Basic Principles of Endocrine Physiology

Introduction

 Coordination of Body Functions by Chemical Messengers:

The multiple activities of the cells, tissues, and organs of the
body are coordinated by the interplay of different chemical
messenger systems:
1. Neurotransmitters are released by axon terminals of neurons
into the synaptic junctions and act locally to control neuronal
functions.

2. Neuroendocrine hormones are secreted by neurons into the

circulating blood and influence the function of cells at another
location in the body.
3. Paracrines are secreted by cells into the extracellular
fluid and affect neighboring cells of a different type.

4. Autocrines are secreted by cells into the extracellular

fluid and affect the function of the same cells that
produced them by binding to cell surface receptors.
5. Cytokines are peptides secreted by cells into the extracellular fluid
and can function as autocrines, paracrines, or endocrine hormones.
Examples of cytokines include the interleukins and other
lymphokines that are secreted by helper cells and act on other cells
of the immune system.
Cytokine hormones (e.g., leptin) produced by adipocytes are
sometimes called adipokines.

6. Endocrine hormones are released by glands or specialized cells into

the circulating blood and influence the function of cells at another
location in the body.
Introduction cont……..

The work hormone comes from the Greek hormaein, which means “to
excite”, or “to stir up”.
The classical definition of a hormone is a chemical substance that is
released into the blood stream in small amounts and is delivered by the
circulatory system to its target cells where it elicits a typical response.

However, it is now recognized that there is a wide spectrum of hormones or

hormone-like substances that are involved in cell-to-cell communication
without being secreted directly into the blood stream. They reach target cells
by diffusion through interstitial fluids.
The classical endocrine glands are :
i. Adrenal gland
ii. Islets of Langerhans
iii. Gonads
iv. Pituitary gland
v. Parathyroid glands
vi. Placenta
vii. Thyroid gland

• The classic hormones can be divided into three categories

Categories of classical hormones

1. Amino acids and their derivatives

o Epinephrine and other catecholamines, dopamine.
 While thyroid hormones are considered amine hormones,
they have little physiologic similarity to the other hormones
in this class aside from similar precursors.
 They are most similar to the steroid hormones and will be discussed below.
Categories of classical hormones

1. Four hormones are known – epinephrine, norepinephrine, dopamine and

serotonin. They are synthesized from tyrosine (first 3) and tryptophan
(serotonin).
2. These hormones do not have a hierarchic “feedback system”. Their release
is determined by a physiologic “end effect” of the hormones e.g. blood
pressure. They are stored in secretory granules called chromaffin granules.
They do not have binding proteins, a reflection of their relatively high
water solubility.
3. Amine hormones act via cell surface receptors which are G-protein linked
to cAMP, in general.
2. Steroids

They include: Cortisol, testosterone, estradiol etc

1. All steroid hormones share a common precursor –
cholesterol. Their synthesis is regulated by a series of
enzymatic pathways, which are present only in the adrenal
gland and the gonads.

2. Steroid hormones are not stored in secretory granules. Their

synthesis is closely linked temporally to their secretion. They
have specialized binding proteins, which carry them to their
target cells since they are relatively water-insoluble hormones.
3. Steroid hormones enter cells by simple diffusion and bind to receptors
located in the cytosol. The steroid hormone-receptor complex translocates
to the nucleus and interacts with a specific DNA sequence called steroid
response element (SRE) stimulating transcription of the appropriate gene.

Note: Thyroid hormones, which do not share structural homology with

steroid hormones, interact with their receptors, which are similar to steroid
receptors, in a mechanism very similar to steroid hormones.
 Thyroid hormone receptors, however, are located in the nucleus. Once the

thyroid hormone binds to the receptor, this complex interacts with the
thyroid response element (TRE) of thyroid- responsive genes thereby
regulating gene transcription.
3. Peptides and proteins

They include: Insulin, growth hormone, oxytocin, angiotensin, parathyroid

hormone etc
1. Most hormones in the body are polypeptides and proteins. They range in
size from small peptides with as few as 3 amino acids (thyrotropin-
releasing hormone) to proteins with almost 200 amino acids (growth
hormone and prolactin).

2. In general, polypeptides with 100 or more amino acids are called

proteins, and those with fewer than 100 amino acids are referred to as
peptides.
3. They are synthesized in the rough endoplasmic
reticulum of the different endocrine cells, in the same
way as most other proteins.
4. They are first synthesized as pre-prohormones:
large biologically inactive proteins. It has a signal
peptide of hydrophobic amino acids that guide it into
the cisterna of the RER. Here, the signal peptide is
cleaved off and the remainder of the polypeptide is
now a prohormone.
5. The prohormones are transferred to the Golgi apparatus where they
are packaged into secretory vesicles.

Enzymes in the vesicles cleave the prohormones to produce smaller,

biologically active hormones and inactive fragments.

The vesicles are stored within the cytoplasm, and many are bound to the
cell membrane until their secretion is needed.
Example: Insulin
Begins as preproinsulin. When the signal peptide is
removed, the chain folds back on itself and forms three
disulfide bridges.
It is now called proinsulin. Enzymes in the Golgi
complex then remove a large middle segment called the
connecting (C) peptide.
The remainder is now insulin, composed of two
polypeptide chains totaling 51 amino acids, connected
to each other by two of the three disulfide bridges.
6. Secretion of the hormones (plus the inactive fragments) occurs when the
secretory vesicles fuse with the cell membrane and the granular contents
are extruded into the interstitial fluid or directly into the blood stream by
exocytosis following an increase in cytosolic calcium concentration caused
by depolarization of the plasma membrane.

• In other instances, stimulation of an endocrine cell surface receptor causes

increased cyclic adenosine monophosphate (cAMP) and subsequently
activation of protein kinases that initiate secretion of the hormone.
7. The peptide hormones are water soluble, allowing them to enter the
circulatory system easily, where they are carried to their target tissues.
Thyroid Hormones

 They are derived from Tyrosine. They are synthesized and stored in the
thyroid gland and incorporated into macromolecules of the protein
thyroglobulin, which is stored in large follicles within the thyroid gland.

 Hormone secretion occurs when the amines are split from thyroglobulin
(TGB), and the free hormones are then released into the blood stream.

 After entering the blood, most of the thyroid hormones combine with
plasma proteins, mainly an α-globulin named thyroxine-binding globulin
(TBG), which slowly releases the hormones to the target tissues. The
minor transport proteins are albumin and an albumin-like protein called
thyretin. About 99.8% of T3 and 99.98% of T4 are protein-bound.
Role of transport proteins

 Enable hydrophobic hormones (steroids and thyroid hormones) to travel in

the blood.
 They also prolong their half- lives. They protect circulating hormones from
being broken down by enzymes in plasma and liver and from being filtered
out of the blood by the kidneys. Free hormone may be broken down or
removed from the blood in a few minutes, whereas bound hormone circulates
for hours to weeks.

 Bound TH serves as a long-lasting blood reservoir, so even if the thyroid is

surgically removed (as for cancer surgery), no signs of TH deficiency appear
for about 2 weeks. Steroid hormones bind to globulins such as transcortin,
the transport protein for cortisol. Aldosterone is unusual. It has no specific
transport protein, but binds weakly to albumin and others. However, 85% of
it remains unbound, and correspondingly, it has a half-life of only 20
minutes.
II. GENERAL CHARACTERISTICS OF HORMONE SYSTEMS -

 Necessary components of an endocrine regulatory system

a)Ability to detect an actual or threatened homeostatic imbalance
b)Coupling mechanism to activate the secretory apparatus
c)Secretory apparatus
d)Hormone
e)End-organ capable of responding to the hormone
f)Detection system which can recognize that the hormonal effect has
occurred and that the hormone signal can be terminated
g)Mechanism for removing the hormone from the target cells and blood
h)Synthetic apparatus to replenish the hormone in the secretory cell
III. HORMONES IN THE BLOOD

a. Hormones are secreted into the extracellular fluid and can enter the
bloodstream by passive diffusion down steep concentration gradients
or by an active energy-requiring process. The hormones distribute
rapidly throughout all extracellular fluid and are not preferentially
directed toward the target cells. Diffusion through capillary pores
largely accounts for the delivery of hormones to the target cells.
b. Hormone secretion can be episodic, pulsatile, or follow a daily or
circadian rhythm. This makes it necessary to make multiple serial
measurements of a hormone before a diagnosis of an altered hormonal
state can be made.
c. Endocrine-related diseases occur when the hormone concentration in
the blood is inappropriate for the existing physiologic situation. They
are not necessarily related to the absolute amounts of hormone in the
blood.
d. Most amine, peptide and protein hormones are readily soluble in plasma
and no special mechanisms are required for their transport. There
may be exceptions – i.e. growth hormone that has its own binding
protein.

e. In contrast, about 90% of the steroid and thyroid hormones are carried
bound to plasma proteins. Only about of 1-10% of the hormone is
free in solution. Only the free hormone can interact with a receptor.
This interaction or binding is a dynamic equilibrium.
IV. GENERAL ACTIONS OF HORMONES

a) The target cell rather than the hormone determines the specific response
elicited by a given cell. Different cell types may respond to the same
hormone in different ways. Example: Vasopressin affects both renal
tubule collecting ducts and vascular smooth muscle. In the kidney, it
increases the permeability of the collecting ducts to water; it causes
vasoconstriction in vascular smooth muscle.
b)Only cells that have the specific receptors for a particular hormone
respond to that hormone. Specificity for hormone action therefore
resides at the level of the receptors.
c)Some hormones have very restricted distribution. Example: Some
hypothalamic hormones are carried by small blood vessels directly to
the anterior pituitary.
Hormone Receptors and Their Activation

 When the hormone combines with its receptor, it initiates a cascade of

reactions in the cell, with each stage becoming more powerfully activated
so that even small concentrations of the hormone elicit a large effect.
 Each target cell usually has 2000 to 100,000 receptors. Each receptor is

highly specific for a single hormone; this determines the type of hormone
that will act on a particular tissue
 The locations for the different types of hormone receptors are generally the

following:
1. In or on the surface of the cell membrane. The membrane receptors are
specific mostly for the protein, peptide, and catecholamine hormones.
They are linked to second-messenger systems on the inner side of the
plasma membrane. These second messengers do not linger in the cell for
long. cAMP, for example, is broken down very quickly by the enzyme
phosphodiesterase.
2. In the cell cytoplasm. The primary receptors for the different steroid hormones
are found mainly in the cytoplasm. Steroids enter the nucleus and bind to a
receptor associated with the DNA. The receptor has three functional regions that
explain its action on the DNA: one that binds the hormone, one that binds to an
acceptor site on the chromatin, and one that activates DNA transcription at that
site. Transcription produces new mRNA that leads to the synthesis of proteins,
which then alter the metabolism of the target cell.
3. In the cell nucleus. The receptors for the thyroid hormones are found in the
nucleus and are believed to be located in direct association with one or more of
the chromosomes. Unbound T3 and T4 enter the target cell cytoplasm, where
an enzyme converts the T4 to T3 by removing one iodine. T3 binds to
receptors in three sites: on mitochondria, where it increases the rate of
aerobic respiration; on ribosomes, where it stimulates the translation of
mRNA and thus increases the rate of protein synthesis; and in the nucleus,
where it binds to receptors in the chromatin and stimulates DNA transcription
(mRNA synthesis).
Regulation of hormone receptor activity.

 The Number and Sensitivity of Hormone Receptors Are Regulated.

 The number of receptors in a target cell usually does not remain constant

(from day to day, or even from minute to minute).

 The receptors are often inactivated or destroyed during the course of their

function, and at other times they are reactivated or new ones are
manufactured. For instance, increased hormone concentration and
increased binding with its target cell receptors sometimes cause the
number of active receptors to decrease.
 This is called down-regulation of the receptors and may occur as a result

of;
1) Inactivation of some of the receptor molecules,
2) Inactivation of some of the intracellular signaling molecules,
3) Temporary sequestration of the receptor to the inside of the cell, away
from the site of action of hormones,
4) Destruction of the receptors by lysosomes after they are internalized, or
5) Decreased production of new receptors.
 Whatever the mechanism, receptor down-regulation decreases the target

tissue’s responsiveness to the hormone.

Up regulation

 Refers to the mechanisms by which a hormone increases the target tissue’s

responsiveness to it.
 Some hormones cause up-regulation of receptors and intracellular
signaling proteins; that is:
 Stimulating hormone induces greater than normal formation of
receptor or
 Greater synthesis of intracellular signaling molecules, or
 Greater availability of the receptor for interaction with the hormone.
 When this occurs, the target tissue becomes progressively more sensitive
to the stimulating effects of the hormone.
 Second Messenger Mechanisms for Mediating Intracellular Hormonal
Functions- Hormones exert intracellular actions by stimulating formation
of second messengers. The only direct effect that a hormone has on the cell
is to activate a membrane receptor and the second messenger does the rest.
 cAMP second messenger system- Binding of the hormones with the
receptor allows coupling of the receptor to a G protein. If the G protein
stimulates the adenylyl cyclase-cAMP system, it is called a Gs protein,
denoting a stimulatory G protein. This catalyzes the conversion of a small
amount of cytoplasmic ATP into cAMP. cAMP activates cAMP-dependent
protein kinase (PKA), which phosphorylates specific proteins in the cell,
triggering biochemical reactions that ultimately lead to the cell’s response
to the hormone. Hormones that use the cAMP second messenger system
include:
 Adrenocorticotropic hormone (ACTH), Angiotensin II (epithelial cells),
Calcitonin, Catecholamines (b-receptors), Corticotropin-releasing hormone
(CRH), Follicle-stimulating hormone (FSH), Glucagon, Human chorionic
gonadotropin (HCG), Luteinizing hormone (LH),
 Parathyroid hormone (PTH), Secretin, Somatostatin, Thyroid-stimulating
hormone (TSH) and Vasopressin (V-2 receptor, epithelial cells)
The Cell Membrane Phospholipid Second Messenger System

 Some hormones activate transmembrane receptors that activate the enzyme

phospholipase C attached to the inside projections of the receptors. This
enzyme catalyzes the breakdown of phosphatidylinositol biphosphate
(PIP2) into two second messengers, inositol triphosphate (IP3) and
diacylglycerol (DAG). The IP3 mobilizes calcium ions from mitochondria
and the endoplasmic reticulum. Calcium ions then have their own second
messenger effects, such as smooth muscle contraction and changes in cell
secretion. DAG activates the enzyme protein kinase C (PKC), which then
phosphorylates a large number of proteins, leading to the cell’s response.
Some hormones that use the phospholipase C second messenger system:
 Angiotensin II (vascular smooth muscle), Catecholamines (a receptors),
Gonadotropin-releasing hormone (GnRH), Growth hormone–releasing
hormone (GHRH), Oxytocin, Thyroid-releasing hormone (TRH) and
Vasopressin (V1 receptor, vascular smooth muscle)
Calcium-Calmodulin Second Messenger System

 Calcium entry may be initiated by;

(1) Changes in membrane potential that open calcium channels or
(2) A hormone interacts with membrane receptors that open calcium channels. On entering
the cell, calcium ions bind with the protein calmodulin. This protein has four calcium
binding sites, and when three or four of these sites bind calcium, the calmodulin changes
its shape and initiates multiple effects inside the cell, including activation or inhibition of
protein kinases. Activation of calmodulin-dependent protein kinases causes, via
phosphorylation, activation or inhibition of proteins involved in the cell’s response to the
hormone. For example, one specific function of calmodulin is to activate myosin kinase,
which acts directly on the myosin of smooth muscle to cause smooth muscle contraction.
The normal calcium ion concentration in most cells of the body is 10-8 to 10-7 mol/L,
which is not enough to activate the calmodulin system. But when the calcium ion
concentration rises to 10-6 to 10-5 mol/L, enough binding occurs to cause all the
intracellular actions of calmodulin. This is almost exactly the same amount of calcium
ion change that is required in skeletal muscle to activate troponin C, which causes
skeletal muscle contraction. (It is interesting that troponin C is similar to calmodulin in
both function and protein structure).
Hormone Interactions

 Multiple hormones can affect a single target cell simultaneously. There are
three types of hormone interactions:
1. Synergism
 Combined action of the hormones is more than just additive! ► Example:

Blood glucose levels & synergistic effects of glucagon, cortisol and

epinephrine
2. Permissiveness
 ► One hormone allows another hormone to have its full effect .Especially

during growth
 Hypothyroidism reduces effect of steroids

3. Antagonism: Antagonistic hormones have opposing physiological actions

– Hormone B diminishes the effect of hormone A
V. FEEDBACK REGULATION

a. Endocrine cells, in addition to having the ability to synthesize and

secrete their hormones, also have the ability to sense the biological
consequences of secretion of that hormone.
b. First order negative feedback is the simplest type and forms the basis
for more complex modes of regulation.
c. More commonly, second- and third-order feedback loops are present.
These systems can provide better fine-tuning of the control system
and provide some redundancy with a degree of “fail-safe”
mechanisms if one or more components of the system fail.
Negative Feedback Control

 Plasma hormone concentrations are closely controlled. In most instances,

the control is exerted through negative feedback mechanisms that ensure a
proper level of hormone activity at the target tissue.
 After a stimulus causes release of the hormone, conditions or products
resulting from the action of the hormone suppress its further release. i.e.,
the hormone (or one of its products) has a negative feedback effect to
prevent over secretion of the hormone or over activity at the target tissue.
 The controlled variable is usually not the secretory rate/amount of the
hormone itself but the degree of activity of the target tissue. When the
target tissue activity
 rises to an appropriate level, feedback signals to the endocrine gland
become powerful enough to slow further secretion of the hormone.
Feedback regulation occurs at various levels, e.g.;
 gene transcription and translation steps (synthesis of hormones) and
 steps involved in processing hormones or
 Steps involved in releasing stored hormones.
Positive Feedback Mechanism

 It occurs when the biological action of the hormone causes additional

secretion (surges) of the hormone. E.g. the surge of luteinizing hormone
(LH) that occurs due to the stimulatory effect of estrogen on the anterior
pituitary before ovulation.
 The LH then acts on the ovaries stimulating additional secretion of
estrogen, which in turn causes more secretion of LH.
VI. HORMONE DEGRADATION

a. Biological effects of hormones do not generally “use-up” the

hormone, so mechanisms must exist to degrade them once they have
conveyed their information.
b. Hormonal degradation occurs by hydrolysis by degradative enzymes,
oxidation, reduction, aromatization, de-iodination, and conjugation
with glucuronide, sulphate and methylation. Depending on the
hormone, degradation or clearance occurs most commonly in the
liver, and the kidneys. It also the lungs, muscles, blood as well as the
target organ itself. Often, recognizable end products appear in the
urine or blood and can be measured as an index of hormone
production.
VII. ALTERATION OF THE HORMONAL MESSAGE

 The hormonal message is subject to modifications/alteration which may

occur anywhere from its initial synthesis to its final arrival at its target site.
Subsequently, the expression of the message at this site (i.e., its action) is
also modified.
 The alterations of the hormonal message or its final action may be

physiologic or pathologic. They include:

1) Gene mutations which may affect the synthesis of the hormone, its
processing or its receptor.
2)Chromosomal deletions e.g. Turner’s syndrome which is the result of
partial or complete X-chromosomal deletion.
3) Alternative gene processing which may result in two different hormones.
For example, two distinct TSH receptors can arise from one gene; & the
synthesis of calcitonin and the significantly different calcitonin-gene-
related peptide (CGRP), which has different biologic activities, from the
same gene.
4) Posttranslational modification such as occurs in post-translational
glycosylation of pituitary glycoprotein hormones e.g. TSH, LH and FSH.
5) Alterations of binding proteins e.g. increases in thyroxine binding globulin
during pregnancy result in increased levels of total (but not free) thyroid
hormone.
6) Endogenous hormone antagonists.
7) Antibodies to hormones or their receptors e.g. classic example is Grave’s
disease, which is characterized by activating autoantibodies to the TSH
receptor resulting in hyperthyroidism.
8) Receptor alterations or post-receptor changes, which alter signal
transduction (biochemical events beyond receptor binding). Some of the
major pathophysiologic alterations in type 2 diabetes fall into this category.
9) Hormone clearance
VIII. MEASUREMENT OF HORMONES AND THEIR ACTIVITY

a. Radioimmunoassay (RIA) - The discovery and development of the

radioimmunoassay for insulin resulted in the Nobel Prize in Medicine
being awarded in 1977 to Dr. Rosalind Yallow for work done by her and
Dr. Solomon Berson (who died before the award was bestowed) in the
1950’s.
 The development of the RIA technique helped advance endocrinology as a

separate subspecialty of medicine. This competitive binding assay

technique allowed for measurement of very small concentrations of a
hormone. “It is summarized in the competing reactions shown (to the left).
 The concentration of the unknown unlabeled antigen is obtained by

comparing its inhibitory effect on the binding of radioactively labeled

antigen to specific antibody with the inhibitory effect of known standards”
Dr. Rosalyn Yallow, Nobel Lecture December 8, 1977
b. Bioassays – one of the earliest methods for measuring hormone activity. In
these assays, the sample to be studied interacts with a biological system with
a measurable biologic effect. An example of this type of assay are mouse
calvarial cell systems which are used to detect and quantify the stimulation
of bone resorption ability by biologic fluids.
c. Dynamic testing – These tests are either stimulation or suppression tests and
are used clinically to investigate syndromes of hormone excess (suppression
tests) or hormone deficiency (stimulation test). An example here is the
dexamethasone suppression screening test for Cushing’s syndrome – a
syndrome of cortisol excess.
 In this test, dexamethasone, a synthetic glucocorticoid which is not

measured in the cortisol assay, is given to patients to suppress the pituitary

axis (feedback inhibition) and cortisol is measured the next morning. If
endogenous cortisol cannot be suppressed, the patient may have Cushing’s
syndrome.
IX. MEASUREMENT OF HORMONE RESPONSIVENESS

a) Maximum responsiveness - The effect obtained at saturating the

receptor
b) Sensitivity – The hormone concentration required for half-maximal
response - index of sensitivity of target cell.
c) Threshold concentration - Hormone concentration required to elicit a
measurable response
The Hypothalamus and the Anterior Pituitary Gland

INTRODUCTION
 The hypothalamus and the pituitary gland work closely together to control

and coordinate many of the endocrine systems. The pituitary gland

consists of an anterior lobe and a posterior lobe.
ANTERIOR PITUITARY HORMONES
a) The anterior pituitary gland (aka – anterior lobe of the pituitary,
adenohypophysis) consists of histologically distinct types of cells
closely associated with blood sinusoids that drain into the venous
circulation,
b) There are 6 well-known anterior pituitary hormones produced by
separate kinds of cells. All are small proteins. They are:
i. Adrenocorticotrophic hormone (ACTH) secreted by corticotrophs.
ii. Thyroid stimulating hormone (TSH) secreted by thyrotrophs (5%)
iii. Growth hormone (GH) secreted by somatotrophs (20%)
iv. Prolactin (PRL) secreted by lactotrophs (15%)
v. Follicle-stimulating hormone (FSH) secreted by gonadotrophs (15%)
vi. Luteinizing hormone (LH) secreted by gonadotrophs (15%)
 Somatotrophs stain strongly with acidic dyes and are therefore called
acidophils. Thus, pituitary tumors that secrete large quantities of human
growth hormone are called acidophilic tumors.

c. These hormones can be grouped into “families” according to their

structural and functional homology
i. TSH, FSH and LH family are all glycoproteins with sugar
moieties/molecules/subunits covalently linked to asparagine residues in
their polypeptide chains. Each hormone consists of two subunits, α & β,
which are not covalently linked. The α subunits are identical while the β
subunits are unique giving each hormone its biologic specificity.
ii. ACTH family is all derived from the pro-opiomelanocortin (POMC) gene.
The family includes ACTH, γ− & β-lipotropin, β- endorphin and MSH.
Only ACTH has established physiologic actions in humans.
III. HYPOTHALAMIC RELEASING HORMONES

a. The secretory activity of these hormones is regulated by specific releasing

factors, hormones synthesized by neuroendocrine cells in the
hypothalamus as well as neurotransmitters from the CNS.
i. Corticotropin-releasing hormone (CRH or CRF) => ACTH
ii. Thyrotropin-releasing hormone (TRH or TRF) => TSH
iii. Gonadotropin-releasing hormone (GnRH) => FSH and LH
iv. Growth hormone-releasing hormone (GHRH) = > GH v. Growth
hormone-inhibiting hormone (GHRIH or somatostatin (preferred)) =>
inhibits GH
b. The releasing hormones are secreted from hypothalamus in response to
neural inputs from numerous areas of the central nervous system. These
inputs are generated by changes in either the external or internal
environment of the body.
c. Depending on the nature of the event and the signal generated, the
secretion of a particular releasing hormone may be either stimulated or
inhibited which, in turn, affects the rate of secretion of the associated
anterior pituitary hormone.
d. Four of the anterior pituitary hormones have effects on the morphology
and secretory activity of other endocrine glands. They are called trophic
hormones because they turn on or nourish other endocrine cells.
e. ACTH maintains the size of certain cells in the adrenal cortex and
stimulates release of several steroid hormones.
f. TSH maintains the size of the thyroid follicles and stimulates the release
of thyroid hormones.
g. FSH and LH both act on the ovaries and testes
h. The two remaining anterior pituitary hormones are not generally
thought of as trophic hormones.
i. GH directly stimulates the growth of the body during childhood and affects
many cell types.
ii. Prolactin is essential for the synthesis of milk during lactation.
IV. ADENOCORTICOTROPHIC HORMONE (ACTH)

a. ACTH is the physiologic regulator of the synthesis and secretion of

glucocorticoids by the zona fasiculata and zona reticularis of the adrenal
cortex.
b. ACTH stimulates the synthesis of these steroid hormones and promotes the
expression of the genes for various enzymes involved in steroidogenesis.
It also maintains the size and functional integrity of the cells of the zona
fasiculata and zona reticularis.
c. Corticotropin-releasing hormone (CRH or CRF) is synthesized in cells
located in the paraventricular nuclei of the hypothalamus. Secretory
granules containing CRH are stored in the axon terminals and released
when an appropriate stimulus is received. CRH is carried to the anterior
pituitary by the hypophyseal portal circulation.
d. CRH binds to membrane receptors that are coupled to adenylate cyclase by
stimulatory G proteins (Gs). Adenylate cyclase is stimulated and cAMP
rises in the cell. cAMP activates protein kinase A (PKA) which then
phosphorylates the P-proteins which stimulate ACTH secretion and the
expression of the pro-opiomelanocortin (POMC) gene. The POMC gene
and its associated mRNA maintains the capacity of the cell to synthesize the
precursor for ACTH.
e. The increase in glucocorticoid concentration in the blood resulting from the
action of ACTH on the adrenal cortex inhibits the secretion of ACTH and
CRH (negative feedback).
f. Stress (physical or emotional) increases the secretion of ACTH regardless
of the level of glucocorticoids present. Enhanced neural activity associated
with the stress increases the secretion of CRH and thereby increases ACTH
secretion. If the stress persists, glucocorticoid levels remain high and, in
effect, the set point of the hypothalamic-pituitary- adrenal axis is changed.
g. This interactive relationship is called the hypothalamic-pituitary-adrenal
axis and negative feedback is essential for normal operation of this system
h. Glucocorticoid deficiency and certain stresses also increase the
concentration of antidiuretic hormone (ADH or AVP) in the portal blood.
ADH has the capacity to stimulate the secretion of ACTH thus amplifying
the effect of CRH.
i. ACTH is also implicated in the normal sleep-wake cycle of humans (the
circadian rhythm). The hypothalamic-pituitary-adrenal axis functions in a
pulsatile manner that results in a number of bursts of activity over a 24 –
hour period. This appears to be due to rhythmic activity in the central
nervous system itself which then affects CRH secretion.
 Normally, there is nocturnal peak (generally just before waking) of ACTH
that is driven by a burst of CRH secretion. This is followed by an increase
in plasma cortisol (see left). The timing of this cyclic activity can be
shifted by alterations in the normal sleep-wake cycle (e.g., in individuals
who chronically work night shifts. This diurnal pattern is not present in
comatose patients, in blind individuals or if an individual is constantly
exposed to either light or dark. This peak may also be blunted in
Cushing’s syndrome.
 j. Glucocorticoid Deficiency States – Three clinical presentations
i. Removal of the adrenal glands or damage caused by disease (e.g.,
Addison’s disease or TB – not often seen now), stimulates the release of
large amounts of ACTH, which can result in hyperpigmentation because
ACTH in high concentrations stimulates melanocyte activity.
ii. Individual with inherited glucocorticoid deficiency due to lack of the
ability to produce certain necessary enzymes have high blood levels of
ACTH due to the lack of negative feedback on ACTH secretion. The
result is hypertrophy of the adrenal glands and this collection of genetic
disease are collectively called congenital adrenal hyperplasia – CAH
iii. Adrenal cortex atrophy occurs in individuals treated chronically with
large doses of glucocorticoids because ACTH secretion is inhibited and its
trophic influence on the adrenal cortex is lost. This atrophy can be reversed
but can take up to a year, depending upon the dose, duration or potency of
the glucocorticoid.