Endocrinology
Major endocrine glands in the body
CHEMISTRY OF HORMONES
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Peptide hormones: largest, most complex, and most
common hormones. Examples include insulin and prolactin
Steroid hormones: lipid soluble molecules synthesized from
cholesterol. Examples include gonadal steroids (e.g
testosterone and estrogen) and adrenocortical steroids (e.g.
cortisol and aldosterone).
Amines: small molecules derived from individual amino
acids. Include catecholamines (e.g. epinephrine produced by
the adrenal medulla), and thyroid hormones.
Eicosanoids: small molecules synthesized from fatty acid
substrates (e.g. arachidonic acid) located within cell
membranes
MODES OF HORMONE DELIVERY
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ENDOCRINE: Most common (classical) mode,
hormones delivered to target cells by blood.
PARACRINE: Hormone released diffuses to its
target cells through immediate extracellular space.
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Blood is not directly involved in the delivery.
AUTOCRINE: Hormone released feeds-back on the
cell of origin, again without entering blood
circulation.
NEUROENDOCRINE: Hormone is produced and
released by a neuron, delivered to target cells by
blood.
HORMONE-TARGET CELL
SPECIFICITY
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Only target cells, or cells that have specific
receptors, will respond to the hormone’s
presence.
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The strength of this response will depend on:
Blood levels of the hormone
 The relative numbers of receptors for that hormone on
or in the target cells
 The affinity (or strength of interactions) of the hormone
and the receptor.
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HALF-LIFE, ONSET, and
DURATION of HORMONE
ACTIVITY
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The affinity of hormones to their specific
receptors is typically very high
The actual concentration of a circulating
hormone in blood at any time reflects:
Its rate of release.
 The speed of its inactivation and removal from the
body.
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The half-life is the time required for the hormone to
loose half of its original effectiveness (or drop to half
of its original concentration.
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The time required for hormone effects to take place
varies greatly, from almost immediate responses to
hours or even days.
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In addition, some hormones are produced in an
inactive form and must be activated in the target cells
before exerting cellular responses.
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In terms of the duration of hormone action, it ranges
from about 20 minutes to several hours, depending on
the hormone.
CONTROL OF HORMONE RELEASE
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The synthesis and secretion of most hormones are
usually regulated by negative feedback systems.
As hormone levels rise, they stimulate target organ
responses. These in turn, inhibit further hormone
release.
The stimuli that induce endocrine glands to synthesize
and release hormones belong to one of the following
major types:
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Humoral
Neural
Hormonal
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cAMP & IP3
Pituitary Gland
The “Master Gland”
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The pituitary has been
called the “Master” gland
in the body.
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This is because most of
the pituitary hormones
control other endocrine
glands
Hormones of the anterior pituitary
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There are 6 main hormones which are secreted by the
adenohypophysis:
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1) Growth hormone (also known as somatotropin).
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2) Thyroid-stimulating hormone (also known as thyrotropin).
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3) Adrenocorticotropic hormone (also known as corticotropin).
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4) Prolactin.
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5) Follicle-stimulating hormone.
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6) Luteinizing hormone.
Control of pituitary gland secretion
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Secretion of each hormone by the
adenohypophysis is controlled by
neurohormones secreted by nerves in the
hypothalamus.
In most cases there are two neurohormones
controlling the secretion of a pituitary hormone.
One which stimulates pituitary secretion and one
which inhibits pituitary secretion.
Neurohormones:
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Are hormones secreted by nerve cells. These
are true hormones, since they are secreted into
the bloodstream.
All are secreted by neurosecretory neurons in
the hypothalamus.
They are secreted into the hypophyseal portal
system, which then carries the blood to the
anterior pituitary.
Pituitary portal system
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Arterioles break into capillaries in the hypothalamus.
The axons of the neurosecretory cells form plexuses
with these capillaries.
Downstream, the capillaries combine into a vein which
carries the blood to the pars distalis.
The vein breaks into a capillary network which supplies
all the cells of the anterior lobe.
Thus, the neurohormones are carried directly (well, sort
of) from the hypothalamus to the adenohypophysis.
Portal system
Growth hormone (GH)
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Growth hormone is secreted by somatotrophs.
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GH is a protein hormone consisting of a single peptide chain of
191 amino acids.
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GH secretion is stimulated by the secretion of Growth Hormone
Releasing Hormone (GHRH) by the hypothalamus.
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GH secretion is inhibited by the secretion of somatostatin by the
hypothalamus.
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GH activates a tyrosine kinase receptor.
Functions of GH:
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GH has effects of every cell of the body, either directly
or indirectly. Primarily, it decreases the uptake and
metabolism of glucose. (Elevates plasma glucose)
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Increases the breakdown of fat. (Increases the blood
levels of fatty acids)
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Increases the uptake of amino acids from the blood
and increases protein synthesis in cell. (Decreases
plasma amino acids)
Actions of GH on specific cell types:
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Muscle cells:
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Increases amino acid uptake
Increases protein synthesis
Decreases glucose uptake
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Net result: Increased Lean body mass
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Chondrocytes:
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increases uptake of sulfur
increases
 increases
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chondroitin sulfate production
DNA, RNA synthesis
Protein synthesis
Amino acid uptake
Collagen synthesis
Cell size and number
Net result: Increased Linear growth
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Hepatocytes:
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Stimulates the production of somatomedins by
the liver.
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These somatomedins directly regulate metabolic
function in target cells. They are also called
insulin-like growth factors, or IGFs.
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Adipocytes:
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Decreases glucose uptake
Increases lypolysis
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Net result: Decreased Adiposity
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Other cell types in general:
Increased protein synthesis
 Increased DNA, RNA synthesis
 Increased cell size and number
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Net result: Increased organ size
Increased organ function
Other considerations:
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GH has a short half-life of about 20 minutes.
However, the IGFs are much longer lived (T1/2
of about 20 hours).
GH and Insulin actions are correlated:
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When there is ample dietary intake of proteins and carbohydrates,
then amino acids can be used for protein synthesis and growth.
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Under these conditions, both insulin and GH secretion are
stimulated.
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Net result: Amino acids are shunted to protein synthesis and glucose is shunted
to metabolism.
However, under conditions where only carbohydrates are ingested,
insulin secretion is increased, but GH secretion is decreased.
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Net result: Both glucose AND amino acids are shunted to metabolism.
Pathophysiology of abnormal GH
secretion:
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Hyposecretion:
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Pre-adolescents:
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Decreased GH secretion (or sensitivity) results in slow
growth and delayed onset of sexual maturation. These
children also tend to be slightly chubby.
Post-adolescents:
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Generally, no serious problems are associated with
hyposecretion of GH in mature individuals. However, in
very severe cases there can be progeria (rapid and premature
aging).
Hypersecretion:
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Pre-adolescents: (before closure of
epiphyseal plates)
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Hypersecretion results in gigantism, where
affected individuals grow extremely rapidly and
become abnormally tall (even over 2.4 m). Body
proportions remain relatively normal. Usually,
there are cardiovascular complications later in
life.
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Post- adolescents: (after epiphyseal closure).
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Hypersecretion results in tissue enlargement.
This is particularly true of the bones, which get
heavier and thicker. They cannot elongate since
the epiphyseal plates are closed. A common
symptom is a coarsening of the facial features
and enlargement of the hands and feet. This
condition is known as acromegaly.
Treatments of GH secretion disorders:
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Hypersecretion is usually caused by a tumour in
the pituitary gland. Treatment consists of
surgical or radiation ablation of the tumour
mass.
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Hyposecretion is usually treated in children by
hormone replacement therapy. This is generally
not required in adults, unless GH secretion is
completely abolished.
Prolactin (PRL)
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Structurally, very similar to growth hormone
(single peptide chain of 198 amino acids).
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PRL is secreted by mammotrophs (also referred
to as lactotrophs).
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Secretion of PRL is also under dual control by
the hypothalamus.
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Primarily under inhibitory control. This means that if
there is an injury to the hypophyseal portal system
which blocks hypothalamic regulation of the pituitary
gland, PRL levels increase. All other pituitary hormone
levels decrease when this happens.
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Dopamine is secreted by neuroendocrine cells in the
hypothalamus and inhibits PRL release.
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PRL release is stimulated by thyrotropin releasing
hormone (TRH), vasoactive intestinal peptide (VIP)
and at least one other as yet unidentified factor.
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PRL activates a tyrosine kinase receptor.
Functions of PRL:
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In humans, the only effects of PRL so far identified are on reproduction and
nursing.
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PRL is important in stimulating differentiation of breast tissue during
development.
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Stimulates further development of mammary glands during pregnancy.
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Stimulates milk production (lactation) after pregnancy.
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PRL has a role in regulation of the female reproductive cycle. However, its
precise role has not be delineated yet. Excess PRL secretion is know to block
synthesis and release of gonadotropins, disrupting menstruation and causing
infertility.
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PRL also can regulate male fertility, but how it does so remains unclear.
Pathophysiology of PRL secretion:
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Hyposecretion is never seen. However,
hyperprolactinemia (excess secretion of PRL) is
a fairly common disorder. Symptoms in women
usually include amenorrhea (cessation of
menstruation), galactorrhea (abnormal lactation)
and infertility. In men, infertility and
galactorrhea are the most common symptoms.
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Treatment usually consists of administration of
a dopaminergic agonist, such as bromocriptine.
Thyroid Stimulating hormone (TSH)
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TSH is a glycoprotein hormone composed of 2
peptide chains a and b.
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The a subunit is called “unspecific” because it is
also incorporated into two other unrelated
pituitary hormones (LH and FSH).
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The b subunit contains the biologically active
sites. However, it must be combined with the a
subunit in order for the hormone to be active.
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TSH secretion is controlled very tightly by the
hypothalamus.
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TSH secretion is stimulated by Thyrotropinreleasing hormone (TRH). TRH is a tripeptide,
meaning it is composed of three amino acids.
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TRH secretion is stimulated by thermal and
caloric signals in the brain.
Control of TSH secretion
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Negative control of TSH secretion occurs in
two ways:
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Triiodothyronien or T3 (which will be discussed
later) feeds back on the hypothalamus to stimulate
secretion of dopamine and somatostatin. These two
factors both function as TSH-release inhibiting
factors.
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T3 can feed back directly onto the thyrotrophs to
directly inhibit TSH secretion.
Function of TSH:
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TSH stimulates the follicular cells of the thyroid
to induce a number of responses:
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TSH activates both the cAMP and PIP pathways:
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Increased cAMP
Increased [Ca2+]i
TSH can stimulate both cell growth (of
follicular cells) and secretion of T3 and
thyroxine ( T4 ).
Adrenocorticotropic hormone (ACTH)
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ACTH is a single peptide chain which is relatively small (30
amino acids).
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ACTH secretion is primarily under stimulatory control (i.e. there
isn’t an ACTH-release inhibitory factor).
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ACTH secretion is stimulated by corticotropin releasing
hormone (CRH).
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CRH secretion can be stimulated by a large number of factors,
most of which would be considered stress factors.
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Examples; infection, trauma, sleep cycle, anxiety, depression and
others. (Just remember stress).
Functions of ACTH:
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ACTH stimulates the adrenal gland to secrete cortisol.
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ACTH levels are associated with the sleep cycle.
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ACTH stimulates the cAMP pathway in adrenocorticol
cells.
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ACTH can directly inhibit CRH secretion (negative
feedback).
Follicular-Stimulating hormone (FSH)
Luteinizing Hormone (LH)
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These are generally grouped together and called gonadotropines.
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Gonadotropins are secreted by the gonadotrophs, which
synthesize and secrete both LH and FSH.
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Both LH and FSH are peptide hormones.
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Secretion of gonadotropins is mainly under positive control.
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Hypothalamus secretes gonadotropin-releasing hormone
(GnRH) which stimulates gonadotrophs to secrete both LH and
FSH.
Functions of LH and FSH:
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LH and FSH stimulate secretion of the sex steroids by the
gonads. Mainly estrogen in women and testosterone in men.
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FSH also stimulates gonadal release of inhibin, which serves as a
negative feedback factor to block release of FSH by pituitary.
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LH and FSH stimulate the gonadal release of activin, which can
have positive feedback on gonadotropin secretion by the
pituitary.
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Gonadal secretion of estrogen and testosterone can negatively
feedback on both the hypothalamus, to reduce GnRH secretion,
and the gonadotrophs directly, to reduce gonadotropin
secretions.
Hormones of the posterior
pituitary:
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Remember that the neurohypophysis serves as a storage organ
for hormones produced by neurosecretory cells in the
hypothalamus.
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There are two hormones secreted by the neurohypophysis:
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1) antidiuretic hormone (ADH)
2) oxytocin
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Both hormones are peptide hormones containing 9 amino acid
residues.
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They differ in only 2 amino acids, but have very different
functions.
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Both activate the PIP pathway in the target cells.
ADH
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Term: diuresis ö means production of urine.
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ADH inhibits urine production, i.e. conserves water in the body.
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Main target for ADH are the cells in the kidney which reabsorb
water (will be covered in detail in the section on renal
physiology).
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ADH secretion is stimulated by either an increase in the osmotic
concentration of the blood, or by a decrease in blood volume
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usually sensed by a decrease in blood pressure.
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Secretion of ADH causes retention of water, which will
tend to counteract both an increase in blood
concentration and/or decrease in blood volume.
cannot overcome serious blood loss.
Conversely, excess consumption of water will have two
effects:
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increase blood volume (and pressure).
decrease blood concentration.
Under these conditions ADH secretion is inhibited.
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This results in formation of more urine, which is usually
fairly dilute.
Blood loses water and thus volume.
Oxytocin
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Release of oxytocin is under neural control (like with ADH).
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However, unlike ADH, the release of oxytocin is largely controlled by emotional
state.
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Oxytocin is required for nursing.
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Principally know as the “milk letdown factor”.
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It is secreted within seconds of the onset of suckling.
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Sensory receptors in the nipples generate afferent impulses that stimulate the hypothalamus,
triggering oxytocin secretion.
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Can actually be secreted in response to auditory input, i.e. in nursing mothers in response to
hearing their babies cry.
Oxytocin specifically stimulates certain smooth muscles to contract.
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Primarily those of the reproductive tract and mammary glands.
Effects of Oxytocin
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Oxytocin stimulation at low doses causes rhythmic contractions
of the uterus.
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ö Oxytocin stimulation at high dose causes sustained tetanic
uterine contractions.
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ö Oxytocin is often used to induce labour.
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ö It is now generally believed that oxytocin believed that
oxytocin produced by the fetus plays a critical role in labour.
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ö Oxytocin is also used to stop post-partum bleeding.
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The number of oxytocin receptors in uterine smooth muscles
increases towards the end of pregnancy.
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Oxytocin affects smooth muscle cells in uterus and vagina of
non-pregnant women.
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There is clear evidence that oxytocin is involved in sexual arousal
and orgasm in both men and women.
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What role it plays in men is unknown. However, it may play a strong role
in reinforcing the pair-bond.
The role in women is only slightly better known.
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Oxytocin is secreted in response to vaginal distention during intercourse.
Oxytocin is also secreted in response to stimulation of the nipples.
Emotional considerations
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Oxytocin secretion during sexual intercourse probably serves to reinforce the
male-female pair-bond.
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Secretion of oxytocin during and after labour may play an important role in
the formation of the mother-child pair-bond.
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Often referred to as the “the cuddle hormone” or “the love hormone” in the
popular press.
Oxytocin secreted during suckling may serve to reinforce this pair-bond.
Recent studies with knock out mice has shown that oxytocin is critical in
initiating and maintaining maternal care.
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Oxytocin secreted in response to suckling can cause uterine contractions which
may play a role in the recovery of uterine muscle tone after pregnancy and may
serve to shrink the uterus back to normal.