symptomatology? Suggest a likely precipitating factor of her condition.
Question 2: What would be the most appropriate treatment while in hospital, and the
recommended therapy on discharge?
Answer 1: This is a classical presentation of diabetic ketoacidosis in insulin-dependent diabetes
mellitus (IDDM, or type I diabetes). The common symptoms of diabetes mellitus are: polyuria
(increased urine volume and frequency), polydipsia (increased thirst) and polyphagia (increased
appetite). Polyuria is secondary to the osmotic diuresis (caused by excess filtered glucose in the
urine) which then triggers increased thirst. Diabetic ketoacidosis is a serious acute complication
that requires prompt attention. It is usually precipitated in insulin-dependent diabetic patients by a
stressful stimulus (e.g. an infection, surgery or acute illness) or by omitting several insulin
injections. The characteristic sweet smell to the breath is due to excretion of acetone (ketone body)
formed by condensation of excess acetyl CoA in the liver; appearance of other ketone bodies in the
blood (acetoacetate and 3-hydroxybutyrate) decreases blood pH (metabolic acidosis) which
stimulates respiration (hyperventilation).
Answer 2: Following a diagnosis of diabetic ketoacidosis, intravenous fluid replacement and
correction of hyperglycaemia/ketonaemia is crucial for effective hospital management; a
precipitating cause such as an infection should also be sought and treated with appropriate
antibiotics if necessary. The patient was started on intravenous fluid (normal saline) and soluble
insulin infusion (0.2 units/kg bolus followed by 0.1 units/kg per hour) to correct for the
underlying dehydration and metabolic abnormalities. In the next 14 hours, the blood glucose was
stabilized at 7.8 mmol/l and the patient rehydrated. Serum electrolytes returned to normal
(bicarbonate level increased to 22 mmol/l) and arterial blood pH showed normalization to 7.35.
Insulin infusion was continued until next morning, when ketones were no longer present in the
diluted serum. The patient was switched to subcutaneous insulin administered twice daily. She
was instructed in home blood glucose monitoring methods and discharged on stable doses of
insulin three days later.

Laboratory Findings
People with a DR3/DR4 H LA genotype have a high risk of developing IDDM; such individuals
also commonly possess islet b-cell antibodies in their serum. Glycosylated haemoglobin (HbA1C) levels
in the blood are useful for assessing long-term glycaemic control; normal values are between 3.9–6.
8% of total blood Hb.

‘Normal’ values for blood constituents are (mmol/l):

Na+ 135–145; K+ 3.5–5.0; Cl– 98–108; HCO3– 22–26; glucose 3.6–6.4 (65–115 mg/dl).

The normal pH range of the blood serum is 7.42–7.38; metabolic acidosis results when the arterial
blood pH is <7.38 (reflected by the low serum bicarbonate level).
100 BASIC ENDOCRINOLOGY—CHAPTER 5

Patient 2
A 49 year old male was admitted to hospital with symptoms of extreme thirst, fatigue and polyuria.
Investigations were generally normal, although he had detectable glucose and protein but no ketones in his
urine. A BM-Test strip test revealed a blood glucose level of 18 mmol/l. The patient was 5′8″ tall and
weighed 76 kg (12 stone; 168 lb). Clinical examination revealed moderate hypertension (160/104 mmHg)
and tachycardia (100 beats/min) and a soft systolic murmur in the mitral area. On enquiry, the patient
mentioned that for the last 6 months he had noticed chest pain on exertion, but these episodes only lasted 5–
10 min. Lately, the frequency and duration of these chest pains had increased. He also complained of nocturia
(three times nightly). Blood chemistry analysis revealed a plasma glucose level of 12.1 mmol/l and a total
cholesterol level of 12 mmol/l (233 mg/dl); [ideal <5.2 mmol/l (100 mg/dl)]. Glycosylated haemoglobin
was 9.1% (normal <6.8%); no other abnormalities were noted.
Question 1: What is the most likely diagnosis in this patient, and what are the causes of his
symptoms? Describe the typical profile of this condition; how commonly it is encountered in the
population? Is there a hereditary link?
Question 2: How common is hypertension or other cardiovascular problems in such patients?
Question 3: How is the condition treated (while in hospital, and on discharge)?
Answer 1: This is a typical presentation of non-insulin-dependent diabetes mellitus (NIDDM, or
type II diabetes), where hyperglycaemia is discovered on blood chemistry analysis. It is the more
common form of diabetes, but is normally slower to develop, usually in older (>40 years) more
obese individuals. As in type I diabetes, increased urination (polyuria), is due to glucose-induced
osmotic diuresis, which causes an increase in plasma osmolarity and a consequent stimulation of
the thirst centre in the brain (polydipsia); ketosis, however, is typically absent. A strong genetic
link exists in the development of NIDDM.
Answer 2: Many patients will have macrovascular disease (coronary artery disease,
cerebrovascular disease) and a high blood cholesterol level (hypercholesterolaemia) at the time of
presentation. Hypertension is about twice as common in persons with diabetes as in those without
the condition, essential hypertension accounting for the majority of the cases encountered. 30–
75% of chronic diabetic complications can be attributed to hypertension.
Answer 3: On diagnosis of NIDDM, diet, exercise and weight reduction can be very effective in
the treatment of mild cases, and may assist in lowering the blood pressure in associated
hypertension. Use of oral hypoglycaemic drugs may also help to produce adequate glycaemic
control in the vast majority of NIDDM cases; however, insulin will invariably be required to
control the diabetes more effectively, particularly if oral hypoglycaemics have been used for five
or more years. While in the hospital, the patient was placed on a 1600 calorie diet and given
subcutaneous insulin to control his blood glucose; subsequently, he was switched to oral
hypoglycaemic medication (glipizide 5 mg, twice daily). His blood glucose was normalized, with
post-prandial blood glucose rarely exceeding 7.8 mmol/l. Meanwhile, further clinical examination
revealed significant and diffuse coronary artery disease.

Patient 3
A 35 year old female who was 29 weeks pregnant attended her local GP’s office for a routine checkup. Her
GP noted glycosuria and a larger than normal foetus for gestational date, and referred her urgently to the
antenatal clinic. The patient weighed 10.5 stone (147 lb; 66.8 kg) prior to pregnancy, and had no previous
 ENDOCRINE SECRETIONS OF THE PANCREAS 101

history of diabetes, but her two previous babies weighed 9 lb and 10 lb at birth. At the clinic, an oral
glucose tolerance test (OGTT) was given, with the following results:

Fasting (venous) plasma glucose 10.7 mmol/l

30 min post test 21.5 mmol/l
120 min post test 19.2 mmol/l

Question 1: What is the oral glucose tolerance test and what does it involve? How useful is it in
the diagnosis of diabetes?
Question 2: What is the most likely diagnosis in this patient, and how should her condition be
managed? What are the risk factors associated with its development?
Question 3: What are the implications of leaving the condition untreated or inadequately
managed?
Question 4: How likely is it that her condition will resolve after delivery?
Answer 1: The oral glucose tolerance test (OGTT) is a useful and reliable diagnostic test for
diabetes, which measures the ability of an overnight-fasted subject to handle an ingested glucose
load (75 g) over a 2–3 hour period. Plasma glucose levels are measured at zero time and then
every half hour for 2–3 hours after the glucose challenge. In non-diabetics, the plasma glucose
should not exceed 8.5 mmol/l during the test, and should return to normal fasting levels (ca. 4–6
mmol/l; <110 mg/dl) after 2 hours. In a diabetic patient, a high fasting plasma glucose (>7.8
mmol/l) and a higher, more prolonged peak glucose level (>11.1 mmol/l) is observed.
Answer 2: This patient has developed gestational diabetes during pregnancy, diagnosed from the
abnormally high fasting and two hour plasma glucose concentrations seen during the OGTT.
Women that are obese (weight >120% of normal for height), with a family history of diabetes, or
showing previous symptoms of glucose intolerance are particularly at risk of developing the
condition; so also are women with a poor obstetric history i.e. previous babies >9 lb at birth, or
present foetus larger than normal for gestational age (macrosomia), unexplained foetal deaths or
infants with congenital abnormalities. Such women also have a high probability of developing type
II diabetes (NIDDM) at a future date.
Answer 3: Even mild diabetes developing during pregnancy can significantly increase the risk of
major foetal abnormalities (particularly in the cardiovascular and central nervous systems) or
foetal death. Leaving gestational diabetes untreated or poor management can also increase the
maternal risk of infection, hyperglycaemia, diabetic ketoacidosis, retinopathy, nephropathy or
neuropathy. The patient was prescribed biphasic isophane insulin (Human Mixtard 30 pen), 18
units daily (12 units with breakfast, and six units with dinner) adjusted throughout the pregnancy
according to self-monitored blood glucose levels. The goal was to achieve postprandial blood
glucose measurements between 4–10 mmol/l. She was also placed on a reduced calorie diet (1500–
1800 daily) and advised to avoid sugary and fatty foods in favour of more complex carbohydrates.
Her random blood glucose measurement at 32 weeks was 7.8 mmol/l.
Answer 4: The likelihood of gestational diabetes resolving after delivery is very good (>90%);
however, the risk of recurrence during a subsequent pregnancy or development of NIDDM at a
future date remains high (ca. 50% risk). Careful blood glucose monitoring after delivery is therefore
advisable.
102 BASIC ENDOCRINOLOGY—CHAPTER 5

UK/USA Drugs—Trade names

UK USA
Oral hypoglycaemic drugs
Acetohexamide Dymelor
Chlorpropamide Diabinese Diabenese
Glibenclamide Daonil
Gliclazide Diamicron
Glipizide Glibenese Glucotrol
Glyburide DiaBeta/Glynase
Micronase
Metformin Glucophage Glucophage
Tolazamide Tolinase
Tolbutamide Rastinon Orinase
Antidiabetic agents
Acarbose Glucobay Precose
Guar gum Guarem
Troglitazone Romozin Rezulin

Insulin preparations—USA trade names

Short-acting insulins Intermediate-acting insulins
Humulin R Humulin L,N
Iletin l Iletin l, Lente
Novolin R Insulatard
Regular insulin Lente insulin
Semilente insulin Novolin L,N
Velosulin
Humalog (Insulin Lys-Pro)
Long-acting insulins Premixed
Humulin U Humulin 50/50, 70/30
Ultralente insulin Mixtard 70/30
Novolin 70/40

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 ENDOCRINE SECRETIONS OF THE PANCREAS 103

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 6
The Gonads and Reproduction

The Gonads (i.e. ovaries in the female, and the testes in the male) serve two main functions:

1. to produce germ cells (ova or sperm)—gametogenesis

2. to produce certain steroid sex hormones necessary for normal development and function of the
reproductive organs and differentiation of secondary sex characteristics. They also have an important
role during pregnancy, parturition (childbirth) and lactation.

There are three types of sex hormone secreted:

1. Androgens—male sex hormones—e.g. Testosterone

2. Oestrogens—female sex hormones—e.g. 17β—Oestradiol
3. Progestogens—female sex hormones—e.g. Progesterone

Androgens and oestrogens exert masculinizing or feminizing effects in the body respectively, whereas
progestogens mainly affect the uterus in preparation for and during pregnancy (Figure 6.1).
While the testes continuously produce spermatozoa and testosterone from puberty (ca. 13 years) to old
age, in the adult female, usually only one ovum is produced approximately every 28 days, and oestrogen/
progesterone secretion occurs cyclically (the menstrual cycle) until the menopause, when the ovarian cycle
ceases.
The functioning of the gonads and sexual function is primarily controlled by the hypothalamus and
anterior pituitary, under the influence of higher brain centres (the cortex).
Puberty is most probably initiated by a maturation and ‘release from inhibition’ of the hypothalamic
gonadotrophin releasing hormone (GnRH) neurones of the arcuate nucleus, leading to gradual
establishment of pulsatile GnRH release (frequency about 60–90 mins) and a consequent increase in
pulsatile gonadotrophin secretion from the pituitary. Premature activation of this hypothalamic-pituitary
system (e.g. caused by a brain tumour or hydrocephalus) may lead to precocious puberty in children.

The Male Reproductive System

Structure and Histology

Like the female ovary, the testes have both an endocrine and exocrine function. Each testis (about 20 g)
situated in the scrotum, is largely composed of numerous coiled seminiferous tubules surrounded by a
fibrous capsule; the inner walls of these tubules contain a large number of spermatogenic cells
106 BASIC ENDOCRINOLOGY—CHAPTER 6

Figure 6.1. Structures of the principal steroid sex hormones secreted by the testes in males (testosterone) or by the
ovaries in females (17β-oestradiol and progesterone). All bear the same characteristic 4-ringed nucleus (derived from
cholesterol). Note that testosterone and progesterone differ only in the type of grouping attached at position C17,
whereas oestradiol lacks the methyl group at position C10.

(spermatogonia, spermatocytes and spermatids) that undergo various stages of division and development to
produce spermatozoa (an exocrine-holocrine secretion). The tubular epithelium also contains larger Sertoli
cells (extending from the basal membrane to the tubular lumen) that are involved in supporting and
nourishing the sperm cells during their process of maturation. Tight junctions present between adjacent
Sertoli cells form a ‘blood-testes barrier’ (separating basal and adluminal compartments of the tubule) that
creates a unique environment for more advanced germ cells, and may protect them from possible noxious
substances in the general circulation. Fully-formed spermatozoa (about 100–200 ×106/day) are released
from the apex of the Sertoli cells into the lumen of the seminiferous tubules.
Lying in between the seminiferous tubules, together with blood vessels, lymphatics and nerves, are
groups of interstitial Leydig cells which synthesize and secrete testosterone into the circulation. Sertoli
cells are also capable of converting androgens to oestrogens, which may exert a localized paracrine function
on Leydig cells to limit testosterone production. Most (about 70%) of the oestrogen present in the
circulation of adult men is, however, non-testicular—derived from circulating testosterone and
androstenedione through aromatase enzyme activity in peripheral tissues (mainly adipose tissue and liver);
the rate of extraglandular oestrogen production tends to increase with age.

Brain aromatization of testosterone (released by the foetal testis) to 17β-oestradiol within the
foetal hypothalamus, is thought to be responsible for the early differentiation of the ‘male-type’
hypothalamic/pituitary negative feedback axis. The aromatase enzyme system is also found in other
 THE GONADS AND REPRODUCTION 107

Figure 6.2. Control of testosterone secretion by the testes. Pulsatile release of gonadotrophin releasing hormone (GnRH)
by the hypothalamus, stimulates the secretion of the gonadotrophins luteinizing hormone (LH) and follicle stimulating
hormone (FSH) from the anterior pituitary. LH stimulates the testicular Leydig cells to produce testosterone, which in
turn diffuses to adjacent Sertoli cells to affect spermatogenesis and also exerts negative feedback effects on the
hypothalamus and pituitary. FSH release is regulated by the production of peptide factors inhibin and activin by the
tubular Sertoli cells or Leydig cells respectively, which have a direct negative or positive feedback action on the
pituitary.

brain areas, suggesting a more general role for locally-formed oestrogens in prenatal brain
development.

Control of Spermatogenesis and Hormone Release

Testicular function is regulated primarily by the release of anterior pituitary gonadotrophins, LH and FSH,
which in turn, is driven by hypothalamic GnRH. The initiation and maintenance of spermatogenesis by the
seminiferous tubules requires the action of both LH and FSH. FSH action on the Sertoli cells is particularly
important for the initiation of spermatogenesis. Afterwards, LH assumes more importance by stimulating
the Leydig cells to produce testosterone, which diffuses to adjacent Sertoli cells and has a key role in the
maintenance of spermatogenesis. Testosterone is important for the final development of spermatids into
spermatozoa. FSH together with testosterone, also stimulate the Sertoli cells to produce androgen binding
protein (ABP) which sequesters testosterone in the tubular lumen fluid and thus helps to maintain a high
intratubular concentration of the hormone, necessary for normal spermatogenesis. The actions of FSH are
mediated via specific FSH receptors (linked to cAMP production) located primarily, if not exclusively, on
the Sertoli cells. LH and FSH in addition, exert important trophic (growth-promoting) effects on the Leydig
cells and Sertoli cells respectively.
108 BASIC ENDOCRINOLOGY—CHAPTER 6

CONTROL OF RELEASE
The production of testosterone is controlled principally by LH acting on the Leydig cells; this effect is
mediated by surface LH receptors coupled to intracellular cAMP production. Testosterone inhibits LH
release by direct and indirect negative feedback loops acting on the anterior pituitary and hypothalamus
respectively (Figure 6.2). It does not, however, reduce FSH release at normal levels. A peptide hormone
inhibin, secreted by the Sertoli cells under the influence of FSH (see Chapter 2) is believed to exert this
effect by a direct negative feedback action on the pituitary.

Inhibin is a dimeric 32-kDa glycoprotein consisting of two dissimilar subunits, α and β; (two
forms of the β chain, A and B are produced). Interestingly, a second structurally related gonadal
peptide, activin, formed from two inhibin β chains, has the opposite effects to inhibin on pituitary
FSH release and on gonadal steroidogenesis. In males, activin is secreted predominantly by the testicular
Leydig cells. Inhibin and activin may produce important local (paracrine) effects on neighbouring
Leydig and Sertoli cells; the two peptides may also have important regulatory functions outside the
reproductive system e.g. in controlling early cellular differentiation and development. An inhibin-like
peptide is known to be secreted by the adrenal glands, and may be important in adrenocortical cell
proliferation and/or differentiation. A possible use of inhibin as a male contraceptive agent has been
suggested.
A monomeric glycoprotein follistatin, also found in ovarian follicular fluid, has a similar (though
less potent) inhibitory effect to inhibin on pituitary FSH release, but is structurally unrelated to the
inhibin or activin molecules. Follistatin binds circulating activin with high affinity and can therefore
neutralise and limit its biological effects in many tissues; the significance of follistatin in human
reproduction is, however, unclear.

Androgens: Testosterone
The main steroid hormone secreted by the testes is testosterone (synthesized largely from low density
lipoprotein [LDL]-cholesterol, converted to pregnenolone; c.f. adrenal steroids: Chapter 3). Small amounts
of testosterone are also secreted by the adrenal cortex (in both males and females) and also by the ovaries in
females. About 98% of plasma testosterone is protein bound: 65% to a sex hormone binding globulin
(SHBG) (synthesized by the liver) and the remainder to albumin and other proteins. The plasma half-life of
unbound (biologically-active) testosterone is only about 10–20 min, most being rapidly metabolized by the
liver to inactive 17-ketosteroids (mainly androsterone and etiocholanolone) and also to polar metabolites (-
diols, -triols and conjugates [glucuronides and sulphates]) and excreted in the urine. Since albumin-bound
testosterone is readily dissociable, the amount of ‘bioavailable’ testosterone is considered as being the sum
of the unbound and albuminbound hormone.
Testosterone stimulates the growth and development of the entire male genital tract; it also has potent
protein anabolic properties (increase in synthesis of protein, leading to an increase in muscle mass and
nitrogen retention).
The principal effects of testosterone may be summarized as follows:

1. In the foetus, testosterone, secreted by the embryonic testes during a critical foetal period (8–12
weeks), is responsible for differentiation of the male internal and external genitalia and for promoting
the descent of the testes into the scrotum (müllerian inhibiting substance secreted by the foetal testes
prevents development of female genital ducts in the male foetus; see below).
 THE GONADS AND REPRODUCTION 109

2. During puberty, it is responsible for the growth of the male sex organs, and contributes to the pubertal
‘growth spurt’ (accelerated growth phase) and eventual fusion of the bone ends (epiphyses) of the long
bones (cessation of growth at adult height); it also causes deepening of the voice (due to enlargement of
the vocal cords), growth of facial, pubic, axillary (armpit) and body hair, as well as an increase in
muscularity and strength. An increase in secretory activity of the sebaceous glands of the face may lead
to acne.
3. In the adult, it maintains masculinity as well as libido (sexual drive) and sexual potency; its role in the
maintenance of the erectile response is controversial. Along with FSH, it is required to regulate
spermatogenesis in the testes, and exerts an important feedback effect on the hypothalamus and
pituitary (Figure 6.2). Testosterone is also responsible for recession of the scalp and baldness in
genetically disposed individuals. A slight decline in bioavailable testosterone level occurs with age in
healthy men (about 1% per year, between 40 and 70 years), but there is no abrupt decrease analogous to
the female menopause.

MECHANISM OF ACTION
As with other steroid hormones (see Chapter 3), the actions of testosterone are mediated directly via an
intracellular high affinity androgen receptor protein (AR) that ultimately binds to specific androgen-
responsive elements (AREs) on the nuclear DNA; this affects transcription (either positively or negatively)
of specific genes and therefore synthesis of specific proteins within the cell cytoplasm. Conversion of
testosterone to the more potent 5α-dihydrotestosterone (DHT) however, occurs in some target tissues
(particularly skin, prostate gland and seminal vesicles), catalysed by the nuclear enzyme 5-α-reductase.
DHT interacts with the same intracellular receptor as testosterone, but has a two-fold higher binding affinity,
and a slower rate of dissociation; it exerts significant androgenic activity at these sites. Thus, in addition to
its direct effects, testosterone serves as a prohormone for intracellular DHT production within specific
androgen target tissues.
Differentiation of the male external genitalia and prostate gland in the foetus requires the action of DHT
rather than testosterone, whereas the latter is important for mediating the development of the wolffian ducts
into the male internal genitalia. DHT is also the active hormone responsible for prostate and penile growth at
puberty as well as development of facial hair, acne and possible scalp recession in later life.
In women, androstendione is the major precursor of DHT production in the skin. Unlike testosterone,
DHT is a non-aromatizable androgen; i.e. it is not a substrate for aromatase, therefore cannot be converted
peripherally to oestrogens.

In the male embryo during development, immature Sertoli cells secrete an inhibin-like peptide,
müllerian inhibiting substance (MIS), responsible for causing regression of the müllerian duct
system, that would otherwise develop into fallopian tubes and a uterus. MIS is a glycoprotein dimer
that belongs to the transforming growth factor-beta (TGF-β) superfamily of peptides (including
activin, and inhibin), involved in regulating cell growth and differentiation; it requires enzymatic
cleavage by a protease to become biologically active. MIS is also present in the testes postnatally for
several years (up to and including early puberty), before declining to low levels. In females, it can be
found in the ovaries, but not until the onset of puberty; thereafter it continues to be synthesized by the
ovarian granulosa cells throughout reproductive life and may therefore be important in controlling
oocyte maturation. The measurement of serum MIS levels can be useful in diagnosing patients
showing a variety of congenital intersex and gonadal abnormalities. In addition, recombinant human
110 BASIC ENDOCRINOLOGY—CHAPTER 6

MIS (rhMIS) has been shown to cause regression of certain gynaecological tumours in vitro, and may
therefore have a clinical use in the future, as a novel anticancer treatment.

Clinical Disorders
Hyposecretion or hypofunction of testosterone in the male (hypogonadism) may result from several types of
abnormality:

1. Absence of functional testes at birth (e.g. due to chromosomal abnormalities: primary hypogonadism).
2. Underdevelopment of testes due to inadequate secretion of pituitary gonadotrophins (hypopituitarism:
secondary hypogonadism).
3. Non-descent of foetal testes from abdomen into scrotum (cryptorchidism).
4. Loss of testes either prior to or following puberty (castration or testicular destruction by disease).

Loss of testicular function prior to puberty would lead to failure of normal development of the sexual
organs and secondary sexual characteristics. In adults, a decrease in libido, some regression of masculine
characteristics, and sterility would result.
Treatment of hypogonadism will require androgen replacement therapy, depending on the underlying
cause and age of onset. Cryptorchidism may be treated (before puberty) by intramuscular administration of
gonadotrophin (Pregnyl; see below) or by surgery.
Congenital absence of enzymes involved in testosterone action (e.g. 5-α-reductase deficiency: male
pseudohermaphroditism), or molecular defects at the testosterone receptor (or post-receptor) level
(androgen resistance) may also cause serious abnormalities in sexual development. In the former case,
genotypic males show female appearance with ambiguous external genitalia throughout childhood, but
undergo progressive virilization at puberty, due to increased levels of testosterone. Development of facial
hair and acne (dependent on DHT production) are notably absent. The condition is characterized by an
abnormally high plasma testosterone: DHT ratio and may require therapy with high doses of testosterone to
promote penile growth.
Hypersecretion of testosterone, although extremely rare, can result from the development of Leydig cell
tumours in young children, leading to a pseudo-precocious puberty and a premature closure of the bony
epiphyses (with resultant short stature). Treatment would involve the surgical removal of the testicular
tumour followed by replacement therapy if necessary.

Some Clinical Uses of Androgens

Testosterone itself cannot be given orally, because of rapid metabolism by the liver. However depot (slow
release) preparations of testosterone esters e.g. testosterone enanthate (Primoteston Depot) or
propionate (Virormone) may be given by deep intramuscular injection every 2–3 weeks, or the patient can
be treated orally using capsules containing an oily solution of testosterone undecanoate (Restandol). More
longer-acting depot preparations comprising of a mixture of testosterone esters (propionate,
phenylpropionate and isocaproate [Sustanon 100/250]) are also available. The only other orally-active
androgenic steroid currently marketed in the UK is Mesterolone (Pro-Viron). Fluoxymesterone, and
methyltestosterone are used in the USA. Transdermal delivery systems are also now available (Andropatch)
consisting of testosterone-loaded films, applied each day to scrotal or non-scrotal skin (e.g. back, abdomen,
 THE GONADS AND REPRODUCTION 111

thighs, or upper arms) in the form of a patch; local skin irritation and discomfort may however occur as side
effects.
Androgens may be used for:

1. Replacement therapy in castrated adult males, and for treatment of hypogonadism due to testicular or
pituitary insufficiency; in the latter case, androgen therapy would begin at puberty (often in
combination with ongoing growth hormone therapy), to promote the growth spurt and normal
development of sexual characteristics. Treatment of boys must be carefully monitored to avoid premature
closure of the epiphyses. Androgens are not generally used as a treatment for decreased libido and
impotence (unless associated with established hypogonadism).
2. As protein anabolic agents to increase muscle mass after a chronic debilitating or wasting disease (e.g.
severe ulcerative colitis), major surgery or in terminal conditions. Synthetic analogues (so called
anabolic steroids) designed to have less androgenic and more anabolic effects are preferred (e.g.
nandrolone (Deca-Durabolin) or stanozolol (Stromba)). The anabolic action also involves a
remineralization of bone, which may become partly demineralized in some androgen-deficient men
with age (osteoporosis).
Although controversial, the use of anabolic steroids for the treatment of aplastic anaemia is still
considered useful (erythropoietic effect); the use of these agents by body builders or athletes, to
increase aggressiveness, muscle strength, and athletic performance however, is considered unjustified
and is illegal. High doses of anabolic and androgenic steroids used for this purpose can have serious
adverse effects on the liver and the cardiovascular system (see below).

Erythropoietin (EPO) is a glycoprotein hormone secreted mainly by glomerular epithelial

cells of the kidney (and also by the liver), that stimulates the formation of red blood cells from
precursor stem cells of the bone marrow. Its synthesis is stimulated by tissue hypoxia (resulting
from anaemia, high altitude or inadequate haemoglobin oxygenation) and also by androgenic
steroids (oestrogens inhibit erythropoiesis). Recombinant human erythropoietin (rHuEPO)
(Eprex; Recormon: given by intravenous or subcutaneous injection) is now available for treatment
of secondary anaemia due to chronic renal failure (in dialysis patients).
3. Oestrogen-dependent tumour therapy: certain advanced breast carcinomas or cervical cancers in
women may undergo regression when exposed to androgens. Masculinizing side effects are however
inevitable, including growth of facial hair, interruption of the menstrual cycle, deepening of the voice
and development of acne.

Other general side effects associated with androgen therapy include: possible liver damage, hepatic tumours
and cholestatic jaundice, weight gain with oedema due to Na+/H2O retention (especially in patients with
heart or kidney disease), priapism (persistent abnormal erection) and a decrease in male fertility (due to a
negative feedback effect on GnRH and gonadotrophin release). Suppression of spermatogenesis and
decrease of testicular size during treatment with these compounds is normally reversible upon cessation of
therapy.
The anti-androgenic compounds cyproterone acetate (Androcur; Cyprostat), flutamide (Drogenil) and
bicalutamide (Casodex) are competitive antagonists of testosterone at the androgen receptor sites, and may
be used to suppress excessive sexual drive in certain men (sex offenders; Androcur), or in combination with
an oestrogen (Dianette) in the treatment of severe acne/hirsutism in women. Certain advanced androgen-
dependent prostatic cancers (see below) may also respond favourably to anti-androgen therapy (Casodex).
112 BASIC ENDOCRINOLOGY—CHAPTER 6

Side effects associated with their use in men include: possible breast growth (gynaecomastia), reversible
infertility (due to inhibition of spermatogenesis), tiredness, depression, and development of osteoporosis.
Cyproterone is not currently approved for use in the USA.
Finasteride (Proscar) is a selective inhibitor of the 5-α-reductase enzyme responsible for the peripheral
conversion of testosterone into DHT. Since DHT is involved in normal prostatic growth and function, the
inhibitor is used in the treatment of benign prostatic hyperplasia (BPH) to induce a shrinkage of the
enlarged prostate gland and to improve urinary flow rate; several months of treatment may however, be
required before any benefit is observed. BPH is a quite common, nonmalignant condition that can affect
about 80% of men over 60 years of age. Impotence and a decreased libido may also occur as side effects.
The selective α1-adrenoreceptor blockers alfuzosin (Xatral SR), doxazosin (Cardura), indoramin
(Doralese) and tamsulosin (Flowmaz MR) (selective for the α1A receptor subtype, predominant in the
prostate) are also used in the treatment of BPH, to increase urinary flow rate and reduce obstructive
symptoms.

The Female Reproductive System

Structure and Histology

The two ovaries lie either side of the uterus, close to the open ends of the oviducts (fallopian tubes) in the
pelvis. Each ovary (ca. 15 g) is enveloped in a protective capsule of connective tissue and consists of a
cortex containing many thousands of primordial follicles (about 200,000 at puberty) embedded in
supportive tissue (the stroma). Each primordial follicle comprises an ovum (oocyte) surrounded by a single
layer of epithelial granulosa cells. Throughout the reproductive life of the female, only about 450 of these
follicles may develop to maturity and expel an oocyte, the rest undergo spontaneous degeneration (atresia).
At the menopause (when menstruation ceases) only a few primordial follicles are present in the ovaries.

The Ovarian Cycle and Hormone Release

With each phase of the menstrual cycle, ovarian follicles go through three stages of development, the final
mature follicle being termed a Graafian follicle. At the beginning (day 1) of each menstrual cycle
(follicular phase), a group of about 10–20 primordial follicles, stimulated by the increasing FSH
concentration, enlarge to form secondary follicles (recruitment) although after about day 6, only one usually
becomes dominant and matures fully. The remaining follicles regress i.e. become atretic. In mid-cycle (day
14), the Graafian follicle migrates to the edge of the ovary and ruptures, liberating the oocyte into the
abdominal cavity (ovulation) from where it enters one of the fallopian tubes. If the ovum is subsequently
fertilized during its 3–4 day passage down a fallopian tube, cellular division begins (blastocyst stage) before
implantation in the uterus, and further cell development (trophoblast stage). Trophoblast cells, together with
adjacent blastocyst and endometrial cells, divide rapidly to form the placenta. After about 72 hours, if not
fertilized, the ovum dies and is ultimately expelled through the vagina.
The process of follicular maturation may be summarized as follows:

1. Primary (primordial) follicle (ca. 25 mm diameter). An immature oocyte surrounded by a single

follicular epithelial cell layer.
 THE GONADS AND REPRODUCTION 113

2. Secondary follicle (ca. 500 mm diameter). The oocyte increases in diameter and under the influence of
FSH, the follicular cells multiply to form a layer of granulosa cells. A fluid-filled cavity (the antrum)
appears, containing a cocktail of nutritive substances. Like the male Sertoli cells, the granulosa cells
develop gap junctions between them, thus forming a protective barrier around the oocyte.
3. Graafian follicle (ca. 20 mm diameter). The antrum enlarges further and an outer layer of thecal cells
develops from the ovarian stroma, which on stimulation by LH, are responsible for initiating production
of oestrogens; these are essential for preparing the female reproductive tract for conception. The thecal
cells make androgens (mainly androstenedione) which are ultimately converted (via aromatase enzyme
activity) to oestrogens by the granulosa cells (stimulated by FSH and LH). Both of these effects involve
a rise in intracellular cAMP.

FSH (together with oestrogens) increases the number of LH and FSH receptors on granulosa
cells, thereby enhancing their LH/FSH sensitivity.

After ovulation (luteal phase), the granulosa and theca cells of the collapsed, haemorrhaged follicle
proliferate to form a yellowish corpus luteum (ca. 1.5 cm diameter) which, in the non-pregnant woman,
persists for about 10 days, secreting both oestrogens and progesterone, before shrinking to form scar tissue
(corpus albicans). The sudden rise in progesterone level increases the body temperature by ca. 0.5°C, which
is sustained until the end of the cycle. However, if fertilization of the ovum/implantation does occur, the
corpus luteum survives and continues to secrete steroids for two to three months, until the placenta takes
over. The corpus luteum thus maintains the uterine endometrium during early pregnancy. The process of
follicular maturation and ovulation is summarized in Figure 6.3.

The Uterine Cycle

The cyclic changes that occur in the endometrial lining prepare the uterus for possible fertilization and
pregnancy. These changes, along with approximate times of their occurrence, may be summarized as follows:

1. Day 1 of the menstrual cycle begins when the outer endometrial lining from the previous cycle is
sloughed off, with loss of blood through the vagina (menstrual phase).
2. Day 5. Menstruation ceases, and oestrogens secreted by the developing follicles cause the endometrium
to proliferate and to grow in thickness again (follicular/proliferative phase).
3. Day 14 (mid-cycle). A surge in LH secretion occurs, followed 24–48 hours later by ovulation.
Progesterone secreted by the corpus luteum stimulates the oestrogen-developed endometrium to
become more vascular and to secrete mucus (secretory/luteal phase); this preparation is essential if
implantation of a fertilized ovum is to occur.
4. Day 28 (no fertilization). The corpus luteum regresses, hormonal support of the endometrium is lost,
and menstruation begins again. The endometrium becomes necrotic and breaks down due to shut-down
of the spiral arteriolar blood supply.

These cyclical hormonal changes also alter the consistency and pH of the cervical mucus (clear, watery,
stretchy, high pH at the time of ovulation to viscous, cellular, low pH after ovulation.
114 BASIC ENDOCRINOLOGY—CHAPTER 6

Figure 6.3. Sequential development of the ovarian follicle within the female ovary (not drawn to scale). During the
follicular phase, a primordial follicle, consisting of an immature oocyte, protected by a flat layer of follicular cells,
grows to form a primary, then a secondary follicle with surrounding layer of inner granulosa cells and outer thecal
cells. A fluid-filled cavity (the antrum) forms around the oocyte. The mature ovarian follicle (Graafian) moves to
the edge of the ovary and eventually ruptures (on about day 14 of the menstrual cycle) to release the ovum
(ovulation). The follicular lining then collapses to form the corpus luteum (luteal phase) which eventually
regresses if pregnancy does not occur. Only one follicle per cycle normally attains maturity and undergoes
ovulation.
Hormonal Regulation of Menstrual Cycle
During the first 14 days of the cycle, the plasma FSH (and LH) levels slowly rise, which promotes ovarian
follicle maturation and oestrogen secretion. The oestrogen enters the circulation and initially inhibits FSH
secretion by a direct negative feedback effect on the pituitary (LH release is less affected) and
hypothalamus (Figure 6.4), but at a certain maintained high threshold level, a switch to positive feedback
occurs (see Chapter 1), and oestrogen now stimulates a surge in LH (lasting 24–48 hours), leading
ultimately to ovulation, corpus luteum formation and progesterone secretion. Progesterone also exerts a
negative feedback effect on gonadotrophin secretion during the luteal phase.
As the LH level falls, the corpus luteum degenerates, normal negative feedback of oestrogen on the
pituitary and hypothalamus is resumed, and menstruation follows when there is no longer enough oestrogen
and progesterone available from the corpus luteum to maintain the endometrium; the cycle is then repeated.
The cyclic changes in plasma hormone levels that occur during the menstrual cycle are depicted in
Figure 6.5.

Granulosa cells also produce the peptide inhibin (on stimulation by FSH) which provides some
negative feedback inhibition of FSH secretion during the follicular phase; (c.f. similar effect of testicular
inhibin in males, p. 86–87). Inhibin is also produced by the corpus luteum during the luteal phase.
 THE GONADS AND REPRODUCTION 115

Figure 6.4. Control of female gonadal steroid production by the hypothalamus and anterior pituitary. Hypothalamic
release of GnRH (pulsatile) stimulates the release of pituitary gonadotrophins LH and FSH which stimulate the thecal
and granulosa cells of the ovarian follicle to produce oestrogens (17β-oestradiol and oestriol), and the corpus luteum
(following ovulation) to produce progesterone (+ oestrogens). These hormones exert negative feedback effects on the
hypothalamus and pituitary to control release of GnRH and LH; FSH release is regulated by a negative feedback loop
involving the follicular peptide inhibin. [*A switch to positive feedback occurs at the time of ovulation, causing a surge
in LH (and FSH) release].
Hormonal Changes During Pregnancy
If successful fertilization/uterine implantation of the ovum occurs (at about day 20), the trophoblastic cells
surrounding the developing embryo secrete human chorionic gonadotrophin (hCG), an LH-like
glycoprotein hormone (composed of an α and a β subunit; see Chapter 2), which is detectable in the
maternal urine within 9 days of conception and forms the basis of the common pregnancy test (see below).
hCG maintains the corpus luteum (and therefore oestrogen/progesterone production) for about 9 weeks and
so prevents further ovulation and menstruation, as well as maintaining the uterine lining. From about week
9, the placenta functions as an important endocrine gland and begins to secrete oestrogens (mainly oestriol,
with oestradiol and oestrone) and progesterone, and continues to secrete large amounts of hCG. The hCG
level eventually declines from its peak level in early pregnancy, to a maintained plateau after about week 16
(Figure 6.6), and the corpus luteum regresses. The exact functions of hCG during foetal development or the
remaining pregnancy are uncertain, however it is thought to play an important role in stimulating the Leydig
cells of the male foetal testes to produce testosterone and also in stimulating the foetal adrenal gland to
produce the androgenic steroid precursor dehydroepiandrosterone sulphate (DHEAS) (utilized by the
placenta to produce oestrogens).
116 BASIC ENDOCRINOLOGY—CHAPTER 6

Figure 6.5. Changes in plasma levels of the pituitary gonadotrophins (LH and FSH) and ovarian hormones oestradiol
and progesterone) during the 28 day female menstrual cycle. Note the steady rise in oestrogen level during the follicular
phase, and the large surge in LH level at about mid-cycle, responsible for inducing ovulation; thereafter, the residual
corpus luteum secretes progesterone (+ oestrogens) during the luteal phase, peaking at about day 22 (prior to onset of
the next menstrual period). Note that in men, such cyclic fluctuations in plasma LH/FSH levels do not occur.
Chorionic gonadotrophin (hCG) prepared from the urine of pregnant women (Pregnyl; Profasi, given
by intramuscular injection) may be utilized for its LH-like activity to treat anovulatory infertility and also in
the management of delayed male puberty or for stimulating descent of the testes in male children with
cryptorchidism. A rare form of hCGsecreting brain tumour can cause pseudoprecocious puberty in boys.
From about the 5th week of pregnancy, the placenta also secretes human chorionic
somatomammotrophin (hCS) (also called human placental lactogen, hPL), a 191 amino acid peptide,
similar in structure to human GH and prolactin, as well as a range of other hypothalamic/pituitary-like
peptides (e.g. GnRH and prolactin). Although large amounts of hCS are present in maternal blood, the exact
role of this hormone in pregnancy is uncertain; however, it is believed to influence maternal carbohydrate
and lipid metabolism to assure a constant supply of nutrients (particularly glucose) to the foetus. It may also
exert some weak G H-like activity on foetal growth, and stimulate the partial development of breast tissue in
preparation for lactation.
 THE GONADS AND REPRODUCTION 117

Figure 6.6. Maternal blood concentrations of oestrogens, progesterone and human chorionic gonadotrophin (hCG)
during normal human pregnancy. After about week nine, the placenta takes over from the corpus luteum as the major
source of oestrogens and progesterone.

A wide range of other proteins are also produced by placental tissue. In particular, pregnancy-
associated plasma protein A (PAPP-A) and pregnancy-specific beta 1-glycoprotein (SP-1) have
been isolated and studied in some detail, although the exact biological function of these peptides still
remains uncertain. Circulating levels of hPL and SP-1 in the maternal serum (measured by
radioimmunoassay) can be useful indicators of placental weight/function and foetal well-being during
pregnancy. hCG, hPL and SP-1 can also be produced ectopically by certain adrenal or urinary tract
carcinomas and may therefore be useful as diagnostic markers of these malignant tumours.

Relaxin is a small, two-chain polypeptide (53 amino acids) that is structurally similar to insulin and the IGF’s
(see Chapter 5). It is synthesized within the surviving corpus luteum of the ovary (and by the placenta) and
is released into the maternal blood throughout pregnancy (it is also secreted by the male prostate gland and
appears in seminal fluid). The main actions proposed for this peptide are to loosen the pubic ligaments and
to soften (‘ripen’) and dilate the cervix in preparation for delivery. Although relaxin can act synergistically
with progesterone to reduce spontaneous uterine contractions in some animal species, the current view is
that this direct inhibitory action of relaxin on the myometrium may be of little importance in the regulation
of uterine activity in human pregnancy. The possibility of using recombinant human relaxin (rhRlx) as a
potential cervical softening agent applied intravaginally or intracervically prior to parturition is currently
being evaluated.

SYNTHESIS OF STEROIDS BY THE MATERNAL FOETAL-PLACENTAL UNIT

Placental progesterone (synthesized in large quantities from maternal cholesterol, via pregnenolone) is
utilized by the foetal adrenal gland to produce cortisol and aldosterone. It is also important in preventing
uterine contractions during the pregnancy (and therefore premature expulsion of the foetus) and for
preparing the mammary glands for eventual milk secretion.
118 BASIC ENDOCRINOLOGY—CHAPTER 6

Placental oestrogens serve an important function in stimulating the continued growth of the breast ductal
system, and also stimulating the enlargement of the woman’s external genitalia. In addition oestrogens
cause relaxation of the pelvic ligaments, thereby facilitating the further expansion of the pregnant uterus.
Oestradiol and oestrone are synthesized within the placenta from maternal and foetal DHEAS, whereas
oestriol is formed from the hydroxylated precursor (16-OH)-DHEAS, derived from the foetal adrenal gland
and liver (mainly) (Figure 6.7). The high levels of oestrogens exert a maintained negative feedback effect on
the hypothalamus and pituitary during pregnancy, thereby preventing LH/FSH release, further follicle
development and ovulation.

Figure 6.7. Synthesis of steroid hormones within the maternal foetal-placental unit. Progesterone is synthesized by the
placenta from maternal cholesterol, which is then converted (via DHEAS) to oestrogens, oestradiol and oestrone.
Progesterone also passes to the foetus, where it is converted to cortisol and aldosterone by the foetal adrenal gland.
Foetal pregnenolone undergoes conversion to DHEAS in the adrenal and to (16-OH)-DHEAS in the foetal liver. Both
DHEAS and (16-OH)-DHEAS are carried back to the placenta to produce oestrogens (principally oestriol). Placental
progesterone and oestrogens enter the maternal circulation to affect uterine motility/growth and breast development.

The Menopause
Between the ages of 45 to 55, menstruation in women normally becomes irregular and eventually ceases
(the menopause). At this stage, very few functional primordial follicles are left within the ovaries. About
80% of women can then experience unpleasant post-menopausal symptoms that can be largely associated
with the decline in oestrogen production. These include: hot flushes of the skin, sweating, palpitations,
increased irritability, anxiety, depression, vaginal atrophy and the gradual development of osteoporosis
 THE GONADS AND REPRODUCTION 119

(loss of bone mass and demineralization, with increased risk of bone fractures, particularly of the spine and
hip; see Chapter 7).

Due to absence of hormonal negative feedback, plasma LH and FSH levels are high in post-
menopausal women, although no cyclic variation is present. Follicular oestrogens are no longer
secreted, but some oestrogen production can still occur through the peripheral conversion
(aromatization) of ovarian or adrenal androgens; the main oestrogen becomes oestrone rather than
oestradiol (see Figure 3.3).

Menotrophin (Pergonal), a highly purified preparation of gonadotrophins extracted from post-menopausal

urine, may be given by intramuscular injection to stimulate follicular development and to induce ovulation
in cases of infertility due to hypopituitarism; it may also be used to treat hypogonadism due to lack of
gonadotrophins in males. Urofollitrophin (Metrodin) containing purified menopausal FSH, may similarly
be used to induce superovulation (multiple follicular growth) as part of an assisted conception, in vitro
fertilization (IVF) technique.

Female Sex Hormones

OESTROGENS
The major oestrogenic steroid secreted by the ovary is 17β-oestradiol, together with some oestrone (in
chemical equilibrium) and oestriol. Oestrogens are also secreted by the corpus luteum, by the placenta
during pregnancy, and in very small amounts by the adrenal cortex. Only 2% of circulating oestradiol exists
as free hormone, the remainder being bound to plasma albumin (60%) or sex hormone binding globulin
(SHBG) (38%) (c.f. testosterone p. 87); oestriol has a relatively low affinity for SHBG.
Oestrogens are necessary for normal development/ maintenance of the female genital tract and the
breasts.
The principal effects of oestrogenic hormones may be listed as follows:

1. During puberty, they stimulate the growth of the uterus, breasts and vagina, and control fat deposition
and distribution in subcutaneous tissues, thereby determining the characteristic female figure. Like
testosterone in the male, they are the primary cause of the ‘growth spurt’, closure of the epiphyses of
the long bones and development of secondary sexual characteristics.

Growth of pubic and underarm hair in the female is stimulated mainly by adrenal androgen
secretion.
2. In the adult, oestrogens regulate events during the menstrual cycle (growth of endometrial lining), are
important during pregnancy and lactation and contribute to the maintenance of sexual drive (libido) and
female personality.

PROGESTOGENS
The main progestogen secreted by the ovary during the luteal phase is progesterone, responsible for the
secretory changes in the uterine endometrium in preparation for pregnancy and (in cooperation with
oestrogens) for stimulating the glandular development of the breasts in preparation for lactation. It also
120 BASIC ENDOCRINOLOGY—CHAPTER 6

causes the cervical mucus to become thick and acidic, therefore less receptive to spermatozoa. Only 1–2% of
circulating progesterone is unbound, with about 50% bound to albumin and the remainder to the
corticosteroid-binding α2-globulin transcortin (see Chapter 3).
During pregnancy, progesterone reduces the frequency of spontaneous contractions of the myometrium,
which may be important if miscarriages are to be avoided. It has a weak negative feedback effect on the
anterior pituitary and hypothalamus to control LH release.
Mechanism of Hormone Action. In common with other steroids, oestrogens and progesterone exert their
effects by freely diffusing into target cells and combining with specific high affinity intracellular oestrogen
or progesterone receptors respectively; these proteins belong to a superfamily of ligand-activated
transcription factors (LTFs) which include receptors for thyroid hormone and the glucocorticoids. The
resultant activated steroid-receptor complexes undergo conformational changes, loose chaperone heat shock
protein (Hsp-90; see Chapter 3), dimerize, then bind to discrete nuclear DNA sequences and initiate (or
suppress) the expression of specific genes i.e. synthesis of new mRNA and new proteins. The number of
oestrogen and progesterone receptors in target tissues is controlled by prior oestrogen stimulation.
Progesterone can also down-regulate its own receptor numbers. Abnormalities in the expression and
function of oestrogen/progesterone receptors has been implicated in the development of certain disease
states such as breast cancer, uterine fibroids or endometriosis (see below).

Clinical Disorders
Hyposecretion of oestrogens (hypogonadism) may result from the absence or inadequate function of the
ovaries from birth. In this case, the normal female sex organs and secondary sexual characteristics do not
develop, menstruation is absent (primary amenorrhoea), and closure of the epiphyses at the usual stage of
adolescence does not occur. Turner’s syndrome or gonadal dysgenesis (due to chromosomal abnormality:
45,XO) is the most common cause of congenital hypogonadism. This disorder (and related variants) where
the defect lies in the gonad, is collectively termed primary or hypergonadotrophic hypogonadism
(associated with high serum levels of LH and FSH). Premature ovarian failure (leading to secondary
amenorrhoea) may also occur in some women under the age of 40, due to autoimmune disease.
Alternatively, ovarian function may be defective due to lack of hypothalamic or pituitary hormones at
puberty, referred to as secondary or hypogonadotrophic hypogonadism.
Lack of oestrogens due to premature removal of the ovaries in an adult woman, ultimately causes some
regression of the sex organs and uterus and atrophy of the breasts, together with other symptoms
characteristic of the menopause.
Hypersecretion of oestrogens may arise from ovarian granulosa-theca cell tumours (rare) and cause
excessive oestrogenic effects, particularly on the uterus, where hypertrophy and irregular bleeding of the
endometrium may occur.

ENDOMETRIOSIS
Endometriosis is a condition where endometrial tissue develops ectopically in the peritoneal cavity (usually
close to the internal sex organs), most likely caused by retrograde menstruation along the fallopian tubes
(peritoneal soiling). During each menstrual cycle, this ectopic tissue proliferates and degenerates like normal
uterine endometrium, however, the ensuing haemorrhagic material accumulates in the abdomen usually
causing irritation, severe cyclic abdominal or pelvic pain and development of pelvic fibrosis. Cyclical rectal
 THE GONADS AND REPRODUCTION 121

bleeding or haematuria (blood in the urine) may also occur in some patients. If untreated, the condition may
eventually result in infertility, due to fibrotic occlusion of the ovaries and fallopian tubes.
Treatment may involve surgery and/or drug therapy, depending on the severity of the disease. In mild
cases, conservative surgical treatment is aimed at removing ectopic endometrial tissue and adhesions using
a laparoscopic/ laser ablation or laparotomy/microsurgical approach, in order to relieve symptoms and
restore normal pelvic anatomy. In more severe cases, a complete removal of the uterus (hysterectomy) and
ovaries (bilateral oophorectomy) may be necessary. Medical treatment is intended to provide symptomatic
relief; some commonly used preparations include:

1. Gonadotrophin release inhibitors: Danazol (Danol) and gestrinone (Dimetriose) are synthetic
progestogen derivatives (structurally related to testosterone), that inhibit gonadotrophin output at the
pituitary and hypothalamic level, and thereby prevent ovulation; they also possess anti-progestogen and
weak androgenic activity. These drugs are also useful for the treatment of gynaecomastia, benign breast
tumours, cyclical breast pain (mastalgia), excessive menstrual bleeding (menorrhagia) and
premenstrual syndrome, although some mild androgenic side effects (weight gain, hirsutism, greasy
skin/acne, voice change) may follow from their use.
2. The GnRH analogues: Buserelin, Goserelin, Leuprorelin, or Nafarelin (see p. 98 and Chapter 2) may
be given daily in the form of a nasal spray or by subcutaneous/ intramuscular injection every month
over 6 months to induce a hypo-oestrogenic state by suppressing pituitary gonadotrophin release.
Menopausal-type side effects may, however, be induced including: hot flushes, vaginal dryness and
decreased libido.
3. Progestogens: Synthetic progesterone derivatives such as Norethisterone (Primolut N),
Dydrogesterone (Duphaston) or Medroxyprogesterone (Provera) may be given orally for 4–6
months or longer, or by intramuscular injection (Depo-Provera) to arrest endometrial growth and
inhibit cyclic gonadotrophin release and ovulation.
Side effects may include: irregular vaginal bleeding, weight gain, breast tenderness, headache and
nausea.

Some Clinical Uses of Oestrogens and Progestogens

A large variety of natural and synthetic oestrogens and progestogens are currently available for clinical use.
The latter compounds, taken orally, are less prone to metabolism by the liver than the natural hormones, and
are therefore preferred for therapeutic purposes.

CLINICAL USES OF OESTROGENS

Some commonly used oestrogens include: 17β-oestradiol, oestrone, oestriol, ethinyloestradiol,
mestranol, dienoestrol and stilboestrol.
Oestrogens may be used in:

1. Hormone replacement therapy (HRT). Apart from their use in the treatment of various congenital hypo-
ovarian conditions (e.g. primary hypogonadism) in young women (11–13 years), the most common use
of oestrogens is in the amelioration of unpleasant menopausal symptoms (e.g. hot flushes, night
sweating, palpitations, headaches, vaginal dryness and atrophy) due to the lack of natural oestrogens
from the ovary. Such symptoms may also develop earlier, following surgical removal of the ovaries
122 BASIC ENDOCRINOLOGY—CHAPTER 6

alone (oophorectomy) due to cancer, or together with the uterus (hysterectomy) in severe cases of
endometriosis. Since natural oestrogens normally antagonize the Ca2+-mobilizing effect of parathyroid
hormone on bone (see Chapter 7), the provision of oestrogen supplements during HRT is important in
the long-term, for preventing the development of post-menopausal osteoporosis and reducing bone
fracture rate. HRT is also known to protect postmenopausal women from developing coronary heart
disease (myocardial infarction and stroke) most likely by favourably affecting lipid/lipoprotein
metabolism (oestrogens increase high density lipoprotein [HDL]-cholesterol and decrease potentially
atherogenic low density lipoprotein [LDL]-cholesterol levels in the serum) and by also altering
vascular blood flow (increasing arterial compliance); [some progestogens have the opposite effect on
blood lipids, therefore could be reducing the beneficial effects of oestrogens on the lipid profile]. It has
been suggested that HRT may be beneficial in women with existing cardiovascular disease.
Oestrogen-alone (unopposed) HRT is only appropriate for women who do not have an intact uterus
(i.e. following hysterectomy); otherwise, a combined oestrogen/progestogen therapy is employed in
order to reduce the risk of developing endometrial carcinoma (see below). In general, preparations
using ‘natural’ oestrogens (oestradiol, oestrone or oestriol) rather than the more potent synthetic
derivatives such as ethinyloestradiol or mestranol are preferred, always aiming for the lowest possible
effective maintenance dose where possible.

Some commonly-used types of oestrogen-only preparation (listed in Table 6.1) include:

i) Oral ‘natural’ oestrogen therapy: Tablet preparations containing oestradiol valerate, piperazine
oestrone sulphate, oestriol, or conjugated equine oestrogens are taken daily (from 28-tab. blister
strips) on a continual basis,
ii) Transdermal therapy is advised for patients that cannot tolerate oral therapy, or where compliance is
poor. This route avoids the first-pass metabolism of hormone by the liver, but is relatively expensive
and can cause local skin irritation. Currently marketed self-adhesive oestrogen-only reservoir patches
contain 17β-oestradiol (Estraderm TTS or MX [matrix patch]; Evorel; Fematrix) and can be chosen to
release between 25–100 µg hormone/24 hours; patches are placed on the trunk below the waistline
(usually the buttocks, and never on or near the breasts) and replaced with a new patch after 3–4 days,
on a continual basis. New ‘7 day’ oestradiol patches, releasing about 50 µg hormone/24 hours are also
now available (FemSeven; Progynova TS).
An oestrogen-containing gel (Oestrogel) with 0.06% 17β-oestradiol was recently introduced, which
can be rubbed into the skin of the arms, shoulders or inner thighs (but not the breasts or vaginal region)
on a oncedaily, continuous basis, as an alternative therapy for women with skin allergy to patches or
where oral therapy is not preferred. Additional oral progestogen tablets can be co-prescribed where
appropriate, for women with an intact uterus (see below). Skin contact with male partners should be
avoided for an hour after application,
iii) Implant therapy may be used as an alternative to oral or transdermal therapy; implant preparations of
17β-oestradiol are inserted subcutaneously (under clinical supervision) into the buttocks or abdomen
every 4–8 months as necessary. An oral progestogen also needs to be taken for 10–14 days per cycle, if
the uterus is intact,
iv) Vaginal therapy. Oestrogens e.g. 17β-oestradiol, oestriol, conjugated equine oestrogens or
dienoestrol (Ortho Dienoestrol), may also be applied topically as creams or in vaginal pessaries/
modified-release tablets for short-term treatment of atrophic vaginal symptoms.
 THE GONADS AND REPRODUCTION 123

Some vaginal creams can damage latex condoms and diaphragms.

Table 6.1. Some examples of currently available preparations used for unopposed (oestrogen-only) hormone
replacement therapy (HRT) for women without an intact uterus; [from MIMS, June 1997].
Oestrogen Type of preparation Brand name (UK)
Oral ‘natural’ oestrogen therapy
Oestradiol valerate (1–2 mg) Tabs Climaval
Oestradiol valerate (1–2 mg) Tabs Progynova Zumenon
Piperazine oestrone sulphate Tabs Harmogen
[Estropipate] (0.93 mg)
Oestradiol, oestriol and oestrone Tabs Hormonin
mixture (0.27/1.4/0.6 mg)
*Conjugated equine oestrogens (0. Tabs Premarin
625–1.25 mg)
Transdermal therapy
17-β-oestradiol (25–100 µg/24 hr) Patches Estraderm TTS/MX
17-β-oestradiol (25–75 (µg/24 hr) Patches Evorel
17-β-oestradiol (40–80 µg/24 hr) Patches Fematrix
17-β-oestradiol (37.5–75 µg/24 hr) Patches Menorest
17-β-oestradiol (0.06%) Gel Oestrogel
Vaginal therapy
Oestriol Vaginal cream/pessary Ortho-Gynest
Oestriol Vaginal cream Ovestin
Conjugated oestrogens Vaginal cream Premarin
Dienoestrol Vaginal cream Ortho-Dienoestrol
17-β-oestradiol Vaginal tabs Vagifem
17-β-oestradiol Vaginal ring Estring
* Conjugated oestrogens (derived from pregnant mare urine) consist of a mixture of sodium oestrone sulphate (ca.
60%) and sodium equilin sulphate (ca. 30%) (a natural equine oestrogen).

An impregnated silastic vaginal ring is also now available (Estring) which releases a constant amount
(about 7.5 mg) of 17β-oestradiol hemihydrate directly into the vagina every 24 hours; minimal systemic
absorption of oestradiol takes place. It is worn continuously and replaced every three months; therapy may
continue for up to two years. Regular examination of patients (every 3–6 months) is necessary to assess the
need to continue treatment.

2. Treatment of androgen-dependent prostatic cancer

Administration of oestrogens, by altering the hormonal environment, may be used to limit the
stimulatory effects of androgens on prostatic androgen-dependent malignant cells in men. The synthetic
non-steroidal oestrogen stilboestrol may be given orally, although feminization, testicular atrophy,
impotence and breast growth (gynaecomastia) may occur as side effects. In view of these undesirable
actions, administration of potent synthetic GnRH agonists such as buserelin (Suprecur), goserelin
(Zoladex) or leuprorelin (Prostap SR), has become more popular for suppressing androgenic activity in
treatment of advanced prostatic carcinoma. The long-term (non-pulsatile) administration of these
124 BASIC ENDOCRINOLOGY—CHAPTER 6

agents (by nasal spray or by subcutaneous/intramuscular (depot) injection), produces a down-regulation

of pituitary GnRH receptors, and an ultimate decrease in gonadotrophin and androgen secretion (see
Chapter 2). Some initial stimulation (‘flare’) of tumour activity may occur before effective
gonadotrophin inhibition is established; this can be controlled by treatment with an anti-androgen (e.g.
Flutamide; see above, p. 89).
3. Postcoital oral contraception (the ‘morning after’ pill)
Pregnancy can be effectively prevented by short-term administration of a high dose of oestrogen in
combination with a progestogen; (the mode of action is most likely to prevent implantation). The only
preparation currently licensed in the UK is Schering PC4 which consists of four tablets, containing 50
µg of ethinyloestradiol and 0.5 mg of the progestogen norgestrel (equivalent to 0.25 mg of the active
isomer levonorgestrel). Treatment begun within 72 hours of unprotected intercourse (two tablets taken
as soon as possible, followed by a further two after 12 hours), is reported to be at least 98% effective;
some unpleasant side effects may however develop, associated with the high oestrogen content e.g.
nausea, vomiting, (affecting absorbtion), headache, dizziness and breast tenderness; the menstrual
pattern may also be temporarily disturbed. If conception does occur, it is considered unlikely that foetal
development would be adversely affected by the PC4 hormone administration over the recommended
period. Patients should however, be carefully examined for possible ectopic (tubal) pregnancy.

In the USA, stilboestrol (called diethylstilbestrol [DES], 25 mg tablets, twice daily for 5 days)
may be given for emergency post-coital contraception, beginning within 72 hours of intercourse.

Oestrogen Antagonists. Clomiphene (Clomid) is an antioestrogenic drug which competes with oestrogens
for cytoplasmic oestrogen receptors, but has little or no intrinsic oestrogenic activity; it therefore prevents
the normal hormonal negative feedback inhibition on the hypothalamus and anterior pituitary, and induces a
rise in GnRH and LH/ FSH secretion (provided the hypothalamus and pituitary are functioning correctly). This
drug is therefore used to stimulate ovulation in women that are infertile, although hyperovulation and
multiple pregnancies may commonly occur.
Tamoxifen (Tamofen; Nolvadex-D) is a similarly-acting anti-oestrogen which is used to treat anovulatory
infertility and has now become the treatment of choice for the treatment of advanced oestrogen-dependent
breast tumours in women; (also toremifene (Fareston)). The potential use of tamoxifen for preventing the
development of breast tumours in women considered to be at high risk (with positive family history) is
currently being evaluated in the USA.
Side effects associated with the use of anti-oestrogens include hot flushes, vaginal bleeding, abdominal
discomfort, dizziness and visual disturbances. Recent evidence also indicates a small but significant risk of
developing endometrial cancer after long-term (>2 years) tamoxifen treatment.
Aromatase Inhibitors. Aminoglutethimide (Orimeten) is a potent (type II) aromatase enzyme inhibitor
that is used for the management of advanced oestrogen-dependent breast cancer in post-menopausal or
oophorectomized women (particularly in patients who have become resistant to tamoxifen), and also as a
palliative treatment for advanced prostatic carcinoma in men. It blocks several cytochrome P-450 mediated
steroid hydroxylation steps, particularly those involved in the adrenal conversion of cholesterol to
pregnenolone (see Figure 3.3), as well as the peripheral aromatization of androgens to oestrogens (in fat,
muscle and liver cells). Modern treatment schedules utilize lower daily doses of the inhibitor (250–500 mg)
together with a replacement dose of corticosteroid (e.g. cortisone) in an attempt to avoid complicating side
effects (e.g. drowsiness, dermatitis, blood disorders); the therapy is often referred to as ‘medical
adrenalectomy’ (replacing bilateral surgical adrenalectomy).
 THE GONADS AND REPRODUCTION 125

Aminoglutethimide is also used for the medical treatment of Cushing’s syndrome (Chapter 3).
More specific (type I) aromatase inhibitors, formestane (Lentaron, given by deep intramuscular injection),
letrozole (Femara) or anastrozole (Arimidex, both given orally) are also available for treatment of
advanced post-menopausal breast carcinoma; unlike aminoglutethimide, these agents have no effect on
adrenocortical steroid synthesis. Irritation at the injection site (formestane), hot flushes, sweating, vaginal
dryness, thinning of the hair and lethargy/ drowsiness may occur as side effects. Aromatase inhibitors are
not indicated for use as suppressants of oestrogen synthesis in premenopausal breast cancer patients.

CLINICAL USES OF PROGESTOGENS

Several orally-active progestogens are also available; these include: Norethisterone, norgestrel,
levonorgestrel, ethynodiol diacetate, medroxyprogesterone, or the newer derivatives: gestodene,
desogestrel, norgestimate and dydrogesterone.
Progestogens are mainly used in:

1. Control of uterine bleeding and menstrual disturbances

This includes control of painful (dysmenorrhoea) or excessively heavy menstruation (menorrhagia)
and premenstrual syndrome; also in the treatment of endometriosis, and for postponement of
menstruation.
2. Oral contraception
The principal use of progestogens alone is in the form of the oral progestogen-only contraceptive pill
(POC) or ‘mini-pill’. Taken daily (starting from the first day of the period and throughout), the POC is
rather less reliable in preventing pregnancy than the ‘combined’ contraceptive pill described below.
The major contraceptive action is probably due to the unfavourable changes produced in the
endometrium (making implantation less likely) and cervical mucus (becoming thick, sticky and hostile
to sperm), coupled with a weak (and variable) negative feedback inhibition of LH release and ovulation;
fallopian tube motility (affecting ovum transport) may also be reduced. In some women, administration
of POCs can completely suppress gonadotrophin secretion and ovulation, resulting in amenorrhoea
(absent menstruation); in others, ovulation and menstrual cycles occur in a near normal fashion. Some
decrease in motility of the fallopian tubes (important for successful fertilization) may also be induced.
3. Depot injections and capsule implants
Depot (slow release) preparations of progestogens can also be used for more long-term contraception,
particularly in patients unable to tolerate other contraceptives, or where compliance is poor; they are
given either by deep intramuscular injection at 2–3 monthly intervals e.g. Medroxyprogesterone
acetate (Depo-Provera) or norethisterone enanthate (Noristerat), or subdermally as an implant into
the upper part of a non-dominant arm (levonorgestrel; Norplant), the latter giving highly effective
contraceptive protection for up to 5 years (expensive!). Unlike depot injections, fertility may return
quite rapidly (within 48 hours) after removal of the implants.

Depot progestogens may also be used in breast/endometrial cancer therapy.

A novel form of intrauterine device (IUD; see below) that releases levonorgestrel into the uterine
cavity (20 mg/ 24 hrs, over 3 years) has recently been introduced (Mirena) (see below).

Side effects associated with the use of POCs or other progestogen-only preparations are relatively minor and
include: irregular menstrual bleeding/spotting, (particularly on first starting use) due to the continued
126 BASIC ENDOCRINOLOGY—CHAPTER 6

progestogen stimulation of the endometrium, headache, nausea, depression, acne, fluid retention (weight
gain), hypertension, breast discomfort and possible persistence of infertility for several months after
withdrawal of treatment.
In view of the absence of serious side effects, POCs are considered more suitable for use than the
combined pill in older women (over 35 years), heavy smokers, those with a history of thromboembolism or
hypertension, or where oestrogens are generally not advised (e.g. diabetic women; see Chapter 5). The
small doses of progestogen used causes minimal disruption of lipid or carbohydrate metabolism. There is a
weak risk of ectopic pregnancy developing in patients that do become pregnant whilst taking a POC (due to
decreased tubal motility).
Progestogens in combination with oestrogens are mainly used in:

1. Combined oestrogen/progestogen preparations for oral contraception (COCs)

Low dose synthetic oestrogen/progestogen combinations (the ‘pill’) are regarded as very effective,
easy to use and relatively safe contraceptives. The oestrogen content (typically between 20–50 µM)
suppresses ovulation by inhibiting LH/FSH release, thereby mimicking the normal negative feedback
effect of the natural oestrogens at the pituitary and hypothalamic level; the progestogen content induces
the cervical mucus to become thick and more resistant to sperm penetration, and the endometrium to
become thin and inadequately developed for implantation. Three types of preparation are currently
available:
Monophasic combination tablets contain a single synthetic oestrogen/progestogen dose combination,
and are taken daily (from a ‘blister’ pack) starting on the first or fifth day of menstruation, for 21 days
followed by a 7-day interval of dummy (placebo) tablets (or pill-free days) during which the sudden
removal of progestogen initiates ‘withdrawal menstruation’ (the latter may be psychologically
reassuring to some women, that pregnancy has indeed been prevented); the cycle is then repeated. It is
essential that the tablets are taken at the same time each day, as their effectiveness can fall if they are
taken late or missed (i.e. taken more than 12 hours late). Effectiveness can also be reduced if they are
taken in combination with other drugs that influence oestrogen/progestogen metabolism (e.g.
barbiturates, phenytoin, phenylbutazone, rifampicin, griseofulvin) or certain broad-spectrum antibiotics
that affect the gastrointestinal flora (ampicillin and tetracyclines).
Biphasic or triphasic combination tablets contain oestrogen/progestogen combination doses that vary
throughout the cycle; (this may be more suitable for some women, than the monophasic preparations).
The tablets are started on day 1 or day 5 of a period and must be taken in the correct order to be
effective (1 daily for 21 days, then 7 tablet-free [or placebo] days).

Combined oral contraceptive therapy, by providing a regular withdrawal bleed, may also be
useful for some women who normally suffer from excessively heavy, painful or irregular periods.

Mild side effects of the combined pills are mostly related to the oestrogen content and may include:
nausea, vomiting, weight gain (due to Na+/fluid retention), mild hypertension, breast tenderness, leg
pains, cramps, loss of libido, depression (may counteract effect of anti-depressant drugs), migraine-
type headache, visual disturbances, decreased tolerance to contact lenses, increased skin pigmentation
and impairment of glucose tolerance (important for diabetic patients).
 THE GONADS AND REPRODUCTION 127

The health risks associated with unwanted pregnancy resulting from unprotected intercourse
or less reliable methods of contraception are considered to be much greater than those of
combined pill therapy, particularly in less developed countries.

In very rare cases: venous thromboembolism (oestrogens increase blood coagulation), cerebral
haemorrhage/ embolism/stroke, myocardial infarction (particularly in heavy smokers over 35 years of
age) or breast/cervical cancer can occur: (the suppression of the ovarian cycle by the oral
contraceptives actually reduces the risk of developing ovarian or endometrial cancer). Withdrawal of
treatment may cause amenorrhoea in some patients; however, this should not last longer than a few
months. It is advisable to discontinue combined pill therapy prior to any major surgery, in order to
avoid the risk of thromboembolism.
The two synthetic oestrogens commonly used for oral contraception are ethinyloestradiol and
mestranol. Some currently available preparations are listed in Table 6.2.

A warning issued to doctors in October 1995 by the UK committee on safety of medicines,

indicated that the use of the newer generation combined contraceptive pills containing the
progestogens desogestrel or gestodene was associated with a twofold greater risk of developing
thromboembolisms compared with formulations containing the androgenic progestogens
levonorgestrel or norethisterone. Prescribers were advised to switch their patients to alternative
pills where possible, or where this was not acceptable, to fully explain the increased health risks
to patients before continuing treatment. Affected women also needed to be assured that the risk of
suffering thrombosis from an unplanned pregnancy was still considered to be greater than that
posed by taking COCs.
2. Oestrogen/progestogen preparations for postmenopausal HRT
Since prolonged (>1 year) unopposed exposure to oestrogens in postmenopausal women with an
intact uterus can lead to excessive endometrial stimulation (hyperplasia) and possible endometrial
cancer, it is important to include a progestogen for the last 10–14 days of every treatment cycle, in
addition to the oestrogen, as part of the HRT protocol. Synthetic progestogens such as levonorgestrel,
norethisterone, medroxyprogesterone or norgestrel are used, rather than progesterone itself, which
is metabolised too quickly to be effective (plasma half-life ca. 5 min). ‘Combined’ HRT is usually
begun as soon as possible after onset of the menopause, or in the ‘peri-menopausal’ phase (when
periods are becoming irregular) and may involve a wide range of hormone preparations, depending on
individual requirements, tolerance and preference. The usual therapy period is between 18 months-5
years, although some women persist with HRT for longer periods of time (up to 10 years or more); the
possible increased risk of developing breast cancer following long-term HRT is still controversial.
Examples of some combined HRT preparations (for women with an intact uterus) containing
oestradiol valerate or conjugated equine oestrogens with either norethisterone, levonorgestrel,
dydrogesterone, or medroxyprogesterone are listed in Table 6.3.

In sequential therapy, tablets are usually taken daily (from 28 tab. blister packs) starting with 1 oestrogen-
containing tablet/day for up to 16 days, followed by 1 combined oestrogen/progestogen-containing tablet/
day for the remaining 12 days (repeated on a monthly cyclical basis) with a regular withdrawal bleed
occurring at the end of each cycle; this may, however be unacceptable to many menopausal women
receiving HRT for the first time. Indeed, poor patient compliance in HRT is a substantial problem.
128 BASIC ENDOCRINOLOGY—CHAPTER 6

In women of 54 years of age (or at least 1 year after the last period), continuous combined HRT is
recommended, in which daily doses of oestrogen and progestogen are taken over a 25 day regimen, with no
cyclical withdrawal bleed.
Transdermal reservoir patches releasing 17β-oestradiol (50 µg/24 hr) and norethisterone (250 µg/24
hr) (Estracombi) may also be used, applied to the skin below the waistline and replaced every 3–4 days
using a different site; oestrogen-only patches are applied for 2 weeks, followed by combined patches for 2
weeks on a cyclical basis. A similar matrix patch formulation (Nuvelle TS) releasing 80 µg oestradiol/24 h
(twice weekly for 2 weeks) followed by a combined patch (delivering 50 µg oestradiol plus 20 µg
levonorgestrel/24 h, twice weekly for next 2 weeks) has also recently been introduced.
Side effects of combined HRT are similar (though less severe) to those described above for combined oral
contraceptives.

Table 6.2. Some examples of currently available oral contraceptive preparation .

Oestrogen Progestogen Brand name (UK)
Combine (monophasic) type
Ethinyloestradiol (30 µg) Norethisterone (1.5 mg) Loestrin (30)
Ethinyloestradiol (30 µg) Levonorgestrel (0.15 mg) Microgynon 30
Ethinyloestradiol (30 µg) Gestodene (75 µg) Femodene ED*
Mestranol (50 µg) Noresthisterone (1 mg) Norinyl-1
Biphasic/triphasic type
Ethinyloestradiol (35/35 µg) Norethisterone (0.5/1mg) BiNovum
Ethinyloestradiol (30/40/30 µg) Gestodene (50/70/100 µg) Triadene
Ethinyloestradiol (30/40/30 µg) Levonorgestrel (50/75/125 µg) Logynon ED*
Progestogen only
— Ethynodiol diacetate(0.5 mg) Femulen
— Levonorgestrel (30 µg) Norgeston
— Norethisterone (0.35 mg) Noriday
*28 ED (‘everyday’packs) also contain 7 inert lactose tablets.
[Compiled from MIMS, June 1997]
Oral contraceptive preparations Marketed in the USA consist of various combination of oestrogenic compounds
(ethinyloestradiol or mestranol) together with synthetic progestogens (norethindrone, norgestrel,
levonorgestrel, norgestimate desogestrel or ethynodiol diacetate). The brand names include:
Brevicon, demulen, levlen, Lo-Ovral, Modicon, Nelova, Norinyl, Nordette, Ortho-cept, Ortho-cyclen, Ortho-Novum,
Ortho-Tricyclen, Ovcon, Ovral, Tri-Levlen, Tri Norinyl and Triphasil.

Adjuctive progestogens. Progestogen-only tablets containing Norethisterone (Micronor-HRT) or

dydrogesterone (Duphaston-HRT) can be given daily with oestrogen-alone preparations on a cyclical or
continuous basis, whenever a combined HRT approach is required.
Tibolone (Livial) is a synthetic hormone derivative that possesses both oestrogenic and progestogenic (as
well as weak androgenic) activity, and has therefore been recently introduced in HRT for short-term
treatment of vasomotor symptoms resulting from the menopause, without the need for cyclical progestogen
supplements; the ‘withdrawal bleeding’ that occurs with other combination preparations is thus avoided. It
is more costly than other forms of treatment, and some androgenic side effects (hirsutism) may develop with
 THE GONADS AND REPRODUCTION 129

its use. It is not recommended for long-term protection against osteoporosis or for treatment of atrophic
vaginitis.

Progestogen Antagonist
Mifepristone (Mifegyne; RU 486) competes with progesterone for binding to cytoplasmic progesterone
receptors and thereby acts as a progestogen antagonist. It is given orally (followed in 36–48 hours by an
intra-vaginal prostaglandin pessary [Gemeprost], under careful medical supervision) as an abortifacient
agent in obstetrics to terminate intrauterine pregnancies of up to 63 days of gestation (ca. 85% effective).
Severe vaginal bleeding, nausea, vomiting and incomplete abortion may occur as side effects.

Intrauterine Devices (IUDs)

These have been use in family planning for many years, and are popular with women who require a highly
effective

Table 6.3. Some examples of currently available prepar women with an intact uterus. rations used for combined
hormone replacement therapy (HRT) for
Oestrogen Progestogen Brand name (UK)
Tablets (sequential therapy)
Oestradiol valerate (1–2 mg) Norethisterone (1 mg) Climagest
Oestradiol valerate (2 mg) Levonorgestrel (75 µg) Nuvelle
Oestradiol valerate (2 mg) Norgestrel (500 (µg) Cyclo-Progynova
Oestradiol valerate (2 mg) Dydrogesterone (10 mg) Femoston 2/10
Conjugated equine oestrogens (0.625–1.25 mg) Norgestrel (150 µg) Prempak-C
Oestradiol (2 mg)+Oestriol (1 mg) Norethisterone (1 mg) Trisequens
Tablets (Continuous therapy)
Oestradiol valerate (2 mg) Norethisterone (0.7/1 mg) Climesse
Kliofem
Conjugated oestrogens (0.625 mg) Medroxy-progesterone (5 mg) Premique
Transdermal patches
17-β-oestradiol (50 µg/24 hr) Norethisterone (250 µg/24 hr) Estracombi
17-β-oestradiol (50 µg/24 hr) Norethisterone (1 mg) Estrapak (patches and tabs)
17-β-oestradiol (80/50 µg/24 hr) Levonorgestrel (20 µg) Nuvelle TS (matrix patches)
[Compiled from MIMS, June 1997].

and continuous mode of contraception, but do not wish to use hormonal methods. Nowadays, they all
consist of a copper wire wound onto an inert polythene T-shaped carrier (with a thread attached to the base
of the stem for removal) that is inserted into the uterus under medical supervision, and changed every 3–5
years as the Cu is gradually eluted; [devices fitted in women over 40 years may be left in place until the
menopause]. The Cu wire has a silver core to avoid fragmentation (ca. 200–350 mm2 Cu surface is
exposed). Their exact mode of action in preventing conception is still unclear, but most probably involves
130 BASIC ENDOCRINOLOGY—CHAPTER 6

the induction of a local inflammatory response and alteration in enzyme activity within the uterus that
interferes with egg implantation, coupled with a direct spermicidal effect of the Cu ions.
Side effects associated with the use of IUDs include: abnormal uterine bleeding and pain, heavy
menstruation (menorrhagia), development of pelvic inflammatory disease (PID; due to transmitted infection)
or more rarely: risk of ectopic pregnancy, uterine/cervical perforation, displacement or expulsion of the
IUD from the uterus, Cu allergy and epileptic attack on insertion. The devices should be removed
immediately if accidental pregnancy occurs.
Some currently available IUDs in the UK include:
the Multiload Cu 375, Novagard, Ortho-gyne T/38o Slimline and the Nova-T.

The only Cu-containing IUDs presently marketed in the USA are the Paragard T-380A
intrauterine copper contraceptive and the Lippes Loop Double-S intrauterine device.

Progestogen-releasing IUD
A new form of intrauterine contraceptive device is now available (Mirena), consisting of a plastic T-shaped
carrier frame impregnated with a levonorgestrel/silastic mixture, designed to release 20 µg of hormone/24 hr
into the uterine cavity. Once fitted, it is effective in preventing conception for up to 3 years, mainly due to a
potent local endometrial suppression, although suppression of ovulation may also occur in some women.
Rapid return of fertility occurs after removal. It is particularly recommended for women with heavy
menstrual periods or those who require long-term contraception, but are unable or unwilling to take oral
contraceptives. Intrauterine release of levonorgestrel is also being considered as an alternative way of
adding a progestogen component to continuous HRT regimens.
Side effects (particularly during the first month of use) include: changes in menstrual pattern, headache,
acne, and nausea- declining with prolonged use. The risk of developing PID or ectopic pregnancy, is
significantly less than that associated with Cu-containing IUDs.

Pregnancy Testing
Several varieties of home pregnancy testing kit are readily available from retail pharmacy outlets, which are
relatively quick (3–5 min), easy to use and highly accurate (e.g. Clearblue One Step; First response;
Discover Today). All are based on the detection of human chorionic gonadotrophin (hCG) in a fresh
(ideally first of the day) urine sample, by means of a sensitive indicator kit; a change in colour of the
indicator generally shows a positive result. The test is normally performed on the day a period is due, with a
re-test after 3 days to confirm a negative result.
Home ovulation prediction tests (First Response; Clear Plan One Step) can also be performed on urine
samples to detect the pre-ovulatory surge in LH that occurs during the menstrual cycle, and therefore help to
pinpoint the most fertile period for conception. They are not meant to be used as a means of contraception.

Review Questions
Question 1: State the location and main functions of the gonads.
 THE GONADS AND REPRODUCTION 131

Question 2: Define the terms androgen, oestrogen, progestogen. Give examples of the naturally
secreted hormones of each group.
Question 3: Outline the structure and histology of the testes.
Question 4: State from which testicular cells testosterone is secreted.
Question 5: Describe the mechanisms controlling testosterone release.
Question 6: Summarize the main effects of testosterone:
(a) in the foetus,
(b) during puberty,
(c) in the adult.
Question 7: What is the function of müllerian inhibiting substance (MIS) during male foetal
development?
Question 8: Outline, how testosterone exerts its effects via intracellular receptors.
Question 9: Explain the importance of 5α-dihydrotestosterone (DHT) in mediating the actions of
testosterone in some tissues; how is the conversion of testosterone to DHT brought out?
Question 10: Describe the conditions that may lead to hyposecretion or hypofunction of
testosterone, and explain their consequences.
Question 11: Describe (giving named drug examples) the clinical uses for androgens:
(a) in replacement therapy,
(b) as protein anabolic agents,
(c) in breast/cervical cancer treatment.
Question 12: What general side effects would you associate with androgen therapy?
Question 13: Give examples of anti-androgenic compounds and their uses/side effects.
Question 14: What is benign prostatic hyperplasia (BPH)? How may this condition be treated?
Question 15: Outline the structure of the ovaries and ovarian follicles.
Question 16: Explain the processes of:
(a) follicular maturation under influence of LH/FSH,
(b) ovulation (after LH surge).
Question 17: State from which ovarian cells oestrogens and progesterone are secreted.
Question 18: Describe the cyclic changes occurring in the endometrium during the menstrual
cycle.
Question 19: Describe the cyclic hormonal changes that occur (a) during the menstrual cycle
(b) during pregnancy.
Question 20: Explain the significance of human chorionic gonadotrophin (hCG) as the basis of
the pregnancy test.
Question 21: What is the source and proposed role of relaxin during pregnancy?
Question 22: Outline the synthetic pathways for steroid synthesis by the maternal foetal-placental
unit.
Question 23: Give the major symptoms that may be associated with the female menopause.
Question 24: Summarize the main effects of oestrogens (a) during puberty, (b) in the adult.
Question 25: Summarize the main effects of progesterone (a) during the menstrual cycle, (b)
during pregnancy.
Question 26: Outline how oestrogens and progestogens exert their biological effects via
intracellular receptors.
Question 27: Describe the conditions leading to hyposecretion and hypersecretion of oestrogens
and their consequences.
132 BASIC ENDOCRINOLOGY—CHAPTER 6

Question 28: Describe the condition of endometriosis and its treatment.

Question 29: Give (with named examples) some clinical uses of oestrogens and progestogens
including: Oestrogen-only preparations: for (a) hormone replacement therapy (HRT). (b)
treatment of prostatic cancer, (c) post-coital contraception; Progestogen-only preparations: for (a)
treatment of menstrual disturbances. (b) oral contraception (POCs), (c) depot injections/
implants; Combined preparations: for (a) oral contraception (COCs). (b) HRT.
Question 30: Give examples of oestrogen and progestogen antagonists and their clinical uses.
Question 31: What are aromatase inhibitors? How are these drugs used clinically?
Question 32: Describe the use of combined oestrogen/progestogen preparations for oral
contraception; give examples of the types of preparation currently available and explain their
mode of action.
Question 33: List the side effects associated with the use of POCs and combined oral
contraceptive pills.
Question 34: Explain the nature and mode of action of intrauterine devices (IUD’s), and list the
side effects associated with their use.

Clinical Case Studies

Patient 1
An 18 year old boy was brought to the clinic with a history of bifrontal headaches and blurred vision of
three months duration. There was no previous medical illness. Clinical examination revealed a lack of
secondary sex characteristics (sparse axillary and pubic hair, absence of beard/moustache and chest hair,
decreased muscle mass). Examination of the eyes revealed papilloedema (swollen discs). The remainder of
the clinical examination was unremarkable. An MRI (magnetic resonance image) scan of the hypothalamic-
pituitary area showed the presence of a suprasellar mass.
Laboratory investigation revealed a normal FBC, urinalysis and blood chemistry. Hormonal studies gave
a serum testosterone level of 25 ng/dl (normal male 300–1110 ng/dl), an LH level of 3 mlU/ml (normal 4–
30 mlU/ml) and an FSH level of 2 mlU/ml (normal 4–30 mlU/ml). Serum prolactin was normal.
Question 1: What is the most likely cause of this patient’s problem?
Question 2: How is the condition diagnosed?
Question 3: What is the recommended treatment?
Answer 1: This patient has a low testosterone level, low-normal gonadotrophin levels and a lack of
secondary sexual characteristics, suggestive of hypogonadotrophic hypogonadism (secondary
hypogonadism). Broadly, hypogonadism is classified as primary (where the defect lies in the
gonads) or secondary (where the defect is in the pituitary or hypothalamus). The former is also
known as hypergonadotropic hypogonadism.
Answer 2: Diagnosis of hypogonadism is made by documentation of low gonadal sex steroid
hormone levels. Clinically, the signs of secondary sexual maturation may be lacking. Whether the
defect is primary or secondary, the sex steroid levels will be characteristically low. However in
secondary hypogonadism, treatment with gonadotrophins should raise the sex steroid level. A
decrease in circulating testosterone normally results in escape of the pituitary/hypothalamic axis
from negative feedback, leading to a rise in LH and FSH levels. Absence of such a rise, as in this
case, points to a defect in the hypothalamo-pituitary region. Blurred vision and papilloedema
 THE GONADS AND REPRODUCTION 133

(swelling of the optic disc) also suggests a hypothalamic/pituitary lesion that is compressing the
optic chiasm. An alternative cause of the patient’s hypogonadotropic hypogonadism i.e. a
prolactin-secreting pituitary adenoma (causing hyperprolactinaemia) is ruled out by the normal
serum prolactin levels.
Answer 3: Patients with secondary hypogonadism can be treated with replacement androgens and/
or gonadotrophins (Menotrophin: human menopausal gonadotrophins [hMG], LH/FSH, by
intramuscular injection) or pulsatile GnRH (subcutaneously via portable pump, provided the
pituitary gland is normal) or intramuscular human chorionic gonadotrophin (hCG; LH-like)/ hMG
combination treatment. However, when the defect is at the testicular level, replacement androgens
are the only available form of treatment, since the testes would be incapable of responding to
administered gonadotrophins.
A diagnosis of acquired hypogonadism secondary to craniopharyngioma was made, and the
patient underwent successful surgical (transsphenoidal) resection of the pituitary mass. He was
subsequently placed on androgen replacement therapy (three-weekly intramuscular injections of
testosterone enanthate) to promote normal development of sexual characteristics and muscle
mass, with additional later treatment with menotrophin to establish fertility.

Patient 2
A 32 year old female was referred to the hospital Endocrinology Department for evaluation of amenorrhoea
(absent menstruation). The patient was in good health until eight months previous, when she started noticing
scanty menstruation followed by complete cessation two months later. One year earlier, she had started
experiencing occasional episodes of hot flushes and anxiety. This had become more pronounced in the last
four months. The patient had been married for the past eight years, and had had two successful pregnancies
in this time, but reported loss of libido in the past one year. She had no other medical history. Physical
examination revealed fine wrinkles under the eyes, and a thin dry skin; the remainder of the examination
was normal.
Laboratory data indicated a serum oestradiol level of 18 pg/ml (normal >25 pg/ml) with serum levels of
LH and FSH at 57 mlU/ml and 40 mlU/ml respectively (normal female 4–30 mlU/ml for both LH and FSH).
Thyroid hormone levels were normal, and she did not test positive for thyroid antibodies; serum prolactin
measurement also revealed a normal level. There was no evidence of adrenal insufficiency or diabetes
mellitus.
Question 1: Based upon the patient’s history, physical examination and laboratory data, what is
the most likely diagnosis of her condition?
Question 2: How may this condition arise?
Question 3: What would be the recommended therapy for this patient?
Answer 1: This case is characterized by a low oestrogen level, associated with increased levels of
gonadotrophins (hypergonadotropic hypogonadism), suggesting the ovaries as the most likely
target of dysfunction. Usually, this hormonal pattern, coupled with amenorrhoea, hot flushes of
the skin and anxiety, is only seen at the time of the menopause.
Answer 2: The patient is most likely suffering from a premature ovarian failure (POF), leading to
secondary amenorrhoea; [this refers to individuals who once menstruated, but subsequently
stopped menstruating; primary amenorrhoea refers to patients who have never menstruated]. In
about 20% of cases of POF, the condition is due to specific autoimmune disease, accompanied by
the presence of serum antiovarian antibodies (causing accelerated oocyte degeneration) or it may
134 BASIC ENDOCRINOLOGY—CHAPTER 6

be part of a polyglandular autoimmune syndrome, where the thyroid, adrenal glands and pancreas
are also affected. Most commonly, abnormal thyroid function may be detected, hence the need to
check thyroid hormone levels and thyroid antibodies. Classically, ovarian failure precedes adrenal
failure, and a case can be made for continuing adrenal surveillance.
Answer 3: Ovulation can sometimes be temporarily restored with oral corticosteroid treatment
however, in general the return of normal menses (and fertility) is unlikely. In this case, the
clinical symptoms of hypogonadism and the long-term risk of osteoporosis warrant hormone
replacement therapy (HRT). Since the uterus is intact, oestrogens should be cycled with
progestogens to induce regular withdrawal menstruation (artificial periods) and to avoid
endometrial hyperplasia.

UK/USA Drugs—Trade names

UK USA
Androgens
Testosterone enanthate Primoteston Depot Delatestryl
Testosterone cypionate Depo-Testosterone
Virilon IM
Testosterone (transdermal delivery) Andropatch Testoderm
Androderm
Fluoxymesterone Halotestin
Methyltestosterone Testred
Orethon Methyl
Nandrolone Deca-Durabolin Durabolin
Stanozol Stromba Winstrol
Oxymetholone Anadrol 50
Anti-androgens and gonadotrophin release inhibitors
Cyproterone acetate Androcur [Not approved for use in the USA]
Flutamide Drogenil Eulexin
Danazol Danol Danocrine
Oestrogens
17β-Oestradiol Zumenon Emcyt
Estrace
Piperazine oestrone sulphate [Estropipate] Harmogen Ortho-Est
Esterified oestrogens (mixture of sodium salts of Estratab
sulphate esters of oestrogens, mainly oestrone) Menest
Esterified oestrogens plus methyltestosterone Estratest
Oestrogen antagonists
Clomiphene Clomid Serophene
Tamoxifen Tamofen, Noltam Nolvadex
Progestogens
Medroxyprogesterone Provera Provera
Depo-Provera Depo-Provera
Norethindrone Norlutin
 THE GONADS AND REPRODUCTION 135

UK/USA Drugs—Trade names

Gonadotrophins (injectable)
Urofollitrophin (FSH) Metrodin Metrodin
Human Chorionic Gonadotrophin (hCG) Profasi Profasi
Pregnyl

References

Books

• Braunstein GD. (1994). Testes. In Basic & Clinical Endocrinology, edited by FS Greenspan, JD Baxter, 4th ed.
Appleton & Lange, Connecticut, pp. 391–418
• Ganong WF. (1995). The gonads: development & function of the reproductive system. In Review of Medical
Physiology, 17th ed. Appleton & Lange, Connecticut, pp. 379–417
• Genuth SM. (1993). The reproductive glands. In Physiology, edited by RM Berne, MN Levy, 3rd ed. Mosby-Year
Book Inc., USA, pp. 980–1024
• Goldfien A, Monroe SE. (1994). Ovaries. In Basic & Clinical Endocrinology , edited by FS Greenspan, JD Baxter,
4th ed. Appleton & Lange, Connecticut, pp. 419–470
• Goodman HM. (1988). Basic Medical Endocrinology. Raven Press, New York, Chapters 11–12, pp. 253–302
• Goldfein A. (1989). The gonadal hormones and inhibitors. In Basic and Clinical Pharmacology, edited by BG
Katzung. Appleton & Lange, Connecticut, pp. 493–516
• Griffin JE, Wilson JD. (1987). Disorders of the testes/disorders of the ovary and female reproductive tract. In
Harrison’s principles of internal medicine, edited by E Braunwald, KJ Isselbacher et al, 11th ed. McGraw-Hill,
Inc., USA, Chapters 330–331, pp. 1807–1837
• Griffin JE. (1992). Male reproductive function. In Textbook of Endocrine Physiology, edited by JE Griffin, SR Ojeda,
2nd ed. Oxford University Press, New York, pp. 169–188
• Harvey RA, Champe PC. et al. (1992). Steroid hormones. In Lippincott’s Illustrated Reviews: Pharmacology. JB
Lippincott Company, USA, pp. 243–252
• Hedge GA, Colby HD, Goodman RL. (1987). Endocrine systems. In Clinical Endocrine Physiology. WB Saunders
Co., Philadelphia, Chapters 8–9, pp. 161–221
• Junqueira LC, Carneiro J, Long JA. (1986). The male/the female reproductive systems. In Basic Histology, 5th ed.
Lange Medical Publications, Connecticut, Chapters 23–24, pp. 468–512
• Laurence DR, Bennett PN. (1992). Endocrinology IV: hypothalamic and pituitary hormones, sex hormones,
contraception, uterus. In Clinical Pharmacology. Churchill Livingstone, pp. 591–614
• Laycock J, Wise P. (1983). The gonads. In Essential Endocrinology, 2nd ed. Oxford University Press, Oxford,
pp. 123–192
• Martin J. (1991). Contraception. In Handbook of Pharmacy Health Education. The Pharmaceutical Press, Chapter 4,
PP. 73–97
• Nachtigall RD. (1992). Female reproductive disorders. In: Handbook of Clinical Endocrinology, edited by PA
Fitzgerald, 2nd ed. Prentice-Hall, USA, pp. 402–462
• Ojeda SR. (1992). Female reproductive function. In Textbook of Endocrine Physiology, edited by JE Griffin, SR Ojeda,
2nd ed. Oxford University Press, New York, pp. 134–168
• Rang HP, Dale MM, Ritter JM. (1995). The reproductive system. In Pharmacology, 3rd ed. Churchill Livingstone,
pp. 454–474
136 BASIC ENDOCRINOLOGY—CHAPTER 6

• Sharlip ID. (1992). Male reproductive disorders. In Handbook of Clinical Endocrinology, edited by PA Fitzgerald,
2nd ed. PrenticeHall, USA, pp. 352–400
• West JB. (1991). The testis/the female reproductive system. In Best and Taylor’s Physiological Basis of Medical
Practice, 12th ed. Williams & Wilkins, Baltimore, Chapters 58–59, pp. 849–873
• Williams CL. & Stancel GM. (1996). Estrogens and progestins. In Goodman d[Gilman’s The Pharmacological Basis
of Therapeutics, edited by JG Hardman, LE Limbird, A Goodman Gilman et al., 9th ed. McGraw-Hill, USA,
pp. 1411–1440
• Wilson JD. Androgens. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics, edited by JG Hardman,
LE Limbird, A Goodman Gilman et al., 9th ed. McGraw-Hill, USA, pp. 1441–1457

Journal Articles

• Adashi EY. (1994). Endocrinology of the ovary. Hum Reprod, 9, 815–827

• Baird DT. (1993). Antiestrogens. Br Med Bull, 49, 73–87
• Craig Jordan V. (1993). A current view of tamoxifen for the treatment and prevention of breast cancer. BrJ
Pharmacol, no, 507–517
• Gevers Leuven JA. (1994). Sex steroids and lipoprotein metabolism. Pharmac Ther, 64, 99–126
• Glasier A. (1994). How and when to use postcoital contraception. Prescriber, 5(18), 59–63
• Hampton N. (1994). Hormonal contraceptives: their properties and uses. Prescriber, 5(12), 35–46
• Huhtaniemi I. (1994). Anabolic-androgenic steroids-a double edged sword? Int J Androl, 17, 57–62
• Hillier SG. (1994). Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in
folliculogenesis. Hum Reprod, 9, 188–191
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• Knight PG. (1996). Roles of inhibins, activins and follistatin in the female reproductive system. Frontiers in
Neuroendocrinol, 17, 476–509
• Kubba A, Guillebaud J. (1993). Combined oral contraceptives: acceptability and effective use. Br Med Bull, 49,
140–157
• Lee MM, Donahoe PK. (1993). Mullerian inhibiting substance: A gonadal hormone with multiple functions.
Endocrine Rev, 14, 152–164
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• Naftolin F. (1994). Brain aromatization of androgens. J Reprod Med Obst Gynecol, 39, 257–261
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Fertil Steril, 59, 277–284
• Spitz IM, Bardin CW. (1993). Clinical pharmacology of RU 486-an antiprogestin and antiglucocorticoid.
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• Thorogood M, Villard-Mackintosh L. (1993). Combined oral contraceptives: risks and benefits. Br Med Bull, 49,
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• Smith C. (1994). Norplant: a long-term hormonal contraceptive. Prescriber, 5(10), 19–23
• Webb A. (1997). A GP guide to non-oral methods of contraception. Prescriber, 8(4), 37–58
• Woodruff TK, Mather JP. (1995). Inhibin, activin and the female reproductive axis. Annu Rev Physiol, 57, 219–244
 7
The Parathyroid Glands, Vitamin D and Hormonal Control
of Calcium Metabolism

Calcium ions (Ca2+) are necessary for bone and teeth formation, normal skeletal and smooth muscle
function, cellular division adhesion and growth, blood coagulation, and for the normal activity of many
intracellular enzymes. Calcium is also important for maintaining the activity of excitable tissue (acting as a
membrane ‘stabilizer’) and is involved in neuromuscular transmission, cellular hormone release (stimulus-
secretion coupling), and in the normal functioning of the heart.
The concentration of total extracellular calcium in the plasma is maintained within narrow limits (2.2–2.
67 mmol/ l; 8.4–10.7 mg/dl). By contrast, the cytosolic Ca2+ concentration is maintained at a very low level
(10–100 nmol/l) by the active pumping of Ca2+ from the cytosol, and by uptake into mitochondria and the
endoplasmic reticulum.
Plasma calcium exists in three forms:

1. Free ionized (50%). This is the metabolically and physiologically active form (ca. 1–1.4 mmol/l)
2. Protein bound (45%)—mainly to albumin and globulins
3. Complexed with several anions (5%) e.g. bicarbonate, citrate, phosphate and sulphate.

This distribution is influenced by the pH of the plasma, with a low plasma pH (acidosis) increasing free
ionized calcium and vice versa.
Dietary calcium is mainly derived from white bread and dairy products such as milk, cheese and eggs.
The calcium level of the body is influenced by dietary intake (ca. 1g/day) and by the regulatory activity of
three principal hormones, acting on bone, kidney and the intestinal tract (Figure 7.1):

1. Parathyroid Hormone—secreted by the parathyroid glands

2. Calcitonin—secreted by thyroid parafollicular ‘C’ cells
3. 1α, 25-Dihydroxycholecalciferol—a metabolite of Vitamin D.

Most (99%) of the body calcium is stored in bone. A fraction of this (readily exchangeable or labile pool) may
be rapidly mobilized when necessary. Metabolism of phosphate (in the form of , and ),
although not as finely controlled, is closely linked with that of calcium. Phosphate is necessary for the
synthesis of many important molecules in the body e.g. nucleic acids (DNA, RNA), ATP, cAMP,
membrane phospholipids (phosphatidylcholine) and is also an essential component of bone (as calcium
phosphate and complex hydroxyapatite salts, containing calcium, phosphate and water). The normal plasma
phosphate in adults is within the range 0.8–1.5 mmol/l (2.5–4.8 mg/dl).
138 BASIC ENDOCRINOLOGY—CHAPTER 7

The Parathyroid Glands

Structure and Histology

The parathyroid glands, consist of four ovoid-shaped bodies, each the size of a pea, embedded posteriorly
in the four poles of the thyroid gland, within the thyroid capsule. Each gland is composed of densely packed
epithelial cells of two distinct types, the chief cells and the oxyphil cells, surrounded by a thin layer of
connective tissue. The chief cells are small and more numerous, with a clear cytoplasm containing small
dense granules; these cells secrete parathyroid hormone, which regulates calcium and phosphate
metabolism. The oxyphil cells are larger with a less granular cytoplasm, and have no known hormonal
function.

Parathyroid Hormone
Parathyroid hormone (PTH) is an 84 amino acid linear peptide derived sequentially from larger precursor
polypeptides, prepro-PTH and pro-PTH respectively. Following release, PTH is cleaved mainly by liver
and kidney cells (plasma half-life ca. 2–5 min) to yield an active N-terminal portion containing the first 34
amino acids (residues 1–27 are essential), and an inactive C-terminal fragment; some cleavage also occurs
within the parathyroid gland. The structure of human PTH is very similar to that of porcine or bovine PTH.

Control of Release
Unlike other endocrine hormones, PTH secretion is not controlled by the anterior pituitary gland: its
secretion from parathyroid chief cells is determined by the circulating blood level of ionized Ca2+. A low
plasma Ca2+ concentration directly stimulates PTH release by the parathyroid glands, and a high level
suppresses it (negative feedback). The latter effect is opposite to the more general effect of intracellular Ca2
+ in promoting cellular hormone release, and is believed to involve a G-protein coupled cell-surface

receptor for Ca2+ (CaR1). Plasma Mg2+ has a similar, though weaker effect than Ca2+ on PTH secretion; the
physiological relevance of this, however, is uncertain. Plasma phosphate levels have no direct effect on
parathyroid PTH secretion. [The active vitamin D metabolite 1,25.(OH)2D3 (see below) can, however,
reduce PTH production by the parathyroid glands].

Principal Actions
The principal action of PTH is to increase plasma ionized calcium concentration: it is a Ca2+-raising factor.
This is achieved by influencing bone and renal tubular reabsorption of Ca2+, and by increasing intestinal
absorption. Plasma phosphate levels are lowered by PTH.
The main actions of PTH may be summarized as follows:

1. In the kidney, PTH causes a rapid increase in distal tubular reabsorption of Ca2+ (and Mg2+) from the
glomerular filtrate, and increases the excretion of phosphate in the urine (i.e. phosphate reabsorption
via a Na+/phosphate-cotransport mechanism in the proximal tubule is inhibited: the phosphaturic
effect). Plasma Ca2+ concentration is therefore increased, while the plasma phosphate level falls. PTH also
promotes the formation of the active vitamin D metabolite 1α, 25-dihydroxycholecalciferol (1,25-(OH)
2+ from bone and
2D3) within the kidney tubular cells, which in turn, facilitates the release of Ca
 HORMONAL CONTROL OF CALCIUM METABOLISM 139

Figure 7.1. Calcium homeostasis. Major hormonal factors involved in the control of the plasma Ca2+ level, and their
effects on the three principal target organs (bone, small intestine and kidney). Parathyroid hormone (PTH) and vitamin
D (as 1,25-(OH)2 vitamin D3) stimulate bone resorption and reabsorption of Ca2+ from the renal tubular fluid and small
intestine, whereas calcitonin (CT) inhibits bone resorption and kidney reabsorption of Ca2+ with little effect on
intestinal Ca2+ absorption. PTH stimulates gut absorption of Ca2+ indirectly, by stimulating the renal conversion of
vitamin D to its active metabolite 1,25-(OH)2 vitamin D3.

enhances the rate of absorption of Ca2+ from the small intestine and the kidney. Synthesis of 1,25-(OH)
2D3 is mediated through stimulation of the renal mitochondrial enzyme 25-hydroxyvitamin D-1α-
hydroxylase.
2. On bone, PTH has a dual action: it stimulates the rapid efflux of Ca2+ from the labile calcium pool
across the osteocyte-osteoblast bone membrane (see below) into the extracellular fluid (facilitated by 1,
25-(OH)2D3); it also stimulates osteodast bone cells (indirectly) to release calcium (and phosphate) by a
slower process of bone dissolution or resorption, and increases the number of osteoclasts involved in this
process. Eventually, osteoblast cells are also stimulated to synthesize new bone matrix.
3. On the gastrointestinal tract, PTH stimulates intestinal absorption of Ca2+ and phosphate indirectly.
This effect (requiring 24 hours or longer) is mediated by the vitamin D metabolite 1,25-(OH)2D3 and is
therefore absent in vitamin D-deficient states. PTH stimulates the activity of the enzyme 1α-
hydroxylase involved in the production of 1,25-(OH)2D3 in the kidney (see below).
140 BASIC ENDOCRINOLOGY—CHAPTER 7

Bone Cells Affected by Parathyroid Hormone

The two principal cell types in bone are osteoblasts and osteoclasts. Osteoblasts are specialized fibroblast-
like cells (derived from marrow osteoprogenitor cells) responsible for new bone formation, by secreting
type I collagen and glycoproteins into the extracellular space to form osteoid, which then calcifies to form
an organic matrix containing initially, calcium phosphate (as CaHPO4.2H2O), and later, crystals of
hydroxyapatite [Ca10(PO4)6(OH)2] (mineralization). Osteoblasts that become entirely surrounded by
mineralized bone are termed interior osteocytes; these cells maintain cytoplasmic contact with each other
and with active osteoblasts via gap junctions (forming a ‘bone membrane’). The enzyme alkaline
phosphatase (believed to be important for normal bone mineralization), is present in osteoblast cells and
appears in the plasma as a measure of osteoblastic activity.
Osteoclasts, on the other hand, are larger multinucleated cells (of haemopoietic origin) lining the bone-
forming surface of bone tissue, that are capable of digesting previously formed bone matrix to release
calcium and phosphate into the extracellular bone fluid (bone resorption); bone absorption occurs beneath
the ruffled border area of the osteoclast, which releases hydrolytic enzymes (collagenase and proteinases) as
well as protons. The slow continual (cyclic) process of resorption (lasting 2–4 weeks) is followed by new
matrix deposition and mineralization (bone formation; lasting 3–7 months), so that total bone mass remains
constant; this is known as bone remodeling (Figure 7.2) and is important for maintaining normal bone
strength, repairing microfractures incurred during normal use, and for preserving calcium homeostasis. The
sites on the bone surface at which remodeling occurs are termed basic multicellular units (BMUs). It has
been suggested that only osteoblast cells respond to PTH directly, and that the effects of PTH on osteoclast
bone resorption are mediated indirectly through the release of cytokines (particularly interleukins-1, and 6
[IL-1, IL-6] and granulocyte macrophage-colony stimulating factor [GM-CSF]) which are responsible for
activation and for differentiation of osteoclasts from precursor cells.

Recently, a group of low molecular weight glycoproteins, bone morphogenic proteins (BMPs 2–
8), belonging to the transforming growth factor-β (TGF-β) superfamily of regulatory proteins, have
been isolated from bone matrix; [BMP-7 (also known as osteogenic protein-1: OP-1) is actually
synthesized within the kidney]. These molecules promote osteoblast and collagen cell (chondrocyte)
differentiation from mesochymal stem cells, and may play an important role in cartilage and bone
formation during embryonic development. Local implants containing recombinant human BMP7
(hBMP7) could prove useful in the future, for treating severe bone defects and for repairing tooth
interiors.

Mechanism of Action
The effect of PTH on renal tubular and bone cell activity is believed to be mediated mainly via stimulation
of specific plasma membrane receptors coupled through a G-protein to adenylate cyclase and a consequent
rise in intracellular cAMP and cytosolic Ca2+; [an increased urinary excretion of cAMP occurs in direct
response to PTH]. Activation of other second messenger pathways (e.g. involving phospho-inositide
metabolism, with production of inositol trisphosphate [IP3 and diacylglycerol [DAG]) may also be involved
in PTH actions.

A parathyroid hormone-related protein (PTHrP), secreted by a wide range of normal and

malignant tissues, can also interact with the same membrane receptors as PTH in bone and kidney,
and is believed to be responsible for the condition of humoral hypercalcaemia of malignancy (HHM)
 HORMONAL CONTROL OF CALCIUM METABOLISM 141

Figure 7.2. Bone remodeling by osteoblastic and osteoclastic cell activity. Osteoclosts are responsible for bone
breakdown and de-mineralization (resorption) of mature bone, whereas osteoblasts form new bone and mineralize it.
Parathyroid hormone (PTH) and 1,25-(OH)2 vitamin D3 stimulate osteoclastic bone resorption indirectly by facilitating
release of osteoblastic cytokines (IL-6; GM-CSF), whereas calcitonin has a direct inhibitory effect on osteoclast activity.
The inhibitory effects of oestrogens on resorption are thought to be mediated indirectly via inhibition of osteoblastic
cytokine (IL-6) release.

that can occur in ca. 10% of cancer patients (particularly with lung or breast carcinomas). PTHrP
shares limited sequence homology with the 1–34 amino acid region of PTH. Recent studies also
suggest that circulating PTHrP may have an important bone calcium mobilizing effect in the course of
lactation, as well as other paracrine and/or autocrine effects independent of PTH receptor activation;
[the PTHrP molecule can be post-translationally cleaved to yield a complex family of biologically
active peptides].

Clinical Disorders

Hypersecretion (Hyperparathyroidism)
Primary hyperparathyroidism is a fairly prevalent, and slowly developing condition that is about 2–3
times more common in adult women than in men. The excess secretion of PTH causes hyperclacaemia and
phosphaturia (excess loss of phosphate in the urine) resulting in a low plasma phosphate level
(hypophosphataemia); a raised level of urinary cAMP may also be present. The disorder may be caused by
a single chief cell tumour (adenoma) or enlargement of one or all four of the parathyroids (hyperplasia) or
142 BASIC ENDOCRINOLOGY—CHAPTER 7

by a parathyroid carcinoma (rare). Hyperparathyroidism may also be associated with a more general
inherited endocrine syndrome —multiple endocrine neoplasia type 1 (MEN-1 disease) also known as multiple
endocrine adenomatosis (MEA), involving many endocrine glands (e.g. pancreas, pituitary, adrenal or
thyroid).
A secondary overactivity and hyperplasia of all four parathyroids (not associated with hypercalcaemia)
can also develop as a compensatory response to longstanding hypocalcaemia due to intestinal calcium/vitamin
D malabsorption (or deficiency) or chronic renal failure. PTH levels remain elevated until the cause of the
hypocalcaemia can be corrected. Mild hyperparathyroidism may produce few clinical signs initially;
however, chronic PTH excess may result in symptoms directly attributable to the elevated blood calcium
level.
The main symptoms of hyperparathyroidism include:

1. Tiredness, general malaise, depression, weakness, lethargy, dizziness, excessive thirst, anorexia, nausea,
vomiting and dehydration (due to excessive loss of urine), psychiatric disorders (depression, paranoia),
cardiac arrhythmias (shortened QT interval on EGG recordings) and possible heart block. Anaemia and
hypertension may be seen in some cases.
2. Renal stones (calculi) made from insoluble calcium phosphate (or oxalate), due to increased urinary
excretion of Ca2+ and phosphate; this may cause renal colic and haematuria (appearance of blood in the
urine), eventually leading to renal failure. Gallstones may also occur.
3. Gastrointestinal complaints: abdominal pain, constipation, dyspepsia, peptic and duodenal ulceration.
4. Bone lesions due to generalized loss (resorption) of calcium from bone. In severe cases, osteitis fibrosa
(bone cysts) accompanied by bone pain and increased incidence of fractures can occur.
Hyperparathyroidism has been described as a disease of ‘bones, stones and abdominal groans.

Treatment. This is by careful surgical removal of the overactive parathyroid tissue (subtotal
parathyroidectomy), although some tumours can be extremely difficult to locate (ectopic—at other sites).
Parathyroid carcinomas can also be treated by local excision; however, postoperative persistence of
hyperparathyroid symptoms or development of permanent hypoparathyroidism (with hypocalcaemia) are
common. In rare instances, inadvertent damage to the recurrent laryngeal nerves may occur. Recurrence of
the hyperparathyroid condition may require further surgery.
Severe hypercalcaemia (hypercalcaemic crisis) can be corrected by immediate administration of oral or
intravenous rehydration fluids (normal saline solution) together with a loop diuretic (e.g. frusemide) to
increase urinary Ca2+ excretion; additional administration of salmon calcitonin (Salcatonin; Calsynar) (by
subcutaneous or intramuscular injection) or slow intravenous infusion of disodium pamidronate (Aredia)
(see below) to inhibit bone resorption may be necessary in some patients.
Future development of selective inhibitors of PTH action could provide a novel form of treatment for
acute hyper-parathyroidism.

Hyposecretion (Hypoparathyroidism)
Lack of PTH causes hypocalcaemia and a high blood phosphate level (hyperphosphataemia) due to
increased reabsorption of tubular phosphate. The most common cause is accidental damage of the
parathyroids during thyroid surgery (surgical hypoparathyroidism; see Chapter 4). A rare form of primary
(idiopathic) hypoparathyroidism can also result from autoimmune disease, usually co-existing with other
organ-specific endocrine autoimmune disorders (e.g. adrenal insufficiency, hypothyroidism, type I
diabetes); such individuals may possess specific serum antibodies directed against their parathyroid tissue.
 HORMONAL CONTROL OF CALCIUM METABOLISM 143

In the unusual hereditary condition of pseudohyper-pamthyroidism, parathyroid function is normal,

but the primary target tissues (bone and kidney) are insensitive to the actions of PTH (‘end-organ’
resistance); this has been linked to a deficiency in the α-subunit structure of the stimulatory Gs-protein
complex involved in PTH receptor transduction. Apart from a low plasma calcium level (ranging from
mild to severe), affected patients show a characteristic rounded face, short stature, obesity, short
fingers and may be mentally retarded.

A persistent low plasma calcium level can induce;

1. Hyper-excitability of nerve and neuromuscular tissue, characterized by a tingling sensation

(paraesthesia: ‘pins and needles’) in the face or fingers, muscle cramps and spasms (particularly in the
hands and feet) leading to hypocalcaemic tetany and even epileptic seizures/convulsions. A prolonged
QT interval may be revealed on EGG recordings.
2. Chvostek’s sign—a twitching of the facial muscles following light tapping over the facial nerve, and
Trousseau’s sign—a characteristic tetanic spasm of the wrist and fingers following over-inflation of a
sphygmomanometer cuff placed over the upper arm for more than three minutes.
3. Dental abnormalities, dry scaly skin and hair, brittle nails and cataracts may also be present in more
chronic persistent cases.

Treatment. Depending on the severity of the hypocalcaemia, this requires administration of vitamin D
supplements in the form of calciferol tablets (vitamin D2) or an oral solution of the vitamin D derivative
dihydrotacysterol (AT 10) to enhance calcium absorption and utilization (see below); this must be coupled
with frequent serum and urinary calcium measurements to ensure that overtreatment and consequent
hypercalcaemia does not occur. Careful dose adjustment should then be made in order to maintain a normal
blood calcium level. In acute cases of hypocalcaemic tetany, a more rapid elevation in blood calcium may
be achieved by means of an intravenous infusion of 10% calcium gluconate solution given over 10 mins or
longer as needed to counteract symptoms. PTH itself is not available for replacement therapy.

Calcitonin
Calcitonin (CT) is a 32 amino acid single-chain peptide hormone secreted by the parafollicular ‘C’ cells of
the thyroid gland (see Chapter 4). It is derived from larger precursor peptides pre-procalcitonin and
procalcitonin respectively, and stored in secretory vesicles within the parafollicular cells from which it is
released by exocytosis [some procalcitonin and a dimeric form of calcitonin are also released, both being
inactive]. The entire amino acid sequence of the molecule is required for significant biological activity,
although interestingly, the structures of human and animal (porcine, bovine, ovine) calcitonins vary
considerably (by up to 19 amino acids). The fish and avian calcitonin molecules show the highest degree of
activity compared with other calcitonins.

Control of Release
The main factor involved in regulating calcitonin release from ‘C’ cells is the free ionized Ca2+
concentration in the blood. A rise in plasma Ca2+ stimulates calcitonin release, and vice versa [note the
opposite effect of Ca2+ on PTH secretion]. Release of calcitonin is also promoted by the gastrointestinal
hormone gastrin, which could be an important feedback mechanism guarding against the development of
144 BASIC ENDOCRINOLOGY—CHAPTER 7

hypercalcaemia following a meal. The plasma half-life of calcitonin is relatively short (2–15 min) due to
rapid degradation of the peptide in the plasma and kidney.

Principal Actions
Unlike PTH, calcitonin is a Ca2+-lowering factor; it decreases plasma calcium (and phosphate) levels
principally by:

1. Decreasing the efflux of Ca2+ across the osteocyte-osteoblast bone membrane and also by inhibiting
bone resorption through a direct suppression of osteoclast bone cell activity and a decreased formation
of new osteoclasts from bone marrow precursors. The effects of calcitonin are greater when the rate of
bone resorption is high.
2. Inhibiting renal tubular reabsorption of calcium and phosphate (from ascending loop of Henle and
distal tubules). Calcitonin has no significant effect on intestinal Ca2+ fluxes.

Although these effects are generally opposite to those of PTH (physiological antagonism), calcitonin is not
considered to be as important as PTH and vitamin D in the normal regulation of calcium or skeletal
homeostasis in humans. Calcitonin affects target tissues (e.g. osteoclast cells) by interacting with specific
surface membrane receptors linked to the production of intracellular cAMP. The areas of the kidney tubule
that respond to calcitonin are different from those responding to PTH.

Clinical Disorders
Clinical disorders involving calcitonin under or over secretion are very rare. Excessive secretion of
calcitonin (together with some dimeric and polymeric molecular forms) can however, be produced by
certain medullary thyroid carcinomas (derived from parafollicular ‘C’ cells) or by ectopic tumours (e.g. in
the lung or breast). In such cases, there is no significant imbalance in plasma calcium and phosphate levels,
but the excess calcitonin can be useful as a tumour marker. Similarly, removal of the thyroid gland in
thyrotoxicosis, does not result in overt hypercalcaemia.

Therapeutic Uses
The two main therapeutic uses of calcitonin are in the treatment of severe Paget’s disease of bone and the
management of severe hypercalcaemic states:

1. Paget’s disease is a common chronic disorder of unknown cause (possibly viral) that affects ca. 0.5%
of the population (particularly men) over the age of 40. It is characterized by an abnormally high level
of bone turnover due to excessive osteoclastic bone resorption, followed by increased activity of
osteoblasts, attempting to repair the bone damage. The affected bones (usually the skull, spine, pelvis
and long bones) ultimately become deformed and show an abnormal density under X-ray. Despite the
increased bone turnover, the condition is initially largely asymptomatic; plasma Ca2+ and phosphate
levels are normal, although an elevated level of alkaline phosphatase (reflecting osteoblastic cell
activity and bone turnover) may be present.
 HORMONAL CONTROL OF CALCIUM METABOLISM 145

Clinical features include: joint and bone pain, fractures, bone deformities—particularly affecting the
legs (‘bowed’ tibia), and skull enlargement, leading to auditory and optic nerve compression (deafness/
blindness).
Porcine calcitonin (from pork parathyroids: Calcitare) or salcatonin (synthetic salmon calcitonin:
Miacalcic; Calsynar, expensive!) may be given daily by subcutaneous or intramuscular injection over
3–6 months to reduce bone resorption, improve bone abnormalities and relieve the bone pain and
neurological complications associated with the disease; nausea and facial flushing can occur as side
effects. Prolonged use may also result in neutralizing antibodies against calcitonin being formed
(salcatonin is less immunogenic).

Other drugs (bisphosphonates; analogues of pyrophosphate, a natural inhibitor of bone

mineralization) are also available for treatment of Paget’s disease of bone; these compounds
reduce osteoclastic bone resorption by a dual mechanism: they are adsorbed strongly onto bone
hydroxyapatite crystals (especially at bone remodeling sites) and slow their rate of formation and
dissolution, and they also inhibit osteoclast cell activity indirectly, by decreasing the production of
osteoclast-stimulating factors by osteoblasts. Disodium etidronate (Didronel) tablets may be
given daily for 3–6 months (avoiding food two hr before or after taking doses). Unwanted effects
are few and include: nausea, diarrhoea and a temporary metallic/altered taste sensation.
Oral disodium etidronate (Didronel PMO), alternating with a calcium carbonate supplement,
taken on an intermittent cyclical basis (two weeks etidronate. 76 days calcium every three
months, for up to 3 years) or subcutaneous salcatonin [expensive!] (daily, together with dietary
calcium and vitamin D supplements for 2–3 years) have been found effective in increasing bone
mineral content and preventing excessive bone loss in established postmenopausal vertebral
osteoporosis: (see below) [useful for patients that are unable or unwilling to take HRT;
Chapter 6]. A recently introduced (more potent) oral bisphosphonate sodium alendronate
(Fosamax) can be administered continuously (with calcium supplementation) for this purpose,
with no restriction on the duration of treatment. Intranasal preparations of salcatonin are
available in the USA (Miacalcin) and in some European countries, but not currently in the UK.
2. Hypercalcaemic states. Porcine calcitonin or salcatonin (subcutaneous or intramuscular) can be used to
produce a rapid (within 24 hr) reduction in the plasma Ca2+ concentration in some patients with
hypercalcaemia (particularly when induced by malignant disease: see above). In severe cases, a slow
intravenous infusion of salcatonin may be given. Long-term use of calcitonin or salcatonin over several
months can however, lead to clinical resistance due to a down-regulation of calcitonin receptors on
target tissues and (in the case of the former), the development of neutralizing plasma antibodies.
Slow intravenous infusion of bisphosphonate drugs e.g. disodium pamidronate (Aredia) or sodium
clodronate (Loron; Bonefos) are also now widely used in the control of tumour-induced
hypercalcaemia of malignancy.

Vitamin D
This term describes a group of essential fat soluble sterols with a steroid-like structure, which can influence
calcium and phosphate metabolism. Although traditionally regarded as a vitamin (essential food nutrient), it
is more correctly classified as a hormone, since it can be produced endogenously in small amounts within
one organ and travels via the blood to affect the activity of cells at distant sites. Vitamin D ingested from
dietary sources or synthesized in the skin after sunlight exposure is biologically inert, and must undergo
146 BASIC ENDOCRINOLOGY—CHAPTER 7

successive transformation in the liver and kidneys to produce an active form 1α,25-dihydroxychole-
calciferol (1,25-(OH)2D3) before being released into the bloodstream to affect a wide variety of target
tissues — principally the small intestine, bone and kidney. Other target tissues include the brain, bone
marrow, lymphocytes, spinal cord, endocrine pancreas and other endocrine cells, skin keratinocytes, breast
tissue, and the male and female reproductive organs; however, the physiological relevance of vitamin D
action at many of these sites is not yet entirely clear.

1,25-(OH)2D3 is known to be a potent stimulator of cell differentiation and an inhibitor of

proliferation, and may therefore be important in the growth and development of certain tissues,
particularly immune cells and keratinocytes. In addition there is increasing evidence favouring a role
for vitamin D in the modulation of seasonal and daily (light-driven) biorhythms (unrelated to its
effects on calcium homeostasis) through its effects on the brain and endocrine tissues.

Vitamin D is found mainly in two forms:

1. Vitamin D2 (calciferol; ergocalciferol), a plant-derived vitamin, produced by solar ultraviolet light

irradiation of a plant sterol (ergosterol) and contained in most clinically available preparations.
2. Vitamin D3 (cholecalciferol), the natural animal vitamin D, synthesized within the skin of man and
higher mammals from an inactive precursor 7-dehydrocholesterol (provitamin D3) by the ultraviolet
effect of sunlight (300– 320 nm wavelength). To become active, it is first hydroxylated in the liver to
25-hydroxy-cholecalciferol (25-(OH)D3) and then to the active form 1α,25-dihydroxychole-calciferol
(1,25-(OH)2D3; calcitriol) in the proximal convoluted tubules of the kidneys, under the influence of
parathyroid hormone; [some production of 1,25-(OH)2D3 from 25-(OH)D3 also takes place in the
skin]. 1,25-(OH)2D3 is also often referred to as soltriol or the ‘heliogenic’ steroid hormone. 1,25-(OH)
2D3 can regulate its own production by inhibiting the renal 25-hydroxyvitamin D-1α-hydroxylase
enzyme activity and also by inducing kidney 24-hydroxylase enzyme activity to yield the weakly active
metabolite 24,25-(OH)2D3 (Figure 7.3). Phosphate depletion also stimulates 1-α-hydroxylase activity,
leading to an increased formation of 1,25-(OH)2D3.
1,25-(OH)2D3 is transported in the blood largely bound to a specific vitamin D-binding α-globulin,
transcalciferin (which can also bind vitamin D3 and 25-(OH)D3), secreted mainly by the liver; as with
other steroidal hormones (see Chapters 3 and 6), only the free unbound 1,25-(OH)2D3 is biologically
active (plasma half-life ca. 3–6 h). The daily requirement of vitamin D to maintain calcium homeostasis
in adults is very small (ca. 10 µg/day).

Vitamin D2 (calciferol) differs from vitamin D3 in having an additional double bond between side
chain positions C22−23 and a methyl group attached at C24 (Figure 7.3). In humans, following ingestion
and absorption by the small intestine (incorporated into chylomicrons), it is metabolised via similar
pathways to yield 1α,25-dihydroxycalciferol (1,25-(OH)2D2), which is equivalent in biological
activity to 1,25-(OH)2D3.

Principal Actions
1,25-(OH)2D3 promotes the active absorption of calcium from the upper small intestine (main action) and
from bone and kidney (weak action), with a secondary increase in phosphate absorption. Like the steroid
hormones (see Chapters 3 and 6), the action of 1,25-(OH)2D3 on its target tissues is mediated by a specific
 HORMONAL CONTROL OF CALCIUM METABOLISM 147

cytosolic vitamin D receptor protein (VDR) which then interacts with DNA within the cell nucleus to activate
specific genes; in the intestine and kidney, this results in the enhanced synthesis of cytosolic calcium
binding proteins [CaBP(9K) and CaBP(28K) also termed calbindins] as well a transporter pump protein
(Ca-Mg-ATPase) involved in calcium absorption. The VDR is considered to be a ‘primitive’ form of the
thyroid hormone receptor protein (TR), possibly having evolved from the same primordial gene.
Consequently, the effect of 1,25-(OH)2D3 may show a lag period of 1–3 days before the plasma calcium
level rises: [genetic susceptibility of individuals to osteoporosis (see below) may be linked to molecular
variations in the structure of the VDR].
1,25-(OH)2D3 may also exert a more rapid, directly-mediated stimulation of duodenal Ca2+ transport by a
non-genomic mechanism (transcaltachia), most likely involving a separate receptor system with a different
conformational requirement for the hormone ligand.
The action of 1,25-(OH)2D3 on osteoclast bone resorption may be indirectly mediated by release of
paracrine factors from stimulated osteoblast cells; (only osteoblasts possess intracellular VDRs). 1,25-(OH)
2D3 also induces an increase in the synthesis and release of the bone-specific protein osteocalcin by
osteoblasts, which is deposited in the matrix and could be involved in osteoclast recruitment or activation.
Plasma osteocalcin levels (together with alkaline phosphatase) are useful clinical metabolic markers of bone
osteoblastic activity.

Clinical Disorders

DEFICIENCY OF VITAMIN D
This causes rickets in young children and osteomalacia (soft bones) in adults (particularly heavily-veiled
female immigrants living in the UK, and in housebound elderly). Both conditions still occur quite
commonly in tropical and subtropical countries, and are characterized by an inadequate calcification of the
bone matrix and a softening of the skeleton.
In children the growing ends of bone are swollen, and the bone becomes bent and deformed, giving a
characteristic ‘bowed legs’ appearance.
In adults the main feature is bone pain, partial bone fractures and muscle weakness (which may lead to
falls).

A natural decrease in the ability of the skin to synthesize vitamin D3 occurs with increasing age.

Vitamin D deficiency may be due to a metabolic abnormality (e.g. inherited absence or reduced renal 1α-
hydroxylase activity (vitamin D-dependent rickets type 1 [VDDR 1]), intestinal fat malabsorption, chronic
liver disease, insufficient exposure to sunlight or simple dietary lack; [the main sources of vitamin D
include fish, liver, eggs, cod liver oil and fortified milk, cereals and margarine].
Treatment of simple dietary deficiency involves giving small oral doses of vitamin D (up to 10 µg daily;
400 units*) to enhance calcium absorption, together with a calcium supplement if necessary.
Currently available vitamin D supplement preparations include:

1. Chocovite tablets (Ca gluconate with 1.25 µg vitamin D2)

*[1 unit ≡ 25 ng of vitamin D2 or D3.]

148 BASIC ENDOCRINOLOGY—CHAPTER 7

Figure 7.3. Metabolic conversion of vitamin D3 (synthesized in the skin or ingested) to the active form (1,25-(OH)2
vitamin D3) via liver 25-hydroxylase and kidney 1α-hydroxylase enzyme activity respectively. Parathyroid hormone
(PTH) stimulates 1α-hydroxylase activity but inhibits 24-hydroxylase activity in the kidney. 1,25-(OH)2 vitamin D3 can
regulate its own production by stimulating 24-hydroxylase activity to produce the inactive metabolite 24,25-(OH)2
vitamin D3, and also by inhibiting 1α-hydroxylase activity (negative feedback).
The transformation of the plant precursor steroid ergosterol to vitamin D2 (ergocalciferol) by the action of UV light and
heat is also shown above. Ergocalciferol is converted (after ingestion in humans) to its corresponding active form 1,25-
(OH)2D2 by the liver and kidney.
 HORMONAL CONTROL OF CALCIUM METABOLISM 149

2. Calcichew D3 tablets (Ca carbonate with 5 µg vitamin D3) or Calcium and ergocalciferol (vitamin D2)
tablets (Ca lactate and phosphate with 10 µg vitamin D2);

Chronic administration of certain anticonvulsant drugs (e.g. phenytoin or phenobarbitone)

that cause induction of hepatic microsomal enzymes, can increase the rate of clearance of vitamin
D metabolites from the body and therefore induce symptoms of vitamin D deficiency; oral
vitamin D supplements may be preventative in such cases.
In cases of intestinal malabsorption or hepatic disease, higher vitamin D doses (up to 1 mg
daily) may be necessary in the form of higher strength preparations:
3. Calciferol (ergocalciferol vitamin D2) or cholecalciferol (vitamin D3) (in 250 µg tablets, or by
intramuscular injection in vegetable oil); [1.25 mg tablets are also available for treatment of
hypoparathyroidism which may require doses up to 2.5 mg daily].

Treatment of severe rickets or osteomalacia may require a large intramuscular dose of vitamin D initially,
followed by regular oral supplements. Patients with renal impairment who cannot adequately hydroxylate
vitamin D to its active form, may be treated with the newer active derivatives alfacalcidiol (1α-
hydroxycholecalciferol: One-Alpha; AlfaD) or calcitriol (1α,25-dihydroxycholecalciferol: Calcijex;
Rocaltrol) given in the form of capsules, oral solution or by slow intravenous injection; these analogues
have a more rapid onset and a shorter duration of action than vitamin D2 or D3. Calcitriol can also be used
for treating patients with the metabolic VDDR 1 abnormality.
All patients taking high doses of vitamin D preparations require regular monitoring of their plasma and
urinary Ca2+ concentration (particularly in early stages of treatment) to check for development of
hypercalcaemia and possible vitamin D toxicity.

Vitamin D supplements should be avoided by women during lactation, since excess vitamin D
secreted into breast milk could induce hypercalcaemia in infants.

VITAMIN D-DEPENDENT RICKETS TYPE 2 [VDDR 2]

This disease (also known as vitamin D-resistant rickets) is a relatively common hereditary condition caused
by a defect in the gene encoding the 1,25-(OH)2D3 receptor; such individuals develop a nutritional-type
rickets but show a resistance to physiological doses of vitamin D and its metabolites, despite having high
plasma levels of 1,25-(OH)2D3. Patients with this disorder will therefore require higher doses of vitamin D
or vitamin D metabolites for treatment; severe alopecia (hair-loss) of uncertain cause, may also be present.

VITAMIN D EXCESS (HYPERVITAMINOSIS D)

Hypervitaminosis D usually results from overtreatment with a vitamin D preparation. Initial hypercalcaemic
symptoms include tiredness, loss of appetite and nausea. It may also occur spontaneously (with resultant
hypercalcaemia) in some patients with sarcoidosis, where an enhanced synthesis of vitamin D3 (and a
consequent increase in production of 1,25-(OH)2D3) occurs in the skin after sun exposure.

Sarcoidosis is a chronic (usually benign) systemic disease of unknown cause, in which nodules of
inflamed tissue (granulomas) infiltrate the skin and other body organs e.g. lungs, lymph nodes, liver,
and the spleen. These bodies consist of compact accumulations of epithelioid cells, monocytes and
150 BASIC ENDOCRINOLOGY—CHAPTER 7

macrophages, that may be induced by toxic irritants or other unknown antigens. The condition can
appear as a localized inflammation of the skin on the shins (erythema nodosum), but can also affect
other body areas (face, hands, eyes). Skin sarcoidosis is characterized by a hypersensitivity to vitamin
D and development of hypercalcaemic symptoms in some patients after prolonged exposure to
sunlight or excessive ingestion of vitamin D-containing products. The increased metabolism of
vitamin D is thought to occur within the sarcoid macrophages and lymphoid cells associated with the
granulomatous follicles. The condition responds well to systemic or local corticosteroid therapy and
may resolve spontaneously after a few years.

Keratinocyte Differentiation
In addition to their important role in synthesizing vitamin D3, skin keratinocytes are also capable of
producing 1,25-(OH)2D3 from circulating 25-(OH)D3, which in turn exerts a localized function (together
with Ca2+) to regulate keratinocyte differentiation. The synthetic vitamin D analogues calcipotriol and
tacalcitol stimulate the differentiation and inhibit the proliferation of keratinocytes, and have proved useful
(as an alternative to corticosteroid therapy) in the topical treatment of psoriasis (Dovonex cream;
Curatoderm ointment). Regular monitoring of the plasma calcium level is not considered necessary during
usage since calcipotriol possesses only weak ‘calcaemic’ activity.The arrival of newer systemically active
‘non-calcaemic’ vitamin D analogues in the future, could provide a useful and novel class of antitumour
drugs for the treatment of cancer.

Other Hormones Affecting Calcium Homeostasis

Gonadal Steroids
Oestrogens have a well recognized role in maintaining the bone mass in women, by preventing bone
resorption. After the menopause when oestrogen levels decrease, the imbalance between bone resorption
and bone formation may lead to osteoporosis (decalcification of bone and reduction in bone density) which
in some women could lead to bone fragility and potentially fatal hip and vertebral compression fractures [in
men, testosterone has a similar function in protecting against the development of osteoporosis]. Oestrogen
deficiency also increases the sensitivity of the bone to PTH, by an unknown mechanism. Oestrogens have
an inhibitory effect on osteoclast cell activity (and hence bone resorption), however oestrogen receptors
(that also bind androgens) are present predominantly in osteoblast cells; their main protective effects may
therefore be mediated indirectly, by inhibiting the release of specific osteoclast-activating/differentiating
factors from osteoblasts (e.g. IL-6 and granulocyte-macrophage-colony stimulating factor [GM-CSF]) and
also from peripheral blood monocytes (interleukin-1 [IL-1], tumour necrosis factor-a [TNF-α] and GM-
CSF) [a direct inhibitory action of Oestrogens on osteoclast function may also occur]. Osteoblasts also
respond to oestrogen by increasing their production of the paracrine factor transforming growth factor beta
(TGF-β) which has an inhibitory effect on osteoclastic activity. In addition, progestogens can stimulate new
bone formation by binding to osteoclast cells (facilitated by oestrogens). It has been suggested that the main
protective effects of androgens on bone turnover in men could involve an intermediate local aromatization
into oestrogens via skeletal aromatases.
 HORMONAL CONTROL OF CALCIUM METABOLISM 151

Glucocorticoids
Glucocorticoids administered in high (pharmacologic) doses or chronically present in excess in patients
with Cushing’s syndrome (see Chapter 3) are known to affect bone metabolism and calcium turnover,
leading ultimately to a characteristic ‘glucocorticoid-induced osteoporosis’. The precise mechanisms
responsible for this bone loss, however, are incompletely understood. High concentrations of
glucocorticoids inhibit osteoblastic bone formation and stimulate PTH-mediated bone resorption by
osteoclasts resulting in an ‘uncoupling’ of the bone remodeling cycle. High affinity glucocorticoid receptors
have been demonstrated in osteoblasts, but not osteoclast cells, indicating that the effects of glucocorticoids
on bone resorption are indirect. The vitamin D-induced production of the marker protein osteocalcin by
osteoblasts is also suppressed via an action at the 1,25-(OH)2D3 receptor level. Other factors contributing to
the glucocorticoid effect include a decrease in Ca2+ absorption from the gut (by a vitamin D-independent
mechanism) and an increase in urinary excretion of Ca2+ (reduction in renal Ca2+ reabsorption), leading to a
fall in plasma calcium level.

Growth Hormone
Growth hormone (GH) is essential for promoting longitudinal bone growth of the skeleton (see Chapter 2).
Recent studies of the effects of prolonged treatment of elderly individuals with biosynthetic human growth
hormone (hGH) (produced using recombinant DNA technology) indicate that hGH can effectively inhibit
age-related loss of bone mineral. The safety and efficacy of chronically-administrated hGH in such cases
however, remains to be fully evaluated, and this form of therapy at current prices of the hormone, would be
very expensive in the long run. Treatment with hGH may also have other important benefits in the elderly,
including improved muscle strength and reduction in adiposity.

Osteoporosis
Osteoporosis refers to a group of metabolic bone disorders characterized by a decreased bone mass
(osteopenia). The bone (particularly trabecular) becomes abnormally thin and porous, due to an
uncompensated loss of bone mineral and matrix. Along with a progressive decrease in bone mass, there is a
micro-architectural deterioration of osteoporotic bone tissue, contributing further to the ease with which
fractures occur. The prevalence of osteoporosis increases with age in both sexes, although women are more
prone to develop the condition after the menopause. Increasingly, men are also being diagnosed with the
condition, although a generally lower incidence in males would be expected, partly due to their larger initial
bone mass, and partly because of the protective anabolic effects of secreted androgens.
Primary osteoporosis may be classified into two main clinical types: postmenopausal (oestrogen-
deficiency; type I) and age-related (senile; type II). The former is seen in women between the ages of 55–75
years, and is attributed to the lack of ovarian oestrogens, whereas the latter is commonly found in both men
and women between 70–75 years, and attributed to a progressive inefficiency of the bone remodeling
process and decrease in renal 1,25-(OH)2D3 formation/ gastrointestinal Ca2+ absorption with age.
The major increase in bone mass occurs during adolescence, attaining a peak in early adulthood (ca. 30
years of age), and thereafter declines steadily during adult life, due to a cumulative remodeling-induced
deficit. Early bone acquisition is dependent upon adequate dietary intake of calcium, circulating levels of
oestrogens/androgens and physical activity, as well as other genetically programmed factors. In the elderly,
bone density will thus be determined by their peak bone mass attained in early adulthood and the
subsequent bone loss; after the age of 55–60 years, both sexes lose bone at a rate of ca. 1% per year. Bone
152 BASIC ENDOCRINOLOGY—CHAPTER 7

loss can also be increased by certain endocrine disorders (see below), long-term administration of
glucocorticoids, or prolonged immobilization. Following menopause, the rate of bone loss in women is
significantly accelerated due to loss of oestrogen production (about 15% of bone is lost within five to ten
years). Men avoid this rapid menopausal bone loss seen in women, and consequently have a lower
susceptibility to bone fractures.
In osteoporosis, as in hypertension, there is often a long latent period before clinical symptoms and signs
become evident, therefore patients may show no initial symptoms. However, when they do occur, the
major symptoms are:

1. Bone pain due to a fracture (occurring spontaneously or following minimal trauma), or severe back
pain due to vertebral collapse.
2. Loss of height and dorsal kyphosis (curvature of the spine; dowager’s hump). These are classic signs of
more well-established osteoporosis.
3. Fractures. Since osteoporosis increases the fragility of the entire skeleton, fractures may occur
anywhere, but typical sites include the hip (most dangerous), vertebrae, ribs, distal radius (Colles’
fracture), humerus and proximal femur. A greater tendency to fall with increasing age is a further
important factor governing the incidence of fractures.

Such fractures create a major public health and disability problem for elderly men and women in the
western world, leading to a considerable number of premature deaths. The annual fracture burden (ca. 150,
000 cases/year in the UK) imposed on the health services in the UK as the result of osteoporotic (mostly hip)
fractures has been estimated at £742 million.

Risk Factors
Several risk factors are recognized: female gender; a tall slender body build (<58 kg); Caucasian racial
origin; blonde hair colour; family history of hip; wrist or spine fracture; cigarette smoking; alcoholism
(which reduces osteoblastic activity); excessive caffeine intake; lack of weight-bearing exercise; prolonged
immobility; deficiency of gonadal hormones; endocrine abnormalities such as Cushing’s syndrome,
hyperparathyroidism, hyperthyroidism and hyperprolactinaemia with hypogonadism. Women athletes and
ballet dancers suffering from secondary amenorrhoea may also show an accelerated bone loss (also found in
women with chronic anorexia nervosa).
Osteoporosis is also seen in dietary vitamin C or D deficiency (or abnormalities in the vitamin D receptor
gene), renal tubular acidosis, chronic renal, liver or inflammatory bowel disease, rheumatoid arthritis, and in
certain genetic disorders such as osteogenesis imperfecta (brittle bone syndrome) and homocystinuria (an
inborn error of amino acid metabolism).

Bone Density Measurements

Non-invasive, quantitative measures of bone mass are a valuable indicator of bone strength and fracture risk
in osteoporotic patients, and are also useful in the evaluation of therapeutic interventions. Bone mineral
density (BMD) can now be measured precisely at selected skeletal sites prone to osteoporotic fractures, e.g.
the lumbar spine (L2– L4) or femoral neck, using low irradiation dual-energy X-ray absorptiometry (DXA).
Alternative methods currently in use include single or dual-photon absorptiometry (SPA, DPA) or
quantitative computerized tomography (QCT) [regular calibration of instruments is essential]. In general,
 HORMONAL CONTROL OF CALCIUM METABOLISM 153

the risk of bone fracture increases as BMD decreases: osteoporosis is considered to be present when BMD
is more than 2.5 standard deviations below the expected mean for young (20–40 year old) healthy adults of
the same gender [a BMD value ≤1 SD below the young adult mean is regarded as normal].

Prevention and Treatment

Treatment of osteoporosis emphasizes prevention as the most effective therapy, since lost bone mass in this
disorder is difficult to replace. No drug yet exists that can reverse the effects of osteoporosis. Adequate
dietary intake of calcium or oral calcium supplementation in the form of tablets (or effervescent
formulations) containing Ca gluconate, lactate or carbonate salts (Calcit; Calcichew; Sandocal) is thus very
crucial in the perimenopausal period; women in their reproductive years should consume about 1 g of
calcium per day, whereas in pregnant or lactating women, or after the postmenopause, the requirement is
about 1.5 g daily. Taking regular moderate physical exercise (especially walking) and avoiding cigarette
smoking, excess alcohol consumption and drugs like steroids, especially during adolescence and young
adulthood, should also help in maintaining bone mass.
In postmenopausal women, oestrogen replacement as part of HRT (see Chapter 6) is the most effective
method of decreasing the rapid bone loss and reducing fracture rate in both the spine and the hip. To be
fully effective, HRT should preferably be started within the first 5 years following menopause and
continued for at least 5–10 years. Although some benefit is seen when the treatment is begun later, it is
significantly less pronounced. In women with an intact uterus, combined oestrogen/progestogen HRT is
necessary to reduce the risk of developing endometrial cancer (see Table 6.3). The usefulness of long-term
androgen replacement therapy (e.g. using transdermal testosterone patches: Andropatch; [Testoderm;
Androderm: USA]) in hypogonadal men with osteoporosis remains unclear.
Other main pharmacologic approaches include antiresorptive agents such as salcatonin (given by daily
subcutaneous or intramuscular injection or by intranasal spray [Miacalcin: USA] together with oral calcium
and vitamin D supplements) or oral bisphosphonates taken on an intermittent cyclical basis (disodium
etidronate; Didronel PMO) or administered continuously (sodium alendronate; Fosamax) (both with
calcium supplementation). The increase in spinal BMD achieved with the bisphosphonates is associated
with an ca. 50% decrease in vertebral fracture rate, comparable to that seen with HRT. For elderly patients
over 75 years of age, the use of antiresorptive agents is not considered to be beneficial; modest amounts of
vitamin D (20 µg daily) taken together with a calcium supplement may then be the most effective method
for reducing fracture risk among such people.
The possible use of an oral slow-release form of sodium fluoride (given with calcium) to stimulate bone
formation in post-menopausal osteoporosis and decrease vertebral fracture rate is controversial. Another
novel form of ‘anabolic’ therapy currently being evaluated, involves the administration of daily
subcutaneous injections of the 1–34 amino acid fragment of human parathyroid hormone [hPTH (1–34);
teriparatide] which, in low doses, stimulates osteoblastic bone formation without affecting blood Ca2+
levels. Future development of intranasally or oral formulations of this (or related PTH fragments) could thus
provide an exciting new therapeutic approach for the treatment of osteoporosis.
Raloxifene hydrochloride is a non-steroidal tissue-specific oestrogen receptor ligand (or selective
oestrogen receptor modulator, SERM) that is currently being evaluated as an effective alternative to HRT in
the treatment of osteoporosis in post-menopausal women, but may also be useful in preventing the
development of breast and endometrial cancers. This novel benzothiopene compound acts as a selective
oestrogen agonist on bone, but unlike oestradiol, is an oestrogen antagonist on other tissue; it is therefore
free of endometrial hyperplastic effects, and should not increase the risk of endometrial cancer.
154 BASIC ENDOCRINOLOGY—CHAPTER 7

Review Questions
Question 1: Explain the physiological importance of Ca2+ in the body.
Question 2: State the normal concentration of total calcium in the plasma and name the three
hormones involved in calcium regulation.
Question 3: List the three forms in which calcium exists in the plasma.
Question 4: State the major forms of inorganic phosphate in the body.
Question 5: Describe the location, and structure of the parathyroid glands; name their principal
hormone secretion, and state its effect on the plasma Ca2+ level.
Question 6: Describe the mechanisms controlling parathyroid hormone (PTH) release.
Question 7: Describe the main actions of PTH on:
a) the kidney,
b) bone resorption,
c) the gastrointestinal tract.
Question 8: State the two principal types of bone cell and outline their function in bone formation/
resorption.
Question 9: Outline the mechanisms by which PTH exerts its effects on osteoclast bone resorption.
Question 10: Explain the metabolic significance of plasma alkaline phosphatase and osteocalcin
levels.
Question 11: Outline the second messenger pathways that are believed to be involved in
mediating the effects of PTH.
Question 12: Explain the source and physiological significance of the PTH-related protein
(PTHrP).
Question 13: Describe the causes, symptoms and treatment of (a) hyperparathyroidism, (b)
hypoparathyroidism. What are Chvostek’s and Trousseau’s signs?
Question 14: State the location of the parafollicular C cells, name their principal hormone
secretion and give its effect on the plasma Ca2+ level.
Question 15: Describe the mechanisms regulating calcitonin release.
Question 16: Describe the main actions of calcitonin on (a) bone, (b) kidney; contrast the
physiological significance of calcitonin, compared with PTH or vitamin D in regulating blood
calcium levels?
Question 17: Outline the therapeutic uses of calcitonin in the treatment of Paget’s disease and
severe hypercalcaemia.
Question 18: Explain (giving named examples) the use of bisphosphonates in the treatment of (a)
Paget’s disease, (b) postmenopausal osteoporosis, (c) tumour-induced hypercalcaemia of
malignancy.
Question 19: State the two natural forms of vitamin D and give its main effects on the plasma Ca2
+ level.

Question 20: Give the main dietary sources of vitamin D.

Question 21: Outline the synthesis of vitamin D3 in the skin and its conversion in the liver and
kidney to active calcitriol.
Question 22: Describe the main actions of calcitriol on the gastrointestinal tract, bone and
kidney.
Question 23: Outline how calcitriol exerts its effects via genomic and non-genomic receptor
mechanisms.
 HORMONAL CONTROL OF CALCIUM METABOLISM 155

Question 24: Describe the causes, symptoms (in children and adults) and treatment of vitamin D
deficiency.
Question 25: List some commonly used vitamin D supplement preparations.
Question 26: Explain why patients taking high doses of vitamin D preparations require regular
monitoring of plasma Ca2+.
Question 27: Describe the causes, symptoms and treatment of vitamin D excess (hypervitaminosis
D).
Question 28: Outline the role of vitamin D in keratinocyte differentiation; what is the therapeutic
significance of this effect?
Question 29: Explain how other hormones can affect calcium homeostasis.
Question 30: Describe the main types of primary osteoporosis; list the causes, symptoms and risk
factors associated with this disorder and outline the therapeutic options available for treatment.

Clinical Case Studies

Patient 1
A 71 year old male was admitted to the emergency room in a confused, semi-comatose state, with
dehydration, fatigue and abdominal pain; no other obvious abnormalities were evident. His blood pressure
was 144/68 mmHg and heart rate 68 beats/min. The patient had lost 20 lb (9 kg) in the last four months, and
was losing appetite. A neoplastic process was suspected and work up begun. On initial screening, he was
found to have a high serum calcium level. A tentative diagnosis of humoral hypercalcaemia of malignancy
(HHM) was made, an endocrinology consultation was sought and further studies undertaken.
On laboratory investigation, his full blood count (FBC) and urinalysis were normal; however, total serum
calcium was 17.8 mg/dl (normal 8.4–10.7 mg/dl: 2.2–2.67 mmol/l), phosphate was 2.1 mg/dl (normal 2.5–4.
8 mg/dl: 0.8–1.5 mmol/l), and alkaline phosphatase was elevated to 180 U/ml (normal 25–115 U/ml). The
serum level of immunoreactive parathyroid hormone (iPTH) was 348 pg/ml (normal <65 pg/ml), while the
level of parathyroid hormone-related protein (PTHrP) was normal. A 24 hour urinary calcium (total)
measurement gave 420 mg/24 hours (normal 100–300 mg/24 hours).
An ultrasound of the neck revealed a left inferior parathyroid adenoma.
Question 1: What is the most probable diagnosis in this case?
Question 2: What are the usual causes and symptoms of hypercalcaemia?
Question 3: How would this patient be managed?
Answer 1: This patient has hyperparathyroidism arising from a primary parathyroid adenoma.
The resultant high blood levels of PTH are associated with hypercalcaemia, a low serum
phosphate (hypophosphataemia) and an excessive urinary excretion of calcium (hypercalciuria)
and phosphate (phosphaturia); elevated serum levels of alkaline phosphatase are also present,
reflecting an increase in bone osteoclast activity. A normal level of PTHrP (secreted by lung or
breast carcinomas) supports the diagnosis of primary hyperparathyroidism, rather than humoral
hypercalcaemia of malignancy (HHM). The plasma concentration of calcium normally regulates
PTH release by a negative feedback mechanism exerted directly at the level of the parathyroid
glands. In patients with parathyroid adenomas, the normal feedback mechanism is absent, and an
increased secretion of PTH is maintained despite an elevated blood calcium level.
156 BASIC ENDOCRINOLOGY—CHAPTER 7

Answer 2: Primary hyperparathyroidism is the most common cause of hypercalcaemia, and

subtotal parathyroidectomy is the preferred treatment. Other causes of hypercalcaemia include:
drugs (thiazide diuretics, chronic lithium treatment), vitamin D intoxication, malignancy,
granulomatous diseases (sarcoidosis, berylliosis [systemic poisoning following inhalation of Be-Cu
alloy], tuberculosis), immobilization (in Paget’s disease) or in hyperthyroidism, acromegaly or
acute adrenal failure (hypoadrenalism).
The usual signs and symptoms of hypercalcaemia include: tiredness, lethargy, depression,
insomnia, headaches, general muscle weakness, anorexia, nausea/vomiting, dehydration (due to
excessive urine loss), increased gastric acid/pepsin secretion, renal or uretic colic due to calculi,
hypertension, and ECG changes (shortened QT interval)/cardiac arrhythmias.
Answer 3: Following diagnosis, the patient was provided with intravenous hydration therapy with
normal saline (over 10 days), in conjunction with an intravenous bisphosphonate (disodium
pamidronate) to reduce his serum calcium level; [more acute cases of hypercalcaemia might
require the use of a loop diuretic (frusemide) to promote a more rapid renal calcium excretion].
Once hydration was achieved, the patient underwent surgery, where an adenoma weighing 1.7 g
was removed from the left parathyroid gland. The patient remained eucalcaemic after surgery and
was discharged home.

Patient 2
A 32 year old female underwent sub-total thyroidectomy for treatment of Graves’ disease. On the second
hospital day the patient was complaining of a tingling sensation in her fingertips, tingling and numbness
around the mouth and lips, and cramps in her legs and hands. Laboratory studies had previously been
unremarkable for any calcium deficiency. On examination, the patient was alert and oriented; her heart rate
was 112 beats/min, and blood pressure (BP) 146/96 mmHg. During BP recording, the patients hand went
into a spasm (Trousseau’s sign). Her deep tendon reflexes were brisk. The remainder of the examination was
unremarkable. Clinical examination was consistent with hypocalcaemia and blood samples were drawn for
immediate calcium measurement.
Laboratory data indicated a serum calcium level of 6.5 mg/dl (normal 8.4–10.7 mg/ dl), ionized calcium
2.3 mg/dl (normal 3.6–4.1 mg/dl), phosphate 4.9 mg/dl (normal 2.5–4.8 mg/dl), and alkaline phosphatase 68
U/ml (normal 25–115 U/ml). Other laboratory data were normal.
Question 1: What is the likely cause of the patients hypocalcaemia? What major symptoms would
you associate with the condition?
Question 2: How would this patient be managed?
Answer 1: Hypocalcaemia in adults is usually an acquired phenomenon. It may be secondary to
absence of parathyroid hormone (PTH) secretion, or a functional resistance to PTH (as seen in
magnesium deficiency-hypomagnesaemia). It may also arise from nutritional deficiency of
vitamin D (or inadequate exposure to UV light), chronic malabsorption, chronic renal disease,
infiltration of the parathyroids by tumours or in haemochromatosis [an inherited condition
characterized by excess iron deposition in the liver and endocrine glands). In this patient, the most
plausible diagnosis would be surgical hypoparathyroidism arising from an inadvertent removal of
parathyroid tissue, leading to mild hypocalcaemia and hyperphosphataemia (due to increased renal
phosphate absorption) with a normal alkaline phosphatase; a low or undetectable serum iPTH
level would also be expected [a similar condition can arise following radioactive iodine treatment
for Graves’ disease].
 HORMONAL CONTROL OF CALCIUM METABOLISM 157

The major symptoms of hypocalcaemia include: tingling and numbness of the fingers, muscle
cramps/spasm of the extremities, laryngeal stridor (harsh inspiratory sound, caused by laryngeal
spasm) and in severe cases, tetany or general convulsions. Positive Trousseau’s sign (wrist spasm
induced by sphygmomanometer cuff inflation) and Chvostek’s sign (twitching of facial muscles
on tapping facial nerve) may be present; ECG changes (prolonged QT interval) and cardiac failure
may also occur. In chronic cases, there is loss of body hair, drying of the skin and possible
development of cataracts.
Answer 2: On confirming the hypocalcaemia, the patient was treated with an intravenous infusion
of 10% calcium gluconate over 48 hours to normalize the serum calcium level, at which point she
was stable enough to be placed on oral calcium and vitamin D supplements for long-term
maintenance. Regular serum and 24 hour urinary calcium measurements were made over the next
two months to check for supplement overdosage, with possible development of hypercalcaemia.

UK/USA—Trade names
UK USA
Bisphosphonates
Disodlum etidronate Didronel Didronel
Disodium pamidronate Aredia Aredia
Sodium clodronate Loron; Bonefos
Sodium alendronate Fosamax Fosamax
Vitamin D analogues
Alfacalcidiol One-Alpha; Alfa D
Calcitriol Calcijex Calcijex
Rocaltrol Rocaltrol
Dihydrotachysterol AT 10 DHT
Tacalcitol Curatoderm ointment
Calcipotriol (Calcipotriene) Dovonex cream Dovonex ointment
Calcitonin
Calcitonin (porcine) Calcitare
Salcatonin Miacalcic Miacalcin
(synthetic salmon calcitonin) Calsynar Calcimar
Loop diuretic
Frusemide (furosemide) Lasix Lasix

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 HORMONAL CONTROL OF CALCIUM METABOLISM 159

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 Abbreviations

ABP androgen binding protein

ACE angiotensin-converting enzyme
ACTH adrenocorticotrophic hormone (corticotrophin)
ADH antidiuretic hormone
AIDS acquired immune deficiency syndrome
ANP atrial natriuretic peptide
AP-1 activator protein-1
AR androgen receptor protein
AREs androgen-responsive elements
ATP adenosine triphosphate
AVP arginine vasopressin
BMPs bone morphogenic proteins
BMR basal metabolic rate
BPH benign prostatic hyperplasia
CaBP calcium binding protein
cAMP cyclic 3′,5′-adenosine monophosphate
CgA chromogranin A
cGMP cyclic 3′,5′-guanosine monophosphate
CNS central nervous system
COC combined oral contraceptive
CRH corticotrophin releasing hormone
CSII continuous subcutaneous insulin infusion
CT calcitonin
CTBP cytosolic thyroid hormone binding protein
DAG diacylglycerol
DHEAS dehydroepiandrosterone sulphate
DHT 5α-dihydrotestosterone
DIT diiodotyrosine
 161

EPO erythropoietin
FSH follicle stimulating hormone
GABA γ-aminobutyric acid
GH growth hormone
GH growth hormone (somatotrophin)
GHRH growth hormone releasing hormone
GIP gastric inhibitory peptide
GLUT4 glucose transporter protein-4
GM-CSF granulocyte macrophage-colony stimulating factor
GnRH gonadotrophin-releasing hormone
GR glucocorticoid receptor protein
HbA1C glycosylated haemoglobin fraction
hCG human chorionic gonadotrophin
hCS human chorionic somatomammotrophin
HDL high density lipoprotein
hGH human growth hormone
HHM humoral hypercalcaemia of malignancy
HLA human leucocyte antigen
hPL human placental lactogen
HRT hormone replacement therapy
11-HSD 11-β-hydroxysteroid dehydrogenase
Hsp heat shock protein
5-HT 5-hydroxytryptamine
ICAs islet cell antibodies
IDDM insulin-dependent diabetes mellitus
IGF insulin-like growth factor
IGF-1 insulin-like growth factor-1
IGFs insulin-like growth factors
IL interleukin
IP3 inositol-1,4,5-trisphosphate
IRMA immunoradiometric assay
IRS-1 insulin receptor substrate-1
IUD intrauterine device
IVF in vitro fertilization
LDL low density lipoprotein
LH luteinizing hormone
LHRH luteinizing hormone releasing hormone
ßLPH β-lipotrophin
162 BASIC ENDOCRINOLOGY

LTFs ligand-activated transcription factors

MHC major histocompatability complex
MIS müllerian inhibiting substance
MIT monoiodotyrosine
MR mineralocorticoid receptor protein
MSH melanocyte stimulating hormone
NIDDM non-insulin-dependent diabetes mellitus
OGTT oral glucose tolerance test
1,25-(OH)2D2) 1α,25-dihydroxycalciferol
1,25-(OH)2D3 1α,25-dihydroxycholecalciferol
25-(OH)D3 25-hydroxycholecalciferol
OP-1 osteogenic protein-1
PAPP-A pregnancy-associated plasma protein-A
PID pelvic inflammatory disease
PLA2 phospholipase A2
POC progestogen-only contraceptive
POMC preproopiomelanocortin
PRL prolactin
PST pancreastatin
PTH parathyroid hormone
PTHrP parathyroid hormone-related protein
PVN paraventricular nucleus
rhRlx recombinant human relaxin
rHuEPO recombinant human erythropoietin
RIA radioimmunoassay
rT3 reverse T3
SHBC sex hormone binding globulin
SON supraoptic nucleus
SP-1 pregnancy-specific beta 1-glycoprotein
SRIH somatotrophin release inhibiting hormone
SS somatostatin
T3 triiodothyronine
T4 thyroxine
TBG thyroxine binding globulin
TGF-β transforming growth factor-β
tGLP-1 truncated glucagon-like peptide-1
TNF tumour necrosis factor
TNF-α tumour necrosis factor-α
 163

TR thyroid hormone receptor protein

TRAP thyroid hormone auxiliary protein
TREs thyroid hormone response elements
TRH thyrotrophin releasing hormone
TSH thyroid stimulating hormone (thyrotrophin)
TSI thyroid-stimulating immunoglobulin
VDDR vitamin D-dependent rickets
VDR vitamin D receptor protein
VIP vasoactive intestinal polypeptide
 UK/USA Spelling

UK USA
Amenorrhoea Amenorrhea
Analogue Analog
Chiropodist Podiatrist
Diarrhoea Diarrhea
Foetus, Foetal Galactorrhea
Fetus, Fetal Galactorrhoea
Goitre Goiter
Haemoglobin Hemoglobin
Haemorrhage Hemorrhage
Hormone Replacement Therapy Estrogen Replacement Therapy (ERT)
Hypo-(hyper-) cholesterolaemia -cholesterolemia
Hypo- (hyper-) calcaemia -calcemia
Hypo-(hyper-) phosphataemia -phosphatemia
Hypo- (hyper-) glycaemia -glycemia
Hyperlipidaemia Hyperlipidemia
Myxedema Myxoedema
Neurone(s) Neuron(s)
Oedema Edema
Oestradiol, Oestriol Estradiol, Estriol
Oestrogen, Oestrone Estrogen, Estrone
Proteinurea Proteinuria
Stilboestrol (Diethyl)stilbestrol
Sulphonylurea Sulfonylurea
Tumour Tumor
 Index

ABP see Androgen binding protein Adrenal medulla,

Acarbose, 75 hormones secreted by, 25
ACE see Angiotensin-converting enzyme Adrenalectomy, effects of, 30
Acetylcholine, in regulation of CRH release, 9 Adrenaline, 25, 29
Acidosis, in diabetes, 67, 76, 78, 79, 81 metabolites, 40
Acne, androgens affecting development of, 87, 88, 89 Adrenocortical hormones, 25
Acromegaly, 10, 14, 15, 20 anatomical considerations, 25
ACTH (Corticotrophin) see Adrenocorticotrophic biosynthesis of, 26
hormone; actions, 26–30, 34
ACTH stimulation test (short), 32, 39 anti-inflammatory activity, 28, 29
Activator protein-1 (AP-1), 30 deficiencies of, 30, 32, 36
Activin, 87 excess of, 32, 36
Addison’s disease, 30, 39, 40 receptors, 30, 31, 34, 35
Adenohypophysis: structure of, 26, 27
see also Pituitary gland, 7 uses, 28, 29, 32
Adenomas, Adrenocortical hyperfunction, 32, 36, 38, 40
adrenal, 32, 36, 38, 41 Adrenocortical insufficiency, 30, 32, 36, 39
parathyroid, 114, 125 Adrenocorticotrophic hormone (ACTH);
pituitary, 12, 15, 19, 38, 66, 106 (Corticotrophin): 11, 26
thyroid, 52 actions, 11, 26
Adenylate cyclase/CAMP system, 1, 4 biosynthesis/release, 11–12
ADH see Antidiuretic hormone; Vasopressin glucocorticoid secretion affected by, 11, 26
Adipose tissue, insulin effects on, 60, 62 hypersecretion of, 12, 32
Adrenal androgens, 32, 33, 94 insufficiency of, 12, 30
Adrenal cortex stress affecting secretion of, 12, 30
and angiotensin 11, 34 β-Adrenoreceptor blockers, in hyperthyroidism, 51, 54
hormones secreted by, 25 AIDS (acquired immune deficiency syndrome), and
malfunctions of, 30–33, 36 adrenal insufficiency, 30, 36
Adrenal crisis, 32 Albumin, glucocorticoid binding to, 26
Adrenal glands Aldosterone, 33
ACTH effects on, 26, 32 actions of, 34
androgen secretion by, 25 antagonists, 34, 36, 41
carcinoma of, 32 control of release, 34
dexamethasone effect on, 33, 38 hypersecretion, 36
foetal, 93, 94 hyposecretion, 36, 39
structure and function of, 25 mechanism of action, 35
Adrenal hyperplasia, congenital, 32 secretion and angiotensin 11, 34

165
166 BASIC ENDOCRINOLOGY

Aldosteronism, 36 Adenohypophyseal hormones, 7, 10–16

Aldosteronoma, 41 Anti-adrenal antibodies, 39
Alfacalcidiol, 120 Anti-androgens, 89, 98, 108,
Alkaline phosphatase, 113, 116, 118, 125, 126 see also Oestrogens
Alpha (α) islet cells (glucagon-secreting), 59 Antidiabetic drugs:
Alpha (α)-MSH (melanocyte stimulating hormone), 7, 11, see Oral hypoglycemic drugs
12, 32, 39 Antidiuretic hormone (ADH);
Amino acids arginine vasopressin;
and GH secretion, 15 vasopressin, 16–17
and glucagon secretion, 65 actions, 16
and insulin secretion, 60 and ACTH release, 16
Amenorrhoea, 33, 37, 53 analogues, 17
see also Menstruation control of release, 16–17
Aminoglutethimide, 33 deficiency of, 17
for cancer chemotherapy, 98 excess, 17,
for Cushing’s disease, 33 see also SIADH
Amiodarone, receptors, 16
interference with thyroid function, 50, 52 synthesis/transport of, 16
Amylin (islet amyloid polypeptide; IAPP), 65 Anti-oestrogens, 98
AMP, cyclic (cAMP), for breast cancer, 98
see also Adenylate cyclase/cAMP system, 1, 4 Anti-inflammatory action of glucocorticoids, see
Anabolic effects of androgens, 89 Adrenocortical hormones
Anabolic steroids, 89, Anti-progestogen, 101
see also Androgens Antithyroid drugs, 51, 56,
Androgens (male sex hormones), 87–89 see also Thioureas
actions, 87 AP-1 (activator protein-1), 30
adrenal, 87, 93, 94 Aqueous iodine solution, 51,
biosynthesis and structure, 27, 85 see also Lugol’s iodine
control of release, 86 Arachidonic acid, 3, 29
on breast cancer, 89 Arginine vasopressin (AVP); vasopressin: see Antidiuretic
preparations available, 88, 108 hormone
receptors, 87, 88, 89 Aromatase, in oestrogen synthesis, 27
side effects, 89 Aromatase enzyme inhibitors, 33, 38, 98
uses, 89 for breast/prostate cancer, 98
Androgen-binding protein (ABP), 86 for Cushing’s disease, 33
Androgen replacement therapy, 88–89, 106 ATP (adenosine triphosphate)
preparations for, 88 potassium channels and, 60
Androgen resistance, 88 Atrial natriuretic peptide (ANP), 17
Androstenedione, 32, 88 Autocrine secretion, 66
Angiotensin(s), 34–36,
see also Renin-angiotensin system Bedomethasone, 28
Angiotensin receptors (ATI–IV), 35 Benign prostatic hyperplasia (BPH), 89
Angiotensin-converting enzyme (ACE), 34 Beta (β)-MSH (melanocyte stimulating hormone), 11, 12
ACE inhibitors, 35 Beta (β) islet cells (insulin-secreting), 59
Angiotensinogen, 34 Beta (β)-lipotrophin (β-LPH), 11
ANP see Atrial natriuretic peptide Betamethasone, 28
Anterior pituitary gland, 7 Basal metabolic rate (BMR) thyroid hormone effects on,
Anterior pituitary hormones, 7, 10–16 47
hypothalamic control of, 8 Beta (β)-endorphin, 11, 12
 INDEX 167

Biguanides, 75, hormonal control of, 111

see also Oral hypoglycemic drugs parathyroid hormone secretion and, 112
Bisphosphonates, 128 Calcium-binding proteins, 118
for Paget’s disease of bone, 117 Calcium supplements
for osteoporosis, 117, 123 therapeutic uses, 117, 118, 120, 122–123
Blastocyst, 90 cAMP, 1, 4
‘Block-and-replace’ treatment for Graves’ disease, 51 Canrenoate (potassium), 34
Blood-testis barrier, 86 Captopril, 35
Bone Carbimazole, 51
resorption of, 112, 113–116, 117–118, 121 Chief cells in parathyroid gland,
calcium and, 111, 112–118 secretions of, 111, 112
continual remodeling of, 113, 114 Chlorpropamide, 75, 82
fracture, in osteoporosis, 121, 122–123 Cholecystokinin, 65, 66
glucocorticoid effects on, 121, 122 Cholesterol, and synthesis of steroids, 26
oestrogen effects on, 114, 121 Chorionic gonadotrophin, see Human chorionic
Breast gonadotrophin (hCG)
carcinoma of, 89, 95, 98, 100 Chromaffin cells, 25
chemotherapy for, 89, 98 Chvostek’s sign, in tetany, 115
oxytocin effects, 7, 17 Circadian rhythm,
prolactin effects, 13 ACTH/glucocorticoid secretion affected by, 12, 26
Breast milk, CLIP (corticotrophin-like intermediate lobe peptide), 12
and prolactin, 13 Colles’ fracture, in osteoporosis, 122
and oxytocin, 17 Colloid, thyroglobulin and, 45, 46
Bromocriptine, 13, 14, 16, 19, 21 Congenital adrenal hyperplasia, 32
uses in the treatment of, Conn’s syndrome, 36
acromegaly, 16 Contraception,
hyperprolactinaemia, 14 hormonal, 98, 99–100
“Buffalo hump”, in Cushing’s syndrome, 33 intrauterine, 101–103
Buserelin, 8, 95, 98 ‘morning after’, 98
Contraceptive pills oral, 101
C-peptide (connection peptide), in insulin structure, combined (COC’s), 99
59–60, 73 progestogen-only (POC), 99
C18–21 steroids, 26 Corpus luteum,
Cabergoline, 14 in menstrual cycle, 90–93
Calcitonin, in, 115, 116–117 in pregnancy, 92–93
actions, 116 and relaxin secretion, 93
uses in the treatment of, Corticosteroids, 25, 28, 30, 33,
hypercalcaemia, 115 see also Adrenocortical hormones;
osteoporosis, 123 Glucocorticoids;
Paget’s disease, 117 Mineralocorticoids;
control of release, 116 Steroids:
Calcitonin gene-related peptides (CGRP), 65 blood glucose, effects on, 26, 28, 30, 33, 38
Calciferol, 117, 118, 119, 120 deficiency, effects of, 32, 36
Calcitriol, 120 excess, effects of, 32–33, 36
Calcium (ions), 111 synthesis/release, 26, 34–36
abnormal levels of, Corticotrophin (ACTH):
in hypercalcaemia, 114, 115, 116, 117, 120, 125–126 see Adrenocorticotrophic hormone
in hypocalcaemia, 115, 116, 126–127 Corticotrophin-like intermediate lobe peptide (CLIP), 12
calcitonin and, 116 Corticotrophs, 8, 9
168 BASIC ENDOCRINOLOGY

Corticotrophin releasing hormone (CRH); 1,25-Dihydroxycholecalciferol (1,25-Dihydroxyvitamin

corticoliberin; D3), 112, 113, 114, 117–118, 119, 120–122
corticotrophin releasing factor (CRF), 9, 13 Direct negative feedback, 3
Cortisol (hydrocortisone), 11–13, 26–33 DIT (diiodotyrosine),
actions, 26, 28–30 in thyroid hormone synthesis, 46
intracellular mechanism, 30, 31 Dopamine, prolactin secretion and, 13
Cortisone, 32, 34 TSH secretion and, 11
Cretinism, 48, 50 Dopamine receptor agonists, (bromocriptine, cabergoline,
Creutzfeldt-Jakob disease, 15 quinagolide),
CRH (corticotrophin releasing hormone), 9, 13 for acromegaly, 16
-stimulation test, 33 for hyperprolactinaemia, 14
Cryptorchidism, 88 Drugs, effects on
Cushing’s disease, 32, 38 adrenal steroidogenesis, 33
Cushing’s syndrome, 32–33, 38 oestrogen synthesis, 98
pituitary gland tumours causing, 32 Drugs,
Cyclic 3′,5′-adenosine monophosphate, (cyclic AMP; effects on thyroid function, 51
cAMP), 1, 4 male sexual function, 89
Cyclic 3′,5′-guanosine monophosphate (cyclic GMP; pancreatic function, 70
cGMP), 3 tranquillizers, effects on the endocrine system, 13
Cyclo-oxygenase (COX), 29 Drug-induced hypothyroidism, 51
Cyclopentanoperhydrophenanthrene nucleus of steroid Dwarfism,
hormones, 26 associated with cretinism, 50
Cyproterone, anti-androgenic activity, 89 pituitary, 15
Cytokines, 29, 30 Laron-type, 15

Dehydroepiandrosterone (DHEAS), 25, 33 Ectopic secretion of ACTH,

Delta (δ) islet cells (somatostatin-secreting), 59 Enalapril, 35 12, 32
Demeclocycline, 17 Endocrine glands, location and principal secretions of, 2, 3
Deoxycorticosterone, 33 Endocrine hypertension, 40
Desmopressin, 17 Endocrine pancreas, secretions of, 59
Dexamethasone, 28, 33 Endocrine system, introduction, 1
Dexamethasone suppression test, for Cushing’s Endocrine target cells,
syndrome, 33, 38 hormones that act on, 2
Diabetes insipidus, 17 Endometrial (uterine) cycle, 90–91, 92
Diabetes mellitus, 68–76 Endometriosis, 95–96, 99
acidosis in, 67, 73, 76, 78–79 Endometrium, carcinoma of, 96, 98, 99, 100
coma in, 67, 76 Endorphin(s), 11;
glucose tolerance test in, 72 see also: Beta-endorphin(s)
ketosis in, 67, 76 Epiphyses (bone),
symptoms of, 67 hormones affecting, 87, 94
types of, 68–69 Erythropoietin, 89
treatment, 72–75 Estrogens, see Oestrogens
long-term complications of, 69–70 Ethinyloestmdiol, 96, 98, 100, 101
Diacylglycerol (DAG), and hormone effects, 3 Ethynodiol diaacetate, 98, 101
Diazoxide, 70 Etidronate, 117, 123
Diethylstilbestrol (DES), 98 Exocrine glands, definition of, 1
Diet-induced thyroid disease (from ingestion goitrogens), Exophthalmos, 50
49
Dihydrotestosterone (DHT), 87–88 Familial glucocorticoid deficiency (FGD), 32
 INDEX 169

F islet cells, pancreatic, 59 actions, 69, 65

Facial changes, synthesis/release, 64–65
and growth hormone excess, 15 and insulin-glucagon molar ratio, 65
and thyroid hormones, 49, 50 Glucocorticoids, 25–33,
Feedback control see also Adrenocortical hormones;
of hormone secretion, 3–5 Corticosteroids;
Female hypogonadism, 95, 96, 106 Steroids:
Female reproductive system, 90–95 actions, 26–30
hormonal control of uterine cycle, 90–92 anti-allergic effects, 29
ovarian cycle and hormone release, 90 as anti-inflammatory agents, 28–29
structure, 90, 91 as antirheumatoid agents, 28
Female sex steroids: as immunosuppressants, 29–30
see Oestrogens control of release, 26
Finasteride, 89 effects on blood glucose, 26, 28, 33, 38
Fludrocortisone, 32, 40 effects on bone calcium metabolism, 32–33, 121
Fluocinolone, 28 excess of, 32–33
Flutamide, 89 in Cushing’s syndrome, 32–33, 37–38
Fluoride, and osteoporosis, 123 insufficiency of, 30, 32
Follicle, intracellular mechanism of action, 30–31
Graafian, 90, 91 preparations, 28, 42
thyroid, 45 receptors, 30–31
Follicle stimulating hormone (FSH), and resistance to “stress”, 30
in females, 10, 90–92, 93–94, 95, 98, 99, 106 Glucocorticoid receptor protein (GR), 30–31
in males, 10, 86–87 Glucocorticoid response elements (GREs), 30–31
Follicular cells (in thyroid), 45–47, 105 Gluconeogenesis, hormones affecting, 62, 63, 65
Follicular development and regression, Glycogenolysis, hormones affecting, 62, 63, 65
during menstrual cycle, 90–92 Glucose,
Follistatin, 87 blood level of, 67, 79
Frusemide, 40–41, 115, 126 glucagon secretion affected by, 65
insulin secretion affected by, 60
G-protein(s), renal threshold for, 67
hormone receptors coupled to, 4 -suppression test for acromegaly, 16
GABA (γ-aminobutyric acid), 9, 13 tests for, 70, 71
Galactorrhoea, 13, 18 -tolerance test (oral), for diabetes, 72, 80–81
Gamma (γ)-lipotrophin, 11, 12 Glycolysis, insulin effects, 62
Gastric inhibitory peptide (GIP), 60, 66 Glycosuria, 67
Gastrin, 60, 66 Glycosylated haemoglobin (HbA), 70, 78–79
Gastrin-releasing peptide (GRP), 66 Glyburide (Glibenclamide), 75, 82
Gastrinoma, 66 GnRH-associated peptide (GAP), 9
Gastrointestinal hormones, 66–67 Goitre, 49, 50, 52
effects on glucagon secretion, 65 toxic multinodular, 52
effects on insulin secretion, 60 Goitrogens, 49
Gestational diabetes, 69 Gonad(s), malfunctions of, 88, 95, 105–106
Gigantism, pituitary, 15 Gonadal hormones and reproduction, 85
Glibenclamide (glyburide), 75, 82 Gonadorelin, 8–9
Gliclazide, 75, 82 Gonadotrophin(s), 10, 86, 88, 90–92, 94, 105–106;
Glipizide, 75, 82 see also Follicle-stimulating hormone;
Gliquidone, 75 Luteinizing hormone
Glucagon, 59, 64–65, 66, 67 Gonadotrophin releasing hormone (GnRH);
170 BASIC ENDOCRINOLOGY

Luteinizing hormone releasing hormone (LHRH) response elements, 1, 3, 30–31, 48, 87

analogues of, 8–9, 95, 98 steroid, 1, 26, 85, 87, 93, 94–95
Gonadotrophin release inhibitors, 95 thyroid, 45–49
Gonadotrophs, 8–9 types of, 1
Goserelin, 95, 98 Hormone receptors (types of), 1, 3, 4
Graafian (ovarian) follicle, 90–91 Hormone replacement therapy (HRT), 96–97, 101, 102
Granulocyte macrophage colony stimulating factor (GM- Hormone-sensitive lipase, 62, 64, 65, 68
CSF), 29, 113, 114, 121 5-HT (serotonin),
Granulosa cells, in regulation of CRH release, 9
and oestrogen secretion, 90 Human chorionic gonadotropin (hCG), 92–93, 103, 106
and inhibin production, 91 Human insulin, 73, 74, 82
Graves’ disease, 50, 53–54 Human leucocyte antigens (HLA),
Growth factors see Insulin-like growth factors and diabetes, 68–69, 78–79
Growth hormone (GH), 14–16; Human menopausal gonadotropins (hMG), 94, 106;
see also Somatotrophin see also Menotrophin
actions, 14 Human placental lactogen (hPL), 93
clinical use, 15 Humoral hypercalcaemia of malignancy (HHM), 114, 117,
control of release, 14–15 125
deficiency of, 15 Humulin (human insulin), 73, 74, 82
diabetogenic effect of, 14 Hydrocortisone, 29, 32, 40;
excess, 15–16 see also Cortisol
human (somatropin), 15 25-hydroxycholecalciferol (25-Hydroxyvitamin D3), 118,
Growth hormone releasing hormone (GHRH); 119, 120
somatocrinin, 9–10, 14–15 11β-Hydroxylase, in steroid synthesis, 33
Growth hormone release-inhibiting hormone, see 21β-Hydroxylase, in steroid synthesis, 32
Somatostatin 11β-hydroxysteroid dehydrogenase, 34
Guar Gum, 75 Hyperaldosteronism,
Guanine nucleotide regulatory protein(s), see G-protein(s) primary (Conn’s syndrome), 36, 40
Guanylate cyclase, 3 secondary, 36
Guanosine diphosphate (GDP), 4 Hypercalcaemia
Guanoside triphosphate (GTP), 4 effects of, 115, 125–126
Gut glucagon, 64 in hyperparathyaroidism, 114–115, 125–126
treatment, 115, 117, 125–126
Haloperidol, 13 Hypercortisolism, 32, 33;
Hashimoto’s thyroiditis, 49 see also Cushing’s Syndrome
Heat shock protein(s) (Hsp), 30, 31 Hyper glycaemia,
Hexarelin, 9 effects of, in diabetes, 67
HDLs (high-density lipoproteins), 96 in Cushing’s syndrome, 33
Hirsutism, 3.3, 37–38 management of (diabetes), 72–75
HLA system, and susceptibility to diabetes, 68–69, 78–79 Hyperinsulinism, 69, 70
Homeostasis, plasma calcium, 112, 113, 116–118, 121 Hyperparathyroidism, 114–115, 125–126
Hormone (s); Hyperphosphataemia, 115, 126
see also specific types: Hyperpituitarism;
communication, 1, 3 see individual pituitary hormones
definition of, 1 Hyperprolactinaemia, 13, 18–19
feedback mechanisms, 3–5 Hyperthyroidism (thyrotoxicosis), 50–52
mechanisms of action, 1, 3 basal metabolic rate (BMR) and, 50
of endocrine system, 2 causes of, 50, 52
of gastrointestinal tract (endocrine), 66–67 drugs used in treatment, 51, 56
 INDEX 171

main symptoms of, 50, 52, 53–54 -glucagon molar ratio, 65

secondary, 52 human, 73, 74, 82
TRH test for, 52 injection pens, 72
Hypervitaminosis D, 120 mechanism of action, 63–64
Hypoaldosteronism, 36 metabolic effects of, 60–63
Hypoadrenalism, 30, 32, 39; mixtures of, 73–74, 82
see also Addison’s disease pumps, 72
Hypocalcaemia, receptor, 63–64
tetany from, 115 receptor substrate-I (IRS-I), 64
Hypoglycaemia, 75–76 resistance, 69, 75
due to insulin excess, 70, 75 preparations, 73–74, 82
symptoms of, 76 synthesis/secretion, 59–60, 61
treatment, 76 structure, 59
Hypoglycaemic drugs, oral, 74–75, 82 and sulphonylureas,
Hypogonadism, 88, 95 combined therapy with, 80
Hypokalaemia, 36, 40 -tolerance test, 15
Hypoparathyroidism, 115–116, 120, 126–127 treatment with, 72–74
Hypophosphataemia, 114, 125 Insulin-dependent diabetes mellitus (IDDM; Type
Hypopituitarism, 15, 20 diabetes mellitus), 68
Hypothalamic-hypophyseal portal system, 8 Insulin-like growth factors (IGFs; Somatomedins), 14–15,
Hypothalamohypophyseal tract, 16 19–20, 64
Hypothalamus, 7 and GH release, 15
hormones secreted by, 8–10 receptors for, 64
feedback effects on, 3–5 Insulin lispro, 73–74
Hypothyroidism, 49–50 Insulinoma, 70
childhood (congenital), 50 Intrauterine devices (IUDs), 101–103
drug therapy, 49–50 progestogen-impregnated, 102–103
main symptoms of, 49–50 Interferon-γ, 29
tests for, 49–50 Interleukins (ILs), 13, 29, 113, 114, 121
Interstitial cells of Leydig, 10, 86–88
131I (radioactive iodine), 51 Iodination of thyroglobulin, 45–47
Immunoglobulins, thyroid-stimulating, 50, 54 Iodine (iodide)
Immunosuppression, and thyroid gland, 46–47
by corticosteroids, 29–30 use in hyperthyroidism, 51
Implants (subcutanaeous), radioactive, uses, 51
of progestogens, 99 Iodine deficiency goitre, 50
Indirect negative feedback, 4–5 Islet amyloid polypeptide (IAPP), see Amylin
Inflammatory response, inhibition by corticosteroids, 28– Islets (pancreatic) of Langerhans, 59
29 Islet cell,
Inhibin, 10, 86–87, 91–92 antibodies (ICAs), 68
Inositol (1, 4, 5)-trisphosphate (IP3), tumour of (insulinoma), 70
and mediation of hormone effects, 34, 35 transplants, 73
Insulin, 59–64 Islet cells (pancreatic), hormones secreted by, 59
actions, 60–62
deficiency of, 67–69; Juxtaglomerular cells, renin secretion by, 34
see also Diabetes mellitus
effects on glucose transporter proteins, 61–62 Ketone bodies (in diabetes), tests for, 70, 78
enzymes affected by, 63, 64 Ketosis (ketoacidosis), diabetic, 67, 76, 78–79
excess, 69, 70
172 BASIC ENDOCRINOLOGY

Lactation, Methimazole, 51
secretion and ejection of milk, 13, 17 Methyltestosterone, 89, 108
Laron dwarfism, 15 Microadenoma, 32, 38
LDL (low-density lipoprotein)-cholesterol, 48, 87, 96 Mifepristone, 101
Levonorgestrel, 98–102 Milk, see also Breast milk,
Lente insulin, 74, 82 inappropriate production of (galactorrhoea), 13, 18–19
Leuprorelin, 8, 95, 98 let-down, 17
Leydig, interstitial cells of, 10, 86–88 oxytocin and, 17
Liothyronine, (Levothyroxine sodium), 49, 56 secretion and ejection of, 13, 17
Lipodystrophy, insulin-induced, 72 Mineralocorticoids, 33–36;
Lipolysis, hormones affecting, 28, 48, 62, 65, 68 see also Corticosteroids;
Lithium carbonate, Steroids:
and thyroid hormone release, 49 actions, 34
Losartan, 36 control of release, 34–36
Lugol’s iodine solution, 51 deficiency, effects of, 36
Luteinizing hormone (LH), 10, 11, 18–20, 86, 90–95, 99, excess, effects of, 36
105–106 mechanism(s) of action, 34
preovulatory surge of, 90–92 receptors, 34, 35
Luteinizing hormone releasing hormone (LHRH), Mineralocorticoid receptor protein (MR), 34, 35
see Gonodotrophin releasing hormone Mini-pumps for insulin delivery, 72–73
Lymphokines, 29 MIT (monoiodotyrosine), 46–47
Lypressin, 17 “Moon face”, in Cushing’s syndrome, 33, 37–39
“Morning after” contraceptive pill, 98
Male hypogonadism, 88, 105–106 α/β-MSH, see Melanocyte-stimulating homone
treatment of, 88–89, 105–106 Müllerian inhibiting substance (MIS), 88
Male reproductive system, 85–89 Multiple endocrine neoplasia (MEN-1 disease);
hormonal control of, 86–87 (Multiple endocrine adenomatosis; MEA), 114–115
endocrine function of, 85 Myoepithelial cells, oxytocin effects on, 17
Mammary gland, see Breast Myxoedema, and hypothyroidism, 49, 54–55
Major histocompatability complex, 68
Median eminence, 8 Nadolol, 51
Medroxyprogesterone, 96, 98–100, 102 Nafarelin, 8, 95
Medullary carcinoma of thyroid, Nandrolone, 89
calcitonin excess in, 116 Natriuretic peptide, atrial, see Atrial natriuretic peptide
Melanocyte stimulating hormone(s) (MSH), 7, 11, 12, 32 (ANP)
Menopause, symptoms of, 93–94, 96 Nelson’s syndrome, 12
hormone replacement therapy (HRT) and, 96–97, 100– Negative feedback inhibition, 3–5
101 Neurogenic feedback (during suckling), 13–14, 17
osteoporosis and, 93–94, 121–122 Neurohypophysis:
Menotrophin (human menopausal gonadotrophins; hMG), see Pituitary gland, 7, 16
94, 106 Neurohypophyseal hormones (posterior pituitary
Menstrual cycle hormones), 16–17
hormonal control of, 91–92 Neuropeptide Y (NPY), 66
Menstruation Neurophysins, for oxytocin and vasopressin, 16
cessation of (amenorrhoea), 32, 33, 37–39, 53 Neurotensin, 66
Mesterolone, 89 Non-insulin dependent diabetes mellitus (NIDDM; Type 2
Mestranol, 96, 100, 101 diabetes mellitus), 68–69
Metformin, 75, 82 Noradrenaline, 25
Metyrapone, 33 Noradrenaline metabolites, 40
 INDEX 173

Norethisterone, 96, 98–102 Ovary,

Norgestrel, 98, 100, 102 tumours of, 95
structure, 90–91
Octreotide, 10, 16, 19–21 Ovulation, 90–92
Oestradiol, 85–86, 92–94, 96, 97, 100, 102, 108 luteinizing hormone in, 90–92
binding to plasma proteins, 94 menstrual cycle and, 91
structure of, 85 Ovulation-inducing agents, 92, 94, 98
Oestradiol valerate, 96, 97, 102 Oxyphil cells, in parathyroid gland, in
Oestriol, 92, 94, 96, 97, 102 Oxytocin, 7, 9, 16, 17
Oestrogens (female sex hormones); Estrogens: actions, 17
actions, 5, 94 clinical uses, 17
biosynthesis of by granulosa cells, 90 control of release, 17
and bone mineral homeostasis, 93–94, 96, 114, 121– in parturition, 17
123 in prolactin release, 13
in HRT preparations, 96–97, 100–102 synthesis/transport, 16
natural, 96–97
and progestogens, combinations of (for Paget’s disease of bone, 116–117
contraception), 89, 101 Pancreas, endocrine secretions of, 59–67
receptors, 95 Pancreastatin, 66
uses, 96–102 Pancreatic islets of Langerhans, hormones
Oestrone, 92, 93–94, 96–97 produced by,
Oral contraceptives, 98, 99–101; glucagon, 64–65
see also Oestrogens; insulin, 59–64
Progestogens: miscellaneous, 65–67
mechanism of action, 98, 99 Pancreatic polypeptide, 59, 66
preparations, 101 Panhypopituitarism, 15
side effects, 99, 100 Paracrine (hormone) action, 1, 10, 59, 66, 86, 87, 114,
Oral glucose tolerance test, 72, 80–81 118, 121
Oral hypoglycaemic drugs, 74–75, 82 Parafollicular cells, calcitonin secretion by, 45, 116
Osteoblasts, deposition of bone by, 113, 114, 116–118, Parathyroid glands,
121, 123 structure of, 111
Osteoclasts, bone calcium mobilization by, 113, 114, 116– inadvertent removal of, 52, 115, 126–127
118, 121, 122 Parathyroid hormone (PTH), 111–116
Osteocytes, formation of, 113 actions of, 112–114
Osteomalacia, 118, 120 control of release, 112
Osteopenia, 19, 121 cyclic AMP and, 113
Osteoporosis, 117, 118, 121–123 deficiency, 115–116, 126–127
bisphosphonates for, 123 excess, 14–115, 125–126
calcitonin for, 123 Parathyroid hormone-related protein (PTHrP), 114
glucocorticoid-induced, 121 Parathyroidectomy, effects of, 115, 126–127
oestrogens for (HRT), 96–97, 102, 123 Paraventricular nucleus (oxytocin secretion by), 16, 17
Ovarian cycle, and hormone release, 90–92 Pars distalis, 7
follicular development during, 90, 91 Pars intermedia, 7, 11, 12
hormonal regulation of, 92 Pars nervosa, 7
luteal phase of, 90–92 Peptide YY (PYY), 66
Ovarian follicle, 90–93 Perchlorate, 46
Ovarian hormones, 90–93; Pertechnetate, 46
see also Oestrogens; Phaeochromocytoma, 40
Progesterone Phosphate, 111–116, 117–118, 125–127
174 BASIC ENDOCRINOLOGY

abnormal levels of, 114, 115 Pregnancy,

in hypercalcaemia, 114, 125–126 -associated plasma protein-A (PAPP-A), 93
Phosphatidylinositol metabolism foetal-placental unit and, 93, 94
and hormone action, 3, 16, 17, 113 hormonal changes during, 92–93
Phosphodiesterase, cAMP hydrolysis by, 4 placental hormones, 92–94
Phospholipase A2 (PLA2) testing, 103
glucocorticoid inhibition by, 29 Pregnant mare urine (conjugated oestrogens from), 96, 97,
Phospholipase C, activation by hormone action, 35 102
Phosphorylation Preproglucagon, 60, 64
of insulin receptor, 63–64 Preproinsulin, 59
of key enzymes (and insulin action), 64 Preproopiomelanocortin (POMC), 11–12
Pituicytes, 16 Primordial (ovarian) follicle, 90–91
Pigmentation (skin), agents affecting, 7, 11–12, 32 Progesterone, 10, 85, 90–96, 100–101
Pituitary gland, actions, 94–95
anterior (adenohypophysis), 7 in menstrual cycle, 90–92
hyperfunction, 10–16 receptors, 95
insufficiency, 10–16 secretion, 90–92
microadenomas of, 12, 18–19, 32, 38 Progestogens, 85, 94–96, 98–103, 108
posterior (neurohypophysis), 7, 16 combined with oestrogens (for contraception), 99–101
structure of, 7 preparations, 96, 98–103, 108
Pituitary hormones, uses, 98–103
anterior, 10–16 Proinsulin, 14, 59
posterior, 16–17 Prolactin (PRL), 13–14
Pituitary function tests, 8, 15–16 actions, 13
Pituitary gonadotrophins, see Gonadotrophins control of release (dopamine and), 13, 14
Placenta, endocrine secretions of, 10, 92–94 drugs affecting secretion, 13, 14
Placental lactogen, see Human placental lactogen excess of, 13–14, 18–19
Polydipsia, Prolactin releasing/inhibiting factors, 9–10, 14
in Cushing’s syndrome, 33 Prolactinoma, 13
in diabetes mellitus, 67 Proliferative phase of menstrual cycle, 90
in diabetes insipidus, 17 Propranolol, 51
Polyuria, Propylthiouracil, 51
in Cushing’s syndrome, 33 Prostaglandins, 3, 29
in diabetes insipidus, 17 Prostaglandin synthesis (inhibition of), 29
in diabetes mellitus, 67 Prostate, benign hyperplasia of (BPH), 89
Positive feedback, 5, 91–92 Protein anabolic steroids (androgens), 87, 89
short-loop, 5, 14, 15 Protein kinase(s)
Postcoital contraception, “morning after pill”, 98 and insulin action, 63–64
Posterior pituitary gland, 7, 16 Protein kinase A, 4
Posterior pituitary hormones, 16–17 Protein kinase C, 3
see also Neurohypophyseal hormones Protirelin (synthetic TRH), 9
Postmenopausal women, hormone replacement therapy Pseudohypoparathyroidism, 115
(HRT) for, 96–97, 101, 102 PTH,
Potassium (ions), and vitamin D, interaction of, 112, 115, 119
and aldosterone secretion, 36 Pumps, for insulin delivery, 72–73
Potassium channels, ATP-sensitive, 60–61, 74
Potassium iodide tablets, 51 Quinagolide, 14
Precocious puberty, 10, 88
Prednisolone, 28 Radioactive iodine (131I),
 INDEX 175

and thyroid gland, 51, 52 and oral contraceptives, 100

Receptors (hormone), and signal transduction and thyroid hormones, 48–50, 54–55
mechanisms, 1, 2, 4 Sodium
5-α-Reductase, 87 and water, balance of, effects of mineralocorticoids,
deficiency, 88 34
inhibitor, 89 Somatomedins, 14, 15;
Relaxin, 93 see also: Insulin-like growth factors (IGFs),
Releasing hormones (hypothalamic), 8–10 and GH release, 15
Renin, Somatostatin (SS);
secretion, 34 Somatotrophin-release
hypersecretion, 36 inhibiting hormone (SRIH), 10, 11, 15, 16, 19–21, 59,
Renin-angiotensin (-aldosterone) system, 34 60, 65, 66
Reproductive organs, effects of sex steroids, 87, 94 actions, 10
Retinoic acid, 30 analogue, 10, 16, 21
Reverse T3 (rT3), 46, 48, 50, 52 and GH release, 14–15
structure of, 46 clinical uses, 10, 16, 21
Rheumatoid arthritis, glucocorticoids in, 28 and TSH secretion, 11
Rickets Somatotrophin (GH; growth hormone),
nutritional, 118, 120 actions, 14
vitamin D-dependent (type 1), 118 clinical use, 15
vitamin D-dependent (type 2), 120 control of release, 14–15
deficiency of, 15
Sodium (ions), diabetogenic effect of, 14
retention, hormones causing, 34, 36, 40–41, 89, 99, excess, 15–16
100 human (somatropin), 15
Salcatonin, 115, 117, 123 Somatotrophs, 8
Saline diuresis, in hypercalcaemia, 115, 126 Somatropin, 15
Sarcoidosis, 120, 125 Sotalol, 51
Schwartz-Bartter Syndrome, 17; Spermatogenesis, control of, 86
see also Syndrome of inappropriate ADH (SIADH) Spironolactone, 34, 36, 41
Second messenger systems, 1 Src-homology 2 (SH2) protein domain, 64
Secondary diabetes, 68 Stanozolol, 89
Secondary hypoadrenalism, 32 Steroid(s)/steroid hormone(s), 1, 3, 26, 27, 30–31, 85–87,
Secondary (ovarian) follicles, 90, 91 94–95, 117–119;
Secretin, 60, 66 see also Glucocorticoids;
Selective oestrogen receptor modulator (SERM), 123 Mineralocorticoids;
Sermorelin, 9 Vitamin D:
Serotonin (5-hydroxytryptamine; 5-HT), 9, 13 adrenal, see Corticosteroids
Sertoli cells, 10, 86 anabolic, 89
Sex characteristics, anti-inflammatory action, 29
oestrogens affecting (female), 94 receptors, 30–31, 34–35, 87–88, 95, 118
testosterone affecting (male), 87 synthesis inhibitor drugs, for cancer chemotherapy,
Sex hormone-binding globulin (SHBG), 87, 94 98
Sex steroids, 25, 85 -treatment cards, 30
SH2 domain proteins, 64 Steroid-carrying plasma proteins, 26, 87, 94, 95, 118
Short-acting insulin, 74 Stilboestrol, 97–98
‘Short-loop’ feedback, 5 Stones, renal, and hyperparathyroidism, 115
‘Sick euthyroid’ syndrome, 52 Stress,
Skin, and ACTH/cortisol secretion, 12, 13, 30
176 BASIC ENDOCRINOLOGY

and GH secretion, 14–16 structure, 45

and prolactin secretion, 13–14 Thyroid function tests, 53–54
glucocorticoids affecting resistance to, 30 Thyroid hormone(s), see T3/T4
Striae (abdominal), in Cushing’s syndrome, 33 actions, 47–49
Sulphonylureas, 74–75, 82; receptor mechanisms, 48–49
see also Oral hypoglycaemic drugs, structure, 46
potassium channels and, 61, 74 synthesis, 46–47
Subcutaneous implants, see Implants transport of, 46
Supraoptic nucleus (ADH secretion by), 7, 16 control of release, 10–11, 47
Syndrome of inappropriate hypersecretion of ADH Thyroid stimulating hormone (TSH; thyrotrophin), 3–4,
(SIADH), 17 10–11, 46–47, 49–50, 52, 53–55
Thyroid-stimulating immunoglobulins (TSIs), 50, 53–54
T3 (triiodothyronine), and T4, (tetraiodothyronine; Thyroid storm, 52
thyroxine), 10, 11, 45–52, 53–55 Thyroidectomy, 51–52
Tamoxifen, Thyroiditis, subacute, 52
for breast cancer, 98 Thyroid-pituitary relationships, 11, 47
TBG (thyroxine-binding globulin), 46, 52 Thyrotoxic crisis, 51, 52
Testes, 85–89 Thyrotoxicosis, see also Hyperthyroidism
-blood barrier and, 86 effects of, 50
endocrine function of, 87 factitia, 52
hyperfunction, 88 treatment, 51
hypofunction, 88, 105–106 Thyrotrophin (TSH):
structure, 85–86 see Thyroid stimulating hormone
undescended (cryptorchidism), 88, 92 Thyrotrophin releasing hormone (TRH), 9–11, 13, 14, 47,
Testosterone, 85–88; 52
see also Androgens Thyrotrophs, 8
actions, 87 Thyroxine (L-thyroxine sodium)
baldness and, 87 actions, see T4
clinical uses, 88–89 -binding globulin (TBG), 46, 52
control of release, 10–11, 86–87 -binding prealbumin, 46
mechanism of action, 87–88 biosynthesis/secretion, 45–47
preparations, 88, 108 control of release, 47
structure, 85 structure, 46
Tetany, in hypocalcaemia, 115, 126–127 uses, 49–50
Testosterone enanthate, 88 TNF-α:
Testosterone proprionate, 88 see Tumour necrosis factor-α
Testosterone undecanoate, 88 Tolazamide, 75, 82
Tetracosactrin, 11, 32, 39–40 Tolbutamide, 75–82
Thiazolidinediones, 75 Toxic multinodular goitre, 52
Thiocyanate, 46 Toxic nodule (solitary), 52
Thiourea derivatives (thionamides), 51 Transcalciferin, 118
Thyroglobulin, 10, 45–47 Transcortin, 26
Thyroid gland, 45 Transforming growth factor-β (TGF-β), 88, 121
and antithyroid drugs, 51, 56 TRH test, 52
and beta-blockers, 51 Triamcinolone, 28
carcinoma of (follicular type), 52 Trifluoperazine, 13
dysfunction, 49–52 Tri-iodothyronine (liothyronine),
function, control of hormone release, 10–11, 47 actions, see T3
medullary carcinoma of, 116 receptors for, 48–49
 INDEX 177

secretion, 47 Vitamin D3 (cholecalciferol), 117–120

structure, 46 VMA (vanillylmandelic acid), 40
3, 3′,5′-Triiodothyronine (T3), structure of, 46
3, 5,3′-Triiodothyronine (rT3), structure of, 46 Water (fluid) excretion of, hormones affecting, 16–17,
Troglitazone, 75 33–36
Trophic hormone(s), 3–5, 7, 10–16 Weight gain, due to oral contraceptives, 99, 100
Trousseau’s sign, in tetany, 115, 126–127 Withdrawal bleeding,
Truncated glucagon-like peptide (tGLP-1), 60 in oral contraception, 99, 100
Tumour necrosis factor-a, 13, 29, 121 in HRT, 100, 101
Turner’s syndrome, 95
Type I diabetes mellitus: Zinc, insulin preparations containing, 73, 74
see Insulin-dependent diabetes mellitus (IDDM) Zollinger-Ellison syndrome, 66
Type 2 diabetes mellitus: Zona fasciculata of adrenal cortex, 25
see Non-insulin dependent diabetes mellitus Zona glomerulosa of adrenal cortex, aldosterone release
(NIDDM) from, 25, 27, 34, 36
Tyrosine derivatives, iodination of, and thyroglobulin, 46, Zona reticularis of adrenal cortex, 25
47

Ultralente insulin, 82
Urine, glucose tests of, 70, 78
Uterus
and oral contraceptives, 99–100
endometrial cancer of, 98, 99, 100
oxytocin stimulation by, 17

Valsartan, 36
Vasoactive intestinal polypeptide (VIP), 66, 67
Vasopressin:
see Antidiuretic hormone (ADH)
Verner-Morrison Syndrome, 67
Virilization,
21β-hydroxylase enzyme deficiency and, 32
in Cushing’s syndrome, 33
5-α-reductase deficiency and, 88
Vitamin D, 111–114, 116, 117–121
actions, 118, 120
analogues, 120, 128
and PTH, interaction of, 112, 113, 118, 119
deficiency, 118, 120
excess (hypervitaminosis D), 120
malabsorption/deficiency and hypocalcaemia, 118,
126–127
metabolism, 113, 117–119
receptors(VDRs) for, 118
structure, 119
Vitamin D-binding globulin (transcalciferin), 118
Vitamin D-dependent rickets (type 1), 118
Vitamin D-dependent rickets (type 2), 120
Vitamin D2 (ergocalciferol), 117–120