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HYPOTHALAMIC

AND PITUITARY
HORMONES
Functional Anatomy of the
Hypothalamus and Pituitary Gland

 The hypothalamus is a region of the brain


that controls an immense number of bodily
functions
 It is located in the middle of the base of
the brain, and encapsulates the ventral
portion of the third ventricle.
Hypthalamus
Optic chiasm

Pituitary Gland
HYPOTHALAMIC
HORMONES
HYPOTHALAMIC HORMONES
 Controls the release of pituitary hormones
 Hypothalamic hormones are released from
the hypothalamic nerve fiber endings
around the capillaries of the hypothalamic-
hypophysial system in the pituitary stalk
 Released in a pulsatile manner
Growth-hormone-releasing
hormone (GHRH)
 Also known as growth-hormone-releasing
factor (GRF or GHRF) or somatocrinin
 a 44-amino acid peptide hormone
produced in the arcuate nucleus of the
hypothalamus
 GHRH is released from neurosecretory
nerve terminals of these arcuate neurons,
and is carried by the hypothalamo-
hypophysial portal circulation to the
anterior pituitary gland where it stimulates
growth hormone secretion
 The actions of GHRH are opposed by another
hypothalamic hormone, somatostatin, also
known as "growth-hormone-inhibiting hormone"
(GHIH).
 Somatostatin is released from neurosecretory
nerve terminals of periventricular somatostatin
neurons, and is carried by the hypothalamo-
hypophysial portal circulation to the anterior
pituitary where it inhibits GH secretion by
hyperpolarising the somatotropes.
• Somatostatin and GHRH are secreted in
alternation, giving rise to the markedly
pulsatile secretion of GH. However
recently it had been discovered that
somatostatin does not affect the secretion
of GH
 The amino acid sequence of GHRH is:
Tyr - Ala - Asp - Ala - Ile - Phe - Thr - Asn - Ser -
Tyr - Arg - Lys - Val - Leu - Gly - Glu - Leu - Ser -
Ala - Arg - Lys - Leu - Leu - Gln - Asp - Ile - Met -
Ser - Arg - Glu - Gln - Gly - Glu - Ser - Asn - Gln -
Glu - Arg - Gly - Ala - Arg - Ala - Arg - LeuNH2
Somatostatin
 a peptide hormone that regulates the
endocrine system and affects
neurotransmission and cell proliferation via
interaction with G-protein-coupled
somatostatin receptors and inhibition of the
release of numerous secondary hormones
Somatostatin
 has two active forms produced
by alternative cleavage of a
single preproprotein: one of 14
amino acids, the other of 28
amino acids. Somatostatin
 Somatostatin is secreted not only
by cells of the hypothalamus but
also by delta cells of stomach,
intestine, and pancreas. It binds
to somatostatin receptors.

Octreotide
Octreotide
 is an octopeptide that mimics natural
somatostatin pharmacologically, though is
a more potent inhibitor of growth hormone,
glucagon, and insulin than the natural
hormone
Somatostatin is classified as an inhibitory hormone, whose main actions
are to:
•Inhibit the release of growth hormone (GH)
•Inhibit the release of thyroid-stimulating hormone (TSH)
•Suppress the release of gastrointestinal hormones
•Gastrin
•Cholecystokinin (CCK)
•Secretin
•Motilin
•Vasoactive intestinal peptid (VIP)
•Gastric inhibitory polypeptide (GIP)
•Enteroglucagon (GIP)
•Lowers the rate of gastric emptying, and reduces smooth muscle
contractions and blood flow within the intestine.
•Suppress the release of pancreatic hormones
•Inhibit the release of insulin
•Inhibit the release of glucagon
•Suppress the exocrine secretory action of pancreas
Somatostatin opposes the effects of Growth Hormone-Releasing
Hormone (GHRH)
Corticotropin-releasing hormone
(CRH)
 originally named corticotropin-releasing
factor (CRF), and also called
corticoliberin, is a polypeptide hormone
and neurotransmitter involved in the stress
response
Corticotropin-releasing hormone
(CRH)
 produced by neuroendocrine cells in the
paraventricular nucleus of the hypothalamus
 The portal system carries the CRH to the
anterior lobe of the pituitary, where it stimulates
corticotropes to secrete corticotropin (ACTH)
and other biologically active substances (for
example β-endorphin).
Corticotropin-releasing hormone
(CRH)
 Role in parturition
CRH is also synthesized by the placenta
and seems to determine the duration of
pregnancy
Corticotropin-releasing hormone
(CRH)
 The 41-amino acid
sequence of CRH was
first discovered in
sheep by Vale et al in
1981 Its full sequence
is
 SQEPPISLDLTFHLLR
EVLEMTKADQLAQQA
HSNRKLLDIA
Thyrotropin-releasing hormone
(TRH)
 also called thyrotropin-releasing factor
(TRF), thyroliberin or protirelin, is a
tripeptide hormone that stimulates the release
of thyroid-stimulating hormone and prolactin
by the anterior pituitary
 TRH is produced by the hypothalamus and
travels across the median eminence to the
pituitary via the hypophyseal portal system
Thyrotropin-releasing hormone
(TRH)
 In addition to the brain, TRH can also be
detected in other areas of the body including
the gastrointestinal system and pancreatic
islets
 Medical preparations of TRH are used in
diagnostic tests of thyroid disorders
 It is used in pharmacology to test the
response of the anterior pituitary gland and in
acromegaly
Thyrotropin-releasing hormone
(TRH)
 The sequence of TRH was first determined and
the hormone synthesized by Roger Guillemin
and Andrew V. Schally in 1969. Its molecular
weight is 359.5 Da and its structure is:
 (pyro)Glu-His-Pro-NH2
Gonadotropin-releasing
hormone 1 (GNRH1)
• is a peptide hormone responsible for the release of
FSH and LH from the anterior pituitary
• GNRH1 is synthesized and released by the
hypothalamus
• GnRH was previously called LHRH (luteinizing
hormone-releasing hormone)
Gonadotropin-releasing
hormone 1 (GNRH1)
 The gene, GNRH1, for the
GNRH1 precursor is
located on chromosome 8.
 This precursor contains 92
amino acids and is
processed to GNRH1, a
decapeptide (10 amino
acids) in mammals.

pyroGlu-His-Trp-Ser-Tyr-
Gly-Leu-Arg-Pro-Gly
CONH2.
Gonadotropin-releasing
hormone 1 (GNRH1)
GNRH1 is considered a neurohormone, a
hormone produced in a specific neural cell and
released at its neural terminal
 A key area for production of GNRH1 is the
preoptic area of the hypothalamus, that
contains most of the GNRH1-secreting
neurons. GNRH1 is secreted in the
hypophysial portal bloodstream at the median
eminence
Gonadotropin-releasing
hormone 1 (GNRH1)
 The portal blood carries the GNRH1 to the
pituitary gland, which contains the gonadotrope
cells, where GNRH1 activates its own receptor,
gonadotropin-releasing hormone receptor
(GNRHR), located in the cell membrane
 GNRH1 is degraded by proteolysis within a few
minutes.
Gonadotropin-releasing
hormone 1 (GNRH1)
 In males, GNRH1 is secreted in pulses at
a constant frequency, but in females the
frequency of the pulses varies during the
menstrual cycle and there is a large surge
of GNRH1 just before ovulation.
Gonadotropin-releasing
hormone 1 (GNRH1)
 GNRH1 activity is very low during
childhood, and is activated at puberty
 During the reproductive years, pulse
activity is critical for successful
reproductive function as controlled by
feedback loops
 However, once a pregnancy is
established, GNRH1 activity is not
required
Dopamine
 In the brain, dopamine functions as a
neurotransmitter, activating dopamine receptors
 Dopamine is also a neurohormone released by the
hypothalamus
 Its main function as a hormone is to inhibit the
release of prolactin from the anterior lobe of the
pituitary
 Dopamine has the chemical formula (C6H3(OH)2-
CH2-CH2-NH2)
 Its chemical name is 4-(2-aminoethyl)benzene-1,2-
diol and it is abbreviated "DA."
PITUITARY
HORMONES
GROWTH HORMONE (GH)
 Also called somatropin or somatotropin
 Synthesized in somatotropes, a subclass of the
pituitary acidophilic cells
 The genes for human growth hormone are
localized in the q22-24 region of chromosome 17
Disulfide bonds
GROWTH HORMONE (GH)
 Peptides released by neurosecretory
nuclei of the hypothalamus into the portal
venous blood surrounding the pituitary are
the major controllers of GH secretion by
the somatotropes.
GROWTH HORMONE (GH)
 Growth hormone releasing hormone
(GHRH) from the arcuate nucleus of the
hypothalamus and ghrelin* promote GH
secretion, and somatostatin from the
periventricular nucleus inhibits it.
Secretes GHRH
 Ghrelin is a hormone produced by P/D1 cells
lining the fundus of the human stomach that
stimulate appetite
 Ghrelin levels increase before meals and
decrease after meals
 It is considered the counterpart of the hormone
leptin, produced by adipose tissue, which
induces satiation when present at higher levels.
 Much of the growth hormone in the
circulation is bound to a protein (growth
hormone binding protein, GHBP) which is
derived from the growth hormone receptor
 Growth hormone receptor is a member of
the cytokine receptor superfamily.
 One growth hormone molecule binds to
one receptor and then recruits a second
receptor to form a dimer through which
signalling occurs.
 The effects of growth hormone on the
tissues of the body can generally be
described as anabolic
 Height growth in childhood is the best known
effect of GH action, and appears to be
stimulated by at least two mechanisms:

1. GH directly stimulates division and


multiplication of chondrocytes of cartilage.

These are the primary cells in the growing ends


(epiphyses) of children's long bones
2. GH also stimulates production of insulin-
like growth factor 1 (IGF1, formerly known
as somatomedin C), a hormone
homologous to proinsulin

The liver is a major target organ of GH for


this process, and is the principal site of
IGF-1 production
GROWTH HORMONE (GH)
 GH secretion is also affected by negative
feedback from circulating concentrations
of GH and IGF-1
EFFECTS OF GROWTH
HORMONE
 Stimulators of GH secretion include exercise,
hypoglycemia, dietary protein, and estradiol. Inhibitors
of GH secretion include dietary carbohydrate and
glucocorticoids.
 Increases the transport of amino acids into muscle cells
and also increases protein synthesis
 Antagonizes the effects of insulin
 Decreases the peripheral utilization of glucose
 Increases hepatic glucose glucose production via
gluconeogenesis
EFFECTS OF GROWTH
HORMONE
 In liver, GH increases liver glycogen
 Promotes the release of free fatty acids and glycerol from
adipose tissue
 Increases oxidation of free fatty acids in the liver
 Promotes a positive calcium, magnesium, and phosphate
balance
 Causes retention of sodium, potassium and chloride ions
 Promotes the growth of long bones
 Stimulates lactogenesis
Genetic deficiencies associated
with GH
 GH-deficient dwarfs lack the ability to
synthesize or secrete GH, and these short-
statured individuals respond well to GH
therapy
 Pygmies lack the IGF-1 response to GH but
not its metabolic effects; thus in pygmies the
deficiency is post-receptor in nature
 Laron dwarfs have normal or excess plasma
GH, but lack liver GH receptors and have low
levels of circulating IGF-1. The defect in
these individuals is clearly related to an
inability to respond to GH by the production
of IGF-1
 The production of excessive amounts of
GH before epiphyseal closure of the long
bones leads to gigantism
 When GH becomes excessive after
epiphyseal closure, acral bone growth
leads to the characteristic features of
acromegaly
PROLACTIN
 Peptide hormone
synthesized and secreted
by lactotrope cells in the
anterior pituitary gland
 Prolactin is a single chain
polypeptide of 199 amino
acids with a molecular
weight of about 24,000
daltons
 The molecule is folded due
to the activity of three
disulfide bonds
 The prolactin receptor - encoded by a
gene on Chromosome 5 - interacts with the
prolactin molecule as a transmembrane
receptor
 A specific second messenger has not yet
been identified.
 Pituitary prolactin
secretion is regulated by
neuroendocrine
neurons in the
hypothalamus, most
importantly by
neurosecretory
dopamine neurons of
the arcuate nucleus,
which inhibit prolactin
secretion.
 Prolactin has many effects, the most important
of which is to stimulate the mammary glands to
produce milk (lactation).
 Increased serum concentrations of prolactin
during pregnancy cause enlargement of the
mammary glands of the breasts and increases
the production of milk.
 However, the high levels of progesterone during
pregnancy act directly on the breasts to stop
ejection of milk. It is only when the levels of this
hormone fall after childbirth that milk ejection is
possible.
 Another effect, recently discovered by the
University of Paisley and the Technische
Hochschule Zürich, is to provide the body
with sexual gratification after sexual acts
 The hormone represses the effect of
dopamine, which is responsible for sexual
arousal, thus causing the male's refractory
period. The amount of prolactin can be an
indicator for the amount of sexual
satisfaction and relaxation. Unusual high
amounts are suspected to be responsible
for impotence and loss of libido
 The prolactin receptor, a member of the
hematopoietin/cytokine receptor
superfamily, is ubiquitously expressed by
cells in the immune system
 Certain subpopulations of lymphocytes
synthesize and secrete biologically active
prolactin, which suggests that prolactin
can act as an autocrine and/or paracrine
factor to modulate the activities of cells of
the immune system.
 Tumors of prolactin-secreting cells
cause amenorrhea and galactorrhea in
women
 Excess PRL is associated with
gynecomastia and impotence in men
CHORIONIC
SOMATOMAMMOTROPIN (CS) OR
HUMAN PLACENTAL LACTOGEN
(HPL)
 a polypeptide placental hormone
 structure and function is similar to that of human
growth hormone
 modifies the metabolic state of the mother during
pregnancy to facilitate the energy supply of the
fetus
 HPL is an anti-insulin.
 No definite funcion in humans
GLYCOPROTEIN
HORMONES
GLYCOPROTEIN HORMONES

 Each of the glycoprotein hormones is


an (α :β ) heterodimer, with the a
subunit being identical in all members
of the family
 The biological activity of the hormone
is determined by the b-subunit, which
is not active in the absence of the a
subunit
GLYCOPROTEIN HORMONES

 The molecular weight of the gonadotropins FSH,


LH, and CG is about 25,000, whereas that of the
thyroid tropic hormone TSH is about 30,000
 All members of the glycoprotein family
transduce their intracellular effects via the
receptor, G-protein, adenylate cyclase, second-
messenger system
GONADOTROPINS

 Responsible for gametogenesis and


steroidogenesis in the gonads
FSH (Follicle-stimulating
hormone)
 a hormone synthesised and secreted by
gonadotropes in the anterior pituitary
gland
FSH (Follicle-stimulating
hormone)
 In the ovary FSH stimulates the growth of immature
Graafian follicles to maturation
 As the follicle grows it releases inhibin, which shuts off
the FSH production
 In men, FSH enhances the production of androgen-
binding protein by the Sertoli cells of the testes and is
critical for spermatogenesis
 FSH and LH act synergistically in reproduction
 FSH is a glycoprotein
 Protein dimer contains 2
polypeptide units, labelled
alpha and beta subunits.
 The alpha subunits of LH,
FSH, TSH, and hCG are
identical, and contain 92 amino
acids
 FSH has a beta subunit of 118
amino acids (FSHB) that
confers its specific biologic
action and is responsible for
interaction with the FSH-
receptor
 The sugar part of the hormone
is composed of fructose,
galactose, mannose ,
galactosamine, glucosamine,
and sialic acid, the latter being
critical for its biologic half-life
 The half-life of FSH is 3-4
hours.
FSH (Follicle-stimulating
hormone)
 The gene for the alpha subunit is located
on chromosome 6
 The gene for the FSH beta subunit is
located on chromosome 11 and is
expressed in gonadotropes of the pituitary
cells, controlled by GnRH, inhibited by
inhibin, and enhanced by activin
FSH
 High FSH levels are typical in menopause
 Diminished secretion of FSH can result in
failure of gonadal function
(hypogonadism).
LH (Luteinizing hormone)

 a hormone synthesized and secreted


by gonadotropes in the anterior lobe
of the pituitary gland
 It is necessary for proper
reproductive function
LH (Luteinizing hormone)

 In the female, an acute rise of LH – the


LH surge – triggers ovulation
 In the male, where LH had also been
called Interstitial Cell Stimulating
Hormone (ICSH), it stimulates Leydig
cell production of testosterone
LH (Luteinizing hormone)

 Alpha subunit same as FSH


 LH has a beta subunit of 121 amino acids (LHB)
that confers its specific biologic action and is
responsible for interaction with the LH receptor
 This beta subunit contains the same amino acids
in sequence as the beta sub unit of hCG and
both stimulate the same receptor
LH
 However, the hCG beta subunit contains an
additional 24 amino acids, and both hormones differ
in the composition of their sugar moieties
 The different composition of these oligosaccharides
affects bioactivity and speed of degradation
 The biologic half-life of LH is 20 minutes, shorter than
that of FSH (3-4 hours) or hCG (24 hours).
LH
 The gene for the alpha subunit is located on
chromosome 6
 The luteinizing hormone beta-subunit gene is localized in
the LHB/CGB gene cluster on chromosome 19
 In contrast to the alpha gene activity, beta LH subunit
gene activity is restricted to the pituitary gonadotropic
cells
 It is regulated by the gonadotropin releasing hormone
from the hypothalamus
 Inhibin, activin, and sex hormones do not affect genetic
activity for the beta subunit production of LH.
LH
LH levels are normally low during
childhood and high after menopause in
women
 The detection of the LH surge has
become useful for people who want to
know when ovulation occurs
 Diminished secretion of LH can result in
failure of gonadal function (hypogonadism)
 This condition is typically manifest in
males as failure in production of normal
numbers of sperm
 In females, amenorrhea is commonly
observed.
Human Chorionic Gonadotropin
(hCG)
 a peptide hormone produced in
pregnancy, that is made by the embryo
soon after conception and later by the
syncytiotrophoblast
hCG
 Its role is to prevent the disintegration of the
corpus luteum of the ovary and thereby maintain
progesterone production that is critical for a
pregnancy in humans
 hCG may have additional functions, for instance
it is thought that it affects the immune tolerance
of the pregnancy
 Early pregnancy testing generally is based on
the detection or measurement of hCG.
hCG
 hCG is an oligosaccharide glycoprotein composed of 244
amin acids with a molecular mass of 36.7 kDa
 It is heterodimeric, with an α (alpha) subunit identical to
that of luteinizing hormone (LH), follicle-stimulating
hormone (FSH), and thyroid-stimulating hormone (TSH)
and β (beta) subunit that is unique to hCG
 βhCG is encoded by six highly homologous genes which
are arranged in tandem and inverted pairs on
chromosome 19
 The two subunits create a small hydrophobic core
surrounded by a high surface area to volume ratio 2.8
times that of a sphere. The vast majority of the outer
amino acids are hydrophilic
 βhCG is also secreted by some cancers
including teratomas, choriocarcinomas
and islet cell tumors
 hCG is extensively used as a parenteral
medication in fertility therapy in lieu of
luteinizing hormo
 As hCG supports the corpus luteum,
administration of hCG is used in certain
circumstances to enhance the production
of progesterone
 In the male, hCG injections are used to
stimulate the leydig cells to synthesize
testosterone
 In the world of performance enhancing
drugs, hCG is increasingly used in
combination with various Anabolic
Androgenic Steroid (AAS) cycles.
 hCG mimics LH and helps restore /
maintain testosterone production in the
testes
Thyroid-stimulating hormone (also
known as TSH or thyrotropin)
 is a hormone synthesized and secreted by
thyrotrope cells in the anterior pituitary
gland which regulates the endocrine
function of the thyroid gland
TSH
 TSH stimulates the thyroid gland to secrete the
hormones thyroxine (T4) and triiodothyronine
(T3)
 TSH production is controlled by a Thyrotropin
Releasing Hormone, (TRH), which is
manufactured in the hypothalamus and
transported to the pituitary gland, where it
increases TSH production and release
 Somatostatin is also produced by the
hypothalamus, and has an opposite effect on the
pituitary production of TSH, decreasing or
inhibiting its release.
TSH
 When the levels of T3 and T4 are low, the
production of TSH is increased, and
conversely, when levels of T3 and T4 are
high, then TSH production is decreased.
This effect creates a regulatory negative
feedback loop
TSH
 TSH consists of two subunits, the alpha
and the beta subunit. The α subunit is
identical to that of hCG, LH, and FSH
 The β (beta) subunit is unique to TSH, and
therefore determines its function
TSH
 The TSH receptor is found mainly on
thyroid follicular cells
 Stimulation of the receptor increases T3
and T4 production and secretion
 Stimulating antibodies to this receptor
mimic TSH action and are found in
Graves' disease
TSH
 The alpha chain is located on chromosome 6
 The beta chain is located on chromosome 1
TSH
 TSH levels are tested in the blood of
patients suspected of suffering from
excess (hyperthyroidism), or deficiency
(hypothyroidism) of thyroid homone
Primarily Abnormal Pituitary
Function
 Higher than normal levels of TSH combined with high
levels of thyroid hormone (T3 and T4) may indicate
dysfunction of the hypothalamus and pituitary gland
 In this case, a high TSH is often produced by a benign
tumor of the pituitary (adenoma)
 Conversely, low levels of TSH, while blood levels of T3
and T4 are also low, indicates abnormally low function of
the pituitary, known as hypopituitarism
Primarily Abnormal Thyroid function

 On the other hand, abnormally high levels of


Thyroid hormone, due to overproduction in the
thyroid, results in low TSH levels
 This occurs in diseases such as hyperthyroidism
or Grave's disease
 Conversely, an underproduction of T3 and T4
caused by diseases such as congenital
hypothyroidism (cretinism), hypothyroidism or
thyroid hormone resistance, gives rise to an
increase in the measured TSH.
PROOPIOMELANOCORTIN
(POMC)
 The POMC gene is expressed in both the
anterior and intermediate lobes of the
pituitary gland
 The primary protein product of the POMC
gene is a 285 amino acid precursor that can
undergo differential processing to yield at
least 8 peptides, dependent upon the
location of synthesis and the stimulus
leading to their production.
ACTH
 secreted from corticotropes in the anterior
lobe of the pituitary gland in response to
the hormone corticotropin-releasing
hormone (CRH) released by the
hypothalamus.
ACTH
consists of 39 amino acids, the first 13 of
which (counting from the N-terminus) may
be cleaved to form α-MSH
 The half-life of ACTH in human blood is
about 10 minutes.
ACTH
 ACTH acts through the stimulation of cell
surface ACTH receptors, which are
primarily located on the adrenocortical
cells
 ACTH stimulates the cortex of the adrenal
gland and boosts the synthesis of
corticosteroids, mainly glucocorticoids but
also mineralcorticoids and sex steroids
(androgens).
ACTH
 Together with ACTH the hormones
lipotropin, melanocyte-stimulating
hormone (MSH), β-endorphin and met-
enkephalin are also released
 ACTH is also related to the circadian
rhythm in many organisms.
ACTH- adrenocorticotropic hormone
CLIP- corticotropin-like intermediate lobe
peptide
MSH-melanocyte-stimulating hormone

Cleavage sites are indicated by the numbers 1 to 7


and consist of the sequences, Arg-Lys, Lys-Arg or
Lys-Lys
ACTH
 Excessive production results in Cushing’s
syndrome causing:
1. Negative N, K, and P balance
2. Na retention
3. Glucose intolerance
4. Increased plasma fatty acids
5. Decreased circulating eosinophils and
lymphocytes
β -LIPOTROPIN (β -lph)

 causes lipolysis and fatty acid


mobilization, but its physiologic role
is minimal
ENDORPHINS

 Bind to CNS receptors like opiates and


may play a role in pain perception
MELANOCYTE-STIMULATING
HORMONE (MSH)
 Stimulates darkening of the skin
POSTERIOR PITUITARY
HORMONES
 Nonapeptides oxytocin and vasopressin
 These substances are synthesized as
prohormones in neural cell bodies of the
hypothalamus and mature as they pass down
axons in association with carrier proteins
termed neurophysins
 The axons terminate in the posterior
pituitary, and the hormones are secreted
directly into the systemic circulation
 Neurophysin is a carrier protein with a size of
10 KDa and containing 90 to 97 aminoacids that
transports neurohypophysial hormones along
axons, from the hypothalamus to the posterior
lobe of the pituitary.
 This protein is necessary to prevent diffusion of
peptide hormones out of the axons
 Hormones of the posterior lobe of the pituitary
are synthesized in hypothalamic nuclei and are
packaged in secretory granules with their
respective neurophysins.

Vasopressin or antidiuretic
hormone (ADH)
 Arginine vasopressin (AVP), also known
as argipressin or antidiuretic hormone
(ADH), is a human hormone that is mainly
released when the body is low on water
 It causes the kidneys to conserve water by
concentrating the urine and reducing urine
volume.
ADH
 A very similar substance, lysine
vasopressin (LVP) or lypressin, has the
same function in pigs and is often used in
human therapy.
 Vasopressin is a peptide hormone
liberated from a preprohormone precursor
that is synthesized in the hypothalamus as
it is transported to the posterior pituitary
 Most of it is stored in the posterior part of
the pituitary gland to be released into the
blood stream; some of it is also released
directly into the brain.
 Vasopressin is secreted from the posterior
pituitary gland in response to reductions in
plasma volume and in response to increases in
the plasma osmolality
 Secretion in response to reduced plasma
volume is activated by pressure receptors in the
veins, atria, and carotids
 Secretion in response to increases in plasma
osmotic pressure is mediated by osmoreceptors
in the hypothalamus
ADH
 Many factors influence the secretion of
vasopressin; for instance, ethanol and
caffeine reduce vasopressin secretion
 The resulting decrease in water
reabsorption by the kidneys leads to a
higher urine output
 Angiotensin II stimulates the secretion of
vasopressin
ADH
 Vasopressin acts on three different receptors,
termed V1a, V1 and V2. The receptors are
differently expressed in different tissues, and exert
different actions:
1. V1a - vasoconstriction, gluconeogenesis in the liver,
platelet aggregation and release of factor VIII and
von Willebrand factor.
2. V1b - corticotropin secretion from the pituitary gland
3. V2 - control of free water reabsorption in the
collecting ducts of the kidneys (especially the
cortical and outer medullary collecting ducts)
ADH
 Activation of adenylate cyclase causes
increase in cAMP which leads to the insertion
of aquaporin-2 (AQP2) channels (water
channels) into the apical membrane of the
cells lining the collecting duct
 This allows water to be reabsorbed down an
osmotic gradient, and so the urine is more
concentrated.
ADH
 The vasopressins are peptides consisting
of nine amino acids (nonapeptides)
 The amino acid sequence of arginine
vasopressin is Cys-Tyr-Phe-Gln-Asn-Cys-
Pro-Arg-Gly, with the cysteine residues
form a sulfur bridge
 Lysine vasopressin has a lysine in place of
the arginine.
ADH
 Decreased vasopressin release or
decreased renal sensitivity to vasopressin
leads to diabetes insipidus, a condition
featuring hypernatremia (increased blood
sodium content), polyuria (excess urine
production), and polydipsia (thirst).
ADH
 High levels of vasopressin secretion
(syndrome of inappropriate antidiuretic
hormone, SIADH) and resultant
hyponatremia (low blood sodium levels)
occurs in brain diseases and conditions of
the lungs
Oxytocin
 (Greek: "quick birth") is a mammalian
hormone that also acts as a
neurotransmitter in the brain
 In women, it is released mainly after
distension of the cervix and vagina during
labor, and after stimulation of the nipples,
facilitating birth and breastfeeding
 Oxytocin is released during orgasm in
both sexes
 In the brain, oxytocin is involved in social
recognition and bonding, and might be
involved in the formation of trust between
people.
 Oxytocin is made in magnocellular
neurosecretory cells in the supraoptic
nucleus and paraventricular nucleus of the
hypothalamus and is released into the
blood from the posterior lobe of the
pituitary gland
 Oxytocin is also made by some neurons in
the paraventricular nucleus that project to
other parts of the brain and to the spinal
cord.
 In the pituitary gland, oxytocin is packaged
in large, dense-core vesicles, where it is
bound to neurophysin
 Oxytocin is a peptide of nine amino acids (a
nonapeptide)
 The sequence is cysteine - tyrosine - isoleucine -
glutamine - asparagine - cysteine - proline -
leucine - glycine (CYIQNCPLG)
 The cysteine residues form a sulfur bridge
 Oxytocin has a molecular mass of 1007 daltons
Oxytocin receptors are expressed by the
myoepithelial cells of the mammary gland,
and in both the myometrium and
endometrium of the uterus at the end of
pregnancy
 Due to its similarity to vasopressin, it can
reduce the excretion of urine slightly
THYROID HORMONES

• Require the trace element iodine for


biologic activity
• Thyroglobulin is the precursor of T4

(Tetraiodothyronine or thyroxine) and


T3 (Triiodothyronine)
• Thyroglobulin is produced on rough
endoplasmic reticulum has a molecular
weight of 660,000
• It is glycosylated and contains more
than 100 tyrosine residues, which
become iodinated and are used to
synthesize T3 and T4
STEPS IN THYROID
HORMONE SYNTHESIS

A Na+/K+-ATPase-driven pump
concentrates iodide (I-) in thyroid
cells, and the iodide is transported
to the follicle lumen
In the follicle lumen, it is oxidized by a
thyroperoxidase found only in thyroid
tissue.
Thiourea drugs, which are antithyroid
drugs, act on this step
The addition of oxidized iodide to tyrosine
residues of thyroglobulin is catalyzed by
the same thyroperoxidase enzyme,
leading to the production of thyroglobulin
containing monoiodotyrosyl (MIT) and
diiodotyrosyl (DIT) residues. This
reaction is called organification.
 The thyronines, T3 and T4, are formed by
combining MIT and DIT residues on thyroglobulin
in a process called coupling
 The thyroid is the only tissue that can oxidize I– to
a higher valence state, an obligatory step in I–
organification and thyroid hormone biosynthesis
Mature, iodinated thyroglobulin is
taken up in vesicles by thyrocytes
and fuses with lysosomes
 Lysosomal proteases degrade
thyroglobulin releasing amino acids
and T3 and T4, which are secreted into
the circulation
(Organification)
Thiourea
drugs

*inherited enzyme defects occur, causing goiter

activity is primarily controlled by TSH


T3 and T4 are very hydrophobic and require a
carrier protein for delivery to target tissues.
In the plasma, T3 and T4 are bound to a
carrier glycoprotein known as thyroxin-
binding globulin (TBG) and are
disseminated throughout the body in this
form
 Most of the thyroid hormone circulating in the blood is
bound to transport proteins:
1. Thyroxine-binding globulin (TBG, 70%)
2. Thyroxine-binding prealbumin (TBPA, 10-15%): this
protein is also responsible for the transport of retinol,
and so now has the preferred name of transthyretin
(TTR)
3. Albumin (15-20%).
 Only a very small fraction of the circulating hormone is
free (unbound) - T4 0.03% and T3 0.3%.
Drugs such as phenytoin and
salicylates compete with T3 and T4
for binding to TBG
• Unbound thyroid hormone is
responsible for the biologic activity
• T3 binds to the thyroid receptor in

target cells 10 times more than T4, so it


is more metabolically active.
• However, T4 has 5x the half life of T3
• A peripheral deiodinase in target tissues
such as pituitary, kidney, and liver
selectively removes Iodide from the 5'
position of T4 to make T3
• 80% of circulating T4 is converted to T3.
This conversion is inhibited by
propylthiouracil (PTU) and Propranolol
 Thyroid hormones act by binding to
cytosolic receptors very similar to
steroid hormone receptors
 The thyronines act on the body to increase
the basal metabolic rate, affect protein
synthesis and increase the body's
sensitivity to catecholamines
 These hormones also regulate protein, fat,
and carbohydrate metabolism, affecting
how human cells use energetic
compounds.
 In the embryo, thyroid hormone is
necessary for normal development.
Hypothyroidism in the embryo is
responsible for cretinism, which is
characterized by multiple congenital
defects and mental retardation
Effects of thyroxine

 Increased cardiac output


 Increased heart rate
 Increased ventilation rate
 Increased basal metabolic rate
 Development of brain
 Thickens endometrium
 Thyroid stimulating autoantibodies
(TSAb) also activate the human thyroid
TSH receptor, leading to the
hyperthyroidism of Graves' disease.
TSAbs bind to the TSH receptor and
mimic the TSH stimulation of the gland
by increasing intracellular cAMP
• Any enlargement of the thyroid is called a goiter
• Insufficient Free T3 or T4 results in hypothyroidism
causing slow heart rate, diastolic HPN, Sluggishness,
constipation, cold intolerance, and dry skin
• Excess thyroid hormone results in thyrotoxicosis. Its
symptoms are the opposite of hypothyroidism
HORMONES THAT
REGULATE CALCIUM
METABOLISM
 There is approx. 1 kg of Ca in the body,
99% of which is in bone where it forms
hydroxyapatite crystals with
phosphates
 Ionized calcium, which is not
complexed with organic acids or bound
to proteins, is the biologically active
fraction of calcium
 Low ionized calcium levels causes
tetanic convulsions, while elevated
calcium causes muscle paralysis and
coma
 Albumin, which binds calcium, may
alter circulating calcium levels
PARATHYROID HORMONE (PTH)

 Parathyroid hormone (molecular weight


9,500) is synthesized and secreted by
chief cells of the parathyroid in
response to systemic Ca2+ levels
 PTH Is Secreted as an 84-Amino-Acid Peptide
 The immediate precursor of PTH is proPTH,
which differs from the native 84-amino-acid
hormone by having a highly basic hexapeptide
amino terminal extension
 The primary gene product and the immediate
precursor for proPTH is the 115-amino-acid
preproPTH
 This differs from proPTH by having an additional 25-
amino-acid amino terminal extension that is
hydrophobic
 PTH 1–34 has full biologic activity, and the region
25–34 is primarily responsible for receptor binding.
Structure of bovine preproparathyroid hormone. Arrows indicate sites cleaved by
processing enzymes in the parathyroid gland (1–5) and in the liver after secretion of the
hormone (4–5).
 Parathyroid hormone also exists in
storage vesicles
 As much as 80–90% of the proPTH
synthesized is degraded before it enters
this final storage compartment, especially
when Ca2+ levels are high in the
parathyroid cell
PTH
 An acute decrease of calcium results in
marked increase of PTH mRNA
 The role of PTH is to regulate Ca2+
concentration in extracellular fluids
 PTH acts by binding to cAMP-coupled
plasma membrane receptors
 The body response to PTH is complex
but is aimed in all tissues at increasing
Ca2+ levels in extracellular fluids
 PTH induces the dissolution of bone by
stimulating osteoclast activity, which leads
to elevated plasma Ca2+ and phosphate
 In the kidney, PTH reduces renal Ca2+
clearance by stimulating its reabsorption
 At the same time, PTH reduces the
reabsorption of phosphate and thereby
increases its excretion in the kidneys
 PTH acts on the liver, kidney, and
intestine to stimulate the production of
the steroid hormone 1,25-
dihydroxycholecalciferol (calcitriol) or
Vitamin D, which is responsible for Ca2+
absorption in the intestine
 Hypoparathyroidism results in muscle
cramps and tetany. It is usually due to
accidental removal of the parathyroid
gland during neck surgery
 In pseudohypoparathyroidism, PTH is
produced, but there is end-organ
resistance to its effects
 Hyperparathyroidism is usually due to cancer
causing high ionized calcium and low serum
phosphate levels.
 Secondary hyperparathyroidism may be seen
in patients with progressive renal failure due
to inefficient calcium absorption caused by
decreased activity of vitamin D which is not
activated by the kidney
1,25 -DIHYDROXYCHOLECALCIFEROL
(VITAMIN D)

 The only hormone that can promote the


translocation of calcium against the
concentration gradient which exists
across the intestinal cell membrane
 Deficiency causes Rickets in children
and osteomalacia in adults, both due to
deficient bone mineralization
 Vitamin D is normally found in persons
exposed to sufficient sunlight
 1,25 -DIHYDROXYCHOLECALCIFEROL OR
CALCITRIOL [1,25(OH)2-D3],is the most
potent naturally occurring metabolite of
vitamin D
(calcidiol)

In the skin, Vitamin D is produced from 7-


dehydrocholesterol during the photolysis reaction
In the liver, Vitamin D-binding protein binds Vit D3 from the
skin or intestine where it undergoes hydroxylation in the
endoplasmic reticulum (by 25-hydroxylase). This reaction
requires Mg, NADPH, and oxygen.
In the mitochondria of the renal proximal convoluted tubule,
25-mono-hydroxy D3 from the liver is converted to its active
form by hydroxylation at position C1 (by 1 α -hydroxylase)
 NADPH, Mg2+, molecular oxygen, and at
least three enzymes are needed for the
activation of Vitamin D in the kidney:
(1) a flavoprotein, renal ferredoxin reductase
(2) an iron sulfur protein, renal ferredoxin
(3) cytochrome P450
 Low-Ca diets and hypocalcemia
increases 1-α -hydroxylase activity
Calcitonin (CT)
 32-amino acid peptide secreted by
parafollicular C cells of the thyroid
gland
 Employed therapeutically to relieve the
symptoms of osteoporosis
 formed by proteolytic cleavage of a
larger prepropeptide which is the
product of the CALC1 gene
CT
 Calcitonin has the counter effects of
parathyroid hormone but most
evidence indicates that calcitonin is of
very little physiological importance to
humans. Rather, calcium and
phosphate homeostasis is primarily
under the control of PTH.
 CT has been shown to reduce the
synthesis of osteoporin (Opn), a
protein made by osteoclasts and
responsible for attaching osteoclasts
to bone
ACTIONS OF CT
Calcitonin reduces blood calcium levels in
three ways:
 Decreasing calcium absorption by the
intestines
 Decreasing osteoclast activity in bones
 Decreasing calcium and phosphate
reabsorption by the kidney tubules
 CT prevents postprandial hypercalcemia
resulting from absorption of Ca++ from foods
during a meal
 CT promotes mineralization of skeletal bone
 CT protects against Ca++ loss from skeleton
during periods of Ca++ stress such as
pregnancy and lactation
 CT regulates Vitamin D
 CT is a satiety hormone
It Inhibits food intake in rats and monkeys
It may have CNS action involving the
regulation of feeding and appetite
 Like the PTH receptor, the receptor of
calcitonin is a serpentine G protein-
coupled receptor with seven membrane
spanning regions which is coupled by Gs
to adenylyl cyclase and thereby to the
generation of cAMP in target cells.

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