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 hypothalamichypophysial 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 hypothalamohypophysial 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 hypothalamohypophysial 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 is secreted not only by cells of the hypothalamus but also by delta cells of stomach, intestine, and pancreas. It binds to somatostatin receptors.

Somatostatin

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-TyrGly-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
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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)2CH2-CH2-NH2) Its chemical name is 4-(2-aminoethyl)benzene-1,2diol 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 insulinlike 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

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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
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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 shortstatured 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)
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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, secondmessenger 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)
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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 androgenbinding protein by the Sertoli cells of the testes and is critical for spermatogenesis FSH and LH act synergistically in reproduction

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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 FSHreceptor 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)
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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
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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
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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

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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

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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 metenkephalin 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
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Excessive production results in Cushing’s syndrome causing: Negative N, K, and P balance Na retention Glucose intolerance Increased plasma fatty acids 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
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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

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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

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2. 3.

Vasopressin acts on three different receptors, termed V1a, V1 and V2. The receptors are differently expressed in different tissues, and exert different actions: V1a - vasoconstriction, gluconeogenesis in the liver, platelet aggregation and release of factor VIII and von Willebrand factor. V1b - corticotropin secretion from the pituitary gland 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-CysPro-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

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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 thyroxinbinding globulin (TBG) and are disseminated throughout the body in this form

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3. 

Most of the thyroid hormone circulating in the blood is bound to transport proteins: Thyroxine-binding globulin (TBG, 70%) 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) 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

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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 25amino-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 1,25dihydroxycholecalciferol (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 7dehydrocholesterol 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)

(1) (2) (3)

NADPH, Mg2+, molecular oxygen, and at least three enzymes are needed for the activation of Vitamin D in the kidney: a flavoprotein, renal ferredoxin reductase an iron sulfur protein, renal ferredoxin 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 proteincoupled 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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