UMSLE REVIEW STEP 1

ENDOCRINE
PHYSIOLOGY

© 2017JUAN CRUZ-ECHEVARRIA

PHYSIOLOGY
LECTURE NOTES
 Endocrine Physiology | Physiology 101
I. Introduction to endocrinology:
1. Endocrine glands (Ductless glands) = glands that secrete their product directly into the blood
stream rather than through a duct. In other words, produce hormones and release them into
blood circulation.
• Pancreas is an example of an organ with endocrine (islets of pancreas) and exocrine
(enzymes through ducts) glands.
2. Hormone (means I Excite / arouse) = chemical messengers released from endocrine glands
directly into blood stream and enters target organs.
Hormone Specificity:
• A hormone affects only cells that possess receptors specific to that particular hormone.
• Example: ACTH & LH (both produced by anterior pituitary) ↑secretion of steroid
hormones; but ACTH does this in Adrenal cortex & LH in gonadal tissue (because of
specific receptors that are present in target tissue).
3. Major Endocrine Organs in our body
• Hypothalamus is an endocrine gland. Made up of • Adrenal cortex:
neurons that can produce hormones Aldosterone, cortisol,
• Anterior Pituitary Gland: FSH, LH, ACTH, TSH, PRL, androgens
and GH • Adrenal medulla: E, NE
• Posterior Pituitary: Oxytocin and ADH • Ovary: Estrogen,
• Thyroid: TH, Calcitonin progesterone
• Parathyroid: PTH • Testis: Testosterone
• Pancreas: somatostatin, glucagon, insulin • Pineal gland: melatonin

4. Some of the Non- Endocrine Organs producing hormones

Organ Hormone Function
Heart ANP and BNP produced from heart ventricles. When chambers of heart are filled
with lots of blood volume. If congestive heart failure, ANP and BNP
levels are increased because of volume overload in heart chambers.
GIT CCK, secretin, VIP, and Gastrin VIP = vasoactive intestinal peptide
Kidney Erythropoietin and 1,25 Erythropoietin – stimulate bone marrow to make more RBCs.
Dihydroxycholecalciferol
Pineal Gland Melatonin Sleep wake cycle
Skin 7-dehydrocholesterol from skin gets UV light converts cholesterol to Vit D. The cholesterol in skin made to
converted to cholecalciferol on 7-dehydrocholesterol. Sources of Vit D in body: dietary vit D and skin
exposure to sunlight cholesterol.
Liver Insulin-like growth factors IGF-1&2 stimulated by GH from anterior pituitary

5. Types of Secretion
A. Endocrine Secretion
Example: Thyroid follicular cells release Thyroid hormone (T3 and T4) into the blood stream. These hormones
reach target organs via the blood (most every tissue). It regulates basal metabolic rate (BMR) in all tissues.
B. Neuroendocrine Secretion
Example: Hypothalamic neurons synthesize ADH and Oxytocin which is carried to Posterior Pituitary via
Hypophyseal tract. This later gets released to act on target organs.

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6. Classification of Hormones
I. Based on chemical Structure:
A. Steroid Hormones= derived from cholesterol.
1) Adrenal cortical (adrenal cortex) steroids = Aldosterone, cortisol, and androgens.
2) Gonads:
• Male: testosterone
• Female: estrogen, progesterone.
3) Active Vitamin D (1,25 DHCC)
B. Proteins and Polypeptides Hormones:
• Anterior and posterior pituitary • Calcitonin
hormones • Insulin
• Hypothalamic hormones • Glucagon
• Parathyroid hormones
C. Amino acids derivates (amine hormones)
• Catecholamines = Tyrosine is the precursor of epinephrine (more amount – 80%), Norepi 20%
(adrenal medulla) NE also produced by the postganglionic neurons of the sympathethic nervous
system, dopa, dopamine (Tyrosine Hydroxylase is the rate limiting enzyme)
 Epinephrine
 Norepinephrine
 Dopamine - produced in neurons (CNS and Kidneys – sympathetic post ganglionic
neurons and binds to D1 receptors causing vasodilation).
• Triodothyronine(T3)
• Thyroxine(T4)
II. Receptor location and Receptor interaction - solubility of the hormones in the fluid (if soluble – called
water soluble. If not, called lipid soluble)
Cell Surface Receptors Intracellular Receptors
Solubility Water Soluble Hormones Lipid Soluble Hormones
Examples Rest of all Hormones  Steroid Hormones (cytoplasm or cytosol)
Examples: Peptide hormones & Amine hormones  Thyroid Hormones (nucleus)
(except Thyroid hormones)
Acting Fast acting (mins to hours) Slow acting (hours to days)
Synthesis Already synthesized and stored (this is the reason only synthetized when there is an appropriate stimulus
and Storing of why they are fast acting) (when needed by the body). Exception: TH and Steroid
are synthetized and stored and attached covalently to PP.
Transport Transported (free or unbound) and half-life is > 99% lipid soluble hormones are bound to PP (globulins)
shorter (determined by the MW of these hormone (< 1% is found as free form). Therefore, have a longer
molecules. half-life (greater affinity, longer the half-life)
Action Carry the action within the target cell by activating Produced brand NEW proteins within the target cells.
second messenger system (cAMP, IP3+DAG, NO, Ex. Aldosterone stimulus increases production of ENaC in
cGMP, tyrosine kinase (insulin’s)) and modify the P cells at the Late DT and CD.
protein existing within the cell.
7. Hormones acting on cell membrane receptors act via production of second messengers
1) cAMP:
a) CRH f) Calcitonin and PTH
b) ACTH, TSH g) Catecholamines (most actions)
c) FSH, LH h) hCG
d) MSH i) Glucagon
e) ADH/AVP - V2 receptors - P cells of kidney
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 Endocrine Physiology | Physiology 101
2) cGMP - causes smooth muscle relaxation.
a) **ANP = inhibit reabsorption of sodium in Late DT and CD. It also causes relaxation of mesangial cells
increasing surface area for filtration. Therefore, causes loss of water and sodium in the urine.
b) Nitric Oxide or Endothelial Derived Relaxing Factor (EDRF) = in cardiovascular physiology is produced
by the endothelial cells and goes into the smooth muscle and causes relaxation.
3) Calcium\Phosphatidyl Inositol Triphosphate (IP3) = induce muscle contraction
a) TRH
b) GnRH
c) VASOPRESSIN via V1 receptors (in arterioles)
d) GHRH
e) OXYTOCIN - ejection of milk and contraction of uterus during delivery
f) CATECHOLAMINES (some actions in α1):
 NE (sympathetic post ganglionic)
 Epinephrine (in high amounts - freely)
 Dopamine - contraction of smooth muscle
g) ATII - AT1 Receptors that causes vasoconstriction.
4) Tyrosine Kinase/ Phosphatase:
a) Growth Hormone
b) Prolactin
c) Insulin

G-protein contains αβγ subunits. The α (αs =

stimulatory; αi = inhibitory or αq) is bound to GDP when
hormone is not bound. This G protein is coupled with a
hormone receptor and an effector molecule that can
be adenylyl cyclase or phosphatase C. When the
hormone binds to the receptor, there’s a
conformational change (displace GDT and converts
GTP into GDP and Pi = GTPase activity) and αs stimulates the effector molecule.

8. Mechanism of hormone action via interaction with cell membrane receptors

• Mainly takes place via formation of second messengers. (Water soluble hormones)
• Second messengers carry information from cell surface to interior of the cell.
• Second messengers involved are cAMP, IP3 (Inositol triphosphate), Tyrosine Kinase & Ca 2+ -Calmodulin complex
• G-protein is Guanosine triphosphate (GTP) binding protein which helps in coupling hormone receptor to the
effector molecules
I. cAMP / Adenylate cyclase Mechanism:

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Examples:
A. β1 receptors (androgenic receptors) on heart
are present everywhere: SA node, AV node,
atrial muscle, ventricular muscle.
Norepinephrine from postganglionic
sympathetic nerve endings, circulating
epinephrine from medulla or administer
dopamine can stimulate these receptors and
cAMP↑.
1) Ventricles, Ca channels become
phosphorylated. Open them and increase
more Ca into cell. Ca-dependent Ca
release. Also, phospholamban gets
activated; sequesters more Ca into SR.
2) ↑HR (SAN), conduction velocity (AVN), and FOC.
• Positive chronotropic, dromotropic, inotropic effect. All due to cAMP ↑.
B. β2 Receptors in smooth muscle relaxation stimulated by epinephrine which is circulating in blood in blood
vessels and bronchioles (lungs).
C. M2 receptors in heart (no in ventricles) are also associated with G protein (but with alpha-inhibitory subunit,
Gαi subunit). This GPCR is associated with adenylate cyclase. When activated, it inhibits effector molecule.
When parasympathetic nerve endings release Ach onto M2, G protein releases GDP and binds GTP. Now
inhibits adenylate cyclase. cAMP ↓. So, HR, CV, FOC ↓.
D. ADH on V2 receptors in renal tubules phosphorylate and bring AQP-2 channels to membrane.
• Subunit = Gq
• Effector molecule = PLC.
1) Gq activates PLC to break down phospholipids(PIP2) into
DAG and IP3.
2) IP3 goes to endoplasmic reticulum or SR to release Ca2+
o Test Question: **What is the substance that is
released from activation of PLC mechanism? Ca2+
3) DAG and Ca2+ activates Protein Kinase C (PKC* - not PKA as
for cAMP).
• Recall water soluble hormones that uses this mechanism.

II. Mechanism of hormone action via interaction with

intracellular receptors
• Steroid (cytosolic receptors) & Thyroid hormones
(nuclear receptors)
• These hormones diffuse across the cell membrane of target cells and bind to a nuclear receptor
• Binding to a nuclear receptor causes a conformational change in receptor
• Initiates transcription  production of new mRNA  Translation in cytoplasm  production of new
specific proteins which brings about the physiologic actions

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• The steroid hormone diffuses across the cell membrane and
enters its target cell (Step 1),
• Binds to a specific receptor protein (Step 2) that is located in
either the cytosol or nucleus. Steroid hormone receptors are
monomeric phosphoproteins (Each receptor has six domains).
• The steroid hormone binds in the E domain located near the
C-terminus. The central C domain has two zinc fingers*, and
is responsible for DNA-binding.
• With hormone bound, the receptor undergoes a
conformational change and the activated hormone-receptor
complex enters the nucleus of the target cell.
• The hormone-receptor complex dimerizes and binds (at its C
domain) to specific DNA sequences, called steroid-responsive
elements (SREs) located in the 5′ region of target genes (Step
3).
• The hormone-receptor complex has now become a
transcription factor that regulates the rate of transcription of
that gene (Step 4).
• New messenger RNA (mRNA) is transcribed (Step 5), leaves the nucleus (Step 6), and is translated to new
proteins (Step 7) that have specific physiologic actions (Step 8).

➢ Example: Aldosterone in principal cell of the Late DT and CD, makes more Epithelial Na channels, which are
recruited to membrane to reabsorb more Na. Takes several hours. *K+ sparing diuretics blocks the binding of
aldosterone to its receptors.
9. Hormone Synthesis
A. Peptide hormone synthesis:
1) In the nucleus, the gene for the hormone is transcribed to mRNA.
2) The mRNA is transferred to the cytoplasm and translated on the ribosomes of the ER to a protein
(preprohormone) Eg. Preproinsulin = signal peptide + insulin + c-peptide
3) Pre-pro-hormone is precursor of peptide hormone in Rough Endoplasmic reticulum which gets converted to
Prohormone (cleave of signal peptide) and transported to golgi apparatus. (proinsulin = insulin + c-peptide)
4) In Golgi apparatus, Prohormone (proinsulin = insulin + c-peptide) is packaged in the secretory vesicle in
which it gets converted to final hormone (insulin) which then are stored in secretory vesicles.
➢ β Cells of the pancreas produces insulin (insulin and c-peptide are stored in vesicles), when insulin is release,
the insulin and c-peptide (same amount) are released in the blood circulation.
• These cells are stimulated by high concentration of glucose, AA, and FA produced after meal. In between
meals (during fasting), glucose is reduced and insulin production decreases.
• Insulinoma = β Cells tumor excess production of insulin and c-peptide and don’t respond to low glucose levels
and continuous to produce insulin leading to hypoglycemia. This person can lose consciousness. Follow the
protocol at ER: levels of glucose (hallmark: ↓[Glucose] and ↑C-peptide).
• Differential to Type 1 DDM is the levels of C-peptide (because these pts develops hypoglycemia when fasting).
B. Steroid Hormones - are derivatives of Cholesterol
• Amine Hormones: Ex. From Tyrosine
a) Thyroid hormones
b) Catecholamines: Epinephrine, Norepinephrine, and dopamine)
▪ Tyrosine hydroxylase is the rate limiting enzyme*

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10. Regulation of Hormone Secretion - Mainly controlled by the Hypothalamus-pituitary axis through two types of
Regulation.
• Endocrine gland produces only specific amount of hormone. Therefore, it needs a feedback mechanism.
Hypothalamus-pituitary axis: hypothalamus makes (releasing or inhibitory hormones) cause Anterior pituitary
to release hormone to affect endocrine gland.

A. Negative feedback *Every endocrine gland has a negative feedback mechanism. (most important mechanism)
▪ Most common type of feedback mechanism
▪ An ↑ [hormone] or their effect directly/indirectly inhibits further secretion of that hormone (maintain it in
optimal levels)
▪ For example:
1) βcells of Pancreas secrete Insulin due to ↑ [Glucose] and ↓blood [glucose] by
↑ glucose uptake by the cells. Consequently, ↓blood glucose inhibits further
Insulin secretion.
2) Thyroid Hormone Negative Feedback Loop
1. Hypothalamus produces TRH (Thyrotropin releasing hormone)
2. TRH stimulates thyrotropes (basophilic cells) from anterior pituitary gland
to release the TSH.
3. TSH ↑secretion of T3 & T4 by the Thyroid Gland.
TSH is needed to produce thyroid hormones, when no present thyroid goes
into atrophy.
T3 (triiodothyronine) & T4 (thyroxine) are lipid soluble hormones, so > 99%
are bound to plasma proteins in blood; while < 1 % is free T3 & T4. The free
form is the one that will have the negative feedback*.
 If T3 & T4 production by the thyroid gland ↑, the free form of the thyroid hotmones will go to the
hypothalamus and the AP gland to ↓TRH and TSH.
 If T3 & T4 ↓, negative feedback goes down and leads to ↑production of T3 & T4 by ↑production TRH
and TSH.

B. Positive feedback - (rare) a hormone has biologic actions that

directly/indirectly causes more secretion of that hormone.
Example: Luteinizing hormone (LH) from Anterior pituitary gland
stimulates secretion of Estrogen from ovaries. This Estrogen in turn
causes more secretion of LH as a positive feedback mechanism.
1) The normal duration of the menstrual cycle is 28 days. The
menses occurs from the first 1-5 days and at the Day 14,
ovulation happens (Graafian or mature follicle).
2) Hypothalamus makes gonadal releasing hormone (GnRH).
3) GnRH acts on gonadotrophs of anterior pituitary gland to make
LH and FSH – go to ovaries to make estrogen.
4) The estrogen will be low during the first 7 days it is low during menses. Estrogen levels ↑ continually from
day 5 to 14 and peak at mid ovulation (24 to 48 hours before day 14).
5) Once the Estrogen levels gets really high, only when reaches the peak** of estrogen in blood, cause AP gland
to release a lot of LH and FSH (LH and SFH surge). This is positive feedback.
 Estrogen actually has two peaks. Second causes luteal phase.

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 Low levels of estrogen have a negative feedback - suppress LH and FSH. Eg. Oral Contraceptives (Chances of
pregnancy decreased).
11. Regulation of Hormones:
A. Down Regulation of receptors: Chronic high circulating levels of a hormone can ↓ the number of its receptors
on the target cell. This is also known as Tissue resistance = reducing the effect of the hormone in the target
cells.
What determines hormone effect on target tissues?
a) level of hormone
b) number of receptors
Examples:
a) Chronically elevated plasma Insulin ↓ the number of Insulin receptors as seen during early stages of Type II
Diabetes Mellitus. (In late stages, they have to take exogenous insulin).
b) In uterus, Progesterone (affects uterus) down regulates its own receptors and receptors for Estrogen.
➢ Exception to Down regulation: Hormones which are secreted in a pulsatile manner = hormones are produced in
pulses, every few minutes or hours in order to remain constant preventing resistance.
Examples: All hypothalamic hormones (releasing/inhibitory hormones) that regulate AP. GnRH, GH, ACTH,
Cortisol do not have down-regulation of receptors because of their pulsatile release
- The gonadotropin releasing hormone (GnRH) released form hypothalamus go to AP and bind to GnRH receptors
on gonadotrophs. ↑ release of LH and [Link] hypothalamus continually releases it, then AP will downregulate
GnRH receptors. So, it releases it in pulses.
➢ Question: If infuse GnRH, what happens to LH and FSH levels?
a) Continuous infusion: initially high LH and FSH levels. Then, levels decrease over time.
b) Pulsatile infusion: high LH and FSH levels.

B. Upregulation of receptors = ↑number of receptors on the surface of target cells, making the cells more
sensitive to a hormone (when ↓ levels of the hormone).
Examples:
1) In ovary, low levels of estrogen up regulate its own receptors and receptors for LH (Luteinizing hormone)
from 5-14 day of menstrual cycle in order to increase the estrogen levels. This also increases sensitivity for
the cells on ovary for LH.
2) An ↑ in uterine Oxytocin receptors are seen in the third trimester of pregnancy, promoting the uterine
contraction – uterus should be more sensitive to oxytocin.

12. Transport of Hormones = Free form & Bound form - Free and bound form are at equilibrium*
A. Water soluble hormones – Free (unbound) form (globulins, albumins and pre-albumins)
Examples: Peptide, protein hormones, and Catecholamines
• It is the free hormone that is available to the tissues and Free Unbound form normally determines Plasma
Activity.
• It is available for physiological activity (gets out the vascular compartment) and negative feedback
mechanism (present in all endocrine glands).
B. Lipid soluble - Bound form
Examples: Steroid & Thyroid hormones
• Liver produces proteins that bind to these lipid-soluble hormones.
• 70% transported by globulins.
*Examples: Cortisol Binding Globulin (CBG), Thyroid Binding Globulin (TBG), Estrogen/Testosterone Binding
Globulin.

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Condition Total Hormone Bound Free
Liver disease or liver failure ↓ ↓ ↔
Initially ↑ and negative feedback ↑,
so ↓ secretion and free form to
going back to normal.
Pregnancy/Oral Contraceptive ↑ ↑ ↔
- (Estrogen) Initially ↓ and negative feedback ↓,
so ↑ free form to going back to
normal.
Estrogen to a male ↑ testosterone ↑testosterone ↔
Initially ↓ and negative feedback ↓,
so ↑ free form to going back to
normal.
Androgens ** ↓ ↓ ↔
▪ Free form and bound form are in equilibrium.
▪ If total [hormone] ↑ due to ↑bound form, and the free form remains normal = physiological act and negative
feedback remains normal.
▪ If total [hormone] ↓ due to ↓bound form, and the free form remains normal = physiological act and negative
feedback remains normal.

13. Binding proteins = synthesized in Liver

• Estrogen* causes release of more binding proteins by the liver
• Liver dysfunction and Androgens* = ↓ circulating levels of binding proteins = ↓total lipid soluble hormone
levels, but free form levels remain same.
• Body builders and weight lifters taking androgens (testosterone) to increase protein synthesis in order to
increase muscle bulk. ↓Plasma Proteins = T3 and T4 bound form ↓ = free form lipid soluble hormones ↑ =
↑negative feedback = ↓ TRH and TSH = ↓ secretion of T3 and T4 = Total T3 and T4 levels ↓ and bound form ↓,
but Free form is brought back to normal.

14. During Pregnancy:

• Estrogen levels are ↑ and causes release of more binding proteins. Therefore, plasma levels of bound
hormone are elevated, but free hormone is at normal level.
• Since Free hormones are the active form, no signs of Estrogen hyperfunction (excess) are seen (no
hyperthyroidism).
• Blood values - This happens with pregnancy with every lipid soluble hormone in circulation.
▪ Total lipid soluble hormones as Total T3 and T4 ↑
▪ Bound form ↑
▪ Free form ↔ Normal
▪ TRH and TSH ↔ (normal as long as T3 and T4 are normal).

15. Liver failure or Cirrhosis = PP production by liver ↓ = Free T3 and T4 initially ↑ = negative feedback ↑= TRH
(hypothalamus) and TRH (ant pituitary) ↓ = T3 and T4 free in blood levels comes back to normal. Bound form of T3
and T4 ↓ and ↓ Total T3 and T4 = TSH and TRH goes back to normal.

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II. Hypothalamus
1. Hypothalamus connected to Hypophysis by
pituitary stalk (connected functionally):
A. Adenohypophysis (ant pituitary) – grown
from bottom to top from pharyngeal
epithelium (Rathke’s pouch):
1) basophilic cells (blue):
a) Corticotropin = ACTH
b) Thyrotropin = TSH
c) Gonadotrophs = LH and FSH
2) acidophilic (pink) - more abundant:
a) Somatotroph = GH
b) Lactotrophs = PRL
3) chromophores cells = don’t stain due to lack of secretory
granules and no produces any hormone. Both basophilic and
acidophilic cells once they deplete their secretory granules
gave rise to them.
B. Neurohypophysis (post pituitary) – grown from top to down
(neurons and nerve terminals)

▪ Most common tumors are acidophilic tumors (more abundant

cells) that produces hormones (Functional tumors) that can be GH
or PRL, from which Prolactin-oma** is the most common. (Q)
▪ 2nd MC tumors: Chromophobe cells can also lead to tumor, but
they can grow in size, but not produce any hormones (non-
functional tumor)
▪ What regulates function of anterior pituitary gland?
▪ Hypothalamus has a collection of cell bodies are known as
nucleus (arcuate, PVN, preoptic nucleus) that go down through a collection of axons (tracts).
They release:
a) releasing hormones - TRH, CRH, GnRH, GHRH
b) inhibitory hormones - GHIH, PIH.
▪ These hormones are release from median eminence to the AP through the hypothalamic hypophyseal portal
blood vessels* (this is how hypothalamus is connected to Posterior Pituitary Gland). This vessel releases
inhibitory hormones to the AP (they are physiologically connected through this vessels).

2. Action of Hypothalamic Hormones:

Hypothalamic Hormones Target Pituitary Hormones Target Cells
CRH produced by PVN Corticotrophobes cells release Adrenal Cortex produces cortisol (ZF) and androgens (ZR).
ACTH **Deficiency of ACTH can lead to atrophy of these zones. (Don’t
confuse AII that causes release of aldosterone from ZG)
TRH produced by PVN Thyrotrophes cells release TSH Thyroid Gland secretes T3 and T4
GnRH produced by PO Gonadotrophes cells release Hypothalamic-Pituitary-Gonadal Axis:
FSH and LH Ovaries = progesterone (ovulation)
Testes = testosterone (spermatogenesis)
Conditions: Deficiency in any hormone of the pathway leads to
hypogonadism.
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GHRH produced by AN Somatrophes cells release GH Everywhere (generalized) - regulates growth of body.
Somatostatin (GHIH) Inhibit Somatrophes cells *** If GHRH and GHIH are low, overall GH secretion will decrease
produced by PVN blocking the GHRH action and (because GHRH is the most important regulator).
therefore inhibits release GH
Prolactin Inhibitory D2 Receptors in Lactotrophs Prolactin normally stimulates milk production and growth of breast
Hormone (PRIH), also cells of AP to inhibit PRL tissue.
known as Dopamine, is secretion
produced by AN

PVN (PARA VENTRICULAR NUCLEUS) - CRH, TRH, GHIH

AN (ARCUATE NUCLEUS) - acidophil (GH and prolactin) regulating hormones (GHRH and dopamine)
PO (PREOPTIC NUCLEUS) - GnRH

- AP is majorly regulated by releasing hormones (and not inhibitory hormones) except for prolactin.
- Hypothalamic hormones produced in pulsatile fashion (which prevents the down regulation of hormones).
- All hormones from AP are regulated by Releasing Hormones, with the exception of PRL which is regulated by
inhibitory hormone.
- What happened if infusion of hypothalamic hormones continuously, what will be the effect in the AP?
AP secretion initially ↑ and eventually will ↓ because the receptors in the AP will be down regulated.

Condition All AP hormones PRL

Infusion of Hypothalamic Hormones in a ↑ ↓
Pulsatile Manner
Hypothalamic Damage/Pituitary Stalk ↓ ↑ (hyperprolactinemia)
Pituitary Damage (Ischemia to AP) ↓ ↓ * Only form of PRL to decrease.

- *If there is ischemia/destruction to AP, what happens? Depends on where the AP is destroyed. There is a
sequence.
1) Usually 1st to be destroyed is GH. 3) TSH
2) 2nd to be destroyed is FSH, LH 4) ACTH
(gonadotropins) 5) Last to go away is prolactin.
- GH levels (as for the other AP hormones) can ↓ with destruction of:
1) Hypothalamus
2) pituitary stalk
3) AP gland
- GH drop does not affect adults too much.
- If ACTH levels decrease, what portion of adrenal cortex atrophy? Zona fasciulata (cortisol) and
zona reticularis (androgens).
- When do we make prolactin? When PRIH levels ↓. There’s two important physiological
condition when get hyperprolactinemia.
1) During pregnancy
2) during lactation
- **Dopamine will also go to lactotrophs via D2 receptors on it.
1) Parkinson’s disease – ↓levels of dopamine. Give L-dopa. Will bind D-2 receptors.
2) Schizophrenia – dopamine levels ↑, so we give drugs that block dopamine. Dopamine
receptor antagonists. Will block D-2 receptors, and thus result in hyper-prolactinemia
(because PRIH cannot bind).

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3. Hypothalamus as a seat of control for other endocrine glands

▪ ACTH goes to Adrenal Cortex Fasiculata (Cortisol) and Reticularis
(Androgens).
▪ Posterior pituitary has histology. Pitenusites? Are found there.
▪ Posterior pituitary hormones made in Paraventricular nucleus
(Oxytocin) and Supraoptic nucleus (ADH)
▪ Anterior pituitary stimulating hormones are made in
paraventricular (somatostatin, TRH, CRH), preoptic (GnRH) and
arcuate nucleus (GHRH, PRIH or dopamine)).

4. Hypothalamo – Hypophyseal Portal System

a) If damage to hypothalamus = Posterior pituitary hormones ↓
 Deficiency of ADH – Central DI or neurogenic
 Oxytocin levels
b) If the damage to Posterior Pituitary Gland = hormones will not be
deficient because are synthetized in hypothalamus and can be
release whenever are the nerves endings into the blood
circulation.

5. Relationship of Hypothalamus to the Posterior Pituitary:

• Hypothalamic neurons secrete ADH (SON) & Oxytocin (PVN)
which are packaged in secretory granules and transported by
Hypothalamo – Hypophyseal tract (axons) to Posterior Pituitary.
• In Posterior Pituitary, they are stored, to be released when
required.

6. Classification of Hormonal Disorders - all glands controlled by

hypothalamus and anterior pituitary.
Based on site of hormone defect (either increased or decreased
secretion). Endocrine disorders are classified as:
A. Primary Disease: If defect is in the target gland from which
hormone has originated
B. Secondary Disease: If defect is in the Anterior Pituitary
C. Tertiary Disease: If defect is in Hypothalamus
Examples:
• Hypothyroidism:
• Primary Thyroid deficiency is due to decreased secretion of thyroid hormone from the Thyroid gland
(↓bound and free T3 & T4, no negative feedback and TSH and TRH are high in blood) - *most common
• Secondary Thyroid deficiency is due to deficiency of Anterior pituitary hormone which stimulates
production of Thyroid hormone from the Thyroid gland (↓TSH, bound and free T3 & T4, ↑TRH)
• Tertiary Thyroid deficiency is deficiency of Hypothalamic hormone (↓TRH, TSH, bound and free T3 & T4)

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• Hypogonadism
• Primary hypogonadism – gonads stop functioning.
 menopause – gonads stop functioning and estrogen goes ↓, GnRH and LH and FSH ↑.
• Secondary Hypogonadism – problem with AP ↓LH and FSH
• Tertiary Hypogonadism – due to damage to the hypothalamus, ↓ GnRH and LH and FSH.
7. What happens if there is a damage to the Pituitary stalk?
• Pituitary stalk is a connection between Hypothalamus & Pituitary
• In a lesion involving the Pituitary stalk, there is neurovascular damage. Secretion of all pituitary hormones
decrease EXCEPT Prolactin (PRL). Why? Because the only thing produced from anterior pituitary is PRIH or
dopamine which inhibits prolactin.
• If there are ↑levels of PRL = Hyperprolactinemia.
▪ Galactorrhea = milk production in a non-lactating woman.
▪ Can happen with hypothalamic and pituitary stalk damage.
▪ **Males can present with gynecomastia, but never galactorrhea (man can’t lactate).
Note: Growth hormone (GH) ↓ even though GH inhibiting hormone is absent because it is GHRH which is the main
regulator of GH secretion
8. Give Physiological basis for:
1) Hypothyroidism with Galactorrhea? ↑PRL and ↓T3 and T4 that can be due to damage to hypothalamus or
pituitary stalk.
• TSH ↓ = TRH↓ = ↓thyroid hormones.
• Dopamine ↓ = PRL↑ hyperprolactinemia = galactorrhea
2) Dwarfism with Galactorrhea? ↓GH and ↑PRL that can be due to damage to hypothalamus or pituitary stalk
(deficiency of GHRH and dopamine).

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III. Pituitary (Hypophysis) is considered a master gland because it controls various endocrine glands in the body.
▪ Neurons synthetize trophic hormones that
are release into the hypophyseal portal
system which carries the trophic hormones
directly to the AP and neural tract for PP
gland.
▪ Anterior Pituitary Gland:
1) chromophobe – do
not have granules.
Don’t stain.
2) acidophilic (eosin -
pink) = somatotroph,
lactotroph
3) basophilic
(hematoxylin -
blue)– thyrotrophs, gonadotrophs and
corticotrophs.
▪ MC tumors: (1)Acidophilic, (2) chromophobic
tumors, and (3) basophilic tumors.
1. The Pituitary Gland has 2 lobes:
a) Anterior lobe/anterior pituitary/
Adenohypophysis - trophic hormones
1) FSH (Follicle stimulating hormone)
2) LH (Leutinizing hormone) / ICSH (Interstitial cell stimulating hormone)
3) ACTH (Adrenocorticotropic hormone) / Corticotropin
4) TSH (Thyroid stimulating hormone) / Thyrotropin
5) PRL (Prolactin) / Luteotropic hormone (LTH) / Luteotropin /Lactogenic hormone/ Mammotropin
6) GH (Growth hormone) / Somatotropin / STH
b) Posterior lobe/posterior pituitary/ neural lobe: ADH (Vasopressin) and Oxytocin

2. There are 5 types of active chromophilic (cells which can be stained) secretory cells in Anterior pituitary. They can
be acidophilic or Basophilic.
▪ The following are cells seen in Anterior Pituitary:
A. Acidophilic (PG) B. Basophilic (FLAT)
1) Somatotropes - which secrete Growth 3) Corticotropes - secrete ACTH
hormone 4) Thyrotropes - secrete TSH
2) Lactotropes (also called 5) Gonadotropes secrete FSH & LH
Mammotropes) - secrete Prolactin

3. Intermediate lobe of the Pituitary = rudimentary in humans

▪ In lower animals, they secrete α & β MSH (Melanocyte stimulating hormone) / Melanotropin which is
responsible for pigmentation.
▪ In humans - ACTH has MSH like activity
▪ ACTH binds to Melanotropin-1 receptors & causes Melanin production giving rise to pigmentation
▪ Therefore, ↑ACTH secretion as seen in Addison’s Disease causes Hyper pigmentation

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▪ Corticotrophs hyperstimulation will release ACTH which has MSH properties – hyperpigmentation may be seen
(excess ACTH).
4. Pro-opiomelanocortin (POMC) = found in Anterior and Intermediate lobes of Pituitary
▪ POMC is a precursor for ACTH & MSH in corticotropes cells.
▪ When ACTH is produced it is made as large protein POMC (pro opiomelanocortin) – this is broken down
into two important molecules: ACTH and MSH.
▪ MSH has a β melanocyte stimulating property – stimulate monocytes
▪ ACTH can also stimulate melanocytes.
▪ If someone is producing too much ACTH they are making too much β-melanocyte stimulating hormone –
these both stimulate melanocytes to be stimulated.
▪ You would see more ACTH with the problem in the adrenal cortex (Addison’s)
▪ Addison’s Disease = not enough cortisol is being produce and endocrine system lack of negative feedback. It
produces ↑CRH = ↑ ACTH = affects all three levels of adrenal cortex
 more ACTH and more B-MSH will be up as well and you will see hyperpigmentation.

5. Human growth hormone (HGH): (Somatotropin / STH)

• Growth hormone (GH) is a single chain polypeptide, also known as somatropin that is release from somatrophs
from anterior pituitary gland.
• It is species specificity – means only works in human
• Structural resemblance to PRL (Prolactin) & Human Placental Lactogen (HPL) – produced by placenta during
pregnancy. Also, Insulin. (The three uses tyrosine kinase secondary messenger pathway).
• GH released in a pulsatile manner, because GHRH is secreted in pulsatile manner (more frequent during
sleeping)
• Mechanism of action: Acts via cell membrane receptors via Secondary Messenger system: Tyrosine Kinase (as
insulin)***
• **If GH is produced in excess, it can also bind to GH receptors and PRL receptors, because structurally they
resemble. Thus, GH can also have prolactin effects on body.

Regulation of GH secretion
A. Role of Hypothalamus: Hypothalamus regulates GH secretion via Growth hormone releasing hormone (GHRH)
and GH inhibiting hormone (GHIH / Somatostatins)
• GHRH =stimulates synthesis & secretion of GH
• GHIH (Somatostatin) = inhibits secretion of GH by blocking response of anterior Pituitary to GHRH
• Treatment for GH tumor, can prescribe somatostatins to ↓ its effects. Example: Somatostatin analogs. **

B. Negative feedback control by Somatomedins (SM):

• Somatomedins (SM) are also called Insulin-like growth factors (IGF 1 & 2) which are produced mainly by the
LIVER.
• GH binds to its receptors on liver and Somatomedins (IGF-1 or SM-C) are produced.
• ↑GH levels = ↑ secretion of SMs by the liver= inhibits (-) GH secretion by stimulating (+) secretion of
Somatostatin (GHIH) from Hypothalamus
• IGF-1 = SM-C has a negative feedback on the hypothalamus that inhibits GH secretion from AP.

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1) GHRH binds to receptors on somatotrophs
and ↑release of GH.
2) GH goes to target tissues, especially liver,
skeletal muscle, kidney.
3) Liver produce Somatomedins insulin-like
growth factor IGF-1, also own as
somatomedin C (Sm-C). This is the hormone
that primarily and directly makes tissues
grow.
• What makes long bones grow length?
IGF-1 (not because GH directly)
4) The Somatomedin-C ↑ the release of
Somatostatin (GHIH) from hypothalamus
which inhibits GH release from Anterior
pituitary.

6. Factors Affecting Growth Hormone Secretion

A. Stimulatory Factors: B. Inhibitory Factors:
1) ↓ [glucose] (fasting hypoglycemia) ** bc GH 1) ↑ [glucose] (hyperglycemia)
increases blood glucose levels. 2) ↑ [free fatty acid]
2) ↓ [free fatty acid] 3) Obesity
3) Arginine** 4) Senescence – getting older (> 60 years old)
4) Fasting or starvation 5) Somatostatin - (GHIH)
5) Hormones of puberty (estrogen, testosterone - 6) Somatomedins – via negative feedback (IGF-1)
androgens) 7) Growth hormone
6) Exercise and Stress 8) β-Adrenergic agonists
7) Stage III and IV sleep – sleep is recommended in 9) Pregnancy
growing ages due to stimulation to GH. **
8) α-Adrenergic agonists – no imp.

Stimulatory Test – when you suspect deficiency of secretion of a hormone.

1) Induce hypoglycemia (by giving insulin)
2) Administer Arginine
• With this stimulatory test, normally GH levels should ↑ and if GH levels don’t ↑– pt has deficiency. (you can
also give GH if deficiency is suspected).
• Hypofunction (Hypopituitarism/ GH deficiency): Failure of growth hormone release after arginine injection
• Hyperfunction (Growth hormone secreting adenoma): Failure of glucose to suppress growth hormone.

• Counter-regulatory hormones = GH, Glucagon, Catecholamines (E and NE), and Cortisol raise during
hypoglycemia to ↑ [glucose]
• Measure GH at night because this is short half-life and only stays around a short time. (water soluble)

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7. Control of GH secretion:
• GH is regulated by GHRH and GHIH (somatostatin) – produce production of IGF (somatomedins)
• GH secretion is pulsatile more likely to occur during the night in stage III and IV (non-REM) of sleep than during
the day
• **Secretion of GH requires presence of normal levels of thyroid hormone (normal functioning of thyroid gland is
required)
o GH secretion is markedly ↓ in hypothyroid individuals.
o GH and Thyroid Hormones (enhances the effect) work together in order to ↑ the effect in growing
bones (permissive effect).
- Clinical Presentation: If child has hypothyroidism, then child will have lower GH hormones and less
growth. TH has synergistic effect on growth of bones with IGF-1. If thyroid hormone is ↓, then ↓ GH.
• During the 6th Decade of life (60 years old) and later (Senescence), GH secretion ↓ considerably in both men and
women.
• GH is a stress hormone (other stress hormones are Glucagon, cortisol and Epinephrine – these hormones ↑
glucose levels in stress conditions). They are known as counter regulatory hormones.
• ↓ [Glucose] stimulates these hormones during fasting and starvation.
o If one is deficient, they don’t compensate and will not be able to raise glucose levels. The patient will
present with hypoglycemia (during fasting – in between meals which is a stress to the body) ***
o However, one of them in excess can cause hyperglycemia.

8. Actions of Growth Hormone:

A. DIRECT CATABOLIC actions = GH binds to receptor and makes functions (mostly catabolic - Breaks down
glycogen and breaks down fat)
B. INDIRECT ANABOLIC actions = Growth, cartilage & Protein metabolism are Indirect actions of GH & are
mediated by Somatomedins/IGF-1 (essential for the growth of and individual, especially for the skeletal growth).
IGF-1 ↑ protein synthesis and this is known as Anabolic Effect.

Somatomedins = polypeptides synthesized mainly in liver. Also synthesized in kidneys, cartilage & skeletal muscles.
• In humans, most important is Insulin-like growth factor (IGF-1) also called Somatomedin- C
• Circulate in blood binding to protein (half-life is very long 20 hrs because is bound), blood IGF level serves as a
reflection of 24-hr growth hormone secretion as GH is secreted in pulses. (Free GH has a half-life of 20 mins, so
we prefer to measure the IGF-1 because is bound and has a longer half-life).
a) IGFs ↑ the lean body mass, because has anabolic effect.
b) IGF ↓ with age. Therefore, in old age, the ↓ in lean body mass is attributed to ↓ IGF
c) IGF is also ↓ in catabolic states, especially PEM (protein energy malnutrition = ↓AA = ↓IGF-1).

1) Stimulation of growth of bones, cartilage & connective tissue: (main action of GH) – mediated mainly via IGF-1
or Somatomedin C (Indirect Action)
a) On Bones & cartilage (Before epiphyseal closure):
• GH causes liver to secrete IGF-1 (SM) which in turn causes proliferation of Chondrocytes
(Chondrogenesis) at the epiphyseal plates of long bones ↑length of long bones
• GH ↑ of [Osteoblasts] which turns the cartilage into bones.
• It also stimulates DNA & RNA synthesis & collagen formation in cartilage
*Net result = ↑ thickness of epiphyseal cartilaginous end plate - ↑linear skeletal growth. Seen
maximally during puberty due to ↑GH secretion resulting in Pubertal Growth Spurt*, because
hormones associated with puberty such as testosterone and androgens.

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• Bone = is form of an organic matrix made of collagen with an inorganic matrix made of hydroxyapatite,
which is Ca2+ and PO4- (phosphate) deposition together.
• Puberty there is a growth spurt because of hormones associated with puberty. (testosterone and
androgens)
b) After Epiphyseal closure (Fusion) - towards the end of
puberty.
• No ↑ in bone length, because when closed there’s no
cartilage (no linear growth).
• *But, the periosteum still grows resulting ↑ in bone
thickness through periosteal growth.
• ↑ protein synthesis in most organs causing hyperplasia
(↑ cell numbers), hypertrophy (↑ cell size)  ↑tissue
mass and ↑organ size
– All under the influence of IGF-1.

2) Effect of GH on Carbohydrate Metabolism:

a) This is a direct action of GH. Therefore, doesn’t need IGF-1.
• GH is a Diabetogenic hormone ie; ↑blood sugar
• GH causes Hyperglycemia by ↑Hepatic glucose output by:
i. promoting gluconeogenesis* by the liver (also stimulated by cortisol, epinephrine and glucagon)
which needs: amino acids from skeletal mucle, lactate from anaerobic glycolysis, and glycerol
(from TAGs produced from lipolysis)
ii. ↓peripheral utilization of glucose (Anti-Insulin Effect) by skeletal muscle and adipose tissues.
▪ ↓ GLUT-4 transporter recruitment, so glucose↑ leading to hyperglycemia (key symptom of
these patients) will go to the β-cells of pancreas and will produce more insulin.
b) On Fat metabolism = direct Catabolic Effect - mobilizes fat from adipose tissues by ↑Lipolysis (via
hormone sensitive lipase). Doesn’t require IGF for this action.
• ↑ Free fatty acids (FFA) which are further used for Gluconeogenesis (↑ acetyl CoA)
• Ketogenic- GH Produces FFA which undergo hepatic β-oxidation and form Ketone bodies from excess
acetyl CoA
➢ Acidophilic tumor (GH tumor) will present with hyperglycemia. If it last for long time, insulin levels production by β
cells of the pancreas ↑. Eventually, β cells will burn out and insulin levels ↓and patient develops pituitary diabetes
due to chronic hyperglycemia (due to excess of GH).

c) Effect of GH on Protein metabolism: Indirect action which requires IGF

• GH is a Protein Anabolic Hormone
• ↑ uptake of Amino acids and stimulates synthesis of DNA, RNA and Protein
• ↑protein synthesis in muscle & ↑lean body mass
• ↑protein synthesis in organs & ↑ organ size
• GH ↑ protein synthesis indirectly.
• GH secreting tumor = ↑organ size (Liver, heart, kidney)
9. Other actions of GH
• *↑ milk production – as it has structural similarity to PRL (Galactorrhea)
• GH usually (+) erythropoiesis = ↑ RBCs
• GH deficiency will lead to anemia.
• ↑ calcium absorption from GIT (Not major function)
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10. Growth Changes – Testable Facts
• **During puberty, if T3 & T4 is normal, ↑androgens drive ↑GH secretion, which drives ↑IGF-1.
• In males, androgen arise from testes; and in females, from ovaries.
• **Near the end of puberty, androgens promote the mineralization (fusion or closure) of the epiphyseal plates
of long bones and stop bone growth at the end of the puberty. (Test Question)
• If androgens ↓ towards the end of the puberty, the mineralization of the bones will not have happened and
epiphyseal plate will keep growing (Androgen Insensitivity Syndrome (AIS), grow taller because Androgens
receptors are not responding)

11. Clinical correlates of Anterior Pituitary

1) DWARFISM = Occurs due to GH deficiency (due to hypothalamic, pituitary gland or stalk damage) which results
in Short stature/Stunted growth.
• Endocrine causes for dwarfism are:
a) Panhypopituitarism = lack of all Anterior Pituitary hormones (especially during childhood or
adolescence)
b) ↓ GHRH (from hypothalamus) = hypothalamus or stalk damage
(and/or) ↓ IGF-1 = low levels of GH
c) Hypophysectomy = Removal of Pituitary gland
d) Hypothyroidism = GH requires normal thyroid hormone
• Remember: Most important hormone in growing is GH that produces IGF-1 (causes the growth).
A. Pituitary dwarfism= due to GH deficiency results in Short stature due to Growth retardation. Dwarfs**
• Other associated features: ↓hair growth due to ↓protein synthesis, fasting hypoglycemia*,
Immature genital organs leading to sexual immaturity. Hypoglycemia stimulates ↑GH, IGF, and
cortisol in a healthy individual, so GH is not present and the others can compensate during fasting
developing hypoglycemia.
B. Laron Dwarfism = due to GH insensitivity (resistance). In this genetic condition, plasma GH levels ↑,
but GH receptors are defective (tissues are insensitive and can’t produce IGF-1 in liver).
• Investigations reveal, ↑GH and ↑GHRH levels & markedly ↓IGF-1 (as production of IGF-1 is
dependent on interaction of GH with its receptors) due to lack of negative feedback of
somatomedins***. These patients will develop short stature (dwarfism).

➢ Differences between: GH and thyroid hormone have a permissive effect to promote growth. Hence, TH is
needed to secrete GH.
Pituitary Dwarfism: Hypothyroid dwarf (Cretin):
Due to hypothalamus or pituitary stalk damage Cretinism – TH deficiency during first year of life or adolescence
Cause: ↓ GH, ↓GHRH Cause: ↓TH (T3 & T4)
Clinical Features: Clinical Features:
 Plumpness, Immature face,  Gross retardation of mental & physical development***
 Small genitalia  *Infantile body proportion (bigger skull and short trunk)
 Body proportion according to chronological age  Other features of hypothyroidism
 Delayed skeletal & dental development  During the first year of life develops mental retardation,
 ↓circulating levels of GH because TH is needed during this period for CNS maturation.
(hypothyroidism causes irreversible mental retardation)
 Physical retardation can be reverse, but mental is irreversible.

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➢ Clinical Case Study: Parents of a 4year old child come to you with complains that their child is short for his
age. Hormonal assays in the child reveal ↓GH levels:
a) On giving GHRH infusions, if GH levels start increasing, where is the site of defect?
Hypothalamus or Pituitary Stalk
b) On giving GHRH if GH does NOT increase where is the site of defect? Anterior Pituitary Gland

12. Adenomas = tumors arising from glands. They are usually benign tumors (meaning they do not spread or
metastasize to any other organs. They just grow).
1) *1st MC = prolactinoma (PRL)
2) *2nd MC = non-secretory adenoma or non-hormone producer (chromophobes tumors) Patients will not
present with any excess of hormones, but the size of pituitary gland will be growing.
3) 3rd MC = somatotrophs (GH).
4) 4th MC = corticotrophs (ACTH)

• Macroadenomas – tumor growing > 1 cm

• Microadenomas – tumor growing < 1 cm
• Pituitary gland sits in sphenoid bone, Sella turcica. Above of it overlies the optic chiasm.
• Presentation: usually present with headache and visual abnormalities.
• Macroadenomas are dangerous because pituitary gland sits in the sella tursica of the sphenoid bone, so they can
have increased cranial pressure and as tumor grows it can push on optic chiasm presenting visual defects
(bitemporal hemianopia) and the levels of hormones (especially from normal areas) will be decreased.

13. Growth Hormone excess:

A. Before Puberty
• Gigantism = overproduction of GH during adolescence, before puberty (before epiphyseal closure) – Results
in excessive growth of long bones (excess IGF-1)-
• Clinical features:
o ↑↑Tall (8 ft) of hands and feet.
o Other associated features:
▪ Male: Bilateral Gynecomastia (enlargement of breasts due to structural similarity of GH to
PRL)
▪ Female: Galactorrhea
o They can present with hyperglycemia.
o Coarse facial features due to ↑ tissue proliferation
o After pass through puberty can develop acromegaly.

B. After Puberty
• Acromegaly= excessive secretion of GH during adulthood (after
epiphyseal closure)
• Causes of Acromegaly are:
▪ Acidophilic tumor of anterior pituitary
▪ Hypothalamic GHRH secreting tumors (no imp).
• Associated with ↑↑ PRL effects
• Clinical features:
o Mainly seen due to growth of cartilaginous (peripheral) areas

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o Prognathism - elongation & widening of mandible (membranous bones increase in size, supraorbital ridges
become prominent). The patient can develop maloclussion.
o Supra orbital ridges becomes prominent (brow)
o Bulbous nose
o Facial changes seen are described as ACROMEGALIC FACIES – There is thickening of skin & coarse facial
features - Proliferation of connective tissue resulting in Facial edema (also seen in Gigantism)
o Increased Blood glucose levels (as GH is diabetogenic) - hyperglycemia (>200 mg/dL)
▪ So can develop pituitary diabetes.
❖ Glucose tolerance test = give glucose to a pt. who is fasting and you measure glucose levels after 2hrs. In a
normal person, the glucose levels should be normal, but if pt. has GH secreting tumor then they normally
have hyperglycemia so the glucose tolerance test would be positive  they would have high glucose levels
after administration of glucose.
o Kyphosis - periosteal growth of vertebrae
o Enlarged hands & feet (Acral parts) - periosteal growth of metatarsals & metacarpals.
▪ Patient will complaint in ring, glove, hat or shoe sizes. **
o Hypertrophy (and hyperplasia) of soft tissues
▪ Heart (Cardiomegaly) = eventually results in Heart Failure (MCC of death in patients with
acromegaly) **
▪ Liver (Hepatomegaly)
▪ Kidney (Renomegaly)
▪ Spleen (Splenomegaly)
▪ Muscles and Tongue (macroglossia), so will trouble breathing at night = apnea
o In 4% male cases - Gynecomastia (breast enlargement because of structural similarity of GH to PRL)
o Visual field defects if pituitary tumor compresses Optic Chiasma (temporal field is affected because nasal
fibers of the optic nerve are compressed leading to Bilateral hemianopia/hemianopsia) – due to pituitary
tumor growing (a patient trying to move the car)
o Optic nerve arises from retina. Two fibers of the optic nerve.
▪ Vision Towards the nose = nasal-visual field. Fibers carrying this
is temporal fibers (closest to nose) - opposite site.
▪ Vision Away from nose/periphery = Temporal-visual field (fibers
carrying this is nasal fibers (farther from nose) - same site.
▪ Thus, the chiasm has nasal fibers crossing each other. The
pituitary gland can compress nasal fibers, carrying temporal
field/periphery vision.
❖ Do an MRI = detect excess GH and IGF-1.

14. Treatment of GH Excess:

• Surgery to remove the pituitary tumor (approaches through the sphenoid bone through the nose), but initially
medically can be treated with Somatostatin analogues (GHIH)* which inhibits GH secretion
• Example: Octreotide and Lanreotide

➢ Case Study: A 25-year-old lady who has just delivered a baby, has severe Post-partum hemorrhage (delivery of fetus
and placenta). Couple of months later she presents to the Physician with amenorrhea, loss of hair, failure to lactate
and signs of Hypothyroidism. Hormonal assays reveal ↓ TSH, FSH, LH and ACTH levels. What could be the probable
diagnosis in this case?
Dx. post-partum pituitary necrosis or Sheehan’s syndrome (Damage to the Anterior Pituitary Gland)

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• Amenorrhea = absence of menstrual cycle due to FSH and LH ↓ (target cells: ovaries).
• Signs of hypothyroidism because ↓ TSH = secondary hypothyroidism
• Failure to lactate = ↓PRL (not given in stem)
15. Causes for Pituitary Insufficiency:
• Panhypopituitarism = ↓ secretion of all Anterior Pituitary hormones
• Anterior Pituitary insufficiency commonly occurs in females with post-partum hemorrhage resulting in a clinical
condition known as Sheehan’s Syndrome, which is Post-Partum Pituitary necrosis.
• Anterior Pituitary which is highly vascular, gets enlarged during pregnancy.
• During childbirth, if mother suffers Post-partum hemorrhage (that can be from the site the placenta is attached),
↓BV, BP and blood vessels goes into vasocontraction and perfusion to the organs reduced. Therefore, the
pituitary goes into ischemia leading to Pituitary infarction & necrosis – giving rise to ↓ levels of all the anterior
pituitary hormones resulting in Panhypopituitarism.
• Posterior Pituitary hormones are not affected as ADH & Oxytocin are synthesized by Hypothalamic neurons
o Why only after the delivery and not before delivery or no pregnancy?
▪ Because during pregnancy, the pituitary gland grows bigger in size/enlarged due to ↑ in number
and size of lactotrophs to produce more prolactin in pregnancy. Thus, blood flow ↑.
• Treatment for post-partum hemorrhage. Depends on hormones present or deficient.

16. Other pituitary hormones:

• FSH, LH – Reproductive functions
• TSH - Regulation of thyroid secretion
• ACTH: Stimulates release of Adrenocortical hormones

17. Prolactin (Lactogenic / Mammotropic / Galactopoietic hormone) = single chain polypeptide

• Receptors resemble GH receptors (Structurally similar) - GH can bind these receptors and cause lactation.
• ↑during two physiologic events: pregnancy & lactation
• If woman has high prolactin and comes in look for galactorrhea. (first thing you should do is a pregnancy test)
• 2nd messenger for GH and PRL? Tyrosine kinase. Thus, both can affect both.
• PRL is at basal level in males and not lactating female due to pulsatile secretion of PIH.

18. Physiological actions of PRL

• PRL is a major hormone responsible for Lactogenesis
• Stimulates milk production (most important) in the breasts by formation of Casein & Lactalbumin (during
lactation, because during pregnancy women don’t produce milk).
• Stimulates breast development along with Estrogen
• **Inhibits Ovulation by ↓synthesis & release of Gonadotropin Releasing Hormone (GnRH) from Hypothalamus
= ↓LH & FSH = ↓ gonads function leading to hypogonadism (male or women can lead to this effect) –
o female ↓ estrogen and progesterone leading to ↓ ovulation (not ovulate during pregnancy and
lactation)and patient present with amenorrhea
▪ Primary amenorrhea (never got menarche), secondary (reduced ovarian function and
↓Estrogen), and tertiary (hyperprolactinemia)
o Male ↓spermatogenesis (due to ↓FSH) due to ↓ in testosterone (due to↓LH) production.
Sx. Man will complaint of loss of libido (loss sexual desire due to decrease testosterone), infertile and
impotent.
o *Pt with hyperprolactinemia usually present with hypogonadism.

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19. Regulation of prolactin secretion
1) Hypothalamic control: Via Dopamine (PIF) & Thyrotropin releasing
hormone (TRH)
• PRL secretion is tonically inhibited by Dopamine (Prolactin inhibiting
factor – PIF) secreted by Hypothalamus
• TRH from Hypothalamus ↑PRL secretion
2) Negative Feedback Control: PRL (-) its own secretion by stimulating
Hypothalamic release of Dopamine which bind D2 receptors on lactotrophs
of anterior pituitary to decrease prolactin levels.

• If prolactin is high, it goes back to hypothalamus and stimulates

production of dopamine to inhibit prolactin release/synthesis from AP.
• If the patient has hypothyroidism will have high TRH and *prolactin levels
can also be stimulated by high TRH levels. Ex: primary and secondary
hypothyroidism, will have high TRH. = will have hyper-prolactinemia.
 ***TRH can go into anterior pituitary (especially TRH in high levels) can
increase production of prolactin
 In Hypothyroidism (thyroid gland issue – primary) – low T3 and T4 in
blood so there will be no negative feedback so TRH and TSH will be high
the TRH will want to make TSH but will also make prolactin. (Under
normal condition TRH doesn’t affect prolactin)
 Nipple stimulation at the breast, will (+) stimulate brain to produce more
PRL (find pathway).

➢ If the case stem has evidence of ↑ PRL:

1) rule out pregnancy (PRL elevates in pregnancy and lactation)
2) rule out hypothyroidism (due to ↑TSH)
3) if hypogonadism, suspect PRL ↑ = ↓GnRH = ↓FSH and LH

20. Factors affecting PRL secretion:

Factors ↑ PRL Secretion Factors ↓PRL Secretion
1) Estrogen (during pregnancy stimulates lactotrophes 1) Dopamine (PIH)
to secrete PRL) and inhibits milk producing action in 2) Dopamine receptors agonist:
the breast tissue. After delivery of placenta, a) Bromocriptine
estrogen levels ↓ and milk is produced. b) Cabergoline
2) Suckling of nipple due to breast feeding (lactation) 3) Somatostatin analogs (GHIH)
3) TRH in hypothyroidism a) Octreotide
4) Dopamine antagonists (D2 receptor blockers). b) Lanreotide
 Antipsychotics used in schizophrenia (dopamine 4) PRL by negative feedback
levels are elevated)
Prolactinoma treatment: Bromocriptine along with
somatostatin analogs*
NOTE: Estrogen inhibits mRNA production & inhibits synthesis of milk proteins. THEREFORE, ESTROGEN ↑ PRL
secretion but INHIBITS actions of PRL

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▪ Lesions of Hypothalamic – pituitary stalk gives rise to sustained lactation (Galactorrhea), because PIF
(Dopamine) from Hypothalamus cannot inhibit PRL & there is a sustained increase in PRL levels which leads to
Galactorrhea due to hyperprolactinemia.
21. Galactogogues = substances which increase milk secretion used in in treating lactational deficiencies seen in
Anterior pituitary lesions which can result in failure to lactate in nursing mothers.
Examples: TRH analogues and Dopamine (PIF) antagonists

22. Clinical aspects of hyperprolactinemia= PRL excess resulting from:

a) Hypothalamic lesions – due to loss of inhibitory control of PIF (Dopamine) on PRL secretion
b) Prolactinomas – PRL secreting tumors of Anterior Pituitary (MC Ant. Pituitary tumors)
Clinical Features:
• Galactorrhea - production of milk in non lactating women.
• Amenorrhea (Lack of Menstrual cycles) is seen because PRL inhibits GnRH release from Hypothalamus causing
↓FSH & LH & failure to ovulate
• In females – Infertility ↓function of ovaries & Amenorrhea
• In males – inhibits GnRH release from Hypothalamus causing ↓FSH & LH, leading to Gynaecomastia &
Impotence, infertility, loss of libido
Treatment: Dopamine agonists like Bromocryptine/Cabergoline which ↓ PRL secretion and/or somatostatin
analogs.

23. Multiple endocrine neoplasia type 1 (MEN1) = autosomal dominant familial tumor syndrome (also known as
Wermer syndrome) where eople develop tumors of the parathyroid glands, the enteropancreatic neuroendocrine
system, the anterior pituitary gland, pancreatic, and the skin.
o Remember the (3) Ps (or 4 if add peptic ulcers):
1) Parathyroidoma (PTH) that can cause hyperparathyroidism which results in hypercalcemia* most
common and most important presenting feature** Patients can present with renal stones and
drowsiness (hypercalcemia inhibits the nerve and brain function that can even leads to comma or loss of
consciousness).
2) Pancreatic tumors:
a. **Gastrinoma – gastrin secreting tumors. Pancreatic tumor secreting gastrin. Gastrin stimulates
release of HCl from Parietal cells, this can result in peptic ulcers.
b. Insulinoma – insulin secreting tumors.
c. Carcinoid tumors
3) Pituitary adenoma - most common is prolactinoma*

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IV. Posterior Pituitary Gland
1. Posterior Pituitary hormones are:
a) Antidiuretic hormone (ADH) which is also called as
Vasopressin (SON)
b) Oxytocin (PVN)
• Hormones synthesized by the Hypothalamic nuclei
• Travel down nerve axons (tract) and are stored in the
nerve terminals of the Posterior Pituitary gland to be
secreted when required.
• Damage to SON will decrease ADH, but can decrease
OXT too because both nuclei produces both hormones.
Know which principal for what hormone. ***
• Exam Question: A Patient has Central DI and there’s no
SO in choices, just PVN (that’s the answer)!!!

2. Antidiuretic Hormone (ADH) or Arginine Vasopressin (AVP)

• ADH is also called Vasopressin because of its vasoconstrictor action (when is present high levels) via V1
receptors (IP3-DAG secondary messenger mechanism) in blood vessels and arterioles ↑TPR.
• Originates in Supraoptic nucleus (SON) of Hypothalamus, transported by its carrier protein Neurophysin II.
• ADH exerts Antidiuretic effect via V2 receptors (P cells of LDT and CD). ADH action is by stimulating Adenylyl
cyclase activity (cAMP) in renal tubules to recruit AQP2
• The major factors regulating ADH secretion are:
1) Changes in plasma Osmolarity (Osmotic stimuli via osmoreceptors in/around the anterior hypothalamus) =
by regulating [Na+]. Even if there is a 1% change in plasma osmolarity, there will be ADH change. Normal =
275-290 mosm/L
2) Volume changes in ECF or Plasma - If change in ECF/plasma volume, will be change in BP*.
3. Factors that influence ADH secretion
Stimulated by: Inhibited by:
• ↑ plasma/ECF osmolarity (via osmoreceptors)– • ↓ plasma/ECF osmolarity (means ↑ BV)
more sensitive (even 1% change to osmolarity) • ↑ plasma/ECF volume
• ↓ plasma/ECF volume (via baroreceptor) • ANP/BNP – produced by atria when ↑ BV/BP
• Angiotensin II (released when ↓ BV/BP) • Alcohol*
• Pain/stress • Weightlessness*** Example: when going to water
up to the neck. Important concept for USMLE.

▪ Osmoreceptors are simply neurons. If ECF/plasma osmolarity is high, the osmoreceptor neurons shrink and
send signals to the pre-optic (supra-optic) nucleus to release ADH.
▪ *Alcohol = inhibits ADH secretion = ↑ water loss in urine = ↑ECF osmolarity= ↓ Urine Osmolarity = Dilute
urine.
▪ ↓ gravity effects = systemic veins on the leg to get dilated = ↑ VR to the right side of heart = ↑ BP
increases = Baroreceptors gets stretched and send inhibitory signals to the SON = ↓ ADH secretion.
▪ ↓BP/BV = ↑RAA Mechanism = ↑ Renin = ↑ ATII = ↑ ADH.

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4. Osmoreceptors and ADH secreting neurons are located very close to each other in hypothalamus
• ADH is synthesized predominantly in SupraOptic Nucleus of
hypothalamus and stored in posterior pituitary
• Osmoreceptors (OR’s) are stimulated by ↑ osmolarity of
ECF/plasma and in turn activate ADH neurons and thirst center
in the hypothalamus.
• The SO and PVN receive information from arterial baroreceptors
• Secretion of ADH is most sensitive to plasma osmolarity;
however, if BV↓ or cardiac output fails, the high levels of ADH
are secreted even if it causes low plasma osmolarity *** in
order to ↑BV and BP.
• Example: CHF ↓ cardiac output = ↓ BP = ↑ ADH secretion to
↑BV = ↓ osmolarity = ADH will not go down. (Hypoosmotic
volume expansion). This patient will develop hyponatremia –
Aldosterone also increases (more Na to ECF), but ADH adds
more water to ECF.

5. Cellular mechanism of action of ADH in principal cells of DT and CD

1) When ADH secretion is stimulated, it binds to V2 receptors
in the P cells of the Late DT and CD.
2) ADH activates Gs α subunit which activates adenylyl cyclase
and ↑ cAMP.
3) cAMP activates PKA.
4) PKA phosphorylate proteins.
5) These recruit aquaporins (AQP2) to luminal membrane
from intracellular vesicles.
6) Epithelial cell membrane of late distal tubule and
collecting ducts more permeable to water so can absorb
water back.

6. Clinical aspects: Diabetes Insipidus (DI) - syndrome of Vasopressin deficiency or resistance to ADH. These patients
make dilute urine. Principal symptoms: polydipsia and polyuria.
A. Central or Neurogenic Diabetes Insipidus = Complete or Treatment: Treat the cause.
partial failure of ADH secretion (Diseases of ▪ Treat hypercalcemia.
Hypothalamus/Posterior pituitary) ▪ Remove antibiotics.
Causes: ▪ Remove lithium
a) Idiopathic (cause is unknown)- 30% ▪ Also, thiazide diuretics + NSAIDs. Thiazide
b) Malignant or benign tumors of the brain or pituitary - diuretics cause the loss of fluid because of
25% (Eg: Craniopharyngioma in children that arises loss of sodium. ↑ renal function, so more
from Rathke’s pouch remnants to AP and can result in water can be reabsorbed. Not clear
damage to hypothalamus and PP) mechanism, but body tries to respond to
c) Cranial surgery - 20% change in volume by either
d) Head trauma - 16%; ex: MTA (motor traffic accident) downregulating or upregulating AQPs.
e) Stroke that can lead to ischemia.
f) Hypoxia, anoxia to hypothalamus. Infection (encephalitis).

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▪ Case Scenario: Head Trauma patient present to the ER and now in the next 24 hours patient excrete 15L of
urine. Dx. Central/neurogenic DI.

B. Peripheral Diabetes Insipidus = Complete/partial failure of kidneys to respond to ADH due to mutations or
resistance in V2 Receptors / Aquaporins.
Causes
a) Lithium carbonate = treat Bipolar mood disorders, it impairs the ADH stimulatory effect on adenylate
cyclase, resulting in less cAMP (1/3 patients)
b) ↓ Aquaporin 2 expression (↓AQP 2 mRNA levels) results in resistance to actions of ADH)
c) **hypercalcemia (> 11mg/dl) = (Normal Ca2+ Plasma levels: 9-11 mg/dL) if goes > 11mg/dL ↓ effectiveness
of ADH in renal tubules and can’t reclute AQP2 and can’t reabsorb water. Calcium levels ↑ because the
patient is losing more water.
d) Other Drugs:
a. Amphotericin B c. Ofloxacin = fluoroquinolones
b. Demeclocycline = used to block ADH d. Cortisol = blocks ADH receptors.
receptors (Was commonly used in SIADH, e. Hereditary due to mutation in AVP
but now physician use Tolvaptan and receptor gene or the AQP2 (congenital)
Conivaptan)
Clinical features: Differentials Between DI and Primary Polydipsia:
• Polyuria = loss of large volumes of urine (3-20 Liters/day) A patient comes to your clinic with polydipsia and
due to deficiency of ADH that leads to ↓renal water polyuria, and Low Uosm:
reabsorption by CD. (Normal urine levels = 0.05-3 L/day) 1) Put the patient in a Water deprivation test.
• These patients produce diluted urine with low This will make primary polydipsia better, as
osmolarity (< 300mOsm/L). Remember from Renal Uosm ↑ to normal, Posm ↑ and Urinary output ↓.
Physiology that the lowest osmolarity that can be However, DI patients will not respond and will
generated is 50 mOsm/L. continue to make dilute urine.
• Low specific gravity (< 1.010) 2) If the patient doesn’t respond. Then, Give the
• Specific gravity = ratio of density of patient exogenous ADH (Desmopressin) to tell
compound to density of reference which type of diabetes insipidus it is:
compound (Normal specific gravity = 1.010) a) Response or Uosm ↑ = Neurogenic DI
Low specific gravity = less dense = b) No response or No ↑ Uosm = Nephrogenic
hypoosmotic. DI
• Polydipsia = ↑ thirst. Loss of water stimulates thirst center and causes polydipsia because ↑plasma osmolarity

• Differentiating features of Diabetes Insipidus and Diabetes Mellitus (DM):

Feature: DI IDDM
[Blood Surgar] Normal Elevated
Uosm Decreased Greater (due to Glucose) In DM, glucose acts as an osmotic diuretic.

7. Primary Polydipsia = neuropsychiatric condition where people keep drinking large volumes of water.
• ↓ECF osmolarity and ↑ECF volume = both inhibit ADH secretion (No water reabsorption)
• Water excretion in urine ↑ = osmolarity ↓ (<300 mOsm/L) – present with large volumes of urine output
(polyuria) and and drinking too much water (polydipsia)

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8. Syndrome of inappropriate ADH (SIADH) = abnormally excessive levels of ADH get secreted either from posterior
pituitary or from ectopic sites like tumor cells of lungs (autonomous small cell carcinoma)
In this clinical condition, ADH secretion is autonomous and not in response to plasma osmolarity or volume changes
↑ ADH levels (seen in Diabetes insipidus of nephrogenic origin and SIADH)

Differentials: SIADH presents with hypertonic urine, while DI presents with hypotonic urine.
• There is excessive H2O reabsorption in LDT and CD leading to ↑ water retention “Euvolemic Hyponatremia”
(close to normal). Hyponatremia: Pt can present with confusion, seizures, impaired mental status.
• Excess ADH = ↑plasma/ECF volume and ↓plasma osmolarity causes hyponatremia due to dilution adding more
water to ECF = Heart produces ANP/BNP in order to slightly compensate (this is why no edema or hypertension
are seen), and blocks reabsorption of sodium and
water. It should be producing diluted urine, but
urine osmolarity ↑, because volume ↓ as ADH is
being produces autonomously and producing even
more concentrated urine.

Treatment: ADH Receptor Antagonist (In the past,

Demeclocycline. Now days, Tolvaptan and Conivaptan)
*Remember: Fluid restriction, but NOT salt restriction
(hypertonic saline can be given)

9. Oxytocin = originates in Paraventricular nucleus (5/6

from PVN and 1/6 from SON) of Hypothalamus
• Transported by its carrier protein Neurophysin I – transporter from OXT.
Factors (+) Oxytocin release: Factors (-) Oxytocin release:
• Nipple Suckling or nipple piercing • Stress
• Sight / smell / sound of baby’s cry • Fright (fear)
• Dilatation of cervix during Parturition (delivery) – • Drugs:
stimulates higher centers in the brain to produce • Opioids
more OXT and causes contraction of uterine muscle • Alcohol
• Orgasm

10. Actions of Oxytocin = stimulates contraction of smooth muscle

1) Myoepithelial cells of Mammary glands = causes Milk Ejection Reflex in lactating breasts.
 Stimulates release of PRL from Anterior pituitary
 Oxytocin is NOT inhibited by Estrogen, only PRL is inhibited.
 After birth, estrogen ↓ and PRL ↑ which inhibits GnRH in the hypothalamus and ↓FSH and LH resulting
in amenorrhea.
2) Myometrium of uterus (smooth muscle) = plays a crucial role in labor by causing the Parturition Reflex (fetus
and placenta*)
▪ IV Oxytocin used induction of labor (fetus and placenta) and prevent postpartum bleeding.

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11. Milk Ejection Reflex:
1) Signals from baby suckling the nipple suckling (stimulus)
travels through the afferent fibers from spinal cord reach
PVN of Hypothalamus
2) Efferent fibers carry Oxytocin to posterior pituitary
(where it was previously stored) and upon stimulus is
released.
3) Release of oxytocin causes inhibition of Dopamine (PIP)
resulting in simultaneous ↑PRL secretion from Anterior
pituitary which maintains constant milk production.
4) Oxytocin causes contraction of Myoepithelial (smooth
muscle) cells of breasts which results in milk expulsion
from mammary alveoli into mammary ducts to the infant.

▪ Release of prolactin = pregnancy and breast feeding.

▪ Breast feeding = oxytocin and prolactin.

12. Parturition Reflex - Positive Feedback

1) During pregnancy, there is ↑ number of Oxytocin receptors in the uterus.
2) Stretching of cervix by fetal head (stimulus) stimulates stretch receptors on cervix.
3) Afferents carried by spinal pathways to PVN of Hypothalamus causes release of Oxytocin.
4) This causes upregulation of Oxytocin receptors in uterus.
5) Efferent fibers carry Oxytocin to posterior pituitary
6) Brings about ↑ contractions of myometrium (Uterine smooth muscle), the fetus pushed down and further
stretch of cervix.
7) This cycle continues till baby and placenta are finally expelled out (Positive Feedback)
• Childbirth usually occurs in three stages:
1) First stage: The time of the onset of true labor until the
cervix is completely dilated > 10 cm.
2) Second stage: The period after the cervix is dilated
from 10 cm until the baby is delivered.
3) Third stage: Delivery of the placenta.

13. Craniopharyngioma = MC tumor affecting the

hypothalamic-pituitary system in children (pituitary
adenomas rare).
• It is a slow-growing, extra-axial, epithelial-squamous,
calcified cystic tumor arising from remnants of the
cricopharyngeal duct and/or Rathke cleft
• Both the Rathke’s pouch (AP) and the infundibulum (PP) develop during the fourth week of gestation and
together form the hypophysis. This tumor is (usually) located in pituitary stalk and projects into Hypothalamus
(causing damage to the nuclei). **Can compress both Anterior & Posterior pituitary.
• **Distribution by age was bimodal, with peak incidence in children aged 5-14 years (first decade of life is most
common craniopharyngioma) and adults aged 65-74 years.
• The most common presenting symptoms are headache (intracranial pressure), endocrine dysfunction and visual
disturbances (bitemporal hemianopia) *** MCC and presentation.

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• Headache is slowly progressive, dull, continuous and it becomes severe in most patients when endocrine
symptoms become obvious.

• Clinical Features:
a) ↓TSH  Hypothyroidism (e.g., weight gain, fatigue, cold intolerance, constipation)
b) ↓ACTH  Adrenal failure (eg: hypotension due to ↓aldosterone, hypoglycemia due to ↓cortisol,
hyperkalemia, cardiac arrhythmias and diabetes insipidus (eg. excessive fluid intake and urination).
c) ↓FSH and LH  Hypogonadism  ↓sex hormones, impotence in men and amenorrhea in women
d) Most young patients present with growth failure and delayed puberty, because ↓GH and thyroid
hormones
e) Optic pathway dysfunction (most common presentation due to compression of optic chiasm) on
presentation is noted in 40-70% of patients, (bitemporal hemianopia)

V. Thyroid Gland
• Thyroid hormone is synthesized in the follicular epithelial cells of the thyroid gland
• The follicular epithelial cells are arranged in circular follicles 200 to 300 μm in diameter.
• The cells have the basal or lateral membrane facing the blood and an apical or luminal
membrane facing the follicular lumen.
• Colloid = material in the lumen of follicle composed of newly synthesized TH’s attached to
Thyroglobulin (contains T3 and T4 and some mono-iodo tyrosine and di-iodo tyrosine)
• Parafollicular cells or C cells = between follicular cells that secrete calcitonin.
• Parathyroid glands = 2 on each side of the thyroid. Makes PTH. Regulates blood Ca2+.
• Thyroid gland has a very rich blood supply.
• Iodine is needed to form T3 and T4 (lipid soluble hormone)
1. Synthesize and Release Thyroid hormones:
a) Thyroxine (T4), Triiodothyronine (T3) - are the major thyroid hormones.
b) Calcitonin

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2. Steps involved in biosynthesis are:
TRH  TSH from thyrotropes of the AP  TSH receptors in thyroid gland (cAMP)
1) Synthesis of Thyroglobulin (TG):
▪ TG is a glycoprotein containing large quantities of tyrosine
▪ Synthesized on the RER and GA of thyroid follicular cells
▪ TG is then incorporated into secretory vesicles and extruded across the apical membrane into the follicular
lumen
▪ Later tyrosine residues of TG will be iodinated to form thyroid hormones

2) Iodide (I-)Trap mechanism

• Dietary Iodide from blood gets out from the capillaries into insterstitium of the thyroid gland and enters the
thyroid follicle through a secondary active transport of Na+/I- cotransporter which is present un the thyroid
follicular epithelial cells and transports I- from blood into Thyroid follicular cells.
• **The activity of the pump is regulated by I- levels in the body.
• When there is a dietary deficiency of I-, the pump ↑ its activity (up regulate), to compensate for the
deficiency. (If severe I- deficiency pump cannot compensate leading ↓ TH synthesis). Leading to
hypothyroidism.
▪ **MCC of hypothyroidism in world = iodine deficiency. Although, for USMLE is Hashimoto’s Thyroiditis.
• **High levels of Iodide (I-) itself can inhibit the I- pump (down regulation of transporters) thereby inhibits
synthesis of Thyroid hormones.
• This step can be blocked Na+/I- cotransporter antagonist - used as a treatment for Hyperthyroidism
a) Thiocyanate
b) Perchlorate anions

3) Oxidation of Iodide (I-) to Iodine (I2)

• Once inside the cell the Iodide traverses the cell to the apical membrane where Thyroid Peroxidase Enzyme
(TPO) catalyzes the oxidation of Iodide (I-) to Iodine (I2).
• Thioamides inhibits TPO and conversion of T4 to T3.
1) Propyl Thiouracil* - FDA warning as it can cause liver toxicity, but can be safely used in 1st trimester of
pregnancy. Used to treat Thyroid storm which is a severe form of hyperthyroidism, as it prevents
peripheral conversion of T4 to T3.
2) Methimazole
3) Carbimazole
4) Organification of Iodine (Iodination)
• At the apical membrane, just inside the lumen of the follicle, I2 combines with tyrosine moieties of TG
catalyzed by thyroid peroxidase enzyme
• Resulting in formation of Moniodotyrosine (MIT) and Diiodotyrosine (DIT) – more abundant.
**High levels of I- inhibit organification and synthesis of thyroid hormones - Wolff-Chaikoff effect. –Questions
on this.

5) Coupling of MIT & DIT

• With MIT & DIT being attached to Thyroglobulin, two coupling reactions occur catalyzed by TPO:
a) DIT + DIT = T4 (Thyroxine) - (most abundant because DIT is more abundant)
b) DIT + MIT = T3 (Triiodothyronine)
• A portion of MIT and DIT does not couple; remains in the thyroglobulin molecule.
• 10 times more T4 is produced than T3
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• Iodinated Thyroglobulin (containing T3 & T4 left over MIT and DIT is stored in follicular lumen till Thyroid
gland is stimulated by TSH* to secrete thyroid hormones
• TSH cause (1) synthesis and (2) secretion of T3 & T4. Thyrotrope secreting tumor from AP leads to
hyperthyroidism ↑ synthesis and secretion.

▪ TPO is needed for: 1oxidation, 2organification and 3coupling.

▪ TPO inhibitors are used as a treatment for hyperthyroidism.

▪ What is the role of Potassium iodide (KI) in nuclear disasters? USMLE QUESTION
• KI tablets are given before/immediately after exposure to nuclear emissions, these emissions contain
radioactive iodine which can cause thyroid cancers.
• KI saturates the thyroid gland inhibiting further uptake of radioactive iodine. KI competes with
radioactive iodine.
• MC cancer in nuclear disasters is thyroid cancer. Example: Chernobyl

6) Endocytosis of Thyroglobulin
1) TSH stimulates production and secretion of thyroid hormones.
2) Thyroid Gland is stimulated by TSH, iodinated Thyroglobulin (with it attached T4, T3, MIT and DIT) which is
stored in the follicular lumen is endocytosed by the follicular epithelial cells.
3) Once endocytosed into epithelial cell, endosome fuses with lysosome. These lysosomes have proteolytic
enzymes that brake down T3 and T4 and are released into the blood stream.
4) MIT and DIT that did not undergo coupling reaction undergo deiodination by deiodinase enzyme to recycle
iodine in the synthesis of new molecules of T3 and T4
• Deiodination is important – if you don’t have deiodinase enzyme then you can’t recycle iodine so they
develop hypothyroidism.

7) Hydrolysis of T3 and T4
1) T globulin molecules fuse with lysosomes
2) Lysosomal proteases they hydrolyze the peptide bonds to release T4, T3, MIT and DIT from thyroglobulin.
3) T4 and T3 are transported across the basal membrane into nearby capillaries to be delivered to the systemic
circulation
4) MIT and DIT that did not undergo
coupling reaction are deiodinated by
thyroid deiodinase enzyme, and Iodine
is used for synthesis of new molecules of
T3 and T4.
▪ Deiodination is important – if you don’t
have deiodinase enzyme then you can’t
recycle iodine so they develop
hypothyroidism because deficiency of
thyroid deiodinase enzyme therefore
mimics dietary I- deficiency.

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3. Binding of T3 and T4
• In circulation, T3 & T4 bind to Thyroxine Binding Globulin (TBG)
• TBG synthesized in liver
• In hepatic failure - TBG levels ↓
• In pregnancy - TBG levels ↑. Therefore, a pregnant lady is Euthyroid (normal), even though the total Thyroid
hormone levels are increased as most of the hormone is in bound form which is inactive

4. Thyroid Hormones (T3 versus T4)

• T4 levels synthesized is greater (50 times more) than T3
• About 70% of circulating thyroid hormone is bound to TBG. The remainder to thyroxine binding pre-albumin
(transthyretin) and albumin.
• T4 has greater affinity for TBG Binds more tightly and T4 (6 days) has a greater half-life than T3 (1 day).
• In the target tissues, T3 binds more strongly to the nuclear receptor & has greater affinity for its receptor than
T4**. Therefore, T3 is more active form of Thyroid hormone.

5. Activation of T4 in Target tissues

• 5’- monodeiodinase enzyme in the target tissues converts T4 to T3 (more active) by removing one atom of I2.
• Also, 5’-Monodeiodinase converts T4 to reverseT3 (rT3) – inactive form of TH when body don’t need it.
• In starvation target tissue 5’-monodeiodinase plays an interesting role.
▪ Thyroid Hormones = ↑BMR = ↑ utilization of ATP (for which glucose, AA, and FA are needed).
▪ Starvation (Other states like fasting, medical and surgical stress, catabolic states and high cortisol levels)
inhibits 5’-deiodinase in tissues (rT3 is produced) such as skeletal muscle, thus lowering O2 consumption
and BMR to conserve energy sources.
• Drugs: TPO inhibitors (Propyl Thiouracil*, Methimazole, and Carbimazole) and Propanolol also block 5’MDI,
therefore inhibits conversion of T4 to T3. These drugs are used to treat hyperthyroidism.

6. Radioactive Iodine Uptake

• Iodine uptake is an index of thyroid function that can be easily measured by using tracer doses of radioactive
isotopes of Iodine, administered orally, without having any adverse effects on Thyroid gland.
• Index of thyroid function = amount of radioactive Iodine taken up by the Thyroid gland in a given period of
time. 123I is commonly used*.
• Radioactive Iodine uptake is used to differentiate between Hyperthyroidism (Grave’s Disease) &
Hypothyroidism (Hashimoto’s Thyroiditis).
• In Hyperthyroidism due to ↑ synthesis of Thyroid hormones by the Thyroid gland, Radioactive Iodine uptake by
the Thyroid gland↑.
• *In exogenously administered Thyroid
hormones, mostly given as weight loss
supplement, blood Thyroid hormone levels are
↑, synthesis of Thyroid hormone by the gland ↓
due to negative feedback. Radioactive Iodine
uptake is ↓.
• In Hypothyroidism due to defect in synthesis of
THs, Radioactive Iodine uptake by the Thyroid
gland ↓.

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Recapitulation of Important concepts:
What is the Physiological basis for…
a) Using Thiocyanate & Perchlorate in Hyperthyroidism? It inhibits Na+/I- symporter.
b) What is the role of Propyl Thiouracil in Hyperthyroidism? Inhibits the TPO (↓oxidation, organificacion,
coupling) and 5’DMI (↓conversion in peripheral tissue conversion of T4 to T3).
c) What is Wolff-Chaikoff effect? Downregulation of the transporters for I- due to high [I-] resulting in decrease of
oxidation, organification and coupling to synthetize TH.

7. Factors affecting TH secretion:

Stimulatory Factors Inhibitory Factors
▪ TSH ▪ I- Deficiency (MCC Hypothyroidism)
▪ Thyroid Stimulating Immunoglobulins (Grave’s ▪ 5’-Monodeionidase Deficiency (Iodine Recycle)
Disease) ▪ Excessive I- Uptake (Wolff-Chaikoff effect)
▪ ↑TBG levels (pregnancy) ▪ Na+/I- inhibitors: Perchlorate and thiocyanate
▪ Peroxidase Enzyme Inhibitors: propylthiouracil,
methimazole and carbimazole.
▪ ↓TBG levels (liver failure)
8. Regulation of Thyroid hormone secretion
• Hypothalamic-Pituitary Control: TRH and TSH
• TSH = stimulates synthesis and secretion of Thyroid hormones by follicular cells via cAMP mechanism
• Slowly induced (Trophic) effects of TSH = growth effects
• Hyperthyroidism cause proliferation of Thyroid cells (hyperplasia), ↑ hypertrophy of Thyroid cells, leads to ↑
size of the gland (Goiter).
• Hypothyroidism as in iodine deficiency causes ↓ T3 & T4 - leads to ↑ TSH because of lack of negative
feedback. TSH causes Thyroid proliferation & hypertrophy of the Thyroid gland, causing Goiter.
• The Goiter is not differential for Hyper or hypo (seen in both). It just can be
diagnostic for a problem with the thyroid gland.
• **Hyperplasia of the thyroid ↑ blood flow (tuburlent) to the Thyroid gland and a
Bruit can be heard.
• Therefore, chronic ↑TSH causes Hypertrophy of the Thyroid gland.

TRH secreted by Hypothalamus stimulates TSH secretion by Anterior Pituitary. TSH

stimulates the thyroid gland to ↑ levels of T3, T4. Free T3 and T4 down regulates
TRH receptors in anterior pituitary & inhibits TSH secretion (negative feedback
mechanism).

Condition: TRH TSH T3 & T4 Examples

Primary Hypothyroidism ↑ ↑ ↓ Hashimoto’s Disease
Secondary Hypothyroidism ↓ ↓ ↓ Seaham Syndrome (necrosis of AP) or AP tumors (compress cells
and can’t secrete hormones)
Tertiary Hypothyroidism ↓ ↓ ↓ Damage to hypothalamus
Primary Hyperthyroidism ↓ ↓ ↑ Grave’s Disease
Secondary Hyperthyroidism ↓ ↑ ↑ Thyrotrophic Releasing Tumor
Tertiary Hyperthyroidism ↑ ↑ ↑ Not seen in clinical practice (only theoretically)

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• Differential Dx for Test Questions: If you administer TSH and the thyroid hormones fails to raise, the problem is in
the thyroid gland itself and is Primary Hypothyroidism. If it rises, TSH is not being produced and the problem is in the
Anterior Pituitary Gland and is Secondary Hypothyroidism (confirm it by giving TRH and TSH fails to raise).
• Remember: in liver damage, contraceptives, pregnancy, etc, the bound form levels and total levels change, but not
free-form levels.

9. Physiological actions of Thyroid hormones

1) On growth: Thyroid hormones act synergistically with GH & Somatomedins (IGF-1) to promote bone formation
• Thyroid hormones stimulate bone maturation as a result of ossification and fusion of growth plates.
• Therefore, in Thyroid hormone deficiency, bone age is < than chronological age and child has *infantile
body proportions (Cretinism - hypothyroidism durung childhood)
2) On CNS: During perinatal period, maturation of CNS absolutely depends on Thyroid hormones as it causes
formation of synapses, myelination of nerve fibers.
• The perinatal period commences at 20 completed weeks (140 days) of gestation (pregnancy) and ends 28
completed days after birth.
• Thyroid hormone deficiency in a child < 1year, leads to defective myelination causing irreversible mental
retardation (Drugs can reverse growth retardation, but the mental retardation still irreversible).
• Mandatory Neonatal Screening Test:
1) Hypothyroidism:
• Importance of Neonatal Screening: During a brief perinatal period (during first 28 days of life),
Thyroid hormone replacement is helpful & prevents mental retardation**.
• Once the child crosses that period, it can lead to irreversible mental retardation which cannot be
cured
2) Phenylketonuria (PKU)
3) Glucose-6-phosphate dehydrogenase deficiency (G6PD).
In Adults:
• Effects on CNS seen in disorders - DOES NOT ↑BMR in nervous system*
• Hypothyroidism - causes ↓ mental capacity, slowed speech, impaired memory, ↑sleep (daytime too)
known as somnolence.
• Hyperthyroidism - causes hyperexcitability and irritability, anxiety; cannot concentrate/focus; lack of
sleep because neurons too excited.
3) Autonomic nervous system – upregulate β1 and β2
• Thyroid hormones up-regulate β1-adrenergic receptors in heart & have actions similar to that of
sympathetic nervous system (↑HR, CV, CT, FoC, SV and CO). Therefore, palpitations are seen in
Hyperthyroidism as there is an ↑heart rate.
o Case Presentation: Patient present with systolic hypertension, tachycardia and A-Fib
(hyperthyroidism has to be ruled out).
• β2 receptors are in skeletal muscle (↑ sensitivity to epinephrine) = leads to tremors in hands.
• DOC: Propranolol**, a β-adrenergic blocking drug (β1 and β2 Receptors), is used in Hyperthyroidism to treat
palpitations. It also decreases the peripheral conversion of T4 to T3.

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4) Calorigenic action (↑BMR): (receptors in all tissues) except the brain (CNS), gonads and spleen**
• Hyperthyroidism: ↑BMR = ↑Production and utilization of ATP = ↑O2 consumption = ↑ synthesis of Na+-
K+ ATPase thereby causing increased Na+-K+ pump activity & BMR in all tissues except brain, gonads &
spleen. To do so, need more glucose, AA, FA, and O2 (from cardiovascular and respiratory system). TH
mobilizes more glucose, AA, FA into blood to make it more available to tissues.
a) ↑Glycogenolysis to ↑Glucose from Glycogen
b) ↑Rhabdomyolysis to produce more AA
c) ↑Lipolysis to produce FAs from TAs of the adipose tissue (TH for weight loss)
d) ↑TCA cycle to ↑ ATP
e) ↑ sensitivity of β1 receptors and stimulates them to ↑Cardiac Output and ↑O2 delivery to
tissues.
f) ↑Alveolar Ventilation (hyperventilate) in order to ↑O2.
g) Body generates more Heat because ↑in metabolism (patient present with heat intolerance)
h) Heat is dissipated in the form of sweat.
i) Weight loss due to burn more calories.
• Hypothyroidism is the opposite and patient complains of cold intolerance. Don’t sweat. Skins becomes
dry and scaly, weight gain, and decrease cardiac output.

5) Actions on CVS and Respiratory system:

• ↑heart rate and stroke volume, thereby ↑Cardiac output
• Common presentation features:
a) Hyperthyroidism: tachycardia and palpitations.
b) Hypothyroidism: bradycardia and hypotension.
• ↑ Ventilation rate
• These combined effects ensure adequate O2 supply to tissues

6) Metabolic Effects:
a) BMR↑ to keep up with ↑O2 consumption (↑ Sodium-Potassium pump activity)
b) ↑ glucose absorption from GIT, ↑ Glycogenolysis (breakdown of glycogen) and Gluconeogenesis to ↑
blood glucose - ↑ [Glucose] in Blood
c) ↑ Lipolysis producing Glycogen to gluconeogenesis and FAs.
d) Overall effect of Thyroid hormones on protein metabolism is Catabolic*
o TH can promote protein synthesis (anabolic) and breakdown (catabolic), but overall is catabolic***
because more breakdown than synthesis.
e) ↓ circulating Cholesterol levels as it ↑ formation of LDL receptors in liver which ↑ hepatic removal of
cholesterol from circulation.
a) Hyperthyroidism = ↑LDL particles uptake = ↓ LDL blood levels.
b) Hypothyroidism = ↓ in Liver receptors = LDL ↑ in blood leading to hypocholesteremia leading to
atherosclerosis and cardiovascular diseases (CAD).
f) Thyroid hormones convert β- Carotenes to Vitamin-A
Hypothyroidism: Vitamin A ↓, β-carotene levels ↑, which can deposit in skin and make orange pigment in
skin.
g) TH ↑GI tract motility and secretions.
• Hyperthyroidism = present with diarrhea
• Hypothyroidism = present with constipation.
h) Increases RBCs formation in bone marrow. Therefore, hypothyroidism anemia can be present.

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10. Role of Thyroid Stimulating Immunoglobulins (TSI)
• Thyroid Stimulating Immunoglobulins (TSI) = TSH receptor stimulator antibodies or IgG immunoglobulins
which bind to TSH receptors and like TSH, stimulate secretion of T3 & T4 by the Thyroid gland.
• Grave’s Disease, there is high circulating levels of Thyroid stimulating immunoglobulins (TSI) – diagnostic*,
which leads to ↑T3 & T4 and ↓ TSH levels (due to negative feedback) = Primer Hyperparathyroidism.

11. Pathophysiology of Thyroid gland:

A. Hyperthyroidism: ↑ levels of Free T3 & T4
Causes are:
1. 1st MCC in US: Grave’s disease (antibodies to TSH receptors) – Primary Hyperthyroidism Hallmark:
Exophthalmos and pretibial myxedema.
2. 2nd MCC is Multinodular Goiter = Toxic because ↑T3 & T4. Patients who have iodine deficiency** (remember
who is at risk*) can develop hypothyroidism and TSH is produced in excess and overstimulate thyroid gland
developing nodules and when iodine levels come back to normal the nodules become autonomous and
doesn’t respond to regulation leading to hyperthyroidism – Primary Hyperthyroidism
3. Subacute thyroiditis (De querran’s or painful thyroiditis) **– hallmark is pain seen after viral infections
because inflammation there's breakdown of thyroglobulin and T3 and T4 is released ↑ levels in blood leading
to hyperthyroidism. During this time (over a month), no hormone is produced and T 3 and T4 comes down.
Eventually, patient can present with hypothyroidism until the infection resolve itself (no need treatment). –
Primary Hyperthyroidism. These patients doesn’t take radioactive iodine.
4. TSH secreting Pituitary tumors – Secondary Hyperthyroidism
5. Exogenous T4 administration - sometimes used as weight loss alternative.
6. Thyroid neoplasia (cancers) = Choriocarcinoma can present with ↑ levels of β-hCG. It has affinity for TSH
receptor. If high levels, will go to thyroid gland and bind TSH receptor. Release more thyroid hormones.

Symptoms: ↑ BMR - polyphagia

• ↑ heat production - causes sweating, heat intolerance
• ↑ Cardiac output (Palpitations), ↑ BP
• Tremor due to ↑ β2-adrenergic activity* on skeletal muscle
• Weight loss (but weight gain may seen due to ↑ appetite)
• Proximal muscle weakness or myocitis (↑ Protein catabolism)
• Goiter (diffuse enlargement of the thyroid gland), irritability, ↑ excitability
• Exophthalmos* (protrusion of the eye bulbs) and Pretibial myxedema (Dermopathy)* are diagnostic feature
of Grave’s Disease (hallmark and differential to other hyperthyroidisms)

12. Grave’s Disease is an autoimmune disease that produces TSI to TSH Receptors in Thyroid Gland. Usually affects
women between ages 20 to 40 years or reproductive age (recall immunology – autoimmune diseases are more
common in females). These patients present with diffuse Goiter (diffusely enlarged thyroid gland – not multiple
nodules) over which a vascular bruit could be heard. These patients have a “Lid lag” due to retraction of the eyelids
due to sympathetic activity and exophthalmos or protruding eye due to inflammation in extraocular muscles (due
to accumulation of glycosaminoglycans in the orbit).

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13. Thyrotoxicosis = thyroid enlargement with toxic features like Exophthalmos (diagnostic of Grave’s Disease -
inflammation due to TSI)
• Presence of peri -orbital and retro-orbital edema because of Cytokine release which is an inflammatory
mediator.
• Sympathetic over-activity causes lid retraction, giving rise to a Staring Look (lids are reracted)
• Can see in: grave’s disease and multi-nodular goiter
• *Also, accumulation of mucopolysaccharides in all tissues. If accumulate in ISF (interstitial fluid), will attract
water and will form a gel-like. Tissue will look edematous. But, this is non-pitting edema. (Differential to
CHF = pitting edema because changes in oncotic and hydrostatic pressures)

• Primary Hyperthyroidism = ↑ free thyroid hormones cause a negative feedback inhibition on Anterior Pituitary
Gland = TSH levels ↓
• Secondary hyperthyroidism = anterior pituitary produces excessive TSH = ↑ Free T3 and T4 elevated
significantly.

Treatment:
1) MC used Propylthiouracil/Methimazole- Blocks Thyroid Peroxidase enzyme & inhibits Thyroid hormone
synthesis
2) Propranolol = β- receptor blockers (β1 and β2 receptors) used to treat symptoms of adrenergic overactivity
3) Thyroidectomy = Removal of Thyroid gland. Parathyroid gland is removed and patient suffers
hypocalcemia* (Patient will develop primary hypothyroidism and primary hypoparathyroidism). Need to
supplement Ca2+ or PTH.
4) Iodine(I131) = cytotoxic and destroys thyroid follicular cells, because takes up most iodine. This will induce
hypothyroidism (destroys thyroid gland). This is different from I123 used for diagnostic.

14. Why does TRH ↑PRL?

• High levels of TRH can stimulate release of PRL.
• High levels of estrogen can stimulate release of PRL.
• High levels of PRL can inhibit GnRH from hypothalamus.

15. Hypothyroidism
Causes:
• MCC Hashimoto’s Thyroiditis – autoimmune thyroiditis
• Subacute thyroiditis (de Quervain thyroiditis) or painful thyroiditis
• Thyroidectomy
• Pituitary adenoma (Compress secretory cells)
• Tumors impinging on Hypothalamus – tertiary hypoparathyroidism
• Sheehan’s syndrome – secondary hypoparathyroidism
• Iodine deficiency (MCC in world - Not in the USA)
• Drug induced: Amiodarone (used for cardiac arrhythmias) and Lithium
• Radioactive Iodine131- (Treatment for grave’s disease)

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16. Hashimoto’s Thyroiditis - Autoimmune Thyroiditis
• Most common cause of hypothyroidism
• Antibodies are produced against (destroys) - antimicrosial antibidies
– Anti-Thyroglobulin Antibodies (Anti-TG)
– Anti-Thyroid peroxidase enzyme Antibodies (Anti-TPO)
• Results in inflammation due to lymphocytic infiltration leading to structural damage of the Thyroid gland. So, T3
& T4 synthesis ↓.
• Diagnosis: Detect Anti-TPO and/or Anti-TG or biopsy of the infiltrate will show lymphocytes* (hallmark)
• There will be ↓ levels of Thyroid Peroxidase (TPO) enzyme in Hashimoto’s Thyroiditis

Clinical features:
• ↓ metabolic rate and O2 consumption
• ↓ heat production (cold intolerance)
• Dry and cold skin.
• ↓ appetite, Weight gain
• ↓ Cardiac output, hypoventilation
• Lethargy, mental slowness, Psychosis (Myxedema Madness)
• Ptosis (drooping of eyelids due to muscle weakness)
• Goiter - because of increased TSH in Primary Hypothyroidism (due to iodine deficiency)
• *Generalized Myxedema = mucopolysaccharides accumulate (heparan sulfate) in tissues causing non-pitting
edema (↑ heparan sulfate in ICF, water moves to ICF and produces a gel and doesn’t get displaced). It can
happen in pleural cavity, vocal chords, etc. More common in hypothyroidism than hyperthydoirism.
• Peri-orbital edema (around eye bulb due to generalized myxedema*)
• Myxedema coma* is the end stage of untreated hypothyroidism. The major features are hypoventilation,
fluid and electrolyte imbalances and hypothermia and ultimately shock and death
• Constipation (↓GI motility)
• Hoarseness in speech (accumulation of polysaccharides in vocal chords)
• Deep tendon reflexes with slow or delay relaxation phase Ex. Stimulates the patella, leg moves forwards and
slowly comes back.
• Anemia* – along with GH stimulates RBCs production.
• Can have hypotension in beginning because of ↓CO. Later, have hypertension because of ↓LDL uptake, so
↑plasma cholesterol levels ↑diastolic pressure and developing hypertension and the risk of developing
Atherosclerosis* (CAD).
• β-Carotenemia*: Yellowish discoloration of skin due to accumulation of β- Carotenes. (Normally Thyroid
hormones convert β- Carotenes to Vitamin-A)
o To differentiate from Jaundice - look for yellowish discoloration of mucus membrane which is absent
in β-Carotenemia (No important for the exam)
• Menstrual irregularities* – often ranging from absent or infrequent periods to very frequent and heavy
periods.
• Amenorrhea* - In Primary & Secondary Hypothyroidism, T3 and T4 levels are ↓ = TRH ↑ = ↑PRL = inhibits
GnRH which in turn inhibits FSH and LH = Amenorrhea.

• Primary Hypothyroidism (Hashimoto’s Thyroiditis) = give TRH or TSH and T3 & T4 will fails to increase.
• Secondary Hypothyroidism: give TSH and T3 & T4 increases. Confirm by Giving TRH, if no changes are seen to T3 &
T4, but by giving TSH T3 & T4 increases, then is secondary.

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• Treatment: Thyroid hormone replacement T4 (Levothyroxine*) and TSH will go back to normal (start with slow
doses and ↑ the doses until TSH comes back to normal).
• Diagnosis: TSH levels are the most sensitive test.

17. Cretinism – hypothyroidism during child hood.

• Untreated postnatal hypothyroidism results in cretinism (form of dwarfism with mental retardation).
• This condition is characterized by physical + irreversible mental retardation
• Individuals often appear normal following delivery, but may display respiratory difficulty, jaundice, feeding
problems and hypotonia
• Abnormalities rapidly develop with CNS maturation and result in mental retardation
• Mental retardation (Infantile brain) due to defective myelination in axons of cortical neurons
• Crucial up to 1 year of life. Therefore, early diagnosis is very important
• Pubertal growth, including bone ossification is retarded in the absence of thyroid hormones. A stippled
epiphysis (sign of hypothyroidism) - marked by multiple ossification centers that severely deform the long
bone.
• Big head and small torso
• Macroglossia
• CRETINS - have mental retardation, motor rigidity & deafness. WHY?
• This is because, Thyroid hormone deficiency affects functions of cerebral cortex, Basal ganglia (coordinates the
motor movements) & Cochlea (deafness due to undeveloped neurons in the ear).
 Cerebral cortex, basal ganglia and cerebellum = motor movements.
• The mainstay in the treatment of congenital hypothyroidism is: early diagnosis and thyroid hormone
replacement.
• Optimal care may include diagnosis before age 10-13 days and normalization of thyroid hormone blood levels
by age 3 weeks.
• This is why there are mandatory screening tests for hypothyroidism.

18. Goiter = present in hypothyroid, hyperthyroid and euthyroid patients. Doesn’t tell the functional status of the thyroid
gland. It is just enlargement of the Thyroid gland.
• Causes: Endemic Iodine deficiency and is known as Endemic
Colloid Goiter- ↓ thyroid hormone synthesis resulting in
Primary Hypothyroidism. This results in ↑TSH causing
hypertrophic thyroid gland. This hyperstimulation can develop
nodules (multi-nodular goiter) that once the iodine levels are
brought back to normal, can become autonomous and not
respond to the negative feedback. (hypertrophic thyroid
gland)
• Goiter is also seen in Secondary Hyperthyroidism due to ↑
TSH, Primary Hyperthyroidism due to Thyroid tumors. But is
absent in Secondary Hypothyroidism as TSH ↓.

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VI. Parathyroid Gland
1. Calcium homeostasis
• Free ionized Ca 2+ is biologically active and regulated.
• Plasma Ca+2 levels = 9-11 mg/dL** (4.3 to 5.3 mEq/L or 2.2 to 2.7 mmol/L)
• Hypercalcemia > 11 and hypocalcemia < 9 mg/DL
– 10 mg/dL is average. 5 mg/dL Ca is the free ionized form.
• Serum [Ca 2+] depends on :
a. Intestinal absorption (Vitamin D)
b. Renal excretion (PTH and Vitamin D – Early DT)
c. Bone remodeling:
a) Bone resorption – breakdown of bone or demineralization (Vitamin D and PTH)
• Calcitonin inhibits bone resorption.
b) Bone formation or deposition (Vitamin D)
**1 unit ↓ in albumin, will lead to 0.8 unit ↓ in Ca levels
▪ Hypercalcemia can inhibit ADH signaling.
▪ *If patient comes with hypocalcemia, what measure? Albumin levels even before Ca levels.
• Plasma (serum) calcium represents:
a) 45% ionized free calcium
b) 40% attached to proteins (albumin)
c) 15% associated with anions such as phosphate and citrate (can go out and get deposited)
• Bound form is in equilibrium with the free form (bound can’t leave vascular compartment) – if free form ↓,
bound form is released to maintain the equilibrium.

• Alkalosis (Hyperventilation) causes hypocalcemia and hypokalemia because ↓ [H+]

Key points:
will lead to PP to act as buffers and release H+ and free ionic Ca2+ levels will bind to
Acidosis = ↑ H+, Ca+2, and K+
albumin leading to hypocalcemia. These patients present with periorbital numbness
Alkalosis = ↓ H+, Ca+2, and K+
and muscle twitching.
• Acidosis (hypoventilation) causes hypercalcemia
because ↑[H+] by competing with Ca2+ for albumin
and causes hyperkalemia (recall renal physiology).

2. Hormonal control of Calcium:

• 1,25 DHCC (1,25 Dihydroxycholecalciferol) *, also
known as calcitriol is the Active Vitamin D =
↑Ca +2 and phosphate absorption from
intestine.
• PTH = Mobilizes Ca +2 from bones (resorption)
• Calcitonin = Ca+2 lowering hormone secreted by
Parafollicular cells (C cells) of Thyroid Gland
inhibits bone resorption (inhibit osteoclastic
activity) when high levels of Ca+2 in blood.

3. Relationship between Ca 2+ & Phosphate

• Bone contains:
1) Organic Material = special form of connective tissue with collagen framework
2) Inorganic Material = has Ca+2 & Phosphate (PO4) salts - known as Hydroxyapatites

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• +2
[Ca ] x [PO4 ] = a constant (Solubility product)
a) [Ca+2] x [PO4 ] > Solubility product = Bone deposition (mineralization).
- Vitamin D ↑ calcium and phosphate levels in blood.
b) [Ca+2] x [PO4 ] < Solubility product = Bone resorption (demineralization) or break down
- PTH: ↓ [PO4] by excreting it into the urine. The product will be lower than solubility product =
resorption or demineralization.
• In chronic renal failure, cannot get rid of Phosphate, it rises, and binds with calcium to forms bone. Blood
Calcium levels go down. Therefore, Chronic renal failure = ↑Phosphate = ↓Calcium in blood levels.

4. Role of calcium in physiological processes:

• Vital second messenger: IP3-DAG
• Blood coagulation (Hemostasis) = considered as one of the coagulation factors to stop the bleed
• Muscle contraction (all muscles needs calcium to contraction)
▪ In Smooth muscle is released from Sarcoplasmic Reticulum (SR)
▪ Voltage gated Ca2+ = Dihydropyridine Receptors that causes changes to the Ryanodine Receptors.
▪ In Cardiac muscle also open a voltage gated calcium channels in phase 0 (mechanism known as calcium
dependent-calcium release)
• **Nerve excitability – also depends on ECF [Ca+2]
• Hormone & Neurotransmitter release with Ligand gated by exocytosis

5. Parathyroid hormone (PTH)

• Parathyroid gland is located in the posterior wall of the
thyroid gland. It has receptors that senses free ionic calcium
in the serum and if it is low, it stimulates the synthesis and
secretion of PTH (water soluble hormone) by Chief cells of the
Parathyroid glands.
• PTH is release in response to ↓ [calcium] in serum* in order
to try to bring [Ca+2] back to normal.
• If high ECF [Ca+2], stimulates more Ca+2 receptors and activates IP3-DAG (through Gq GPCR) resulting in
inhibition of secretion of PTH.
• When go below 7.5 mg/dL Ca, PTH levels will peak.
• When go above 11 mg/dL Ca, PTH levels are significantly low.
• **Must have normal level of Mg2+ in blood in order to release PTH. *if pt has hypomagnesemia, will have
↓PTH or Hypoparathyroidism leads to Hypocalcemia.
• PTH = major hormone which regulates serum Calcium and acts via cAMP (Gs α subunit protein)**
• PTH secretion is controlled by serum Ca 2+
• ↓serum [Ca+2] = ↑PTH secretion
• **Actions of PTH produces an:
o ↑ in serum [Ca 2+] = by increasing permeability to sodium in the tubular epithelial cells of the Early DT.
o ↓ in serum Phosphate* = inhibits the Na+/Phosphate Cotransporter of phosphate in the luminal
membrane of the PT in the renal nephron and promotes the excretion of phosphate in the urine
(phosphaturia).

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6. Early DT
• Reabsorption of NaCl (5%) without water via *Na+/Cl- symporter.
• Impermeable to water
• Dilution of tubular fluid (cortical diluting segment) and TF becomes even more
hypotonic. *the late DT receive the most dilute/hypotonic fluid.
• Site of action PTH* which stimulates reabsorption of calcium
• 1,25 (OH)2 VitD and PTH ↑ reabsorption of Ca2+ in early DT:
a) **PTH makes membrane more permeable to Ca2+.
b) Vitamin D ↑ Ca2+ uptake in gut epithelial cells by making ↑ calbindin
formation.
• Thiazide diuretics (Eg: Hydrochlorothiazide, Indapamide and metolazone) also inhibit Na+/Cl- symporter in early
DT. Therefore, ↑ loss of Na+ (5%) and water. This leads to ↑reabsorption of Ca2+can lead to hypercalcemia.
Because ↓ICF Na+ = Na+/Ca2+ exchanger ↑= ↓ICF Ca2+, so more Ca2+ comes in.
o Use for Hypertension ↓ECF Na+ = ↓ Volume = ↓BV/BP. These patients can develop hyponatremia and
can develop hypokalemia.
o Can also treat calcium renal stones in patients who have idiopathic hypercalciuria (IH) - unknown
cause, ↓ Ca2+ from going into the renal pelvis and get deposited in the urinary tract, but causes
hypercalcemia.

7. Actions of PTH
• PTH acts on 3 major sites: Directly on Bones and Kidney (direct) & Indirectly in GIT (by ↑ Vitamin D by the
kidney and more reabsorption of calcium in GIT).
A. On Bones: Causes bone resorption (Osteolytic activity) - ↑ serum Ca 2+
• PTH receptors are present on Osteoblasts**, which are precursor of osteocytes. PTH binds to them, causes
release of Cytokines known as Osteoclastic activating factors (IL-1, IL-6, RANK-L, TNF-α)
▪ Qs: Osteoblast are precursors of osteocytes (both have PTH receptors). Questions are given, where
osteoblast are no given as an answer. Also, remember that IL-6* is the major osteoclastic activating
factor.
• These Osteoclastic activating factors released from osteoblasts act on osteoclasts to cause bone resorption:
by activating them and increasing in numbers. Therefore, effect of PTH on bone resorption is Indirect*.
• Osteoclasts are derived from various monocytes together known as multinucleated giant cells. Osteoclasts
DO NOT have PTH receptors*.
• Clinical Application: In women, estrogen inhibits formation of osteoclastic activating factors. (In men,
androgens also have this effect). In menopause, estrogen decreases and withdrawn of inhibitory effect and
increases osteoclast activity resulting in osteoporosis.
B. On Kidneys:
• Inhibits renal Phosphate reabsorption in proximal tubule,
thereby ↑PO4 excretion – Phosphaturia leading to
hypophosphatemia. (Important concept due to PTH secreting
tumors)
• PTH ↑ renal Calcium reabsorption in Early DT of kidneys by ↑
permeability to calcium- ↑serum [Ca+2].
• Activate 1-α-hydroxylase enzyme in the Proximal Tubular
Epithelial cells which converts 25-DihydroxyVitaminD to 1,25
(OH)2VitaminD.

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• Recall Biochemistry: Skin under UV light converts 7-dehydrocholesterol into cholecalciferol (Vitamin D3). In
the liver, it is converted to 25-Dihydroxycholecalciferol by 25-hydroxylase and goes to the kidney where is
converted to 1,25 Dihydroxycholecalciferol by the 1-a-hydroxylase. This is the active form of Vitamin D.
C. On GIT (Indirect): PTH stimulates activity of 1α-
Hydroxylase in kidneys (proximal tubule) and↑
formation of 1,25 DHCC (from 25-
hydroxycholecalciferol) which in turn increases
intestinal Ca 2+ and Phosphate absorption.
Therefore, PTH indirectly increases intestinal Ca
2+
absorption through active Vit D.

Summary of Net Effect of PTH:

8.
-Hypercalcemia, Hypophosphatemia and
9.
Hyperphosphaturia (Phosphate Trashing Hormone)
10.
-↑bone resorption – directly activates osteoblast and
11.
osteocytes to indirectly activating ↑osteoclasts (release
12.
calcium and phosphate which is excreted in urine)
13.
-Stimulates activity of 1α- Hydroxylase in kidneys and
14.
↑formation of 1,25 DHCC which in turn ↑intestinal Ca 2+
15.
absorption.

16. Pathophysiology of PTH - Hyperparathyroidism

A. Primary Hyperparathyroidism (the problem is within the parathyroid gland, not with the calcium levels*).
↑PTH = ↑Ca2+ levels (hypercalcemia) = ↓ PO4- serum levels = ↑ PO4- excretion in urine = ↑osteoclastic
activity (resorption)
Causes:
a) Parathyroid Adenoma (MCC)= benign tumor that arises from one or more parathyroid gland) results in
↑PTH secretion.
b) Hyperplasia or cancer of the parathyroid gland (rare)
▪ This causes are autonomous and doesn’t respond to the negative feedback of the calcium levels.
Clinical features:
• ↑serum [Ca 2+] – Hypercalcemia > 11 mg/dL (Normal: 9-11 mg/dL)
• ↓ serum Phosphate - Hypophosphatemia leading to ↑urinary Phosphate excretion -
Hyperphosphaturia
• ↑bone resorption due to ↑ osteoclasts (osteitis fibrosa cystica) – brown cystic lesions in the
bones***
• ↑ serum Calcium predisposes to Nephrocalcinosis (Calcium stones in renal parenchyma –
renal cortex and medulla). Eventually, Nephrocalcinosis may cause Renal tubular damage
causing Polyuria
– Hypercalcemia blocks action of ADH (decrease sensitivity of V2 receptors in P cells)
resulting in nephrogenic diabetes insipidus ***. Patient presents with polyuria and
dehydration.
• Renal stones (Nephrolithiasis) - ↑ filtered load of calcium and ↑ calcium in urine (hypercalciuria). Calcium can
get deposited in renal pelvis resulting in renal stones. This causes “renal colicky pain” due to pain in ureter
radiating to the groin and genitals**
• Most clinical stems in USMLE refers to STONES, BONES & GROANS

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B. Secondary Hyperparathyroidism: parathyroid glands are normal (can be hyperplastic but no problems). It is the low
calcium (chronic hypocalcemia) that stimulates ↑PTH secretion. Characterized by ↑PTH, ↓plasma calcium and
↓phosphate.
Causes:
1. Vitamin D deficiency (MCC)
• Most case stem refers to Inadequate sun exposure***
• Malabsorption of Vitamin D due to fat malabsorption will lead to deficiency of lipid soluble vitamins ADEK
such in:
a) CFTR due pancreatic enzymes deficiency or chronic pancreatitis
b) Chron’s Disease (damage to ileum that leads to bile salts deficiency needed to emulsification),
c) Celiac Disease (blunted to epithelial cells of the GI),
d) Enzyme deficiencies in the pathway of activation of Vitamin D.
• Vitamin D deficiency in Diet
• Vitamin D normally ↑Calcium and phosphate reabsorption.
• Even though the elevated PTH ↑phosphate resorption from the bone, PTH inhibits phosphate reabsorption
in kidneys thereby ↓phosphate.
• Bone mass is lost to maintain plasma calcium (osteitis fibrosa cystica is also seen)
• Diagnosis: low plasma vitamin D
• Treatment: Supplementation of Vitamin D to bring Calcium levels back to normal.

2. Chronic renal failure

• If someone developed kidney failure and went onto dialysis, the following sequence of events might occur.
• A fall in the ↓ blood level of calcium is the first major change.
o Diseased renal tissue leads to ↓activity of 1α- Hydroxylase enzyme resulting in ↓synthesis of 1,25
DHCC (active Vitamin D) & ↓serum [Ca 2+]
o ↓serum [Ca 2+] in turn causes ↑secretion of PTH from Parathyroid gland, resulting in Secondary
Hyperparathyroidism. This results in ↑bone resorption.
• Treatment: supplementation of active vitamin D.
• Levels of phosphate in the blood rise*** (hyperphosphatemia), because the kidneys are not excreting
excess phosphate into the urine.
• These patients present with hypocalcemia and hyperphosphatemia.
• Chronic Failure Secondary Hyperparathyroidism: ↑PTH = ↓calcium and ↑PO4 (because can’t be
excreted) exception to all the other cause where ↓calcium and phosphate and ↑PTH
• High levels of phosphate can cause itching. *
• Treatment: reduce phosphate levels by diet, dialysis, and medication
• [↑PO4] x [↓calcium] > solubility product resulting in deposition exacerbating hypocalcemia (more
phosphate is available to bind to calcium).

3. ↑demand for calcium in pregnancy (even during lactation)- will lead to hyperplasia of PT glands

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C. Tertiary Hyperparathyroidism:
• Seen in patients with long-term secondary hyperparathyroidism (chronic hypocalcemia) which eventually
leads to hyperplasia of the parathyroid glands (due to high demand of PTH) and become autonomous losing
response to serum calcium levels producing excess PTH (doesn’t respond to negative feedback).
• This disorder is most often seen in patients with chronic renal failure and is an autonomous activity.
• This is analogous to the example of toxic multinodular goiter, where nodules in thyroid gland is continually
stimulated in iodine deficiency, becomes autonomous even when later supplement iodine.

17. Humoral hypercalcemia of malignancy – present with severe hypercalcemia

• Malignant tumors of lung, renal and breast cell carcinoma - secrete PTH related peptide (PTH- rp) which is
structurally similar to PTH and has all physiological actions of PTH (Squamous cell carcinomas of esophagus,
lung, kidneys that can produce PTH-rp acting as PTH = ↑Calcium and ↓PO4 so PTH is low due to negative
feedback in the parathyroid gland.)
• Blood investigations reveal low PTH levels even though patient has symptoms of PTH excess. This is due to
hypercalcemia caused by PTH –rp, which suppresses actual PTH secretion from parathyroid gland
Clinical features: Blood profile very similar to primary hyperparathyroidism but low PTH (due to negative
feedback).
▪ Hypercalcemia - present with severe hypercalcemia can lead to nephrogenic DI, ↑ ClH2O, ↓ECF Volume and
↑osmolarity and ↑calcium.
▪ Hypophosphatemia
▪ Hyperphosphaturia
Treatment:
1) First give, Normal Saline for rehydration.
2) Then, furosemide (loop diuretics) to inhibits calcium reabsorption in the thick ascending loop of henle.
3) Exogenous Calcitonin = hormone to reduce calcium levels
4) Etidronate or Pamidronate = Inhibits bone resorption by blocking effects of PTH-rp.

18. Hypoparathyroidism
Causes: ↓PTH = ↓Calcium = ↑PO4 (are not dumped in the urine)
1) Most commonly seen as a consequence of Thyroidectomy in patients with Grave’s Disease
2) Parathyroidectomy in Hyperparathyroidism patients.
3) Other causes of Hypoparathyroidism are:
a) Auto immune or Congenital are rare
b) Pseudohypoparathyroidism
c) Mg2+ deficiency - needed to secrete PTH.

19. Tetany (because of hypocalcemia)

• Hypoparathyroidism leads to Hypocalcemia and gives rise to Tetany (uncontrolled muscular contractions)
which is due to an ↑excitability of α motor neurons.
• The major reason is that hypocalcemia ↑permeability of neural tissue to sodium resulting in ↑ frequency of
AP.
• Differential: Neuronal excitability or permeability of neurons to sodium ↓ and CNS is less excitable and
↓ conscious levels (loss consciousness) and ↓ mental activity and can lead to comma.

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Clinical features of Tetany:
• Neuromuscular hyperexcitability** - there is ↓threshold for excitability of nerve fibers as there is ↓calcium to
stop activity of Sodium channels.
• Laryngeal spasm - is a life-threatening complication of Tetany (can result in apnea)
• Carpopedal spasm** - Flexion of thumb & wrist with hyperextension of metacarpophalangeal & interphalangeal
joints.
• Seizures* = overexcitability can happen in CNS too, so get seizures. (AP spreads to the brain) *

Two important clinical signs elicited in Tetany are:

a) Trousseau’s Sign: Wrap the BP cuff around the arm & raise the pressure. The hand of the patient will go
in for carpopedal spasm due to increased neuromuscular excitability due to mechanical stimulation
(pressure in neuron).
b) Chvostek’s Sign: Tap the facial nerve over the cheek. There will be puckering of mouth & angle of mouth
deviates to that side. Facial muscles will spasm.

Physiologic Explanation of Tetany caused by Hyperventilation:

• Hyperventilation ↑ plasma pH (↓ [H+]) by ↓PCO2 resulting in Respiratory alkalosis
• At this alkaline pH, plasma proteins act like buffers by ionizing releasing H+, these protein anions bind with
Calcium.
• This in turn leads to ↓serum ionic Calcium levels causing Tetany.

20. Pseudohypoparathyroidism Type 1a or Albright’s hereditary Osteodystrophy = Simply resistance to PTH.

• PTH↑due to ↓calcium, but can act in receptors due to resistance. This patient will have ↑ phosphate
levels. Also seen in primary hypoparathyroidism where PTH↓.
• Inherited autosomal dominant disorder in which the Gs protein is defective (because PTH acts via cAMP) in
kidney & bone. When PTH binds to its receptors in these tissues, it does not activate Adenylyl cyclase. This
leads to resistance to actions of PTH in the target organs.
• Plasma PTH levels are elevated, but PTH cannot act. cAMP levels are ↓. This
cannot be corrected by PTH administration.
• Features: o Hypocalcemia, hyperphosphatemia
o Short stature, short neck, obesity, subcutaneous calcification and
shortened 4th or 5th Metacarpals/Metatarsal bones (fingers and
21. Vitamin D = Provides Calcium
toes will&be
Phosphate to ECF for bone
shortened)
mineralization
Vitamin D metabolism:
• Active form of Vitamin D is 1,25-Dihydroxycholecalciferol
(1,25 DHCC), also known as Calcitriol
• Production of 1,25 DHCC in kidney (Proximal Tubule cells) is
catalyzed by 1α - hydroxylase enzyme which ↑ its activity in
response to PTH that is released due to ↓ serum [Ca 2+]
• Main function of vitamin D is raise Ca and Phosphate in blood
for bone formation (mineralization).
• [Calcium] x [Phosphate] > solubility product = bone formation
(mineralization).
• Lipid soluble vitamin: A, D, E, K

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22. Actions of 1,25 DHCC (Active Vitamin D)
A) On GIT: Main action of Active Vitamin D is on GIT. It causes ↑ synthesis of Calcium binding protein - Calbindin D,
on the intestinal epithelial cells, thereby increasing intestinal Calcium absorption (remember that Vitamin D is a
lipid soluble and MOA is by stimulating synthesis of brand new proteins).
• Also ↑ intestinal PO4 absorption
B) On Kidneys: ↑ renal reabsorption of Calcium & PO4
C) On Bones: Stimulates Osteoblasts & enhances bone formation. Can also causes proliferation of osteoclasts,
increasing bone resorption & provides Ca2+ & PO4 for mineralization of new bone (important role in bone
remodeling, because it activates both osteoblasts and osteoclasts).

23. Clinical Aspects: Vitamin D deficiency:

• Causes:
• inadequate dietary intake
• inadequate exposure to sunlight
• Renal and Liver diseases
• Leads to:
a) Rickets in children = deficiency of
inorganic material due to low calcium and
phosphate and organic material will ↑
(↑ ratio of organic:inorganic material in
bone) Treatment: Sunlight and Calcium
b) Osteomalacia in adults = defective
mineralization of bones - patients have
easy susceptibility to fractures. The ratio of mineral:matrix ratio ↓ (there is too much matrix relative to the
amount of bone). Differential: Osteoporosis mineral:matrix ratio is normal. The problem is due because bone
mass is reduced.
• Leads to ↓ Calcium levels (↑PTH), Phosphate levels = Secondary hyperparathyroidism.

24. Clinical Features of Rickets:

• Deformed bones
• Bow Legs (Knock Knees) - due to bowing of weight bearing areas Bow legs
(genu varum – knees towards outside or genu valgus - inside)
• Thickening of wrists and ankles due to Widening of epiphyseal cartilaginous
plates* (lack of mineralization)
• Retarded growth & dentition
• Frontal bossing
• Rickety Rosary (beaded prominence of costochondral junction)
25. Calcitonin (CT) = synthesized & secreted by Parafollicular cells of the Thyroid in
order to ↓circulating Ca2+ & PO4 levels decreasing bone resorption by inhibiting
osteoclastic activity.
• ↑Serum [Ca 2+] = stimulates Calcitonin secretion = ↑ Ca2+ excretion

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•Clinical applications:
a) Calcitonin (CT) levels are ↑ in pregnancy because it protects mother from excessive Ca2+ loss from
bones during pregnancy
b) ↑CT levels also seen during growing periods as they help in skeletal development.
c) Used as a treatment for (acute diseases - only short period of time):
a. Hypercalcemia as in hyperthyroidism.
b. Paget’s Disease*** in which ↑ osteoclastic activity (bone resorption) in bones and abnormal
bone formation.
c. Multiple myeloma – ↑bone demineralization.
26. Osteoporosis = excessive osteoclastic functions with breakdown of bone matrix. (characterized by a ↓ in bone
mass and bone mineral density which can lead to an ↑risk of fracture of hips and vertebras) – mineral: organic
ratio remains normal.
• Bone formation cannot keep pace with bone resorption.
• Characterized by weakened bones*
• Female sex hormone Estrogens** are protective to bones as they
promote osteoblastic functions and inhibits release of Osteoclastic
Inhibiting Factors (IL-1, IL-6 and RANK-L) which stimulate osteoclasts.
Estrogen also stimulates release of TGF-β which ↑ apoptosis of
osteoclasts.
• Therefore, females after Menopause are more prone for
Osteoporosis
• Treatment: Estrogen Supplementation
USMLE: In people immobilized for prolonged periods bone
resorption exceeds bone formation**.
Case presentation: An astronaut during space flight due to no effect
of gravity or prolonged bed rest as in a person that had a stroke, hip
fracture and are bedridden. (Work with limbs against gravity) Plasma
Calcium is ↑ & Urinary Calcium and Phosphate excretion ↑. PTH &

Disorder PTH 1,25 DHCC (PTH effect Bone Urine Serum Serum
in α-1 hydroxylase) Resorption [Ca2+] [PO4-]
-
Primary ↑* ↑ ↑ ↑ [PO4 ] = Phosphaturia ↑ ↓
Hyperparathyroidism ↑ [Ca2+] = high FL
↑cAMP
Surgical ↓* ↓ ↓ ↓ [PO4-] ↓ ↑
Hypoparathyroidism ↓cAMP
Pseudo ↑ ↓ ↓ ↓ [PO4-] ↓ ↑
hypoparathyroidism ↓cAMP (defective Gq)
Humoral Hypercalcemia of ↓ ↑ ↑ ↑ [PO4-] = Phosphaturia ↑ ↓
Malignancy (↑PTH-rp) ↑ [Ca2+] = high FL
↑cAMP
Chronic Renal Failure2nd ↑ ↓* (Osteomelacia) ↑ ↓ [PO4-] due ↓ GFR ↓ ↑
-
Vitamin D Deficiency ↑ ↓ ↑ ↑ [PO4 ] = Phosphaturia ↓ ↑
Vitamin D levels are ↓. Most important: PTH ↓.

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VII. Adrenal Glands
1. Adrenal medulla is made up of chromaffin cells (derived embryologically from Neural Crest), which release
epinephrine (80%) and NE (20%).
• They release this with ↑ in sympathetic activity (output) will lead to secretion of these hormones.
• Preganglionic sympathetic neurons (cholinergics) release Ach onto Nicotinic receptors (N-N Receptors) on
Chromaffin cells. Thus, adrenal medullary cells are part of sympathetic system and act like post-ganglionic neurons
secreting E and NE into the blood.
2. Adrenal Glands or Suprarenal Glands has (2) layers:
a) Outer Adrenal cortex (80% of the gland) = secretes steroid hormones
b) Inner Adrenal medulla= secretes catecholamines (Adrenal Medulla is an Emergency Gland which prepares an
individual for Fight / Flight)
3. In Fetus - During 3rd - 4th month of intra-uterine life, adrenal glands are larger than kidneys. The Function of fetal
Adrenals is secretion of DHEA (Dehydro-epiandrosterone) which is converted in placenta to sex hormones:
androgen and estrogen.
4. MNEMONIC Zones of the Cortex: GFR
1) Zona Glomerulosa (ZG)= secretes Mineralocorticoids
(Aldosterone** & Deoxy corticosterone) -
Mineralocorticoids play a role in mineral metabolism
(required for survival). Regulated by AT-II and ↑ plasma
K+ ions (hyperkalemia).
2) Zona Fasciculata (ZF)= secretes Glucocorticoids (Cortisol
also known as Hydrocortisone). These play role in
carbohydrate & protein metabolism. The release cortisol
regulated by ACTH.
3) Zona Reticularis (ZR)= Secretes Sex steroids (Androgens -
mainly DHEA and Androstenedione). Minor effect on reproductive functions because gonads secrete most of
sex hormones. Regulated by ACTH
▪ CORTICOSTEROIDS in general contains Mineralocoticoids & Glucocorticoids are collectively included under
corticosteroids.
***Deficiency or suppression of ACTH will ↓cortisol and androgens leading to atrophy of ZF and ZR.
Exam Question: Patient in treatment of cortisol (glucocorticoids) will ↑negative feedback to the hypothalamus
leading to ↓ACTH. Which zones goes into atrophy? ZF and ZR.
1) Primary adrenal insufficiency – ↓ all adrenal cortex hormones.
2) Secondary adrenal insufficiency – ↓ACTH= only leads to deficiency of cortisol and androgens and does NOT
affect aldosterone levels.
▪ Aldosterone* is the most important hormone from the adrenal medulla because it is needed to live. It regulates
total body Na+, which will regulate total body water. If none, will lose Na+ and water leading to hypovolemic
shock and death.
▪ Epinephrine and Norepinephrine bind adrenergic receptors (α and β receptors all over the body)
▪ Receptors in the heart are β1 receptors and bind β2 receptors in blood vessles, and in lungs to cause dilation.
Also, binds to α receptors in blood vessels cause constriction.
▪ Pheochromocytoma – affect all the receptors (constant stimulation) is characterized by ↑Epinephrine and
Norepinephrine.

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Condition: Cortisol ACTH CRH Example
Primary hypercortisolims ↑ ↓ ↓ Adrenal Corticoma
Secondary hypercortisolism ↑ ↑ ↓ Pituitary Adenoma and Paraneoplastic Syndromes
Primary adrenal insufficiency ↓ ↑ ↑ Adrenal Cortex is destroyed (Adison’s Disease)
Secondary adrenal insufficiency ↓ ↓ ↑ AP Damaged (Seaham’s Syndrome)
Tertiary adrenal insufficiency ↓ ↓ ↓ Damage to Hypothalamus
• Under stress state, the high centers
stimulate hypothalamus to produce CRH
goes via median eminence to the
Anterior Pituitary where it binds to the
receptors and activates cAMP second
messenger system to produce ACTH
which goes to adrenal cortex and acts via
cAMP to produce cortisol (ZF) and
androgens (ZR).
• Cortisol and androgens are lipid soluble
hormones, so more than 99% is bound
to globulins and plasma proteins. 1% is
free cortisol (physiologically active)
which regulates the negative feedback.
• Endorphins = usually modulate perception of pain.
• β MSH = melanocyte stimulating hormone.
• α MSH = with ACTH.
o **whenever ACTH is being produced, β MSH is also produced and ACTH (acts as α MSH) also can
stimulate melanocytes.
o **Thus, ↑ACTH levels will lead to hyper-pigmentation.
o Example:
▪ Primary Adrenal Insufficiency (Addison’s disease) = ↓adrenal cortex feedback = ↑ACTH.
▪ Secondary hypercortisolism = small cell carcinoma (ectopic endocrine glands) can also produce
↑ levels of ACTH. Paraneoplastic syndromes (Ectopic sites).
• ACTH is produced from a large precursors peptide known as POMC (pro opiomelanocortin) cleaved into β-
lipotropin and ACTH
• β-lipotropin is broken into endorphins and β-MSH (stimulates melanocytes with ACTH)
• Excess of ACTH causes hyperpigmentation.
5. Regulation of secretion of Adrenocortical hormones:
1) Glucocorticoid (GC) secretion:
• Glucocorticoids (Cortisol) production oscillates with an ACTH -
dependent 24-hour periodicity known as Circadian rhythm
• This diurnal variation is due to a “Biological clock” located in
Suprachiasmatic nucleus of hypothalamus
• Cortisol and ACTH levels are highest in the morning (8 AM),
and lowest in the late evening (12 midnight) - stress hormone
will be higher as you wake up in the morning.
• Rhythm reversed in night workers

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A) Hypothalamic control: Via Corticotropin-Releasing Hormone (CRH)
• CRH released by Paraventricular nucleus of Hypothalamus into Hypothalamo-hypophyseal portal blood &
carried to Anterior Pituitary.
• In anterior pituitary, CRH stimulates synthesis of POMC which is precursor for Adrenocorticotropic hormone
(ACTH) in corticotrph cells & leads to ACTH formation (and β-MSH and endorphins)

B) Pituitary Control:
• ACTH ↑ steroid hormone synthesis in Adrenal cortex by stimulating enzyme Cholesterol desmolase (rate
limiting enzyme in the synthesis of all steroid hormones) which increase conversion of Cholesterol to
Pregnenolone.
• ACTH has lesser effect on Zona glomerulosa which secrete Mineralocorticoids as it is mainly controlled by
Renin- Angiotensin Aldosterone system
• Chronically elevated ACTH (Pituitary Secreting Tumors) causes persistent stimulation of Adrenal cortex
resulting in hypertrophy of Adrenal glands (ZF and ZR).
C) Negative feedback control by Cortisol: Elevated Cortisol inhibits CRH secretion from Hypothalamus & ACTH
from Anterior pituitary by negative feedback.

6. Factors Affecting ACTH Secretion

Stimulating factors Inhibitory factors
• ↓ [Cortisol] in Blood • ↑[Cortisol] in Blood
• Sleep-wake transition (ACTH levels are higher in the morning) • Opiods
• Stress (physically and mentally) - hypoglycemia, surgery, trauma • Somatosatin (GHIH)
• Psychiatric disturbances
▪ **Cortisol is required in stressful situations because ↑ substrates for energy (specially for the brain): glucose,
FA, and AAs.
▪ During fasting, patient develops hypoglycemia – GH, cortisol, epinephrine/norepinephrine and glucagon
counter regulating hormones are secreted to raise levels of plasma glucose.
▪ **Deficiency in one of these hormones and adrenal cortex insufficiency leads to hypoglycemia.

2) Regulation of Aldosterone Secretion:

• Regulated mainly by Renin - Angiotensin system
• Aldosterone secretion is stimulated by ↓ serum Sodium & ↑Potassium levels (hyperkalemia directly
stimulates it).
o ↓Na+ can lead to ↓ECF volume, BV, BP; anything that does this ↑aldosterone.
• Also controlled by ACTH to a lesser extent as ACTH does not have significant effect on Zona
Glomerulosa.
A) Renin-Angiotensin system: ↓blood volume/pressure (↓renal blood flow) renin (juxtaglomerular cells
from the afferent arteriole)  AT-I (produced by the liver) AT-II (ACE in the lungs) which acts on Zona
Glomerulosa of Adrenal cortex where binds to AT1 Receptors to stimulate Aldosterone Synthase enzyme to
form ↑Aldosterone.
• Aldosterone ↑Na+ & H2O reabsorption restoring ECF volume.
• Renin secretion increases due to:
a) ↓RBF (hypovolemia/hypotension)
b) β1 receptors stimulation by sympathetic activity
c) ↓NaCl to the macula densa cells
B) Hyperkalemia ↑Aldosterone secretion which brings about ↑renal K+ excretion

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▪ Aldosterone goes inside P cells in late DT and CD, and upregulates synthesis of epithelial Na+ channels. Na+
comes in and pushes K+ out into lumen.
▪ α-intercalated cells: ↑ secretion of H+ ion by activating H+ ATPase enzyme.

▪ AT-II acts on proximal tubule and activates Na+/H+

exchanger. Secretes more H+, just like aldosterone does.

▪ On afferent arteriole, there are juxtaglomerular cells that

act as baroreceptors. The pressure in AA ↓ and stimulates
release of renin from juxtaglomerular cells.
▪ Hypotension/hypovolemia causes release of renin by ↓ of
renal blood flow.
▪ Other factors are stimulation of β1 receptors.
(norepinephrine – from sympathetic system
(postganglionic neurons))
▪ B1 receptors on JG cells! * Stimulate (only other site is
Heart!)
▪ Macula densa cells are specialized and located thick ascending loop and early distal
tubule that senses Na+ levels flowing through lumen)
▪ When there is low NaCl in renal tubule the macula densa cells send signals to JG cells to
cause release of Renin.
7. Pathway by which an ↑ potassium intake induces greater potassium excretion mediated
by Aldosterone.

8. Physiological actions of Glucocorticoids

• Stress situations such as states of trauma, exposure to cold, Illness, starvation and
Exercise, infections)
• The capacity to withstand stress is dependent on adequate secretion of the
glucocorticoids
• Stress hormones usually act to mobilize energy store. These are Counter-regulatory hormones/oppose
insulin) are:
a) GH (↑glucose, Mobilizes fats by Lipolysis)
b) Glucagon (mobilizes glucose by glycogenolysis in the liver)
c) Cortisol mobilizes fat (FAs), protein (AAs) and carbohydrate (Glucose).
d) Epinephrine (in some form stress as Exercise) mobilizes glucose via glycogenolysis in the muscle and FA by
lipolysis
• Deficiency in one of the stress hormone, causes Episodes of Hypoglycemia (can’t compensate one for the
other)
• All of these raise glucose, FA, AA levels in stressful situations.
a) Breaks glycogen to glucose
b) TAGs or adipose tissue to FAs
c) Protein to Aas
• Treatment (IV or oral) used clinically - similar action to cortisol
a) Prednisone d) Betamethasone
b) Hydrocortisone e) Beclomethasone (inhalation)
c) Dexamethasone

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9. Actions of Glucocorticoids:
Metabolic actions of cortisol:
• ↑ blood sugar levels (Hyperglycemia) by two mechanisms:
1) ↓glucose uptake (Anti-Insulin action) in muscle, adipose and lymphoid (No GLUT-4 transporters)
2) Gluconeogenesis by liver (very important) ***
• Cortisol has a Permissive Effect with Glucagon as it enhances Glycogenolysis (and gluconeogenesis) by ↑ the
levels of the enzymes (lipid soluble by producing brand new proteins). Therefore, without cortisol fasting
hypoglycemia rapidly develops. - if Cortisol is missing, Glucagon can’t work effectively.
• ↑ protein catabolism in muscles (proteolysis), ↓ protein synthesis (anti-insulin effect), provides more Amino
acids to the liver for Gluconeogenesis (Substrates that can use: AA, Glycerol and lactate).
• Can see atrophy of muscles if too much.
• ↑ Lipolysis (by activating the Hormone Sensitive Lipase Enzyme or HSL), and ↑delivery of FA’s and Glycerol.
Glycerol is used for Gluconeogenesis, favors Ketone bodies formation.
• Cortisol is a Ketogenic hormone like GH because lots of FA make lots of Acetyl CoA, which will favor ketone body
formation. These effects can worsen Diabetes Mellitus.
➢ Adrenal diabetes = very high level of glucocorticoids. Patients taking glucocorticoids for long time: People who
have developed autoimmune disorders (SLE, arthritis, asthma) are at risk of adrenal diabetes. Patients will present
with atrophy of muscles due to catabolic effect of this hormone in the muscles.

• Permissive actions of cortisol:

a) Glucagon = promotes gluconeogenesis and glycogenolysis
b) Catecholamines:
▪ Promote glycogenolysis
▪ Promote lipolysis
▪ Promote vasoconstriction (α1 receptors are stimulated by NE) - required to maintain the vascular tone
of the blood vessels and to maintain BP by ↑TPR.
- Excess of cortisol can lead to hypertension due to ↑TPR (also present with hyperglycemia) this
are features seen in Cushing’s Syndrome.
- Cortisol deficiency can lead to hypotension because BP↓ due to lack of permissive effect of
cortisol with catecholamines (also present with hypoglycemia).
▪ Promote Bronchodilation – β2 receptors via permissive effect of cortisol on catecholamines in lungs.
▪ Cortisol can bind with mineralocorticoid receptors (aldosterone receptors)– very mild effect due to
hypercortisolism or in long period treatment with exogenous cortisol resulting in ↑reabsorption of
sodium, ↑ECF, ↑BV/BP (hypertension).

➢ Glucocorticoids (cortisol) are the best drug to reduce inflammation:

a) Heat is increase temp = calor d) Pain = dolor
b) Redness = rubor e) Loss of function
c) Swelling = tumor

• Anti-inflammatory actions: (in pharmacological doses)

• Phospholipase A2 enzyme liberates Arachidonate from membrane Phospholipids
Arachidonate (Phosphatidylinositol). This Arachidonate is precursor for
inflammatory mediators like Prostaglandins (COX) & Leukotrienes (LOX).
• GC induces synthesis of Lipocortin*, an inhibitor of Phospholipase A2, thereby
inhibiting formation of Arachidonate. Thus GC have anti-inflammatory properties
used as a treatment for asthma.
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• PGs are very important in GIT and stomach by secreting bicarbonate and mucous in stomach mucosa
which protects the epithelium from HCl and pepsin produces by the stomach.
• Treatments with glucocorticoids can ↓ this protective mechanism by ↓PGs and resulting in peptic ulcers.
Therefore, Proton Pump Inhibitors (antacids) should be given.

10. Glucocorticoids (Cortisol)

• Inhibits release of Histamine & Serotonin from mast cells & platelets (used to treat allergies - antihistamines
are less potent)
• Inhibits collagen synthesis in skin and bones* and promotes breakdown of collagen leading to easy bruising
(skin) and osteoporosis (bone) – hip and vertebral fractures are commonly seen.

3) GCs used in prevention/reduction of Immune response in organ transplant recipients

• In pharmacological doses, GC suppress the immune response (cellular immunity) by inhibiting production of
Interleukins IL-2 & T-lymphocytes which are crucial for cellular immunity
• Destruction of lymphoid tissues
• Prevents rejection of transplanted organs
• Also inhibit antibody production by the tissues. (lowers humoral immunity) – helpful for autoimmune diseases
• Glucocorticoids suppress both cellular immunity as well as humoral immunity (can be given in acute exacerbation
to prevent type IV hypersensitivity seen in SLE and Rheumatoid Arthritis).

4) Maintenance of vascular responsiveness to Catecholamines

• GC up regulates α1receptors on arterioles, ↑vasoconstrictor effect of Norepinephrine.
• BP↑ with Cortisol excess (Cushing’s Syndrome) & BP↓ with Cortisol deficiency

5) On bones: GC in excess ↑bone resorption by ↑osteoclastic activity and ↓bone formation.

• *similarly, osteoblasts have cortisol receptors, then activate osteoclasts via IL-6 and RANK-L. (may also
directly activate osteoclasts).
• Also causes ↑protein catabolism (↓collagen synthesis and break it down in bone). These effects lead to
breakdown of bone matrix & Osteoporosis.
– Pts on GCs for long time are prone for fractures. MC = hip bone and vertebrae fractures.

11. Actions of Glucocorticoids:

1) ↑gluconeogenesis
2) ↓ glucose utilization - because it needs GLUT-4
3) ↓ insulin sensitivity (↑resistance due to anti-insulin action) – if a diabetic pt is in glucocorticoids the insulin
doses should be ↑ ***
4) ↑lipolysis (via HSL)
5) ↑proteolysis
6) Inhibit inflammatory response (MC used)
7) Suppress immune response (MC used in autoimmune disorders)
8) Enhance vascular responsiveness to catecholamines (α1 receptors) - permissive effect
9) ↑GFR (perhaps by constricting efferent arteriole)
10) *Also block ADH V2 receptors, so ↑ free water clearance.
11) ↓ REM sleep
12) **Mild mineralocorticoid activity - weakly bind and activate aldosterone receptors. Pts on GCs for years, ↑ Na+
and water reabsorption resulting in hypertension.
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12. Actions of Mineralocorticoids (MC Aldosterone):

1) Reabsorption of Sodium and water, excretion of Potassium & Secretion of H+:
• MC act on Principal cells of late distal tubule & collecting ducts
• ↑renal Na+ reabsorption by ↑epithelial Na+ channels (ENaC) in Principal cells of Late DT & CD, also
stimulates Na+- K+ ATPase pump
• ↑renal K+ secretion into tubular lumen in P cells
• ↑renal H+ secretion into tubular lumen (Hydrogen ATPase pump in α(I) cells).
o For every H+ secreted into lumen, HCO3- gets reabsorbed into the blood

➢ Conn’s syndrome = tumor of zona glomerulosa causes hyperaldosteronism ↑Na+ reabsorption. (↑ECF [Na+]
and volume) leading to hypertension. Secrete more K+, so ECF potassium ↓ (hypokalemia) along with H+
resulting in metabolic alkalosis.
➢ Addison’s Disease = Hypoaldosteronism resulting in hyperkalemia and as can’t reabsorb Na+, can’t pump out
K+ and secrete H+ resulting in metabolic acidosis.
➢ Cushing’s Syndrome = ↑[cortisol], ↑ [glucocorticoids] or pituitary adenoma secreting excess ACTH.

13. Adrenocortical excess:

Cushing’s Syndrome* (Hypercortisolism) = result of chronic excess of Glucocorticoids (Cortisol).
Causes:
1. MCC due to administration of high pharmacological doses (exogenous) of Glucocorticoids (used in treatment of
Asthma, Rheumatoid Arthritis, SLE, Organ transplant).
2. Cushing’s Disease* = Pituitary adenoma secreting ACTH* leading to high cortisol and Androgens.
3. Bilateral hyperplasia of Adrenal glands (GC and Androgens arising from ZF and ZR)
4. Adrenal adenoma (GC and Androgens) – benign tumor
5. Adrenal carcinoma (GC and Androgens) - metastatic cancer
6. Ectopic ACTH secretion by oat cell or small cell carcinoma of the lung (variant different to SIADH): (↑cortisol
(GC) and androgens) - Secondary Hypercortisolism

• High androgens can lead to hirsutism (male-pattern hair growth in women).

• Diagnostic: Gold standard test to identify cushing’s syndrome is based in the principle that if high level cortisol,
will be more cortisol in urine:
24-hour cortisol urine levels or “Low Dose Dexamethasone Suppression Test” - helps to differentiate between
primary and secondary causes of Cushing.
▪ Patients under stress or obese (fat, high blood sugar) can have these same symptoms or clinical
presentation because get high levels of ACTH and cortisol, so we have to rule out Cushing’s Syndrome by
giving synthetic glucocorticoid the night before and measure again at 8am. Next morning check for
cortisol levels.
▪ Dexamethasone (DMT) = Synthetic glucocorticoid that will go to hypothalamus and AP and ↓ CRH and
ACTH levels due to negative feedback.
▪ Give low dose 1mg DMT: - Dx. Cushing’s Syndrome
a) Cushing’s Syndrome (any cause) = Cortisol levels remain ↑ in the morning (lack negative feedback)
In ACTH secreting tumors (Secondary or Cushing’s Disease), low dose DMT does not suppress ACTH
& Cortisol secretion, as tumor cells secreting ACTH are less responsive to negative feedback by
Cortisol.
b) Normal/Stressed Patient = Cortisol levels go ↓ in morning (due to negative feedback).

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▪ Once, obesity is ruled out if levels of cortisol remains high, we have to differentiate between Primary
(Cushing’s Disease - Pituitary Adenoma) and Secondary (Cushing’s Syndrome).
▪ Give high dose 8mg DMT: Dx. Cushing’s Disease from other causes of Cushing’s Syndrome.
a) Primary hypercortisolism (Cushing’s Syndrome) ACTH and cortisol will remain ↑.
Example: In Ectopic ACTH secreting tumors, as in Carcinoma of lungs, Low or high dose DMT fail to
decrease both ACTH & Cortisol as the ectopic ACTH is not under Hypothalamo-Pituitary control and
of course adrenal tumors are not suppressed by high dose of synthetic glucocorticoid.
▪ Adrenal cortex is not inhibited by high levels of cortisol/GC directly.
b) Secondary hypercortisolism (Cushing’s Disease - tumor of anterior pituitary) will ↓ both ACTH &
Cortisol. *High Yield Question*

14. Cushing’s Syndrome:

• ↑ Cortisol & Androgen levels
• Androgens = responsible for secondary sex characteristics such as axillary and pubic hair in women.
• Secondary (Cushing’s Disease – pituitary adenoma) ↑ACTH and ↑cortisol
• Primary Adrenocortical excess (BAH, AA, AC) ↓ACTH and ↑cortisol

Clinical features: ↑ Cortisol

• Hyperglycemia = for a long time the β-cells of pancreas will burn out
and develop Adrenal Diabetes.
• ↑ lipolysis (↑ free fatty acids)
• ↑ protein catabolism - muscle wasting (thin extremities)
• ↑ appetite and ↑calorie intake = ↑ TAGs stored (although there’s
lipolysis and ↑ glycerol)
• Redistribution of fat - Central obesity with Pendular abdomen, Moon-
face having a narrow slit-like eye & fish-like mouth, Buffalo-hump
(supraclavicular pad of fat), giving the patient “Lemon-on-stick
appearance”- central obesity and extremities are thin.
• Hyperpigmentation is seen in patients with ectopic ACTH and Pituitary
Adenoma due to excess ACTH.
• Purplish abdominal striae = due to stretching of abdominal skin (can
see blood vessels), breast, and buttock (because skin becomes very thin
due to breakdown of collagen caused by cortisol).
• Poor wound healing (needs collagen) & ↑ susceptibility to infections
due to immunosuppression & ↑blood sugar (hyperglycemia)
• ↑Adrenal Androgens causes “Virilization” of women:
a) Hirsuitism (increase facial hair) c) Impotence
b) Amenorrhea d) Hypertrophy of clitoris.
• Hypertension (GC + MC actions) – miner corticosteroids mild effect in aldosterone receptors and permissive
effect with catecholamines
• Osteoporosis (elevated Cortisol levels increase bone resorption & cause excessive protein catabolism)
• Peptic ulcers, because glucocorticoids inhibit PGs in the stomach. Prostaglandins normally stimulate bicarbonate
and mucous production in stomach mucosa to protect from gastric acid. Tx. proton pump inhibitors (PPIs) when
on glucocorticoids.
• Treatment: Ketoconazole, an inhibitor of steroid hormone synthesis can be used to treat Cushing’s Syndrome

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15. Aldosterone is essential for life:
• Removal of Adrenal cortex causes Na+ & water loss (regulates body water indirectly).
• ↓ECF Volume causing Hypotension, dehydration, circulatory collapse = hypovolemic shock = death
• K+ retention – Hyperkalemia (which can result in arrhythmias), dehydration & circulatory collapse

16. Pathophysiology of Adrenal cortex

A. Adrenocortical insufficiency (deficiency):
1) Primary Adrenocortical insufficiency (Addison’s Disease):
Causes:
a) MCC in US due to autoimmune destruction of Adrenal cortex mediated by antibodies against the three
layers leading to adrenal crisis (MC USMLE)
b) MCC in other countries around the world: Tuberculous bacilli can cause damage to the adrenal cortex.
c) Waterhouse-Friderichsen syndrome may develop in children with meningococcal infection due to
Neisseria meningitides. This syndrome is characterized by hemorrhage of the adrenal gland.
• Clinical Features:
▪ Characterized by ↓ GC, MC (hypoaldosteronism) & Androgen secretion
▪ ↑ACTH because low Cortisol levels stimulate ACTH secretion (lack negative feedback)
▪ Since ACTH has MSH-like activity, this disease is characterized by Hyperpigmentation or generalized
pigmentation of skin, mucous membrane, gums, pressure points, folds & creases like elbow.
▪ Hormone levels: ↓cortisol (lack negative feedback), aldosterone and androgens= ↑ACTH
(hyperpigmentation)
▪ Aldosterone Deficiency can develop hyponatremia, hyperkalemia, thus high H+ too, metabolic acidosis,
hypovolemia.

2) Secondary Adrenocortical insufficiency:

Causes: Pituitary Damage to Corticotrophes cells as in Seaham’s Syndrome or nonfunction adenoma that
compress cells and can’t secrete hormones = ↓ACTH = ↓cortisol = ↓Androgens (zona faciculata and reticularis
will go into atrophy).
▪ Caused by deficiency of ACTH. This in turn leads to ↓Adrenocortical hormones (only cortisol and
androgens).
▪ No hyperpigmentation as ACTH is decreased
▪ ACTH does not affect Aldosterone secretion. Therefore, no signs of Aldosterone insufficiency
▪ Other symptoms similar to Addison’s disease
▪ Hypoglycemia is seen.
ACTH stimulation test* Administer ACTH to the patient, if Cortisol ↑on giving ACTH, defect is in Anterior
pituitary (Secondary Adrenal disease). If no improvement - defect in adrenal gland itself (Primary Adrenal
disease).
B. Primary Hyperaldosteronism:
1) Conn’s Syndrome= caused by an Aldosterone secreting tumor araising from the zona glomerulosa.
Clinical features: (opposite to primary hyperaldosteronism or Adison’s disease)
▪ Hypertension - due to ↑Na+ & H2O retention - ↑ECF & blood volume
▪ *This ↑ECF volume & BP in turn ↓Renin and AT-II secretion, although aldosterone is high**
▪ Hypokalemia - due to ↑K+ excretion by Aldosterone
▪ Metabolic Alkalosis - occurs because Aldosterone causes ↑H+ excretion in exchange for HCO3- reabsorption
2) Congestive Heart Failure (CHF): ↓BP(BV) hypotension = ↓ RBF = ↑ Renin & AT-II = ↑ Aldosterone
▪ DOC: Sperolactone – block aldosterone receptors

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3) ↑ Sympathethic Stimulation to β1 Receptors of Juxtaglomerular cells.

4) Renal Artery Stenosis = ↓ RBF = ↑ Renin, AT-II = ↑ Aldosterone = Hypertension.

17. Exam Question In Hyperaldosteronism, there is no Edema inspite of Na+ and H2O retention. Why?
↑Aldosterone = ↑ Na+ & H2O retention = ↑ ECF volume (↑BV/BP) = ↑venous return = stretches Atria = releases
ANP* (Atrial Natriuretic peptide) which blocks reabsorption of sodium in the renal tubules and causes Natriuresis -
therefore no edema is seen. This phenomenon is known as Aldosterone Escape.

18. Clinical Correlates:

▪ Congenital adrenal hyperplasia (CAH) is due to autosomal recessive deficiencies in the enzymes of the pathway that
leads to the synthesis of cortisol during fetal life. Lacking the negative feedback will lead to hyperproduction of ACTH
leading to hyperplasia (enlargement) of the adrenal glands. Some of the congenital deficiency of enzymes are 21 &
11 β –Hydroxylase. (Only cortisol deficiency causes CAH)
▪ MCC of CAH (>90% cases) is 21 β hydroxylase deficiency, 2nd MC 11 β –Hydroxylase, 3rd MC 17α–Hydroxylase.
▪ Precursor steroids are increased, which get converted to Androgens.
▪ This leads to a clinical condition known as Congenital Virializing Adrenal Hyperplasia / Adrenogenital Syndrome
which is characterized by development of male
secondary sexual characteristics in a female.

▪ All adrenocorticotropic hormones come from

cholesterol precursor.
▪ Cholesterol desmolase is the rate-limiting enzyme
in synthesis of most steroid hormones – converts
cholesterol to pregnenolone (rate limiting step)
▪ ACTH will stimulate cholesterol demsolase.
▪ AG-II stimulates the aldosterone synthase from
zona glomerulosa.
▪ Know the marked enzymes:
▪ If 3β-hydroxysteroid DH, cannot make
aldosterone, cortisol, androstenedione.
▪ Cortisol is the most affected hormone because
4 enzymes needed for cortisol synthesis.
▪ **17,20-lyase will make cholesterol hormone
shorter and add a keto group to 17C (17-keto-
steroids). Makes Androgens. In adrenal medulla, make DHEA and androstenedione. If deficient only causes
deficiency in androgen. Doesn’t cause CAH.
- In ovaries, makes testosterone first. Uses whole pathway up to estrogen. Have theca cells (make
testosterone) and go to granulosa cells and transfer it to estrogen.
- Testis uses whole pathway up to testosterone.

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CONGENITAL ADRENAL HYPERPLASIA (CAH) = all present with low cortisol and hypoglycemia* KNOW THIS!
Enzyme Deficiency Females 46 (XX) = genetically female Males 46 (XY) = genetically male
21-β hydroxylase •••Female Pseudohermaphrotidsm = (SEVERE) High •Normal levels of testosterone during fetal
Mild (MCC), but levels of androgens during fetal life causes the fusion of life, because is required for sexual male
severe CAH form has labia at birth appears as a scrotal sac and hypertrophy of development. During childhood,
marked changes. clitoris appears like penis. At the time of birth, physicians androgens remain elevated.
Patient can’t produce can’t determine by their genital sex and gonadal sex the •Normally in childhood, testosterone
cortisol or sex unless karyotyping. levels will ↓ at basal levels and ↑ during
aldosterone. The •No estrogen is produced during fetal life or childhood. adolescence. In this case, androgens levels
pathways favor the Only produced during adolescence for the development remain ↑ and causes preconscious
formation of of sex organs and secondary sex characteristics. puberty (axillary and pubic hair, genital
+
androgens. •After birth, can’t reabsorb Na (hyponatremia) due to growth) this is known as adrenogenital
lack of aldosterone (↓ECF) resulting in hypotension, syndrome.
↓ cortisol hyperkalemia and metabolic acidosis. •Fetus is normal, but After birth, can’t
↓11-DOC Clinical Features: Baldness, Hirsuitism, small breasts, reabsorb Na+ (hyponatremia) due to lack of
↑ androgens amenorrhea, heavy arms & legs, male pattern of hair aldosterone (↓ECF) resulting in
growth (adrenal virilism) hypotension, hyperkalemia and metabolic
Treatment: Glucocorticoid administration - inhibits ACTH acidosis.
& suppresses Androgen production.
•••MILDER form is identified later in childhood because
of precocious pubic hair and/or clitoromegaly, often
accompanied by accelerated growth and skeletal
maturation (simple virilizing adrenal hyperplasia) These
females may present in with oligomenorrhea, hirsutism,
and/or infertility (nonclassic adrenal hyperplasia). Salt
wasting is not seen in mild form. Normal salt and water
levels.
11-β Hydroxylase Female Pseudohermaphroditism Adrenogenital syndrome
•After birth, 11-deoxycorticosterone acts like a weak •Fetus is normal, but After birth, 11-
↓cortisol mineralocorticosteroid and in excess can stimulate deoxycorticosterone acts like a weak
↑11-DOC aldosterone receptors leading to ↑ sodium reabsorption mineralocorticosteroid and in excess can
↑Androgens (hypernatremia) ↑ECF resulting in hypertension, stimulate aldosterone receptors leading to
hypokalemia and metabolic alkalosis. ↑ sodium reabsorption (hypernatremia)
•Clinical Features: Baldness, Hirsuitism, small breasts, ↑ECF resulting in hypertension,
amenorrhea, heavy arms & legs, male pattern of hair hypokalemia and metabolic alkalosis.
growth (adrenal virilism)
•Treatment: Glucocorticoid administration - inhibits
ACTH & suppresses Androgen production.
17-α hydroxylase - •Normal female external genitalia because no hormonal •Male Pseudohermaphroditism =
needed in the input is required for development of female fetus. Testosterone input is required during fetal
pathway for •After birth, 11-deoxycorticosterone acts like a weak life and fetus can’t produce androgens or
testosterone in testes mineralocorticosteroid and in excess can stimulate testosterone. At the time of birth, no male
and estrogen in aldosterone receptors leading to ↑ sodium reabsorption external genitalia are developed. These
ovaries during puberty (hypernatremia) ↑ECF resulting in hypertension, patients present with blind vaginal pouch
↓cortisol hypokalemia and metabolic alkalosis. (ambiguous genitalia). These children will
↑ 11-DOC •When female approach puberty, no secondary sexual not have menarche or develop breast
↓androgens characteristic is developed due to lack of estrogen (Lack (most likely to be diagnosed at that point).
of pubic & axillary hair, don’t develop breast or •After birth, 11-deoxycorticosterone acts
like a weak mineralocorticosteroid and in
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menstruate). No menarche and present with primary excess can stimulate aldosterone
amenorrhea. receptors leading to ↑ sodium
reabsorption (hypernatremia) ↑ECF
resulting in hypertension, hypokalemia
and metabolic alkalosis* Differential
3-β hydroxysteroid •Normal at birth, approaching adolescence No menarche •Male Pseudohermaphroditism = can’t
dehydrogenase and present with primary amenorrhea. produce testosterone.
•After birth, can’t reabsorb Na+ (hyponatremia) due to •After birth, can’t reabsorb Na+
↓cortisol lack of aldosterone (↓ECF) resulting in hypotension, (hyponatremia) due to lack of aldosterone
↓11-DOC hyperkalemia and metabolic acidosis. *Salt Wasting* (↓ECF) resulting in hypotension,
↑DHEA (only)* hyperkalemia and metabolic acidosis.

19. Adrenal Medulla consist of Chromaffin cells (Pheocromocytes) - derived from Neural Crest (part of ANS)
▪ Secretes Catecholamines (CA):
1. Epinephrine (E) / Adrenaline= 80-90%
2. Nor-epinephrine (NE) / Noradrenaline = 10-
20% (also secreted by post-sympathetic
ganglia and Hypothalamus)
3. Dopamine (not produced by adrenal medulla)
▪ Preganglionic sympathetic neurons (cholinergic)
release Ach onto Nicotinic receptors (N-N
Receptors) on Chromaffin cells. Thus, adrenal
medullary cells are part of sympathetic system and
act like post-ganglionic neurons secreting E and NE
into the blood.

▪ When going from supine to upright position causes

↑ in sympathetic nervous activity because BP falls and release E and ↑NE to raise BP back to normal. (There’s a
theory about NE are released from the sympathetic postganglionic instead of the adrenal medulla).

ANS Preganglionic neurons Receptors Postganglionic Neurons Receptors

Sympathetic Cholinergic NN Cholinergic Muscarinic
Parasympathetic Cholinergic NN Androgenic α&β
Somatic Cholinergic fibers (motor neurons) from spinal cord to muscles release Ach to NM in muscles.

20. Cholinergic fibers

1) All Preganglionic fibers in both Sympathetic and parasympathetic nerves
2) All parasympathetic postganglionic
3) Few sympathetic postganglionic fibers
▪ Sweat glands (pre- and postganglionic are cholinergic) they are sympathetic* but have muscarinic
postganglionic receptors. This is an exception! *** Remember that sweating is stimulated by sympathetic
but is Ach instead of NE. (Atropine will block sweat glands and it will ↑ temperature)
21. Adrenergic fibers = most of the postganglionic sympathetic fibers
22. Main Receptors in ANS = based on the type of neurotransmitter there are Two types of receptors:
1. Cholinergic receptors where Acetylcholine acts
a) Muscarinic (M1 , M2,M3, M4, and M5) = all are G-protein coupled
b) Nicotinic (NM and NN) = ion channel mediated
- NM = autonomic ganglia from spinal cord to motor neurons* it release Ach.
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2. Adrenergic receptors where catecholamines (E/NE/dopamine) acts. Includes 1,  2 and  1, 2 , 3, All are G-
protein coupled
▪ Nicotinic Receptors are neuromuscular junction and ganglionic parasympathetic and sympathetic. Also present
in adrenal medulla.
▪ Muscarinic Receptors are cholinergic. Postganglionic parasympathetic are always muscarinic.

23. Consequences of Receptors activation in different organs

Location Cholinergic Adrenergic* α & β
Heart ↓ HR, FOC, CO ↑ HR, FOC, CO (E to β1 Receptors in heart)
Blood Vasodilatation (No direct innervation. Release of Vasoconstriction = ↑TPR = ↑BP (NE/E to α1
Vessels circulating Ach can binds to muscarinic receptors in Receptors in Blood vessels)
endothelial cells will stimulates the secretion of NO
or EDRF causing smooth muscle relaxation) and BP
Smooth Contraction, bronchospasm (bronchoconstriction), Relaxation: Bronchodilation, constipation,
muscle Diarrhea (↑secretion and motility), Urination Urinary retention (NE/E to β2 Receptors)
Sphincters Relaxation Contraction (α1 Receptors)
Pupils Miosis Mydriasis (α1 Receptors) - dilatation
Glands ↑Salivation, sweating, and gastric acid ---

Receptor: Location: Effect: (Know the *)

M1 Neurons CNS effects
M2* Heart Reduces heart rate (bradycardia)
M3* Smooth muscle and glands Contraction (except in blood vessels), diarrhea, bronchoconstriction, urination, 
Secretions, salivation, stomach acid, sweating, lacrimation
M3 Pupil and ciliary muscle Contracts Miosis, increased flow of aqueous humor
Nm Skeletal muscle end plate Contraction of skeletal muscle
1* Blood vessels Vasoconstriction, Mydriasis
Pupil (Iris) sphincter contraction…so Constipation and Urinary retention
smooth muscle
2 presynaptic neurons Reduces release of norepinephrine…bradycardia, hypotension
1* Heart Contraction, Increased heart rate,
JGA  renin release
2* Smooth muscles Relaxation = bronchodilation, urinary retention, constipation, uterus relaxation
3 Fat tissue Lipolysis

24. Nicotinic Receptors activation:

Target Receptor Response
Adrenal medulla NN Secretion of E and NE
Autonomic Ganglia NN Stimulation - net effect depends on PANS/SANS innervation and
dominance
Neuromuscular junction NN Stimulation - twitch/hyperactivity of skeletal muscle

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25. Actions of Catecholamines = Acts via α & β Receptors *E has high affinity for β1 &
1) α Adrenergic receptors = Mostly excitatory, except inhibitory to GIT motility β2 Receptor; when present
a) α1 receptors = present in smooth muscle = blood vessels (constriction), in high concentrations can
Mydriasis (pupil dilation - dilator pupillae) bind to α1 Receptor.
▪ NE has higher affinity for α1 receptors= vasoconstriction on blood vessel. *NE has high affinity to α1
▪ High circulating [Epinephrine/NE] can bind to α1 receptors. Receptors.
2) β – adrenergic receptors = mostly inhibitory, except excitatory to myocardium
a) β1 Receptors: present in Cardiac muscle = Excitatory = ↑ HR, contractility, conduction velocity
▪ binds all catecholamines.
▪ Also present in JG apparatus.
b) β2 Receptors: Relaxation of smooth muscle – GIT, bronchioles, blood vessels, uterus (everyone dilates, but
uterus relax).
▪ So, motility of GIT ↓
▪ Epinephrine has higher affinity for β2 = smooth muscle vasodilation.
▪ Blood vessels also have β2 receptors for vasodilatation.
▪ No sympathetic innervation of postganglionic to these receptors what binds β2 is E and NE from
blood (from adrenal Medulla) – smooth muscle relaxation (circulating catecholamines)
▪ If circulating epinephrine stimulated α1 and β2 – Epinephrine has greater affinity to β2 (even
stimulated in low concentrations causing vasodilation).

Catecholamines:
A) On CVS: ↑HR, force of contraction
▪ Can cause fibrillation (overstimulation of β1 Receptor) and tachycardia (> 100 bpm) in high doses.
Therefore, not given intravenously (EpiPen is given IM or subcutaneously).
▪ ↑Blood pressure due to ↑CO (CO = HR x SV)
B) On metabolism: ↑BMR*, Glycogenolysis (liver and skeletal muscle - from Skeleal muscle lactic acid is release
because it lack G6P), Gluconeogenesis, ↓peripheral utilization
▪ Net effect: Hyperglycemia*
▪ Lipolytic ↑FFA (Glycerol is used as a substrate) & leads to formation of Ketone bodies (Ketogenic)
▪ Counter-regulatory hormones (cortisol, glucagon, epinephrine, GH)* released when have hypoglycemia.
C) Bronchial muscles - causes Bronchodilatation (β2 Receptor). Therefore, used in treatment of Asthma to relax
bronchioles. (albuterol, terbutaline, salmeterol, adrenaline – only minisquel dose intramuscularly for epi)
D) Selective secretion: ↑secretion of CAs during emergencies & stress due to activation of Sympatho-Adrenal
Medullary system
▪ Gives rise to Flight/Fight Response
▪ Keeps person in Alert and Arousal state due to activation of Reticular activation system (RAS)
• It is active when you’re awake and suppressed when going to sleep (no sensation).
• You can’t sleep when you get scared or stressed before the block exams.
▪ Protective changes seen are:
• Dilates the pupil by contraction of dilator pupillae (contracts to dilate pupil = α1 Receptors), causing
lighter to enter the eyes.
• ↑HR, CO, VR causing better perfusion of vital organs
26. Actions:
▪ Cutaneous vasoconstriction - minimizes bleeding
o Example: Lidocaine - is mixed with adrenaline binds to α1 receptors causing local anesthesia without
being washed away and the effect last longer.
▪ Piloerection of hair (Horripilation) due to pilomotor contraction-
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▪ ↑sweating (Adrenergic sweating) to Muscarinic Receptors (Exception).
▪ Dopamine* is used in treatment of shock because it causes Renal vasodilatation & peripheral vasoconstriction
a) Dopamine binds D1 receptors* in kidney:
▪ vasodilation of afferent arteriole (↑RBF and GFR)
▪ relaxes mesangial cells = capillaries get dilated = ↑ SA for filtration = ↑filtration (GFR)
b) Dopamine binds α1 receptors in periphery = vasoconstriction.

▪ When we have hypovolemia and hypotension our sympathetic activity in the body↑:
o ↑HR, FOC and CO. (This mechanism is needed to deliver blood to tissues).
o Release of dopamine in kidney (by postganglionic sympathetic neurons) causes vasodilation (so we can allow
more blood in the kidney). Otherwise, hypotension and hypovolemia will result in kidney failure due to low
renal blood flow.
o In peripheral dopamine causes vasoconstriction. (can be used to treat shock due to low pressure and low
volume) – tries to ↑blood pressure to normal by vasodilation in kidney to preserve blood flow to kidney.
(prevent renal failure)

27. Pheochromocytoma = tumor of Chromaffin (Pheochromocytes) tissues of Adrenal Medulla which results in episodic
hypersecretion of Catecholamines.
Clinical features: Hypertension, headache*(very common key), sweating (sympathetic overactivity), palpitations,
anxiety, moist skin, blurring of vision because of pupillary dilatation.
• ↑body temperature – ↑BMR, Hyperglycemia leading to Glycosuria
• ↑urinary excretion of CA in the form of VMA (Vanillyl Mandelic acid)
*Hallmark in a 24Hr Urine Collection Test* will present ↑ VMA
▪ These catecholamines are released in episodic fashion = E and NE ↑ in blood circulation and bind β1, β2 and α1
receptors.
▪ Will see more α1 receptors effect than β2* in peripheral circulation at higher concentrations of E and NE,
because β2 is more affected in lower concentrations.
- Treatment: α1 receptors antagonist are given as β2 will be stimulated by epinephrine and will lead to
vasodilatation ↓BP back to normal.
▪ β1 effect on the heart = ↑BP (see headache common with hypertension)
▪ There will be sweating because of sympathetic over activity.
▪ E (metanepherine) and NE (normetanephrine) – these byproduct levels ↑ in blood circulation and the end
product vanillylmandelic acid (see this in the urine).
▪ Hypertension can be: pheochromocytoma, Cushing’s, Conn’s, Renal arterial stenosis (↓RBF = ↑ RAA) – look for
urine levels.

28. Case Study:

A 40-year-old male who is a known Asthmatic had severe exacerbation of Asthmatic attacks for which his physician
prescribed him high dose of Prednisolone (a synthetic steroid). A few days later he felt better. His doctor advised him
to taper the steroid dose and gradually stop the drug. What is the basis for stopping the steroid therapy by slowly
decreasing steroid dose over a long period of time?

• Physiologic Explanation:
▪ Bronchial asthma is an inflammatory disease due to leukotrienes.
▪ Treatment: Β2 agonists can be used or glucocorticoids can also be used.
▪ MOA: Glucocortacoids can relieve inflammation by stimulating synthesis of lipocortin that inhibits
Phospholipase A2. The Β2 agonists are only symptomatic
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▪ Glucocorticoids treatment includes: Prednisolone, prednisone, dexamethasone, betamethasone,
beclomethasone, hydrocortisone (cream). Some are inhalational steroids.
▪ Reason to gradually stop the treatment:
- When a patient is receiving supplemental glucocorticoid in prolonged period, ACTH levels will be ↓ and
endogenous cortisol will be ↓ due to negative feedback.
- Anterior pituitary is unable to secrete normal amounts of ACTH for as long as a month. Thereafter,
ACTH slowly ↑ and will stimulates adrenals to ↑ glucocorticoids.
- If stop treatment abruptly, the patient will develop adrenal atrophy of zona fasiculata and reticulosa
due to ↓ cortisol levels and become unresponsive to ACTH known as adrenal crisis and will develop
Secondary Adrenal Insufficiency due to ↓ACTH and ↓Cortisol.

VIII. Endocrine Pancreas

1. Pancreas is divided into:
A. Exocrine pancreas (major form) = made up of glands that produce
enzymes. All proteases, malase, lipase, bicarbonate.
B. Endocrine pancreas (also known as islets of Langerhans) 1-2% of
pancreatic mass secretes two major peptide hormones: insulin and
glucagon (fasting).
o Coordinated function of both is to regulate glucose,
aminoacidic and fatty acid metabolism.
o Constituted by Islets of Langerhans (1% to 2% of pancreatic mass) contains 3 major cell types:
a) β cells (60-70%)= secretes Insulin after a meal in response to high glucose levels as pre-pro insulin.
(pro is C peptide and inulin – separated in vesicles with appropriate stimulus).
o Tyrosine kinase second messenger for insulin
o Insulin produced by β cells will go into α cell and inhibits secretion of glucagon.***
o In Type I DDM insulin: glucagon ratio is reduced and this inhibitory mechanism is lacking= ↑
levels of glucagon due to ↓ levels of insulin resulting in Hyperglycemia.
b) α cells (20%)= secrete Glucagon to raise blood glucose between meals when fasting and starvation.
(hypoglycemia stimulates this)
c) δ cells (10%)= secrete Somatostatins & Gastrin. It inhibits Insulin & Glucagon secretion. (statin*
always inhibitory, in hypothalamus it inhibits secretion of growth hormone)
o Other cells secrete Pancreatic Polypeptide (function unknown).
2. Insulin contains A-chain & B-chain connected by 2 disulfide bridges*
• Synthesis: Proinsulin is a single peptide chain (A-chain & B-chain + C-
peptide)
o Proteases cleave a Connecting peptide (C-Peptide) to form Insulin
o C-peptide is secreted along with Insulin in equimolar quantities
into the blood
o C-peptide levels important for differentiating between high
endogenous or exogenous levels.
o If pt comes unconscious, you test blood glucose levels. If
hypoglycemic, look for both levels of insulin and C-peptide.
3. Clinical Significance of C-Peptide:
• [C- peptide] = amount of Insulin secreted by the β-cells of Pancreas
• It is measured in diabetic patients receiving exogenous Insulin in order to monitor endogenous Insulin secretion
by β-cells of Pancreas.

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Clinical Case: A patient present to ED with hypoglycemia, Insulin C-Peptide
unconscious, a blood test is performed.
Normal Patient ↓ ↓
Insulinoma = tumor of β-cells of Pancreas ↑ ↑
Type I IDDM ↑ (exogenous) ↓

4. Factors affecting Insulin Secretion: Remember that pancreas have Insulin Independent GLUT-2 transporters.
Stimulating Factors Inhibitory Factors
a) ↑ [Glucose] = major factor regulating Insulin secretion. Glucose binds a) ↓ [Glucose]
to GLUT-2 receptors on β-cells of Pancreas & causes Insulin release by b) Fasting
Exocytosis c) Exercise = Exercising muscle doesn’t need
b) ↑ [Amino Acids] - Arginine, Lysine, Leucine, [Fatty Acids] & insulin for the muscle to uptake of
[Ketoacids] glucose. Best treatment for diabetes.
c) Counter regulatory hormones (Glucagon, GH, Cortisol, E, NE, TH) ↑ d) Somatostatin
insulin indirectly by directly ↑ glucose levels. e) α-Adrenergic agonists (Sympathetic
d) Incretins = increase insulin secretion due to presence of glucose in GIT. inhibits)
Includes GIP and GLP-1. f) Diazoxide
a. Glucose-dependent insulinotropic peptide (GIP) = secreted by
intestinal epithelial cells that senses glucose levels and stimulates
insulin secretion from Beta Cells as an anticipation in glucose raise.
b. Glucagon-like-peptide 1 (GLP-1) = in the presence of glucose in the
small intestine and increases secretion of insulin. GLP-1 agonist
drugs are used clinically only in type II diabetes to secrete insulin.
(remember type 1 no β-cells)
e) Potassium = Insulin ↓potassium levels in extracellular fluid through
the Na+/K+ ATPase pump and lowers potassium levels. Treatment for
hyperkalemia: Insulin + Glucose (prevents hypoglycemia)
f) Parasympathetic Stimulation: Vagal Stimulation & Acetylcholine
g) Sulfonylurea drugs (E.g., tolbutamide, glyburide) = blocks ATP-
Dependent K+ channels causing release of insulin in the liver. The most
important side effect: hypoglycemia in between meals. DOC today is
metformin because bring glucose levels back to normal without
causing hypoglycemia.
h) Obesity = ↑ resistance to insulin = ↑glucose (hyperglycemia) = ↑
insulin (hyperinsulinemia) in early stages of diabetes type 2 DM.

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5. Regulation of Insulin secretion
1) ↑ [glucose] is the major regulation of the insulin secretion it is
transported by GLUT-2 (insulin independent) in the β-cells of
pancreas.
2) Glucose undergoes glycolysis and produce ATP.
3) ↑ATP levels closes ATP Dependent Potassium Channels.
4) Potassium levels ↑ inside the cells and the cell undergoes
depolarization (more positive charge).
• Normally, high K+ in ICF, so normally K flows from inside to
outside through ATP-dependent K+ channels, among others.
5) Voltage sensitive calcium channels get opened.
6) Calcium levels inside the cell ↑
7) Insulin already synthetized and stored in vesicles are release into the
blood by exocytosis along with equimolar C-peptide.
• Sulfonylureas block ATP-Dependent K+ channels causing release of
insulin. The most important side effect: hypoglycemia in between meals.
• Metformin lowers glucose levels from hyperglycemia to normal and doesn’t cause hypoglycemia (New DOC).
• In late stages of Type II DM, β-cells burn out because of high insulin secretion. Sulfonylureas will not work in late
stages and exogenous insulin should be prescribed.
• Insulin works on skeletal, adipose tissue and liver.

6. Insulin Receptor (GLUT-4 in Skeletal Muscle and Adipose Tissue)

• The action of insulin on target cells begins when Insulin binds to its
receptor in the cell membrane.
• The insulin receptor is composed of two α subunits (extracellular)
and two β subunits (transmembrane) connected to each other by
disulfide bonds.
• The β subunits of Insulin have the second messenger Tyrosine
kinase.
• In liver, GLUT-2 transporters are insulin independent and does not promote uptake of glucose in liver, but
promotes different metabolic actions. ↑FA, protein synthesis, glycogenesis, and inhibit gluconeogenesis.

7. Mechanism of Action of Insulin:

1) Insulin binds to the α domain of the insulin receptors
in skeletal muscle and adipose tissues and activates
the tyrosine kinase in the β domain.
2) The tyrosine kinase once activated phosphorylates the
β subunit which is right next to it, a part of it called
auto-phosphorylation.
3) This attracts the Insulin Receptor Substrate-1 (IRS-1)
to bind to the receptor and its phosphorylated on the
tyrosine residues.
4) SH2-domain proteins bind to phosphorylated
tyrosines on IRS forming the PI-3 kinase
(phosphatidylinositol-3 kinase). This leads to
recruitment of GLUT-4 in adipose tissue and skeletal
muscle which will bring glucose form ECF to ICF.
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▪ In liver, insulin also activates protein phosphatase. Dephosphorylate glycogen synthase, glycogen
phosphorylase, etc.
▪ Insulin down-regulates its own receptor by ↓ the rate of synthesis and ↑the rate of degradation of the
receptor. Down-regulation of the insulin receptor is in part responsible for the ↓ insulin sensitivity of target
tissues in obesity and type II diabetes mellitus. Ask patient to lower adipose tissue by exercising.

8. Actions of insulin: Insulin acts on liver, adipose tissue & muscle

1) On carbohydrate metabolism: Insulin ↓blood [glucose] by following mechanisms:
a) ↑uptake of glucose into target cells such as muscle and adipose tissue by directing insertion of glucose
transporters into (GLUT 4) into the cell membranes. Glucose entry into cells decreases the blood glucose levels
• Peripheral uptake of glucose by Insulin
o Tissues requiring Insulin for effective glucose uptake are: adipose tissue and resting skeletal
muscles
o During exercise, glucose can enter muscle without insulin as exercise ↑ the number of Glucose
transporters (GLUT-4). The first thing to do for a Type II Diabetes Patient (lose weight to decrease
resistance)
o Tissues not affected by Insulin are: Nervous tissue, kidney tubules (SGLT), intestinal mucosa, RBCs,
β-cells of Pancreas (GLUT-2).
b) ↑ formation of Glycogen from glucose in muscles & liver - storage of glucose in form of glycogen(enhances
Glucokinase & Glycogen synthetase enzymes) and inhibits Glycogenolysis
c) ↓Gluconeogenesis
d) ↑ Phosphofructokinase (ex, PFK-1) activity (↑ glycolysis)
**In all, Insulin ↓Glucose production (in the liver) & ↑peripheral utilization of
Glucose
Enzymes Glucagon = Phosphorylates Insulin = Dephosphorylates
via Protein Kinase via Protein Phosphatase
Glucokinase Inactive Active
Glycogen synthetase Inactive Active
PFK-1 Inactive Active
Glycogen Phosphorylase Active Inactive

2) On fat metabolism:
• In adipose tissue, Insulin stimulates fat deposition (Triacylglycerol synthesis or
lipogenesis),
• **Insulin Activates Enzyme Lipoprotein lipase (LPL) (activated by apo-CII) which
mediates the uptake down VLDL and Chylomicron (FA into TAG)
• *Insulin ↓ activity of Hormone-sensitive lipase preventing Lipolysis (HSL
inactivated by insulin)
• ↓ fatty acid degradation, provides less of Acetyl CoA for Ketoacid formation.
Thereby, Insulin inhibits Ketoacid formation in liver, so ↓ketone body synthesis.
3) On protein metabolism:
• Insulin is protein Anabolic (as GH) stimulates amino acid uptake into cells,↑ protein synthesis, preventing
protein degradation.
4) Other actions:
• ↑ K+ uptake into cells = ↓ blood K+ levels
• Insulin + glucose are used to treat Hyperkalemia as seen in renal failure, metabolic alkalosis, etc.

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9. Major Actions of Insulin and the Effects on Blood Levels

Actions of Insulin Effects on Blood Levels
↑ Glucose uptake into cells ↓ blood [glucose]
↑ Glycogen formation (glycogenesis ↓ blood [Amino Acids]
in liver* and skeletal muscle) ↓ blood [fatty acids]
↓ glycogenolysis
↓ gluconeogenesis
↑ protein synthesis (anabolic)
↑ TAGs (Adipose Tissue) = lipogenesis
↑ Glycolysis (break down glucose to
release energy) Insulin is not needed by liver to uptake glucose
↓ Potassium in blood (GLUT-2) promotes glycogen synthesis for example.

10. Insulin Glucagon Molar Ratio

a) Insulin = Favors storage of absorbed nutrients and is a “Hormone of energy storage”
b) Glucagon = Mobilizes energy stores and is a “Hormone of energy release”
• Because of their opposite effects, the blood levels of both hormones must be considered in any given situation
• On a balanced diet, Insulin:Glucagon Molar ratio = 2.3
• Arginine infusion ↑ the ratio to about 3
• Starvation for about 3 days ↓ the ratio to 0.4
• Inference:
a. Ratio is low when energy requirements are high (During starvation, exercise) *
b. Ratio is high when energy requirements are less (Post-prandial - more energy available)

11. Glucagon = secreted by α cells under ↓ blood glucose levels (major stimulus)*
***This hormone primary acts on the liver and “maybe” adipocytes.
Factors increasing Glucagon secretion: Factors decreasing Glucagon secretion
• ↓ blood glucose levels (fasting and starvation) • ↑ blood glucose (major factor) -
• ↑ Amino acids especially Arginine = stimulates insulin and glucagon because promotes secretion of insulin
secretion. In Protein (AA) diet*, insulin goes up and lowers blood and it inhibits glucagon.
glucose, inducing hypoglycemia. Glucagon thus secreted to prevent
hypoglycemia.
• CCK, Ach, E, NE
• Sympatethic stimulates glucagon during hypoglycemia

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12. Actions of Glucagon: Glucagon acts on Liver* & Adipose tissue via cAMP*
A. On carbohydrate metabolism: Glucagon is a hyperglycemic hormone
▪ ↑blood [glucose] = hyperglycemia
▪ ↑ Glycogenolysis (liver) by activating Glycogen phosphorylase
(activated by phosphorylation)
▪ ↑Gluconeogenesis (Glycerol, Lactate*, AAs*) - peaks after glycogen
is almost depleted.
▪ ↓ Phosphofructokinase activity
▪ ↑ glucose formation & ↓ Glucose breakdown
*Fructose 1-6-bisphosphatase is rate limiting of Gluconeogenesis.

B. On fat metabolism:
• Lipolytic - fatty acids are used for Gluconeogenesis (β-oxidation and give ATP) - although the most important
substrates are lactate and Amino Acids.
• Acetyl CoA obtained from Fatty acid degradation leads to formation of Ketoacids (Acetoacetate and 3-β-
hydroxybutyrate - in blood)
• Acetone is the other ketone that will be volatile and eliminated through breathing.
• Therefore, Glucagon is Ketogenic, along with GH, cortisol, epinephrine, NE meaning all these promote
lipolysis.
• Ketone bodies, in excessive starvation, are used by the Brain!
• Diabetic ketoacedosis = ↑ ketone bodies (ketosis). As hydrogen is added for every ketone body, Hydrogen
↑ and acetone is ↑ and can leave through lungs (smell fruity odor of acetone being released during
ketoacidosis)
• Glucagon promotes β-oxidation in the liver; while Insulin inhibits β-oxidation.

C. On Protein metabolism:
• Glucagon causes Protein catabolism
• Amino acids are utilized for Gluconeogenesis
• Net effects of Glucagon: Hyperglycemic, Lipolytic, Ketogenic & Protein catabolic

13. Insulin Pathophysiology

• Deficiency of Insulin gives rise to a clinical condition called Diabetes Mellitus
• These patients present with glycosuria.
• Diagnostic criteria by the American Diabetes Association (ADA) include the following:
• A fasting plasma glucose (FPG) level of **126 mg/dL (7.0 mmol/L) or higher (on 2 separate occasions), or
• A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test
(OGTT), or
• A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of
hyperglycemia or hyperglycemic crisis
• Whether a hemoglobin A1c (HbA1c) level of 6.5% or higher should be a primary diagnostic criterion or an
optional criterion remains a point of controversy. (glycosylated Hb = tells glucose levels in past 2-3 months)

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Values of [Glucose] Blood Fasting Sugar (BFS) Post-prandial levels
Normal 70 - 99 mg/dL 70-140 mg/dL
Prediabetic 100-125 mg/dL 140-199 mg/dL
Diabetic > 126 mg/dL > 200 mg/dL (glycosuria
due to renal threshold)

▪ Metformin is the number 1 preferred drug for type 2 DM, because it reduces the glucose levels to normal,
not develop hypoglycemia. Because does not ↑ secretion of insulin from β-cells and it reduces liver output of
glucose. Side effect: metabolic acidosis.
▪ Sulfonylureas: if patient does not eat, can have episodes of hypoglycemia, because it ↑ secretion of insulin
from β-cells.
• Low insulin, high glucagon:
- Have polyuria, because higher glucose in urine resulting in osmotic effect as it pull water in.
- ECF volume has more glucose, become more concentrated, so ↑ thirst. Polydipsia.
- *Ketosis, acidosis, hyperkalemia, hypotension, polydipsia, polyuria.
- ↑ anion gap because ↑ ketone bodies. (beta-hydroxybutyrate,
- Hypotension because lose blood, ECF volume due to polyuria.
Clinical manifestations of Diabetes Mellitus: Differential: A patient
a) Polyuria - ↑excretion of urine come with Polyuria and
• Due to ↑ blood glucose, filtered load of glucose exceeds reabsorptive capacity (Tm) polydipsia. Check for
of kidneys. Unreabsorbed glucose is excreted in urine (Glucosuria). This causes glucose in the urine.
osmotic diuresis as glucose is osmotically active leading to polyuria. (+) glucose = DM
• Renal threshold = plasma concentration at which glucose first appears in the urine = (-) glucose = DI
200 mg/dL even though some nephrons/transporters have not reached transport
maximum due to nephron heterogeneity.
• Cause hyperosmolarity – ↑ glucose raises osmolarity. (Hyperosmolar conditions will be seen)
b) Polydipsia - excessive thirst due excessive loss of water, stimulates thirst center in hypothalamus
c) Polyphagia - excessive hunger
• Insulin has a direct effect on Hypothalamic satiety center**. Normally, satiety center
located in ventromedial hypothalamus inhibits feeding center (which is located in
Lateral Hypothalamus). A normal person should stop eating & gets feeling of fullness.
• In Diabetes Mellitus, because of lack of Insulin, satiety center fails to inhibit feeding
center & person goes on eating
d) Hyperglycemia: In absence of Insulin, glucose uptake into cells is inhibited, storage of glucose as Glycogen also ↓.
This ↑ blood glucose levels:
• There is intracellular glucose deficiency in Skeletal muscle and adipose tissue inspite of increased blood
glucose levels. Therefore, this condition is referred to as “Starvation in midst of plenty”
e) Increased blood levels of amino acids due to excessive protein catabolism & increased fatty acids because of
increased lipolysis
f) Hypotension: Osmotic diuresis causes excessive water loss in urine, ↓ECF volume = ↓BV/BP
g) Hyperkalemia: Insulin deficiency prevents K+ uptake into cells, thereby ↑ blood K+ levels causing Hyperkalemia
(lack of enhance effect of insulin in the Na+/K+ ATPase pump.
h) Metabolic acidosis: Insulin deficiency leads to ↑ lipolysis, ↑ production of Ketoacids (β-hydroxy butyrate and
acetoacetate), causing metabolic acidosis, known as Diabetic Ketoacidosis (DKA)*
• ↑ arterial [H+] in DKA = stimulates Peripheral Chemoreceptors = ↑ ventilation depth (Hyperventilates)

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• Classically patient with DKA presents with rapid (tachypnea), deep breathing (hyperventilation) known as
Air Hunger or Kussmaul’s breathing.
• Metabolic acidosis (pH < 7.4) with hyperventilation respiratory compensation.
• ↑anion gap because ↑organic acids (Normal Anion Gap = 8-12)
• Breath will have fruity sweet odor (due to acetone).
i) ↑ susceptibility to infections:
• ↑ blood glucose with impaired circulation, presence of peripheral neuropathy - demyelination, because
glucose gets into neurons (does not need insulin for glucose uptake) – this predisposes to infections and favors
growth of organisms.
• Diabetics are prone to develop ulcers of foot*, even on minor injuries.
o Can decrease blood flow to lower extremity – necrosis, gangrene and nontraumatic amputation.
Sensation is affected.

14. To summarize Effects of Insulin Deficiency

• Get neuropathy and retinopathy because glucose accumulates in
neurons. Aldose reductase converts glucose to sorbitol,
osmotically active, cannot leave cell, cell swell and damage
neurons.
o Neuropathy = can have sensation loss.
o Can have a silent MI because had it but do not feel pain
because have less sensation.
• Break down of AA = ↑ glucose = ↑ plasma AA = ↑ N metabolism
= ↑ ammonia converted to higher levels of urea.
• Insulin deficiency leads to excess glucagon.
• Lose a lot of electrolytes from body.
• ↑ FA because of lack of insulin.
• Ketonemia = can do dipstick to test ketonuria.
• Water follows ketones and glucose in the urine – volume goes
down (osmotic diuresis) causes dehydration (polydipsia) and polyuria.

15. Treatment for Diabetes Mellitus:

• Oral hypoglycemic agents (Sulfonylureas, Metformin)
o Metformin ↓ insulin resistance, ↓ hepatic glucose output, and enhances peripheral glucose uptake.
Proposed mechanisms of action include enhanced suppression of gluconeogenesis by insulin,
↓glucagon-stimulated gluconeogenesis, and ↑ uptake of glucose by muscle and adipose cells. The net
effects of these changes in diabetic patients are to ↓ fasting and post-prandial blood glucose by 20 to
40 %, ↓ hemoglobin A1C, ↓ body weight slightly, ↓ low density lipoprotein (LDL), and ↑ high density
lipoprotein (HDL)
• Insulin replacement
• Glycosylated Hemoglobin (HbA1c) is the sugar attached to Hemoglobin. Greater the blood sugars, greater
would be the Glycosylated Hemoglobin. Normal levels of HbA1c = 4 - 6%
• HbA1c is used as an index of Diabetic control. HbA1c < 7% for a period of 3 months indicates good diabetic
control.
• GLP-1 agonist (E.g. exenatide) = used clinically only in type II diabetes to secrete insulin. (remember type 1 no β-
cells)

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16. Complications in Diabetes Mellitus:
• If untreated, DM - can lead to Microvascular & Neuropathic complications:
• Myocardial infarction (MCC death in diabetes)
▪ Why? Because predisposition to atherosclerotic changes.
▪ Impaired circulation because of endothelial damage. Glucose goes into endothelial cells and
brings water and causes damage. The damage will accumulate platelets and cause atherosclerotic
changes.
▪ Coronary artery atherosclerosis (50%)*, carotid artery (can embolize leading to ischemic
strokes), popliteal artery* (ischemia, necrosis leading to gangrene; have to amputate)
• Popliteal artery is common artery with atherosclerotic changes in diabetics.
• One of the most common non-traumatic amputations in the world of the extremities*
▪ Causes nephropathy, neuropathy, enteropathy (bloating), retinopathy.
• Atherosclerosis causes efferent arteriole constriction ↑PGC leading to ↑GFR.
▪ Treatment: ACE inhibitors or ARBs.

• Diabetic neuropathy
▪ Aldose reductase converts glucose to sorbitol. Attracts water causing demyelination of neurons.
(called neuropathy – the demyelination)
• Diabetic Retinopathy = proliferative scarring of retina (blindness)
• Diabetic nephropathy
▪ What is first/one of first sign of nephropathy in diabetes? Presence of albumin in urine.
• Diagnostic: Check for albuminuria (proteinuria).
• Physiology: The basement membrane undergoes glycosylation. Once glycosylated, it
becomes permeable to albumin (lose negative charge). Albumin can be freely filtered.
▪ MCC of end-stage renal failure = diabetes.
▪ UTI very common because of glucose present in the urine.

• These complications are due to formation of sugar-derived substances called Advanced glycation end products
(AGEs)
• AGEs form cross-linkages between proteins, which alters their structure and function, as in cellular matrix,
basement membranes and vessel-wall
• AGEs also cause deposition of LDL cholesterol in vessel walls resulting in atherosclerosis

17. Types of Diabetes:

A. Type 1 DM (Insulin dependent DM - IDDM): deficiency of insulin.
• Insulin deficiency due to autoimmune destruction of β-cells (70-80%) of Islets of Pancreas
• Develops before 40 years (known as Juvenile diabetes - first decade of life)
• Patients are not obese
• High incidence of Ketosis & acidosis
• Insulin low, glucagon high = Hyperglycemia.
• Develop DKA because the complete absent of insulin.
• Treatment: Insulin

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B. Type 2 DM: Maturity onset DM
• Insulin levels are high/normal, but resistance to Insulin actions in target tissues due to deficiency of
Insulin receptors / defect in Glucose transporters (GLUT- 4).
• Maybe due to down-regulation of Insulin receptors, ie: Chronically elevated plasma Insulin ↓ the
number of Insulin receptors
• Hyperglycemia due to ↑ glucose output by the liver and/or lack of insulin.
• Affects middle-aged/older people
• Prevalence: 80% patients are usually obese (risk factor)
• Resistin = peptide found in adipose tissues, causes downregulation of Insulin receptors & ↓Insulin
sensitivity.
• Less prone for Ketoacidosis
• Treatment: Reduction of glucose input (decrease demand for insulin) and exercise to decrease in
resistance to insulin by the adipose tissue.
• Treatment should cover these (3) pathophysiology: (Sulfonylurea1 or Metformin2)
a) 1↓ insulin levels (↑ insulin levels but ↓ insulin levels compared to the glucose levels).
b) 2↑ resistance to insulin.
c) 2↑ output of glucose by liver.

▪ Initial stages: high insulin

1) Stage 1: insulin ↑
2) Stage 2: insulin slightly ↓
3) Stage 3: insulin ↓
• Hyperosmolar comma (HHS)* is most commonly seen in patients with type 2 DM who have some concomitant
illness that leads to reduced fluid intake, as seen, for example, in elderly institutionalized persons with decreased
thirst perception and reduced ability to drink water. *Recall formula of osmolarity of body fluids.

18. Differentials:
Condition Cause Insulin C-Peptide Onset
Type I DM (IDDM) Autoimmune destruction ↓ ↓ early onset (less than 40 years)
of β-cells non-obese, more prone for DKA
Type II DM (NIDDM) downregulation of Insulin ↑ ↑ Late-onset (after 40 years) in obese patients
receptors (resistance)
LADA (Type 1.5) autoimmune destruction of ↓ ↓ Late-onset (after 40 years)
β-cells BMI under 25kg/m2 (not obese)

19. Summary of Insulin -related pathologic states

Condition Glucose Insulin C-peptide Ketoacidosis
Type II DM (NIDDM) ↑ ↑ or N ↑ or N Absent (still have a little sensitivity to insulin;
late stages can develop KA).
Type I DM (IDDM) ↑ ↓ ↓ Present due to no insulin (uses FAs)
Insulinoma ↓ ↑ ↑ Absent
Factitious Hypoglycemia ↓ ↑ (exogenous) ↓ Absent
(Injection of Insulin)

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