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Diversity of the Endocrine System Deanne G. Asdala, MD Classification of hormones *Hormones can be classified according to: *Chemical composition *Solubility properties *Location of receptors *Nature of the signal used to mediate hormonal action Classification of hormones by Mechanism of action *Hormones that bind to intracellular receptors *Hormones that bind to cell surface receptors Hormones that bind to Intracellular receptors *Androgens *Calcitriol (1,25[OH]2-D3) *Estrogens *Glucocorticoids *Mineralocorticoids *Progestins *Retinoic acid *Thyroid hormones (T3 and T4) Hormones that bind to cell surface receptors: Second messenger is cAMP *2-Adrenergic catecholamines *-Adrenergic catecholamines *Adrenocorticotropic hormone *Antidiuretic hormone *Calcitonin *Chorionic gonadotropin, human *Corticotropin-releasing hormone *Follicle-stimulating hormone *Glucagon *Lipotropin *Luteinizing hormone *Melanocyte-stimulating hormone *Parathyroid hormone *Somatostatin *Thyroid-stimulating hormone Hormones that bind to cell surface receptors: Second messenger is cGMP *Atrial natriuretic factor Hormones that bind to cell surface receptors: 2nd messenger is Calcium or phosphatidylinositols (or both) *Acetylcholine (muscarinic) *1-Adrenergic catecholamines *Angiotensin II *Antidiuretic hormone (vasopressin) *Cholecystokinin *Gastrin *Gonadotropin-releasing hormone *Oxytocin *Platelet-derived growth factor *Substance P *Thyrotropin-releasing hormone Hormones that bind to cell surface receptors: 2nd messenger is a kinase or phosphatase cascade *Chorionic somatomammotropin *Epidermal growth factor *Erythropoietin *Fibroblast growth factor *Growth hormone *Insulin *Insulin-like growth factors I and II *Nerve growth factor *Platelet-derived growth factor

*Prolactin General features of Hormone classes Hormone synthesis *Hormones synthesized in discrete organs designed *Thyroid (triiodothyronine), *Adrenal (glucocorticoids and mineralocorticoids), *Pituitary (TSH, FSH, LH, growth hormone, prolactin, ACTH) *Hormones produced in specialized cells within other organs *Small intestine (glucagon-like peptide) *Thyroid (calcitonin) *Kidney (angiotensin II) *Synthesis of some hormones requires the parenchymal cells of more than one organ *Skin, liver, and kidney are required for the production of 1,25(OH)2-D3 (calcitriol) Hormone composition *Most hormones are polypeptides or glycoproteins *Adrenal Steroid hormones *Synthesized from cholesterol *Catecholamine Hormones *Derived from Tyrosine *Thyroid and the Adrenal medullary hormones HYPOTHALAMIC AND PITUITARY HORMONES Functional Anatomy of the Hypothalamus and Pituitary Gland *Hypothalamus is in the middle base of the brain, encapsulates the ventral portion of the 3rd ventricle. *Controls the release of pituitary hormones in a pulsatile manner *Hormones are released from the hypothalamic nerve fiber endings in the capillaries of the hypothalamic-hypophyseal system in the pituitary stalk 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 *Carried by the hypothalamo-hypophyseal portal circulation to the anterior pituitary gland *Stimulates Growth hormone secretion Growth-hormone-releasing hormone (GHRH) *Somatostatin, also known as "growth-hormone-inhibiting hormone" (GHIH) opposes GH *Somatostatin is released from periventricular somatostatin neurons *Carried by the hypothalamo-hypophysial portal circulation to the anterior pituitary - inhibits GH secretion by hyperpolarizing the somatotropes Growth-hormone-releasing hormone (GHRH) *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 *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 by the hypothalamus, delta cells of stomach, intestine, and pancreas. 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 *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 peptide (VIP) *Gastric inhibitory polypeptide (GIP) *Enteroglucagon (GIP)

Somatostatin *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 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 *CRH is also synthesized by the placenta and seems to determine the duration of pregnancy Corticotropin-releasing hormone (CRH) *Produced by neuroendocrine cells in the paraventricular nucleus of the hypothalamus *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 -endorphin).

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 SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA Thyrotropin-releasing hormone (TRH) *Thyrotropin-releasing factor (TRF), thyroliberin or protirelin, is a tripeptide hormone that stimulates the release of thyroidstimulating 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 Gonadotropin-releasing hormone 1 (GNRH1) *A peptide hormone responsible for the release of FSH and LH from the anterior pituitary *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 *Preoptic area of the hypothalamus contains most of the GNRH1-secreting neurons. Gonadotropin-releasing hormone 1 (GNRH1) *Portal blood carries GNRH1 to the pituitary gland, which contains the gonadotrope cells *GNRH1 activates its cell membrane receptor, gonadotropin-releasing hormone receptor (GNRHR) *GNRH1 is degraded by proteolysis within a few minutes. Gonadotropin-releasing hormone 1 (GNRH1) *GNRH1 is secreted in pulses at a constant frequency in males *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 *Functions as a neurotransmitter, activating dopamine receptors *Dopamine is also a neurohormone released by the hypothalamus *Inhibit prolactin release 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." GROWTH HORMONE (GH) *Somatropin or somatotropin *Synthesized in somatotropes, a subclass of the pituitary acidophilic cells *Genes for human growth hormone are localized in the q22-24 region of chromosome 17 PITUITARY HORMONES

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. GROWTH HORMONE (GH) *GH receptor is a member of the cytokine receptor superfamily. *GH in the circulation is bound to a protein (growth hormone binding protein, GHBP) derived from the growth hormone receptor *One growth hormone molecule binds to one receptor and then recruits a second receptor to form a dimer through which signalling occurs. GROWTH HORMONE (GH) *Height growth in childhood is the best known effect of GH action, and appears to be stimulated by at least two mechanisms: *directly stimulates division and multiplication of chondrocytes of cartilage. *stimulates production of insulin-like growth factor 1 (IGF1, formerly known as somatomedin C), a hormone homologous to proinsulin 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 *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 *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 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 Prolactin *The prolactin receptor - encoded by a gene on Chromosome 5 - interacts with the prolactin molecule as a transmembrane

receptor Prolactin *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 *Prolactin stimulate the mammary glands to produce milk (lactation). *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. Prolactin *Represses dopamine -responsible for sexual arousal, causing the male's refractory period. *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 Prolactin *The prolactin receptor, a member of the hematopoietin/cytokine receptor superfamily, is expressed by cells in the immune system *Lymphocytes synthesize and secrete biologically active prolactin - act as an autocrine and/or paracrine factor to modulate the activities of cells of the immune system. Prolactin disorders *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 function in humans GLYCOPROTEIN HORMONES GLYCOPROTEIN HORMONES *Each of the glycoprotein hormones is an ( : ) 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) *Synthesized and secreted by gonadotropes in the anterior pituitary gland *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) *Alpha subunit is located on chromosome 6 *Beta subunit is 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) - confers its specific biologic action and is responsible for interaction with the LH receptor *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 *Alpha subunit is located on chromosome 6 *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 LH *Diminished secretion of LH result in failure of gonadal function (hypogonadism) *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 *Prevent the disintegration of the corpus luteum of the ovary - maintain progesterone production that is critical for a pregnancy in humans *hCG affects the immune tolerance of the pregnancy *Early pregnancy testing generally is based on the detection or measurement of hCG. hCG *Oligosaccharide glycoprotein composed of 244 amin acids with a molecular mass of 36.7 kDa *Heterodimeric, with an (alpha) subunit identical to that of LH, FSH and TSH and (beta) subunit that is unique to hCG *hCG 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 *hCG 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) *Synthesized and secreted by thyrotrope cells in the anterior pituitary gland which regulates the endocrine function of the thyroid gland

TSH *Secrete thyroxine (T4) and triiodothyronine (T3) *TSH production is controlled by a Thyrotropin Releasing Hormone, (TRH) from the hypothalamus and transported to the pituitary gland, where it increases TSH production and release *Somatostatin decrease TSH 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 subunit is identical to that of hCG, LH, and FSH *The (beta) subunit is unique to TSH, and therefore determines its function TSH *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 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 -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), -endorphin and metenkephalin are also released *ACTH is also related to the circadian rhythm in many organisms. ACTH *Excessive production results in Cushings syndrome causing: *Negative N, K, and P balance *Na retention *Glucose intolerance *Increased plasma fatty acids *Decreased circulating eosinophils and lymphocytes -LIPOTROPIN ( -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 *Synthesized as prohormones in neural cell bodies of the hypothalamuS

*Axons terminate in the posterior pituitary, and the hormones are secreted directly into the systemic circulation 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 *Vasopressin is a peptide hormone liberated from a preprohormone precursor that is synthesized in the hypothalamus *Stored in the posterior pituitary gland to be released into the blood stream; some of it is also released directly into the brain. ADH *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 *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, V1b 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-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 *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 *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 *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)

THYROID HORMONES *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* STEPS IN THYROID HORMONE SYNTHESIS *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. STEPS IN THYROID HORMONE SYNTHESIS *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

STEPS IN THYROID HORMONE SYNTHESIS *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

Thyroid hormones *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 Thyroid hormones *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 - transthyretin (TTR) *Albumin (15-20%). Thyroid hormones *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 Thyroid hormones *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 *Action: *increase the basal metabolic rate *protein synthesis *increase the body's sensitivity to catecholamines *regulate protein, fat, and carbohydrate metabolism Thyroid hormone *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 Thyroid disorders *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 PARATHYROID HORMONE *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 PARATHYROID HORMONE *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 134 has full biologic activity, and the region 2534 is primarily responsible for receptor binding. 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 *PTH increases Ca2+ levels in extracellular fluids PARATHYROID HORMONE *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 PARATHYROID HORMONE *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 PARATHYROID HORMONE *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 PARATHYROID HORMONE *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 1,25 -DIHYDROXYCHOLECALCIFEROL (VITAMIN D) *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

1,25 -DIHYDROXYCHOLECALCIFEROL (VITAMIN D) *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 1,25 -DIHYDROXYCHOLECALCIFEROL (VITAMIN D) *Low-Ca diets and hypocalcemia increases 1- -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 Calcitonin *Calcitonin has the counter effects of parathyroid hormone *very little physiological importance to humans. *Calcium and phosphate homeostasis is primarily under the control of PTH. Calcitonin *Shown to reduce the synthesis of osteoporin (Opn), a protein made by osteoclasts and responsible for attaching osteoclasts to bone ACTIONS OF CALCITONIN 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 Calcitonin *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 Calcitonin *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 Calcitonin *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. COMPARISON OF INSULIN AND GLUCAGON CELL TYPES OF THE ISLETS OF LANGERHANS REGULATION OF GLUCAGON SECRETION REGULATION OF GLUCAGON SECRETION REGULATION OF INSULIN SECRETION INSULIN *Pathophysiology *DIABETES MELLITUS *Hyperglycemia insulin deficiency *Hypotension ECF volume contraction *Metabolic acidosis overproduction of ketoacids *Hyperkalemia lack of insulin