Pituitary Hormones Notes

NOTES NOTES PITUITARY HORMONES GENERALLY, WHAT ARE THEY? ▪ Pituitary gland: AKA hypophyseal gland/ hypophysis ▪ Connected to hypothalamus via pituitary stalk (infundibulum) which controls pituitary secretory actions ▪ Consists of two embryologically, functionally different parts that secrete different hormones ANTERIOR PITUITARY (ADENOHYPOPHYSIS) ▪ Connects to hypothalamus via blood vessels (hypophyseal portal system) ▪ Hypothalamus produces releasing hormones → pituitary secretes tropic hormones that regulate target tissues Corticotropin-releasing hormone (CRH) ▪ Adrenocorticotropic hormone (ACTH) → adrenal medulla Gonadotropin-releasing hormone (GnRH) ▪ Luteinizing hormone (LH), folliclestimulating hormone (FSH) → ovaries, testes Growth hormone releasing hormone (GHRH) ▪ Stimulates release of somatotropin/ growth hormone (GH) → various tissues throughout body 268 OSMOSIS.ORG Thyrotropin-releasing hormone (TRH) ▪ Thyroid-stimulating hormone → thyroid gland Prolactin (PL) ▪ Acts on breasts (lactogenesis) ▫ Hypothalamus inhibits prolactin production via dopamine ▫ TRH, estrogen, progesterone, oxytocin stimulate prolactin POSTERIOR PITUITARY (NEUROHYPOPHYSIS) ▪ Represents an extension of hypothalamus ▪ Does not secrete its own hormones ▪ Stores, releases neurohormones synthesized in hypothalamus Vasopressin/antidiuretic hormone (ADH) ▪ Acts on kidney tubules, arterioles Oxytocin ▪ Acts on uterus, breasts

Chapter 32 Endocrine Physiology: Pituitary Hormones ADRENOCORTICOTROPIC HORMONE (ACTH) osms.it/adrenocorticotropic-hormone ▪ Hormone secreted by anterior pituitary corticotropic cells ▪ Main action of ACTH involves stimulating adrenocortical cells of zona fasciculata of the adrenal cortex to secrete glucocorticoids (primarily cortisol) ▫ Anti-inflammatory effects ▫ Increases blood glucose levels ▫ Increases fat and protein breakdown SYNTHESIS ▪ Pre-pro-opiomelanocortin (pre-POMC) → proopiomelanocortin (POMC) → ACTH, gamma lipotropin, beta endorphin, melanocyte-stimulating hormone STIMULATION OF ACTH RELEASE ▪ Corticotropin releasing hormone (CRH) secreted by hypothalamus ▫ Stress, low blood glucose, low glucocorticoid levels, increased sympathetic activity, normal diurnal rhythm ▫ Release of ACTH demonstrates circadian rhythm affected by suprachiasmatic nucleus → low evening concentrations, high in morning ACTH RELEASE REGULATION ▪ ACTH release is regulated by hypothalamic-pituitary-adrenal axis negative feedback ▫ Hypothalamus releases CRH → CRH stimulates pituitary to release ACTH → ACTH stimulates adrenal cortex to secrete cortisol → ↑ cortisol inhibits hypothalamic release of CRH → ↓CRH decreases ACTH secretion → closed loop ACTH SIGNALING PATHWAY ▪ ACTH binds to ACTH receptor on adrenal cortex adrenocorticotropic cells, primarily zona fasciculata; also expressed in skin, both white, brown adipocytes ▪ ACTH receptor is a seven-membranespanning G-coupled receptor ▪ ACTH binds to receptor → activates Gs protein → α subunit released → activates adenylate cyclase → ↑ cAMP → activates protein kinase A → phosphorylation cascade → transcription factor activation → effects Figure 32.1 Synthesis of ACTH in the anterior pituitary. Corticotropin releasing hormone (CRH) stimulates the cell to release ACTH. OSMOSIS.ORG 269

Figure 32.2 The negative feedback loop which regulates ACTH release. 270 OSMOSIS.ORG Figure 32.3 ACTH receptors are found on adrenocortical cells in the zona fasciculata of the adrenal cortex, as well as on melanocytes in the skin.

Chapter 32 Endocrine Physiology: Pituitary Hormones GROWTH HORMONE (GH) osms.it/growth-hormone ▪ AKA somatotropin ▪ Peptide hormone secreted by somatotropic cells of anterior pituitary ▫ Regulates tissue growth ▪ Released in pulsatile manner every two hours; peaks one hour after falling asleep REGULATION OF SECRETION Induction of GH release ▪ Hypoglycemia, ↑ estrogen, testosterone (puberty), stress (e.g. trauma, fever), exercise, sleep stages III, IV Three negative feedback loops ▪ ↓ GH stimulates hypothalamus to release GHRH → ↑ GHRH stimulates pituitary to release GH → ↑ GH inhibits release of GHRH → absence of GHRH inhibits GH release → closed loop ▪ ↑ GH stimulates somatomedins production in the liver, bones, muscles → somatomedins inhibit GH release ▪ ↑ GH and somatomedins stimulate somatostatin production in hypothalamus → somatostatin inhibits GH release Figure 32.4 The three negative feedback loops that regulate GH secretion, each highlighted in a different colour. GH and somatomedin together stimulate somatostatin production in the hypothalamus, which inhibits GH release. GH SIGNALING PATHWAY EFFECTS OF GH ▪ Growth hormone receptor (GHR) belongs to cytokine receptor family ▪ To activate intracellular signaling, GH must bind to two GH receptors → dimerization of GHR ▪ GH binds to receptor → conformational change → key tyrosine residue phosphorylation → activation of tyrosine kinase JAK2 → STAT5, Src family kinases, insulin receptor substrate (IRSs) signalling molecule activation → gene transcription, effects ▪ Primary effect of GH is cell metabolism stimulation, growth, division Direct effects ▪ Anti-insulin-like effects ▪ Carbohydrates: ↑ blood glucose levels ▫ Stimulates gluconeogenesis, glycogenolysis in liver ▫ Increases tissue insulin resistance ▪ Fats: ↑ fatty acids in blood ▫ Stimulates adipose tissue lipolysis Indirect effect ▪ Insulin-like effects through insulin-like growth factors (e.g. somatomedins like IGF-1) ▪ Stimulates cell growth, division, and differentiation; reduces apoptosis OSMOSIS.ORG 271

▪ Proteins: anabolic effect ▫ Stimulates amino acid, protein uptake ▫ Stimulates protein synthesis ▫ Decreases protein breakdown ▪ Epiphyseal plates, cartilage ▫ Stimulates bone osteoblast activity, cartilage chondrocyte activity → increased linear growth THYROID-STIMULATING HORMONE (TSH) osms.it/thyroid-hormone ▪ AKA thyrotropin ▪ Glycoprotein hormone secreted by pituitary gland ▪ Main action of TSH involves stimulating thyroid gland growth, thyroid hormone synthesis, release STIMULATION OF TSH RELEASE ▪ Thyrotropin-releasing hormone (TRH) secreted by hypothalamus ▫ Low T3, T4 blood levels ▫ Decreased metabolism ▫ Cold stress ▫ Conditions that increase ATP demand REGULATION OF SECRETION ▪ TRH secreted by hypothalamus, stimulates pituitary thyrotropic cells to release TSH ▪ Thyroid hormones, specifically T3, downregulate TRH receptors on thyrotropic cells, inhibiting TSH secretion ▪ TSH release, thyroid hormone is regulated by negative feedback loop ▫ Hypothalamus releases TRH → TRH stimulates pituitary to release TSH → TSH travels to thyroid follicle → stimulates thyroid hormones synthesis, secretion → thyroid hormones inhibit both TRH, TSH release → absence of TRH, TSH inhibits further thyroid hormone secretion → closed loop 272 OSMOSIS.ORG TSH SIGNALING PATHWAY ▪ TSH binds TSH receptor primarily found on thyroid gland follicular cells ▫ Also found on adipose tissue, fibroblasts ▪ TSH receptor is integral membrane receptor coupled with Gs protein ▪ TSH binds to receptor → activates Gs protein → α subunit released → activates adenylate cyclase → ↑ cAMP → activates protein kinase A → phosphorylation cascade → transcription factor activation → effects EFFECTS OF TSH ▪ TSH has two effects on the thyroid gland ▫ Stimulates all the steps in thyroid hormone synthesis, secretion ▫ Trophic effect: increases growth of thyroid gland

Chapter 32 Endocrine Physiology: Pituitary Hormones THYROID HORMONE osms.it/thyroid-hormone ▪ Glycoprotein hormones T3 (triiodothyronine), T4 (tetraiodothyronine) secreted by thyroid follicular epithelial cells ▪ Less active form thyroid hormone (T4) is secreted, converted in target tissue into more active form (T3) ▪ ▪ ▪ SYNTHESIS OF THYROID HORMONES Six steps ▪ Thyroglobulin (TG) synthesized in follicular cell rough endoplasmic reticulum (RER), secreted into lumen (colloid) ▪ Iodine from blood enters follicular cells on ▪ basolateral side via Na+/I- symport Iodine exits cell on apical side via transporter pendrin Inside follicle lumen at apical side, iodine oxidized by enzyme thyroid peroxidase (I→ I2) I2 iodinates TG tyrosyl residues (organification of I2), catalyzed by thyroid peroxidase, forms monoiodotyrosine (MIT), diiodotyrosine (DIT) On TG, two DIT molecules coupled to form T4 (faster reaction); MIT coupled with DIT to form T3 → TG now contains T3, T4, MIT, DIT residues Figure 32.5 Thyroid hormone synthesis overview. 1. Thyroglobulin (TG) is synthesized in rough endoplasmic reticulum, secreted into colloid. 2. Iodine enters cell from blood via Na+/I- symporter. 3. Iodine exits cell into colloid via pendrin. 4. Iodine is oxidized by thyroid peroxidase, become I2 5. I2 iodinates tyrosyl residues on TG, forming monoiodotyrosine (MIT), diiodotyrosine (DIT). 6. Two DITs combine to form T4; MIT combines with DIT to form T3. OSMOSIS.ORG 273

THYROID HORMONE SECRETION AND TRANSPORT Thyroid hormone secretion ▪ Thyroid hormones stored in colloid until stimulated for secretion ▫ TSH stimulation → endocytosis of iodinated TG by follicular epithelial cells → TG transportation to basal membrane → TG fuses with lysosome → TG hydrolysis, T3, T4, MIT, DIT residue release → T3 (10%), T4 (90%) secreted into circulation ▫ Iodide from MIT, DIT residues recycled for next synthesis Transport of thyroid hormones ▪ Once in circulation, most thyroid hormones travel bound to thyroxine-binding protein (TBP) ▫ Some bound to prealbumin, albumin ▪ Small fraction travels unbound → physiologically active forms Activation of T4 ▪ 90% of secreted thyroid hormone is in less active T4 form ▪ T4 activated in target tissue by 5’-deiodinase → removes one atom of I2 → T4 gets converted to T3 ▪ Starvation inhibits 5’-deiodinase in target tissue, except in brain → lowers O2 consumption, basal metabolic rate (BMR) REGULATION OF SECRETION Negative feedback loop ▪ Regulated by negative feedback loop in hypothalamic-pituitary-thyroid axis ▫ Thyrotropin-releasing hormone (TRH) secreted by hypothalamus, stimulates thyrotropic cells of pituitary to release thyroid-stimulating hormone (TSH) Effects of TSH on thyroid gland ▪ Two effects ▫ Stimulates all steps in thyroid gland synthesis, secretion ▫ Trophic effect: increases thyroid gland growth Other regulatory factors ▪ Iodine deficiency ▪ Excessive iodine intake (Wolff–Chaikoff effect) ▫ Inhibits iodine organification ▪ 5’-deiodinase deficiency (e.g. starvation) ▪ ↓ TBP synthesis (e.g. liver failure) ▫ Increases unbound (active) thyroid hormones fraction Figure 32.6 Thyroid hormone secretion overview. 1. TG in colloid is endocytosed into follicular cell. 2. Lysosome fuses with vesicle; thyroid hormones are cleaved from TG. 3. Hormones are released into blood. 4. In blood, most thyroid hormones travel bound to a protein, thyroxine-binding protein being most common. 274 OSMOSIS.ORG

Chapter 32 Endocrine Physiology: Pituitary Hormones ▫ ↑ catecholamine, glucagon, growth hormone activity → ↑ proteolysis, lipolysis, gluconeogenesis ▪ Cardiovascular system ▫ ↑ β1 adrenergic receptors, Ca2+ ATPase → ↑ inotropic (contractility), chronotropic (heart rate) effect → ↑ cardiac output ▪ Central nervous system (CNS) ▫ Gestational period → CNS development ▫ Adult period → ↑ brain activity, attention span, memory ▪ Growth ▫ ↑ osteoblast, osteoclast activity → ↑ bone formation, maturation Figure 32.7 The negative feedback loop which regulates thyroid hormone secretion. SIGNALING PATHWAY ▪ Thyroid hormones act on all organ systems ▪ Inside target cells, T4 converts to T3 → T3 enters nucleus, binds nuclear receptor → T3 receptor complex binds DNA, stimulates transcription → translation → protein synthesis ▪ T3 stimulates synthesis of Na+-K+ ATPase, Ca2+ ATPase, transport proteins, proteolytic, lysosomal enzymes, β1 adrenergic receptors, structural proteins Figure 32.8 In the target cell, T4 is converted to T3, which enters the nucleus and binds to a receptor. The receptor complex binds to DNA to stimulate transcription. EFFECTS OF THYROID HORMONE ▪ Key hormone in regulating body metabolism; also important for embryological growth ▪ General effect: all tissues except brain, spleen and gonads ▫ ↑ Na+-K+ ATPase → ↑ oxygen consumption → ↑ basal metabolic rate (BMR), body temperature ▪ Catabolic effect: metabolism of macromolecules ▫ ↑ transport proteins → ↑ glucose absorption from GI tract OSMOSIS.ORG 275