Chapter 16
Basic Concepts of Endocrine Regulation
In general, endocrine physiology is concerned with maintaining various
aspects of homeostasis. The mediators of such control mechanisms are
soluble factors known as hormones. The word hormone was derived from
the Greek horman, meaning to set in motion. The endocrine system
differs from other physiological systems in that it cannot be distinctly
defined based on anatomical boundaries. It operates as a distributed
network comprising glands and circulating messengers, often under
the influence of the central nervous system, the autonomic nervous
system, or both.
Evolution of Hormones & Their Actions on Target Cells
Hormones comprise steroids, amines, and peptides. Peptide hormones
are by far the most numerous. Many hormones can be grouped into
families reflecting their structural similarities as well as the
similarities of the receptors they activate. However, the number of
hormones and their diversity increases as one moves from simple to higher
life forms, reflecting the added challenges in providing for homeostasis in
more complex organisms. For example, among the peptide hormones,
several are heterodimers*¹ that share a common α chain, with
specificity being conferred by the β-chain*². In the specific case of
thyroid-stimulating hormone (TSH), follicle-stimulating hormone
(FSH), and luteinizing hormone (LH), there is evidence that the distinctive
β-chains arose from a series of duplications of a common ancestral gene.
For these and other hormones, moreover, this molecular evolution implies
that hormone receptors also need to evolve to allow for the spreading of
hormone actions/specificity. This was accomplished by co-evolution of
the basic G-protein–coupled receptors (GPCR) and receptor tyrosine
kinases that mediate the effects of peptide and amine hormones that act at
the cell surface. Steroids and thyroid hormones are distinguished by their
predominantly intracellular sites of action, since they can diffuse freely
through the cell membrane. They bind to a family of largely cytoplasmic
proteins known as nuclear receptors. Upon ligand binding, the
receptor–ligand complex translocates to the nucleus where it either
homodimerizes, or associates with a distinct liganded nuclear receptor to
form a heterodimer. In either case, the dimer binds to DNA to either
increase or decrease gene transcription in the target tissue.
HORMONE SECRETION
SYNTHESIS & PROCESSING:-
The regulation of hormone synthesis depends on their chemical nature.
For peptide hormones as well as hormone receptors, synthesis is
controlled predominantly at the level of transcription. For amine and
steroid hormones, synthesis is controlled indirectly by regulating the
production of key synthetic enzymes as well as by substrate
availability. Interestingly, the majority of peptide hormones are
synthesized initially as much larger polypeptide chains, and then
processed intracellularly by specific proteases*¹ to yield the final hormone
molecule. In some cases, multiple hormones may be derived from the
same initial precursor*², depending on the specific processing steps
present in a given cell type. Presumably, this provides for a level of
genetic “economy”*³. It is also notable that the hormone precursors
themselves are typically inactive. This may be a mechanism that provides
for an additional measure of regulatory control*⁴, or, in the case of
thyroid hormones, may dictate the site of highest hormone availability.
The synthesis of all of the proteins/peptides discussed above is subject to
the normal mechanisms of transcriptional control in the cell.
In addition, there is provision for exquisitely specific regulation by other
hormones, since the regulatory regions of many peptide hormone genes
contain binding motifs*¹ for the nuclear receptors discussed above. For
example, thyroid hormone directly suppresses TSH expression via the
thyroid hormone receptor. These specific mechanisms to regulate hormone
transcription are essential to the function of feedback loops, as will be
addressed in greater detail below. In some cases, the abundance of
selected hormones may also be regulated via effects on translation. For
example, elevated levels of circulating glucose stimulate the translation of
insulin mRNA. These effects are mediated by the ability of glucose to
increase the interaction of the insulin mRNA with specific RNA-binding
proteins, which increase its stability and enhance its translation. The net
effect*² is a more precise and timely regulation of insulin levels, and thus
energy metabolism, than could be accomplished with transcriptional
regulation alone. The precursors for peptide hormones are processed
through the cellular machinery that handles proteins destined for export,
including trafficking through specific vesicles where the propeptide form can
be cleaved to the final active hormones. Mature hormones are also
subjected to a variety of post translational processing steps, such as
glycosylation, which can influence their ultimate biological activity and/or
stability in circulation. Ultimately, all hormones enter either the constitutive
or regulated secretory pathway.
SECRETION:-
The secretion of many hormones is via a process of exocytosis of stored
granules. The exocytotic machinery is activated when the cell type that
synthesizes and stores the hormone in question is activated by a specific
signal, such as a neurotransmitter or peptide-releasing factor. One
should, however, contrast the secretion of stored hormones with that of
those that are continually released by diffusion (eg, steroids). Control of the
secretion of the latter molecules occurs via kinetic influences on the
synthetic enzymes or carrier proteins involved in hormone production.
For example, the steroidogenic acute regulatory protein (StAR) is a
labile protein whose expression, activation, and deactivation are
regulated by intracellular signaling cascades and their electors,
including a variety of protein kinases and phosphatases. StAR traffics
cholesterol from the outer to the inner membrane leaflet of the
mitochondrion. Because this is a rate-limiting first step in the synthesis of
the steroid precursor, pregnenolone, this arrangement permits changes in
the rate of steroid synthesis, and thus secretion, in response to
homeostatic cues such as trophic hormones, cytokines, and stress (Figure
16–1). An additional complexity related to hormone secretion relates to the
fact that some hormones are secreted in a pulsatile manner. Secretion
rates may peak and ebb relative to circadian rhythms, in response to the
timing of meals, or as regulated by other pattern generators whose
periodicity may range from milliseconds to years. Pulsatile secretion is
often related to the activity of oscillators in the hypothalamus that regulate
the membrane potential of neurons, in turn secreting bursts of hormone
releasing factors into the hypophyseal blood flow that then cause the
release of pituitary and other downstream hormones in a similar pulsatile
manner. There is evidence that these hormone pulses convey different
information to the target tissues that they act upon compared to a steady
exposure to a single concentration of the hormone. Therapeutically,
pulsatile secretion may pose challenges if, due to deficiency, it proves
necessary to replace a particular hormone that is normally secreted in this
way.
FIGURE 16–1 Regulation of steroid biosynthesis by the steroidogenic
acute regulatory protein (StAR). Extracellular signals activate intracellular
kinases that, in turn, phosphorylate transcription factors that upregulate
StAR expression. StAR is activated by phosphorylation, and facilitates
transfer of cholesterol from the outer to inner mitochondrial membrane
leaflet. This then allows conversion of cholesterol into pregnenolone, which
is the first intermediate in the steroid biosynthetic pathway.
HORMONE TRANSPORT IN THE BLOOD
In addition to the rate of secretion and its nature (steady vs. pulsatile),
several factors influence the circulating levels of hormones. These include
the rates of hormone degradation and/or uptake, receptor binding and
availability of receptors, and the affinity of a given hormone for plasma
carriers (Figure 16–2). Stability influences the circulating half-life of a given
hormone and has therapeutic implications for hormone replacement
therapy, in addition to those posed by pulsatile secretion as discussed
above. Plasma carriers for specific hormones have several important
physiologic functions. First, they serve as a reservoir of inactive hormones
and thus provide a hormonal reserve. Bound hormones are typically
prevented from degradation or uptake. Thus, the bound hormone reservoir
can allow fluctuations in hormonal levels to be smoothed over time. Plasma
carriers also restrict the access of the hormone to some sites. Ultimately,
plasma carriers may be vital in modulating levels of the free hormone in
question. Typically, it is only the free hormone that is biologically active in
target tissues or can mediate feedback regulation (see below) since it is the
only form able to access the extravascular compartment. Catecholamine
and most peptide hormones are soluble in plasma and are transported as
such. In contrast, steroid hormones are hydrophobic and are mostly bound
to large proteins called steroid binding proteins (SBP), which are
synthesized in the liver. As a result, only small amounts of the free
hormone are dissolved in the plasma. Specifically, sex hormone–binding
globulin (SHBG) is a glycoprotein that binds to the sex hormones,
testosterone and 17β-estradiol. Progesterone, cortisol, and other
corticosteroids are bound by transcortin. The SBP-hormone complex and
the free hormone are in equilibrium in the plasma, and only the free
hormone can diffuse across cell membranes. SBP have three main
functions: they increase the solubility of lipid-based hormones in the blood;
they reduce the rate of hormone loss in the urine by preventing the
hormones from being altered in the kidney; and as mentioned above, they
provide a source of hormone in the bloodstream that can release free
hormone as the equilibrium changes. It follows that an additional way to
regulate the availability of hormones that bind to carrier proteins, such as
steroids, is to regulate the expression and secretion of the carrier proteins
themselves. This is a critical mechanism that regulates the bioavailability of
thyroid hormones, for example. In a pathophysiologic setting, some
medications can alter levels of binding proteins or displace hormones that
are bound to them. In addition, some binding proteins are promiscuous and
bind multiple hormones (eg, SHBG). These observations may have clinical
implications for endocrine homeostasis, since free hormones are needed to
feedback and control their rates of synthesis and secretion (see below).
Finally, the anatomic relationship of sites of release and action of hormones
may play a key role in their regulation. For example, several hormones are
destroyed by passage through the pulmonary circulation or the liver. This
may markedly curtail the temporal window within which a given hormone
can act.
FIGURE 16–2 Summary of factors that determine the level of free
hormones circulating in the bloodstream. Factors that increase (green
upward arrow) or decrease (red downward arrow) hormone levels are
shown. Free hormones also equilibrate with the forms bound to either
receptors or plasma carrier proteins.
HORMONE ACTION
Hormones exert a wide range of distinctive actions on a huge number of
target cells to effect changes in metabolism, the release of other hormones
and regulatory substances, changes in ion channel activity, and cell growth,
among others. Ultimately, the concerted action of the hormones of the body
ensures the maintenance of homeostasis. Indeed, all hormones affect
homeostasis to some degree. However, a subset of the hormones,
including thyroid hormone, cortisol, parathyroid hormone, vasopressin,
mineralocorticoids, and insulin, are the key contributors to homeostasis
(Table 16–1). Hydrophilic hormones, including peptides and
catecholamines, exert their acute effects by binding to cell surface
receptors. Most of these are from the GPCR family. Hydrophobic
hormones, on the other hand, predominantly exert their actions via nuclear
receptors. Two classes of nuclear receptors are important in endocrine
physiology.
TABLE 16–1 Major hormonal contributors to homeostasis.
The first class provides direct stimulation of transcription via induction of
the binding of a transcriptional co-activator when the hormonal ligand is
bound. In the second class, hormone binding triggers simultaneous
dislodging of a transcriptional co-repressor and recruitment of a
co-activator. The latter class of receptor allows for a wider dynamic range
of regulation of the genes targeted by the hormone in question.
PRINCIPLES OF FEEDBACK CONTROL
A final general principle that is critical for endocrine physiology is that of
feedback regulation. This holds that the responsiveness of target cells to
hormonal action subsequently “feeds back” to control the inciting endocrine
organ. Feedback can regulate the further release of the hormone in either a
negative feedback or (more rarely) a positive feedback loop. Positive
feedback relates to the enhancement or continued stimulation of the
original release mechanism/stimulus. Such mechanisms are only seen in
settings that need to gather momentum for an eventual outcome, such as
parturition. Negative feedback is a far more common control mechanism
and involves the inhibition or dampening of the initial hormone release
mechanism/stimulus. A general scheme for feedback inhibition of
endocrine axes is depicted in Figure 16–3. FIGURE 16–3 Summary of
feedback loops regulating endocrine axes. CNS, central nervous system. In
general, the endocrine system uses a network of feedback responses to
maintain a steady state. Negative feedback control systems such as those
described are the most common feedback/homeostatic systems in the
body. Feedback control loops also provide for diagnostic strategies in
evaluating patients with suspected endocrine disorders. For example, in a
patient being evaluated for hypothyroidism, normal levels of TSH tend to
rule out a primary defect at the level of the thyroid gland itself, and rather
suggest that a defect at the level of the anterior pituitary should be sought.
Conversely, if TSH is elevated, it suggests that the normal ability of
circulating thyroid hormone to suppress TSH synthesis has been lost, likely
due to a reduction in the ability of the thyroid gland to synthesize the
hormone.
Summary ()التلخيص
Chapter 16: Basic Concepts of Endocrine Regulation
Endocrine physiology is primarily concerned with maintaining homeostasis through soluble factors called hormones.
The term "hormone" comes from the Greek horman, meaning "to set in motion." Unlike other physiological systems,
the endocrine system lacks distinct anatomical boundaries and functions as a distributed network of glands and
circulating messengers, often influenced by the central and autonomic nervous systems.
Evolution of Hormones and Their Actions on Target Cells
Hormones include steroids, amines, and peptides, with peptides being the most numerous. Many hormones form
families based on structural and receptor similarities. Their diversity increases with organismal complexity to meet
homeostatic challenges.
Peptide hormones like TSH, FSH, and LH share a common α-chain, with specificity conferred by distinct β-chains,
which evolved from ancestral gene duplications. Hormone receptors have co-evolved, involving GPCRs and receptor
tyrosine kinases for peptide and amine hormones, while steroids and thyroid hormones act intracellularly via nuclear
receptors. These receptor-ligand complexes regulate gene transcription by binding DNA.
Hormone Synthesis and Processing
Hormone synthesis varies by chemical nature:
● Peptide Hormones: Regulated at transcription and processed from inactive precursors into active
hormones by specific proteases.
● Amines and Steroids: Synthesized via regulated enzymes and substrate availability.
Processing pathways include transcriptional control, RNA translation regulation (e.g., glucose-stimulated insulin
synthesis), and posttranslational modifications like glycosylation, affecting hormone stability and activity. Hormones
are ultimately directed into constitutive or regulated secretory pathways.
Hormone Secretion
Hormones are secreted by:
1. Exocytosis of stored granules: Triggered by specific signals (e.g., neurotransmitters).
2. Continuous release by diffusion: Steroids and similar hormones regulated through synthesis kinetics.
Some hormones are secreted in pulsatile patterns influenced by circadian rhythms, meals, or hypothalamic
oscillators. These rhythms can provide distinct signals compared to steady hormone exposure.
Hormone Transport in the Blood
Hormone levels are determined by secretion rate, degradation, receptor binding, and plasma carrier affinity.
Hydrophilic hormones (e.g., peptides) are soluble in plasma, while hydrophobic hormones (e.g., steroids) rely on
binding proteins like SHBG or transcortin. These carriers:
1. Serve as reservoirs.
2. Prevent hormone degradation.
3. Modulate free hormone availability, which alone is biologically active and regulates feedback loops.
Carrier protein expression can influence hormone bioavailability, particularly for steroids and thyroid hormones.
Hormone Action
Hormones regulate metabolism, growth, ion channel activity, and the release of other hormones to maintain
homeostasis. Key contributors include thyroid hormone, cortisol, parathyroid hormone, vasopressin,
mineralocorticoids, and insulin.
● Hydrophilic hormones: Act via GPCRs on cell surfaces.
● Hydrophobic hormones: Bind nuclear receptors to regulate gene transcription.
Nuclear receptors are classified into two groups based on their transcriptional regulation mechanisms, allowing
dynamic gene regulation.
Principles of Feedback Control
Feedback regulation ensures hormonal balance:
● Negative feedback: Commonly inhibits further hormone release, maintaining steady states (e.g., TSH
regulation by thyroid hormone).
● Positive feedback: Rare, amplifying responses for specific events (e.g., childbirth).
Feedback loops are crucial for diagnosing endocrine disorders. For example, elevated TSH levels in hypothyroidism
indicate impaired thyroid hormone synthesis, while normal TSH levels suggest anterior pituitary dysfunction.
