Lecture 8

Functions of peripheral endocrine glands

PLAN
1. Hormones of the thyroid gland and their functions.
2. Endocrine function of the parathyroid glands.
3. Adrenal glands and their hormones.
4. Endocrine part of pancreas and its hormones. Diabetes mellitus and its
consequences.
5. Endocrine tissues of other systems.
6. Hormones interaction.

Functional Anatomy of the Thyroid and Parathyroid Glands

Thyroid glands are located in the neck, in close approximation to the first part of the trachea. In
humans, the thyroid gland has a "butterfly" shape, with two lateral lobes that are connected by a
narrow section called the isthmus. Most animals, however, have two separate glands on either side
of the trachea. Thyroid glands are brownish-red in color.

Close examination of a thyroid gland will reveal one or more small, light-colored nodules on or
protruding from its surface - these are parathyroid glands (meaning "beside the thyroid"). The
image to the right shows a canine thyroid gland and one attached parathyroid gland.

The microscopic structure of the thyroid is quite distinctive. Thyroid epithelial cells - the cells
responsible for synthesis of thyroid hormones - are arranged in spheres called thyroid follicles.
Follicles are filled with colloid, a proteinaceous depot of thyroid hormone precursor. In the low
(left) and high-magnification (right) images of a cat thyroid below, follicles are cut in cross section
at different levels, appearing as roughly circular forms of varying size. In standard histologic
preparations such as these, colloid stains pink.

In addition to thyroid epithelial cells, the thyroid gland houses one other important endocrine cell.
Nestled in spaces between thyroid follicles are parafollicular or C cells, which secrete the hormone
calcitonin.

The structure of a parathyroid gland is distinctly different from a thyroid gland. The cells that
synthesize and secrete parathyroid hormone are arranged in rather dense cords or nests around
abundant capillaries. The image below shows a section of a feline parathyroid gland on the left,
associated with thyroid gland (note the follicles) on the right.
Chemistry of Thyroid Hormones
Thyroid hormones are derivatives of the the amino acid tyrosine bound covalently to iodine. The
two principal thyroid hormones are:

thyroxine (also known as T4 or L-3,5,3',5'-tetraiodothyronine)

triiodothyronine (T3 or L-3,5,3'-triiodothyronine)

As shown in the following diagram, the thyroid hormones are basically two tyrosines linked
together with the critical addition of iodine at three or four positions on the aromatic rings. The
number and position of the iodines is important. Several other iodinated molecules are generated
that have little or no biological activity; so called "reverse T3" (3,3',5'-T3) is such an example.
Thyroid hormones are poorly soluble in water, and more than 99% of the T3 and T4 circulating in
blood is bound to carrier proteins. The principle carrier of thyroid hormones is thyroxine-binding

globulin, a glycoprotein synthesized in the liver. Two other carriers of import are transthyrein and
albumin. Carrier proteins allow maintenance of a stable pool of thyroid hormones from which the
active, free hormones are released for uptake by target cells.

Thyroid Hormone Receptors and Mechanism of Action

Receptors for thyroid hormones are intracellular DNA-binding proteins that function as hormone-
responsive transcription factors, very similar conceptually to the receptors for steroid hormones.

Thyroid hormones enter cells through membrane transporter proteins. A number of plasma
membrane transporters have been identified, some of which require ATP hydrolysis; the relative
importance of different carrier systems is not yet clear and may differ among tissues. Once inside
the nucleus, the hormone binds its receptor, and the hormone-receptor complex interacts with
specific sequences of DNA in the promoters of responsive genes. The effect of the hormone-
receptor complex binding to DNA is to modulate gene expression, either by stimulating or
inhibiting transcription of specific genes.

Physiologic Effects of Thyroid Hormones

It is likely that all cells in the body are targets for thyroid hormones. While not strictly
necessary for life, thyroid hormones have profound effects on many "big time" physiologic
processes, such as development, growth and metabolism, and deficiency in thyroid hormones is not
compatible with normal health. Additionally, many of the effects of thyroid hormone have been
delineated by study of deficiency and excess states, as discussed briefly below.
Metabolism: Thyroid hormones stimulate diverse metabolic activities most tissues, leading to an
increase in basal metabolic rate. One consequence of this activity is to increase body heat
production, which seems to result, at least in part, from increased oxygen consumption and rates of
ATP hydrolysis. By way of analogy, the action of thyroid hormones is akin to blowing on a
smouldering fire. A few examples of specific metabolic effects of thyroid hormones include:

 Lipid metabolism: Increased thyroid hormone levels stimulate fat mobilization, leading to
increased concentrations of fatty acids in plasma. They also enhance oxidation of fatty acids
in many tissues. Finally, plasma concentrations of cholesterol and triglycerides are inversely
correlated with thyroid hormone levels - one diagnostic indiction of hypothyroidism is
increased blood cholesterol concentration.
 Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of carbohydrate
metabolism, including enhancement of insulin-dependent entry of glucose into cells and
increased gluconeogenesis and glycogenolysis to generate free glucose.

Growth: Thyroid hormones are clearly necessary for normal growth in children and young animals,
as evidenced by the growth-retardation observed in thyroid deficiency. Not surprisingly, the
growth-promoting effect of thyroid hormones is intimately intertwined with that of growth hormone,
a clear indiction that complex physiologic processes like growth depend upon multiple endocrine
controls.

Development: A classical experiment in endocrinology was the demonstration that tadpoles

deprived of thyroid hormone failed to undergo metamorphosis into frogs. Of critical importance in
mammals is the fact that normal levels of thyroid hormone are essential to the development of
the fetal and neonatal brain.

Other Effects: As mentioned above, there do not seem to be organs and tissues that are not affected
by thyroid hormones. A few additional, well-documented effects of thyroid hormones include:

 Cardiovascular system: Thyroid hormones increases heart rate, cardiac contractility and
cardiac output. They also promote vasodilation, which leads to enhanced blood flow to
many organs.
 Central nervous system: Both decreased and increased concentrations of thyroid hormones
lead to alterations in mental state. Too little thyroid hormone, and the individual tends to
feel mentally sluggish, while too much induces anxiety and nervousness.
 Reproductive system: Normal reproductive behavior and physiology is dependent on having
essentially normal levels of thyroid hormone. Hypothyroidism in particular is commonly
associated with infertility.

Thyroid Disease States

Disease is associated with both inadequate production and overproduction of thyroid hormones.
Both types of disease are relatively common afflictions of man and animals.

Hypothyroidism is the result from any condition that results in thyroid hormone deficiency. Two
well-known examples include:

 Iodine deficiency: Iodide is absolutely necessary for production of thyroid hormones;

without adequate iodine intake, thyroid hormones cannot be synthesized. Historically, this
problem was seen particularly in areas with iodine-deficient soils, and frank iodine
deficiency has been virtually eliminated by iodine supplementation of salt.
 Primary thyroid disease: Inflammatory diseases of the thyroid that destroy parts of the gland
are clearly an important cause of hypothyroidism.
Common symptoms of hypothyroidism arising after early childhood include lethargy, fatigue, cold-
intolerance, weakness, hair loss and reproductive failure. If these signs are severe, the clinical
condition is called myxedema. In the case of iodide deficiency, the thyroid becomes inordinantly
large and is called a goiter.

The most severe and devestating form of hypothyroidism is seen in young children with congenital
thyroid deficiency. If that condition is not corrected by supplemental therapy soon after birth, the
child will suffer from cretinism, a form of irreversible growth and mental retardation.

Most cases of hypothyroidism are readily treated by oral administration of synthetic thyroid
hormone. In times past, consumption of dessicated animal thyroid gland was used for the same
purpose.

Hyperthyroidism results from secretion of thyroid hormones. In most species, this condition is less
common than hypothyroidism. In humans the most common form of hyperthyroidism is Graves
disease, an immune disease in which autoantibodies bind to and activate the thyroid-stimulating
hormone receptor, leading to continual stimulation of thyroid hormone synthesis..

Common signs of hyperthyroidism are basically the opposite of those seen in hypothyroidism, and
include nervousness, insomnia, high heart rate, eye disease and anxiety. Graves disease is
commonly treated with anti-thyroid drugs (e.g. propylthiourea, methimazole), which suppress
synthesis of thyroid hormones primarily by interfering with iodination of thyroglobulin by thyroid
peroxidase.

Control of Thyroid Hormone Synthesis and Secretion

The chief stimulator of thyroid hormone synthesis is thyroid-stimulating hormone from the anterior
pituitary. Binding of TSH to receptors on thyroid epithelial cells seems to enhance all of the
processes necessary for synthesis of thyroid hormones, including synthesis of the iodide transporter,
thyroid peroxidase and thyroglobulin.

The magnitude of the TSH signal also sets the rate of endocytosis of colloid - high concentrations of
TSH lead to faster rates of endocytosis, and hence, thyroid hormone release into the circulation.
Conversely, when TSH levels are low, rates of thyroid hormone synthesis and release diminish.

The thyroid gland is part of the hypothalamic-pituitary-thyroid axis, and control of thyroid hormone
secretion is exerted by classical negative feedback, as depicted in the diagram. Thyroid-releasing
hormone (TRH) from the hypothalamus stimulates TSH from the pituitary, which stimulates thyroid
hormone release. As blood concentrations of thyroid hormones increase, they inhibit both TSH and
TRH, leading to "shutdown" of thyroid epithelial cells. Later, when blood levels of thyroid hormone
have decayed, the negative feedback signal fades, and the system wakes up again.

A number of other factors have been shown to influence thyroid hormone secretion. In rodents and
young children, exposure to a cold environment triggers TRH secretion, leading to enhanced
thyroid hormone release. This makes sense considering the known ability of thyroid hormones to
spark body heat production.
Calcitonin and its physiological role
Calcitonin is a hormone known to participate in calcium and phosphorus metabolism. In mammals,
the major source of calcitonin is from the parafollicular or C cells in the thyroid gland, but it is also
synthesized in a wide variety of other tissues, including the lung and intestinal tract.
Calcitonin is a 32 amino acid peptide cleaved from a larger prohormone. It contains a single
disulfide bond, which causes the amino terminus to assume the shape of a ring. Alternative splicing
of the calcitonin pre-mRNA can yield a mRNA encoding calcitonin gene-related peptide; that
peptide appears to function in the nervous and vascular systems. The calcitonin receptor has been
cloned and shown to be a member of the seven-transmembrane, G protein-coupled receptor family.

Physiologic Effects of Calcitonin

A large and diverse set of effects has been attributed to calcitonin, but in many cases, these were
seen in response to pharmacologic doses of the hormone, and their physiologic relevance is suspect.
It seems clear however, that calcitonin plays a role in calcium and phosphorus metabolism. In
particular, calcitonin has the ability to decrease blood calcium levels at least in part by effects on
two well-studied target organs:

Bone: Calcitonin suppresses resorption of bone by inhibiting the activity of osteoclasts, a cell
type that "digests" bone matrix, releasing calcium and phosphorus into blood.
Kidney: Calcium and phosphorus are prevented from being lost in urine by reabsorption in the
kidney tubules. Calcitonin inhibits tubular reabsorption of these two ions, leading to increased rates
of their loss in urine.

Control of Calcitonin Secretion

The most prominent factor controlling calcitonin secretion is the extracellular concentration of
ionized calcium. Elevated blood calcium levels strongly stimulate calcitonin secretion, and
secretion is suppressed when calcium concentration falls below normal. A number of other
hormones have been shown to stimulate calcitonin release in certain situations, and nervous controls
also have been demonstrated.
Disease States

A large number of diseases are associated with abnormally increased or decreased levels of
calcitonin, but pathologic effects of abnormal calcitonin secretion per se are not generally
recognized.

There are several therapeutic uses for calcitonin. It is used to treat hypercalcemia resulting from a
number of causes, and has been a valuable therapy for Paget disease, which is a disorder in bone
remodeling. Calcitonin also appears to be a valuable aid in the management of certain types of
osteoporosis.

Parathyroid Hormone
Parathyroid hormone is the most important endocrine regulator of calcium and phosphorus
concentration in extracellular fluid. This hormone is secreted from cells of the parathyroid glands
and finds its major target cells in bone and kidney. Another hormone, parathyroid hormone-related
protein, binds to the same receptor as parathyroid hormone and has major effects on development.

Like most other protein hormones, parathyroid hormone is synthesized as a preprohormone. After
intracellular processing, the mature hormone is packaged within the Golgi into secretory vesicles,
the secreted into blood by exocytosis. Parathyroid hormone is secreted as a linear protein of 84
amino acids.

Physiologic Effects of Parathyroid Hormone

Writing a job description for parathyroid hormone is straightforward: if calcium ion concentrations
in extracellular fluid fall below normal, bring them back within the normal range. In conjunction
with increasing calcium concentration, the concentration of phosphate ion in blood is reduced.
Parathyroid hormone accomplishes its job by stimulating at least three processes:

Mobilization of calcium from bone: Although the mechanisms remain obscure, a well-
documented effect of parathyroid hormone is to stimulate osteoclasts to reabsorb bone mineral,
liberating calcium into blood.
Enhancing absorption of calcium from the small intestine: Facilitating calcium absorption from
the small intestine would clearly serve to elevate blood levels of calcium. Parathyroid hormone
stimulates this process, but indirectly by stimulating production of the active form of vitamin D in
the kidney. Vitamin D induces synthesis of a calcium-binding protein in intestinal epithelial cells
that facilitates efficient absorption of calcium into blood.
Suppression of calcium loss in urine: In addition to stimulating fluxes of calcium into blood
from bone and intestine, parathyroid hormone puts a brake on excretion of calcium in urine, thus
conserving calcium in blood. This effect is mediated by stimulating tubular reabsorption of calcium.
Another effect of parathyroid hormone on the kidney is to stimulate loss of phosphate ions in urine.

Control of Parathyroid Hormone Secretion

Parathyroid hormone is released in response to low extracellular concentrations of free

calcium. Changes in blood phosphate concentration can be associated with changes in parathyroid
hormone secretion, but this appears to be an indirect effect and phosphate per se is not a significant
regulator of this hormone.

When calcium concentrations fall below the normal range, there is a steep increase in secretion of
parathyroid hormone. Low levels of the hormone are secreted even when blood calcium levels are
high. The figure to the right depicts parathyroid hormone release from cells cultured in vitro in
differing concentrations of calcium.

The parathyroid cell monitors extracellular free calcium concentration via an integral membrane
protein that functions as a calcium-sensing receptor.

Disease States

Both increased and decreased secretion of parathyroid hormone are recognized as causes of serious
disease in man and animals.

Excessive secretion of parathyroid hormone is seen in two forms:

 Primary hyperparathyroidism is the result of parathyroid gland disease, most commonly due
to a parathyroid tumor (adenoma) which secretes the hormone without proper regulation.
Common manifestations of this disorder are chronic elevations of blood calcium
concentration (hypercalcemia), kidney stones and decalcification of bone.
 Secondary hyperparathyroidism is the situation where disease outside of the parathyroid
gland leads to excessive secretion of parathyroid hormone. A common cause of this disorder
is kidney disease - if the kidneys are unable to reabsorb calcium, blood calcium levels will
fall, stimulating continual secretion of parathyroid hormone to maintain normal calcium
levels in blood. Secondary hyperparathyroidism can also result from inadequate nutrition -
for example, diets that are deficient in calcium or vitamin D, or which contain excessive
phosphorus (e.g. all meat diets for carnivores). A prominent effect of secondary
hyperparathyroidism is decalcification of bone, leading to pathologic fractures or "rubber
bones".

There is no doubt that chronic secretion or continuous infusion of parathyroid hormone leads to
decalcification of bone and loss of bone mass. However, in certain situations, treatment with
parathyroid hormone can actually stimulate an increase in bone mass and bone strength. This
seemingly paradoxical effect occurs when the hormone is administered in pulses (e.g. by once daily
injection), and such treatment appears to be an effective therapy for diseases such as osteoporosis.

Inadequate production of parathyroid hormone - hypoparathyroidism - typically results in decreased

concentrations of calcium and increased concentrations of phosphorus in blood. Common causes of
this disorder include surgical removal of the parathyroid glands and disease processes that lead to
destruction of parathyroid glands. The resulting hypocalcemia often leads to tetany and convulsions,
and can be acutely life-threatening. Treatment focuses on restoring normal blood calcium
concentrations by calcium infusions, oral calcium supplements and vitamin D therapy.
Functional Anatomy of the Adrenal Gland
The two adrenal glands are located immediately anterior to the kidneys, encased in a connective
tissue capsule and usually partially buried in an island of fat. Like the kidneys, the adrenal glands
lie beneath the peritoneum (i.e. they are retroperitoneal). The exact location relative to the kidney
and the shape of the adrenal gland vary among species.

An inner medulla, which is a source of the catecholamines epinephrine and norepinephrine. The
chromaffin cell is the principle cell type. The medulla is richly innervated by preganglionic
sympathetic fibers and is, in essence, an extension of the sympathetic nervous system.
An outer cortex, which secretes several classes of steroid hormones (glucocorticoids and
mineralocorticoids, plus a few others). Histologic examination of the cortex reveals three concentric
zones of cells that differ in the major steroid hormones they secrete.

Despite their organization into a single gland, the medulla and cortex are functionally different
endocrine organs, and have different embryological origins. The medulla derives from ectoderm
(neural crest), while the cortex develops from mesoderm. The utility, if any, of having them
together in one discrete organ is not obvious. In some species, amphibians and certain fish, for
example, two separate organs are found.

Adrenal Medullary Hormones

Cells in the adrenal medulla synthesize and secrete epinephrine and norepinephrine. The ratio of
these two catecholamines differs considerably among species: in humans, cats and chickens,
roughly 80, 60 and 30% of the catecholamine output is epinephrine. Following release into blood,
these hormones bind adrenergic receptors on target cells, where they induce essentially the same
effects as direct sympathetic nervous stimulation.

Synthesis and Secretion of Catecholamines

Synthesis of catecholamines begins with the amino acid tyrosine, which is taken up by chromaffin
cells in the medulla and converted to norepinephrine and epinephrine through the following steps:

Norepinephine and epinephrine are stored in electron-dense granules which also contain ATP and
several neuropeptides. Secretion of these hormones is stimulated by acetylcholine release from
preganglionic sympathetic fibers innervating the medulla. Many types of "stresses" stimulate such
secretion, including exercise, hypoglycemia and trauma. Following secretion into blood, the
catecholamines bind loosely to and are carried in the circulation by albumin and perhaps other
serum proteins.

Adrenergic Receptors and Mechanism of Action

The physiologic effects of epinephrine and norepinephrine are initiated by their binding to
adrenergic receptors on the surface of target cells. These receptors are prototypical examples of
seven-pass transmembrane proteins that are coupled to G proteins which stimulate or inhibit
intracellular signalling pathways.

In general, circulating epinephrine and norepinephrine released from the adrenal medulla have the
same effects on target organs as direct stimulation by sympathetic nerves, although their effect is
longer lasting. Additionally, of course, circulating hormones can cause effects in cells and tissues
that are not directly innervated. The physiologic consequences of medullary catecholamine release
are justifiably framed as responses which aid in dealing with stress. These effects can be predicted
to some degree by imagining what would be needed if, for example, you were trapped in Jurassic
Park when the power went off. A listing of some major effects mediated by epinephrine and
norepinephrine are:

1. Increased rate and force of contraction of the heart muscle: this is predominantly an effect of
epinephrine acting through beta receptors.
2. Constriction of blood vessels: norepinephrine, in particular, causes widespread
vasoconstriction, resulting in increased resistance and hence arterial blood pressure.
3. Dilation of bronchioles: assists in pulmonary ventilation.
4. Stimulation of lipolysis in fat cells: this provides fatty acids for energy production in many
tissues and aids in conservation of dwindling reserves of blood glucose.
5. Increased metabolic rate: oxygen consumption and heat production increase throughout the
body in response to epinephrine. Medullary hormones also promote breakdown of glycogen
in skeletal muscle to provide glucose for energy production.
6. Dilation of the pupils: particularly important in situations where you are surrounded by
velociraptors under conditions of low ambient light.
7. Inhibition of certain "non-essential" processes: an example is inhibition of gastrointestinal
secretion and motor activity.

Common stimuli for secretion of adrenomedullary hormones include exercise, hypoglycemia,

hemorrhage and emotional distress.

Adrenal Steroids
The adrenal cortex is a factory for steroid hormones. In total, at least two to three dozen different
steroids are synthesized and secreted from this tissue, but two classes are of particular importance:
Major
Class of Steroid Physiologic Effects
Representative
Na+, K+ and water
Mineralocorticoids Aldosterone
homeostasis
Glucose homeostasis
Glucocorticoids Cortisol
and many others

Additionally, the adrenal cortex produces some sex steroids, particularly androgens, a talent of
considerable importance in such diseases as congenital adrenal hyperplasia.
Like all steroids, adrenal "corticosteroids" are synthesized from cholesterol through a series of
enzyme-mediated transformations. The details of these pathways are presented elsewhere, but the
major branches are easy to understand.

Each of the three major pathways involves sequential

processing by a group of enzymes, some of which reside in
endoplasmic reticulum and others inside mitochondria.
Hence, synthesis involves shuttling of the steroids between
these two organelles.

Synthesis of the different steroids is not uniformly

distributed through the cortex. For example, the outermost group of cells (zona glomerulosa)
synthesizes aldosterone, but essentially no cortisol or androgens because those cells do not express
the enzyme 17-alpha-hydroxylase which is necessary for synthesis of 17-hydroxypregnenolone and
17-hydroxyprogesterone. That enzyme is however present in cells of the inner zones of the cortex
(zonae fasiculata and reticularis), which are the major sites of cortisol production.

Like all steroid hormones, cortisol and aldosterone bind to their respective receptors, and the
resulting hormone-receptor complexes bind to a hormone response element to modulate
transcription of responsive genes. Although the physiologic effects of these two steroid hormones
are distinctly different, their receptors are quite similar and, most interestingly, they bind to the
same consensus response element in DNA! How then is it possible to get hormone-specific
responses? Follow the path to the next topic to find out at least part of the answer.

Mineralocorticoids
Removal of the adrenal glands can lead to death within just a few days. Observation of such a
unfortunate subject would reveal several key derangements:

 the concentration of potassium in extracelluar fluid becomes dramatically elevated

 urinary excretion of sodium is high and the concentration of sodium in extracellular fluid
decreases significantly
 volume of extracellular fluid and blood decrease
 the heart begins to function poorly, cardiac output declines and shock ensues

These phenomena are a direct result of loss of mineralocorticoid activity, and can largely be
prevented by replacement of salts and mineralocorticoids. Clearly mineralocorticoids are acutely
critical for maintenance of life!
Aldosterone and Mineralocorticoid Receptors

The principal steroid with mineralocorticoid activity is aldosterone. Cortisol, the major
glucocorticoid in non-rodent species, is said to have "weak mineralocorticoid activity", which is of
some importance because cortisol is secreted very much more abundantly than aldosterone. Another
way to state this is that a small fraction of the mineralocorticoid response in the body is due to
cortisol rather than aldosterone.

The mineralocorticoid receptor binds both aldosterone and cortisol with equal affinity. Moreover,
the same DNA sequence serves as a hormone response element for the activated (steroid-bound)
forms of both mineralocorticoid and glucocorticoid receptors. An obvious question is:

How can aldosterone stimulate specific biological effects in this kind of system, particularly
when blood concentrations of cortisol are something like 2000-fold higher than aldosterone?
A large part of the answer is that, in aldosterone-responsive cells, cortisol is effectively destroyed,
allowing aldosterone to bind its receptor without competition. Target cells for aldosterone express
the enzyme 11-beta-hydroxysteroid dehydrogenase, which has no effect on aldosterone, but
converts cortisol to cortisone, which has only a very weak affinity for the mineralocorticoid
receptor. In essence, this enzyme "protects" the cell from cortisol and allows aldosterone to act
appropriately. Some tissues (e.g. hippocampus) express abundant mineralocorticoid receptors but
not 11-beta HSD - they therefore do not show responses to aldosterone because aldosterone is not
present in quantities sufficient to compete with cortisol.

An interesting demonstration of this enzyme protection system is seen in chronic licorice

intoxication.

The drug spironolactone inhibits the effects of aldosterone by competitively binding to the
aldosterone receptor in target cells; this drug is most commonly used because of its effects on the
kidney to promote water excretion.

Physiologic Effects of Mineralocorticoids

Mineralocorticoids play a critical role in regulating concentrations of minerals - particularly sodium
and potassium - in extracellular fluids. As described above, loss of these hormones leads rapidly to
life-threatening abnormalities in electrolyte and fluid balance.

The major target of aldosterone is the distal tubule of the kidney, where it stimulates exchange of
sodium and potassium. Three primary physiologic effects of aldosterone result:

 Increased resorption of sodium: sodium loss in urine is decreased under aldosterone

stimulation.
 Increased resorption of water, with consequent expansion of extracellular fluid volume. This
is an osmotic effect directly related to increased resorption of sodium.
 Increased renal excretion of potassium.

Knowing these effects should quickly suggest the cellular mechanism of action this hormone.
Aldosterone stimulates transcription of the gene encoding the sodium-potassium ATPase, leading to
increased numbers of "sodium pumps" in the basolateral membranes of tubular epithelial cells.
Aldosterone also stimulates expression of a sodium channel which facilitates uptake of sodium from
the tubular lumen.

Aldosterone has effects on sweat glands, salivary glands and the colon which are essentially
identical to those seen in the distal tubule of the kidney. The major net effect is again to conserve
body sodium by stimulating its resorption or, in the case of the colon, absorption from the intestinal
lumen. Conservation of water follows conservation of sodium.

Control of Aldosterone Secretion

Control over aldosterone secretion is truly multifactorial and tied into a spider web of other factors
which regulate fluid and electrolyte composition and blood pressure. If the major effects of
aldosterone are considered, it is rather easy to predict factors which stimulate or suppress
aldosterone secretion.

The two most significant regulators of aldosterone secretion are:

Concentration of potassium ions in extracellular fluid: Small increases in blood levels of

potassium strongly stimulate aldosterone secretion.
 Angiotensin II: Activation of the renin-angiotensin system as a result of decreased renal blood
flow (usually due to decreased vascular volume) results in release of angiotensin II, which
stimulates aldosterone secretion.

Other factors which stimulate aldosterone secretion include adrenocorticotropic hormone (short-
term stimulation only) and sodium deficiency. Factors which suppress aldosterone secretion include
atrial naturetic hormone, high sodium concentration and potassium deficiency.

Disease States

A deficiency in aldosterone can occur by itself or, more commonly, in conjunction with a
glucocorticoid deficiency, and is known as hypoadrenocorticism or Addison's disease. Without
treatment by mineralocorticoid replacement therapy, a lack of aldosterone is lethal, due to
electrolyte imbalances and resulting hypotension and cardiac failure.

Aldosterone excess is most commonly observed in two conditions: elevated plasma potassium
(hyperkalemia) and low vascular volume. This should make sense considering that plasma
potassium and angiotensin II are the major factors that regulate aldosterone secretion, as described
above. Importantly, it is now recognized that roughly 1 in 10 cases of primary hypertension in
humans is associated with hyperaldosteronism, due most commonly to aldosterone-secreting
adrenal tumors or mutations in potassium channels.

Glucocorticoids
In contrast to loss of mineralocorticoids, failure to produce glucocorticoids is not acutely life-
threatening. Nevertheless, loss or profound diminishment of glucocorticoid secretion leads to a state
of deranged metabolism and an inability to deal with stressors which, if untreated, is fatal.

In addition to their physiologic importance, glucocorticoids are also among the most frequently
used drugs, and often prescribed for their anti-inflammatory and immunosuppressive properties.
Cortisol and Glucocorticoid Receptors

The vast majority of glucocorticoid activity in most mammals is from cortisol, also known as
hydrocortisone. Corticosterone, the major glucocorticoid in rodents, is another glucocorticoid.

Cortisol binds to the glucocorticoid receptor in the cytoplasm and the hormone-receptor complex is
then translocated into the nucleus, where it binds to its DNA response element and modulates
transcription from a battery of genes, leading to changes in the cell's phenotype.

Only about 10% of circulating cortisol is free. The remaining majority circulates bound to plasma
proteins, particularly corticosteroid-binding globulin (transcortin). This protein binding likely
decreases the metabolic clearance rate of glucocorticoids and, because the bound steroid is not
biologically active, tends to act as a buffer and blunt wild fluctuations in cortisol concentration.

Physiologic Effects of Glucocorticoids

There seem to be no cells that lack glucocorticoid receptors and as a consequence, these steroid
hormones have a huge number of effects on physiologic systems. That having been said, it can be
stated that the best known and studied effects of glucocorticoids are on carbohydrate metabolism
and immune function.

Effects on Metabolism
The name glucocorticoid derives from early observations that these hormones were involved in
glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively serve
to increase and maintain normal concentrations of glucose in blood. These effects include:

 Stimulation of gluconeogenesis, particularly in the liver: This pathway results in the

synthesis of glucose from non-hexose substrates such as amino acids and lipids and is
particularly important in carnivores and certain herbivores. Enhancing the expression of
enzymes involved in gluconeogenesis is probably the best known metabolic function of
glucocorticoids.
 Mobilization of amino acids from extrahepatic tissues: These serve as substrates for
gluconeogenesis.
 Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose.
 Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used
for production of energy in tissues like muscle, and the released glycerol provide another
substrate for gluconeogenesis.

Effects on Inflammation and Immune Function

Glucocorticoids have potent anti-inflammatory and immunosuppressive properties. This is

particularly evident when they administered at pharmacologic doses, but also is important in normal
immune responses. As a consequence, glucocorticoids are widely used as drugs to treat
inflammatory conditions such as arthritis or dermatitis, and as adjunction therapy for conditions
such as autoimmune diseases.

Other Effects of Glucocorticoids

Glucocorticoids have multiple effects on fetal development. An important example is their role in
promoting maturation of the lung and production of the surfactant necessary for extrauterine lung
function. Mice with homozygous disruptions in the corticotropin-releasing hormone gene (see
below) die at birth due to pulmonary immaturity.

Several aspects of cognitive function are known to both stimulate glucocorticoid secretion and be
influenced by glucocorticoids. Fear provides an interesting example of this. Fear-inducing stimuli
lead to secretion of glucocorticoids from the adrenal gland, and treatment of phobic individuals with
glucocorticoids prior to a fear-inducing stimulus can blunt the fear response.

Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism

have effects on many systems. Some examples include inhibition of bone formation, suppression of
calcium absorption and delayed wound healing. These observations suggest a multitide of less
dramatic physiologic roles for glucocorticoids.

Control of Cortisol Secretion

Cortisol and other glucocorticoids are secreted in response to a single stimulator:

adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH is itself secreted under
control of the hypothalamic peptide corticotropin-releasing hormone (CRH). The central nervous
system is thus the commander and chief of glucocorticoid responses, providing an excellent
example of close integration between the nervous and endocrine systems.
Virtually any type of physical or mental stress results in elevation of cortisol concentrations in
blood due to enhanced secretion of CRH in the hypothalamus. This fact sometimes makes it very
difficult to assess glucocorticoid levels, particularly in animals. Observing the approach of a
phlebotomist, and especially being
restrained for blood sampling, is
enough stress to artificially elevate
cortisol levels several fold!

Cortisol secretion is suppressed by

classical negative feedback loops.
When blood concentrations rise above
a certain theshold, cortisol inhibits
CRH secretion from the hypothalamus,
which turns off ACTH secretion, which
leads to a turning off of cortisol
secretion from the adrenal. The
combination of positive and negative
control on CRH secretion results in
pulsatile secretion of cortisol. Typically,
pulse amplitude and frequency are
highest in the morning and lowest at
night.

ACTH binds to receptors in the plasma

membrane of cells in the zona
fasiculata and reticularis of the adrenal.
Hormone-receptor engagement
activates adenyl cyclase, leading to
elevated intracellular levels of cyclic
AMP which leads ultimately to activation of the enzyme systems involved in biosynthesis of
cortisol from cholesterol.

Disease States

The most prevalent disorder involving glucocorticoids in man and animals is hyperadrenocorticism
or Cushings disease. Excessive levels of glucocorticoids are seen in two situations:

Excessive endogenous production of cortisol, which can result from a primary adrenal defect
(ACTH-independent) or from excessive secretion of ACTH (ACTH-dependent).
Administration of glucocorticoids for theraputic purposes. This is a common side-effect of these
widely-used drugs.

Cushing's disease has widespread effects on metabolism and organ function, which is not surprising
considering the ubiquitous distribution of glucocorticoid receptors. A diverse set of clinical
manifestations accompany this disorder, including hypertension, apparent obesity, muscle wasting,
thin skin, and metabolic aberrations such as diabetes.

Insufficient production of cortisol, often accompanied by an aldosterone deficiency, is called

hypoadrenocorticism or Addison's disease. Most commonly, this disease is a result of infectious
disease (e.g. tuberculosis in humans) or autoimmune destruction of the adrenal cortex. As with
Cushing's disease, numerous diverse clincial signs accompany Addison's disease, including
cardiovascular disease, lethargy, diarrhea, and weakness. Aldosterone deficiency can be acutely life
threatening due to disorders of electrolyte balance and cardiac function.
Functional Anatomy of the Endocrine Pancreas

The pancreas is an elongated organ nestled next to the first part of the small intestine. Its gross
anatomy and the structure of pancreatic exocrine tissue and ducts are discussed in the context of the
digestive system. The endocrine pancreas refers to those cells within the pancreas that synthesize
and secrete hormones.

The endocrine portion of the pancreas takes the form of

many small clusters of cells called islets of Langerhans or,
more simply, islets. Humans have roughly one million
islets. In standard histological sections of the pancreas,
islets are seen as relatively pale-staining groups of cells
embedded in a sea of darker-staining exocrine tissue. The
image to the right shows three islets in the pancreas of a
horse. Pancreatic islets house three major cell types, each
of which produces a different endocrine product:

 Alpha cells (A cells) secrete the hormone

glucagon.
 Beta cells (B cells) produce insulin and are the
most abundant of the islet cells.
 Delta cells (D cells) secrete the hormone somatostatin, which is also produced by a
number of other endocrine cells in the body.

Interestingly, the different cell types within an islet are not randomly distributed - beta cells
occupy the central portion of the islet and are surrounded by a "rind" of alpha and delta cells.
Aside from the insulin, glucagon and somatostatin, a number of other "minor" hormones have
been identified as products of pancreatic islets cells.

Islets are richly vascularized, allowing their secreted hormones ready access to the circulation.
Although islets comprise only 1-2% of the mass of the pancreas, they receive about 10 to 15%
of the pancreatic blood flow. Additionally, they are innervated by parasympathetic and
sympathetic neurons, and nervous signals clearly modulate secretion of insulin and glucagon.

Insulin Synthesis and Secretion

Structure of Insulin

Insulin is a rather small protein, with a molecular weight

of about 6000 Daltons. It is composed of two chains
held together by disulfide bonds. The figure to the right
shows a molecular model of bovine insulin, with the A
chain colored blue and the larger B chain green. You
can get a better appreciation for the structure of insulin
by manipulating such a model yourself.

The amino acid sequence is highly conserved among

vertebrates, and insulin from one mammal almost
certainly is biologically active in another. Even today,
many diabetic patients are treated with insulin extracted
 from pig pancreas.
Control of Insulin Secretion

Insulin is secreted in primarily in response to elevated blood concentrations of glucose. This

makes sense because insulin is "in charge" of facilitating glucose entry into cells. Some
neural stimuli (e.g. sight and taste of food) and increased blood concentrations of other fuel
molecules, including amino acids and fatty acids, also promote insulin secretion.

Our understanding of the mechanisms behind insulin secretion remain somewhat

fragmentary. Nonetheless, certain features of this process have been clearly and repeatedly
demonstrated, yielding the following model:

 Glucose is transported into the beta cell by facilitated diffusion through a glucose
transporter; elevated concentrations of glucose in extracellular fluid lead to elevated
concentrations of glucose within the beta cell.
 Elevated concentrations of glucose within the beta cell ultimately leads to membrane
depolarization and an influx of extracellular calcium. The resulting increase in
intracellular calcium is thought to be one of the primary triggers for exocytosis of
insulin-containing secretory granules. The mechanisms by which elevated glucose
levels within the beta cell cause depolarization is not clearly established, but seems
to result from metabolism of glucose and other fuel molecules within the cell,
perhaps sensed as an alteration of ATP:ADP ratio and transduced into alterations in
membrane conductance.
 Increased levels of glucose within beta cells also appears to activate calcium-
independent pathways that participate in insulin secretion.

Stimulation of insulin release is readily observed in whole animals or people. The normal
fasting blood glucose concentration in humans and most mammals is 80 to 90 mg per 100
ml, associated with very low levels of insulin secretion.

The figure to the right depicts the effects on insulin secretion when enough glucose is
infused to maintain blood levels two to three times the fasting level for an hour. Almost
immediately after the infusion begins, plasma insulin levels increase dramatically. This
initial increase is due to secretion of preformed insulin, which is soon significantly depleted.
The secondary rise in insulin reflects the considerable amount of newly synthesized insulin
that is released immediately. Clearly, elevated glucose not only simulates insulin secretion,
but also transcription of the insulin gene and translation of its mRNA.

Physiologic Effects of Insulin

Stand on a streetcorner and ask people if they know what insulin is, and many will reply,
"Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response
is a bit like saying "Mozart? Wasn't he some kind of a musician?"

Insulin is a key player in the control of intermediary metabolism, and the big picture is that it
organizes the use of fuels for either storage or oxidation. Through these activities, insulin has
profound effects on both carbohydrate and lipid metabolism, and significant influences on
protein and mineral metabolism. Consequently, derangements in insulin signalling have
widespread and devastating effects on many organs and tissues.
 The Insulin Receptor and Mechanism of Action

Like the receptors for other protein hormones, the receptor for
insulin is embedded in the plasma membrane. The insulin
receptor is composed of two alpha subunits and two beta
subunits linked by disulfide bonds. The alpha chains are
entirely extracellular and house insulin binding domains, while
the linked beta chains penetrate through the plasma membrane.

The insulin receptor is a tyrosine kinase. In other words, it

functions as an enzyme that transfers phosphate groups from
ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits
causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the
catalytic activity of the receptor. The activated receptor then phosphorylates a number of
intracellular proteins, which in turn alters their activity, thereby generating a biological
response.

Several intracellular proteins have been identified as phosphorylation substrates for the insulin
receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is
activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a
type of docking center for recruitment and activation of other enzymes that ultimately mediate
insulin's effects. A more detailed look at these processes is presented in the section on Insulin
Signal Transduction.

Insulin and Carbohydrate Metabolism

Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within
the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in
blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate
uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary
depending on the target tissue. Two important effects are:
1. Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only
mechanism by which cells can take up glucose is by facilitated diffusion through a family of
hexose transporters. In many tissues - muscle being a prime example - the major transporter used
for uptake of glucose (called GLUT4) is made available in the plasma membrane through the
action of insulin.
When insulin concentrations are low, GLUT4 glucose transporters are present in
cytoplasmic< vesicles, where they are useless for transporting glucose. Binding of insulin to
receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane
and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take
up glucose. When blood levels of insulin decrease and insulin receptors are no longer
occupied, the glucose transporters are recycled back into the cytoplasm.

It should be noted here that there are some tissues that do not require insulin for efficient uptake of
glucose: important examples are brain and the liver. This is because these cells don't use GLUT4
for importing glucose, but rather, another transporter that is not insulin-dependent.
large fraction of glucose absorbed from the small intestine is immediately taken up by
hepatocytes, which convert it into the storage polymer glycogen.

Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the
enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently,
insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the
enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and
glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells"
the liver to bank as much of it as possible for use later.
A well-known effect of insulin is to decrease the concentration of glucose in blood, which
should make sense considering the mechanisms described above. Another important
consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense
of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to
using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of
glucose, which in the short term, is provided from glycogen reserves.

When insulin levels in blood fall, glycogen synthesis in the liver diminishes and enzymes
responsible for breakdown of glycogen become active. Glycogen breakdown is stimulated not
only by the absense of insulin but by the presence of glucagon, which is secreted when blood
glucose levels fall below the normal range.

Insulin and Lipid Metabolism

The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately
intertwined. Considering insulin's profound effects on carbohydrate metabolism, it stands to
reason that insulin also has important effects on lipid metabolism, including the following:
Insulin promotes synthesis of fatty acids in the liver. As
discussed above, insulin is stimulatory to synthesis of glycogen in
the liver. However, as glycogen accumulates to high levels
(roughly 5% of liver mass), further synthesis is strongly
suppressed.

When the liver is saturated with glycogen, any additional glucose

taken up by hepatocytes is shunted into pathways leading to
synthesis of fatty acids, which are exported from the liver as
lipoproteins. The lipoproteins are ripped apart in the circulation,
providing free fatty acids for use in other tissues, including
adipocytes, which use them to synthesize triglyceride.

Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that
hydrolyzes triglycerides to release fatty acids.

Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to
synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to
synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further
accumulation of triglyceride in fat cells.

From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most
cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly
stimulates accumulation of fat in adipose tissue.
Other Notable Effects of Insulin
In addition to insulin's effect on entry of glucose into cells, it also stimulates the uptake of
amino acids, again contributing to its overall anabolic effect. When insulin levels are low, as in
the fasting state, the balance is pushed toward intracellular protein degradation.

Insulin also increases the permiability of many cells to potassium, magnesium and phosphate
ions. The effect on potassium is clinically important. Insulin activates sodium-potassium
ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances,
injection of insulin can kill patients because of its ability to acutely suppress plasma potassium
concentrations.

Insulin Deficiency and Excess Diseases

Diabetes mellitus, arguably the most important metabolic disease of man, is an insulin
deficiency state. It also is a significant cause of disease in dogs and cats. Two principal forms
of this disease are recognized:

 Type I or insulin-dependent diabetes mellitus is the result of a frank deficiency of

insulin. The onset of this disease typically is in childhood. It is due to destruction
pancreatic beta cells, most likely the result of autoimmunity to one or more components
of those cells. Many of the acute effects of this disease can be controlled by insulin
replacement therapy. Maintaining tight control of blood glucose concentrations by
monitoring, treatment with insulin and dietary management will minimize the long-term
adverse effects of this disorder on blood vessels, nerves and other organ systems,
allowing a healthy life.
 Type II or non-insulin-dependent diabetes mellitus begins as a syndrome of insulin
resistance. That is, target tissues fail to respond appropriately to insulin. Typically, the
onset of this disease is in adulthood. Despite monumental research efforts, the precise
nature of the defects leading to type II diabetes have been difficult to ascertain, and the
pathogenesis of this condition is plainly multifactorial. Obesity is clearly a major risk
factor, but in some cases of extreme obesity in humans and animals, insulin sensitivity
is normal. Because there is not, at least initially, an inability to secrete adequate
amounts of insulin, insulin injections are not useful for therapy. Rather the disease is
controlled through dietary therapy and hypoglycemic agents.

Hyperinsulinemia or excessive insulin secretion is most commonly a consequence of insulin

resistance, associated with type 2 diabetes or the metabolic syndrome. More rarely,
hyperinsulinemia results from an insulin-secreting tumor (insulinoma) in the pancreas.
Hyperinsulinemia due to accidental or deliberate injection of excessive insulin is dangerous
and can be acutely life-threatening because blood levels of glucose drop rapidly and the brain
becomes starved for energy (insulin shock).

Glucagon

Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is
often described as having the opposite effect of insulin. That is, glucagon has the effect of
 increasing blood glucose levels.

Glucagon is a linear peptide of 29 amino acids. Its primary

sequence is almost perfectly conserved among vertebrates,
and it is structurally related to the secretin family of peptide
hormones. Glucagon is synthesized as proglucagon and
proteolytically processed to yield glucagon within alpha
cells of the pancreatic islets. Proglucagon is also expressed
within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-
like peptides (enteroglucagon).

Physiologic Effects of Glucagon

The major effect of glucagon is to stimulate an increase in blood concentration of glucose. As

discussed previously, the brain in particular has an absolute dependence on glucose as a fuel,
because neurons cannot utilize alternative energy sources like
fatty acids to any significant extent. When blood levels of
glucose begin to fall below the normal range, it is imperative
to find and pump additional glucose into blood. Glucagon
exerts control over two pivotal metabolic pathways within the
liver, leading that organ to dispense glucose to the rest of the
body:

 Glucagon stimulates breakdown of glycogen stored

in the liver. When blood glucose levels are high, large
amounts of glucose are taken up by the liver. Under the
influence of insulin, much of this glucose is stored in
the form of glycogen. Later, when blood glucose levels
begin to fall, glucagon is secreted and acts on
hepatocytes to activate the enzymes that depolymerize
glycogen and release glucose.
 Glucagon activates hepatic gluconeogenesis. Gluconeogenesis is the pathway by
which non-hexose substrates such as amino acids are converted to glucose. As such, it
provides another source of glucose for blood. This is especially important in animals
like cats and sheep that don't absorb much if any glucose from the intestine - in these
species, activation of gluconeogenic enzymes is the chief mechanism by which
glucagon does its job.

Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose
tissue, which could be viewed as an addition means of conserving blood glucose by providing
fatty acid fuel to most cells.

Control of Glucagon Secretion

Knowing that glucagon's major effect is to increase blood glucose levels, it makes sense that
glucagon is secreted in response to hypoglycemia or low blood concentrations of glucose.

Two other conditions are known to trigger glucagon secretion:

 Elevated blood levels of amino acids, as would be seen after consumption of a protein-
rich meal: In this situation, glucagon would foster conversion of excess amino acids to
glucose by enhancing gluconeogenesis. Since high blood levels of amino acids also
stimulate insulin release, this would be a situation in which both insulin and glucagon
 are active.
 Exercise: In this case, it is not clear whether the actual stimulus is exercise per se, or the
accompanying exercise-induced depletion of glucose.

In terms of negative control, glucagon secretion is inhibited by high levels of blood glucose. It
is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect
of insulin, which is known to dampen glucagon release. Another hormone well known to
inhibit glucagon secretion is somatostatin.

Disease States

Diseases associated with excessively high or low secretion of glucagon are rare. Cancers of
alpha cells (glucagonomas) are one situation known to cause excessive glucagon secretion.
These tumors typically lead to a wasting syndrome and, interestingly, rash and other skin
lesions.

Although insulin deficiency is clearly the major defect in type 1 diabetes mellitus, there is
considerable evidence that aberrant secretion of glucagon contributes to the metabolic
derangements seen in this important disease. For example, many diabetic patients with
hyperglycemia also have elevated blood concentrations of glucagon, but glucagon secretion is
normally suppressed by elevated levels of blood glucose.

The Pineal Gland and Melatonin

The pineal gland or epiphysis synthesizes and secretes melatonin, a structurally simple
hormone that communicates information about environmental lighting to various parts of the
body. Ultimately, melatonin has the ability to entrain biological rhythms and has important
effects on reproductive function of many animals. The light-transducing ability of the pineal
gland has led some to call the pineal the "third eye".

Histologically, the pineal is composed of "pinealocytes" and glial cells. In older animals, the
pineal often is contains calcium deposits ("brain sand").

How does the retina transmit information about light-dark exposure to the pineal gland?
Light exposure to the retina is first relayed to the suprachiasmatic nucleus of the hypothalamus,
an area of the brain well known to coordinate biological clock signals. Fibers from the
hypothalamus descend to the spinal cord and ultimately project to the superior cervical ganglia,
from which post-ganglionic neurons ascend back to the pineal gland. Thus, the pineal is similar
to the adrenal medulla in the sense that it transduces signals from the sympathetic nervous
system into a hormonal signal.

Melatonin: Synthesis, Secretion and Receptors

The precursor to melatonin is serotonin, a neurotransmitter that itself is derived from the
amino acid tryptophan. Within the pineal gland, serotonin is acetylated and then methylated to
yield melatonin.
Synthesis and secretion of melatonin is dramatically affected by light exposure to the eyes.
The fundamental pattern observed is that serum concentrations of melatonin are low during the
daylight hours, and increase to a peak during the dark.
The mechanism behind this pattern of secretion during the dark cycle is that activity of the
rate-limiting enzyme in melatonin synthesis - serotonin N-acetyltransferase (NAT) - is low
during daylight and peaks during the dark phase. In some species, circadian changes in NAT
activity are tightly correlated with transcription of the NAT messenger RNA, while in other
species, post-transcriptional regulation of NAT activity is responsible. Activity of the other
enzyme involved in synthesis of melatonin from serotonin - the methyltransferase - does not
show regulation by pattern of light exposure.

Two melatonin receptors have been identified from mammals (designated Mel1A and
Mel1B) that are differentially expressed in different tissues and probably participate in
implementing differing biologic effects. These are G protein-coupled cell surface receptors.
The highest density of receptors has been found in the suprachiasmatic nucleus of the
hypothalamus, the anterior pituitary (predominantly pars tuberalis) and the retina. Receptors
are also found in several other areas of the brain.

Biological Effects of Melatonin

Melatonin has important effects in integrating photoperiod and affecting circadian rhythms.
Consequently, it has been reported to have significant effects on reproduction, sleep-wake
cycles and other phenomena showing circadian rhythm.

Effects on Reproductive Function

Seasonal changes in daylength have profound effects on reproduction in many species,

and melatonin is a key player in controlling such events. In temperate climates, animals
like hamsters, horses and sheep have distinct breeding season. During the non-breeding
season, the gonads become inactive (e.g males fail to produce sperm in any number), but as
the breeding season approaches, the gonads must be rejuvenated. Photoperiod - the length of
day vs night - is the most important cue allowing animals to determine which season it is. As
you've probably deduced by now, the pineal gland is able to measure daylength and adjust
secretion of melatonin accordingly. A hamster without a pineal gland or with a lesion that
prevents the pineal from receiving photoinformation is not able to prepare for the breeding
season.

The effect of melatonin on reproductive systems can be summarized by saying that it is anti-
gonadotropic. In other words, melatonin inhibits the secretion of the gonadotropic hormones
luteinizing hormone and follicle stimulating hormone from the anterior pituitary. Much of
this inhibitory effect seems due to inhibition of gonadotropin-releasing hormone from the
hypothalamus, which is necessary for secretion of the anterior pituitary hormones.

One practical application of melatonin's role in controlling seasonal reproduction is found in

its use to artificially manipulate cycles in seasonal breeders. For example, sheep that
 normally breed only once per year can be induced to have two breeding seasons by treatment
with melatonin.

Effects on Sleep and Activity

Melatonin is probably not a major regulator of normal sleep patterns, but undoubtedly has
some effect. One topic that has garnered a large amount of interest is using melatonin alone,
or in combination with phototherapy, to treat sleep disorders. There is some indication that
melatonin levels are lower in elderly insomniacs relative to age matched non-insomniacs,
and melatonin therapy in such cases appears modestly beneficial in correcting the problem.

Another sleep disorder is seen in shift workers, who often find it difficult to adjust to
working at night and sleeping during the day. The utility of melatonin therapy to aleviate this
problem is equivocal and appears not to be as effective as phototherapy. Still another
condition involving disruption of circadian rhythms is jet lag. In this case, it has repeatedly
been demonstrated that taking melatonin close to the target bedtime of the destination can
alleviate symptoms; it has the

greatest beneficial effect when jet lag is predicted to be worst (e.g. crossing many time
zones).

In various species including humans, administration of melatonin has been shown to decrease
motor activity, induce fatigue and lower body temperature, particularly at high doses. The
effect on body temperature may play a significant role in melatonin's ability to entrain sleep-
wake cycles, as in patients with jet lag.

Other Effects of MelatoninOne of the first experiments conducted to elucidate the function
of the pineal, extracts of pineal glands from cattle were added to water containing tadpoles.
Interestingly, the tadpoles responded by becoming very light in color or almost transparent
due to alterations in melanin pigment distribution. Although such cutaneous effects of
melatonin are seen in a variety of "lower species", the hormone does not have such effects in
mammals or birds.

Other Endocrine Organs

The thymus is in the neck and superior to the heart in the thorax; it secretes a hormone
called thymosin (thī′mō-sin) Both the thymus and thymosin play an important role in the
development and maturation of the immune system.
Several hormones, such as gastrin, secretin, and cholecystokinin, are released from the
gastrointestinal tract. Th ey regulate digestive functions by influencing the activity of the stomach,
intestines, liver, and pancreas.
The kidneys secrete a hormone in response to reduced oxygen levels in the kidney. The
hormone is called erythropoietin. It acts on red bone marrow to increase the production of red blood
cells.
In pregnant women, the placenta is an important source of hormones that maintain
pregnancy and stimulate breast development. Th ese hormones include estrogen, progesterone, and
human chorionic gonadotropin, which is similar in structure and function to LH. These hormones
are essential to the maintenance of pregnancy.