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ENDOCRINOLOGY For Biochemistry Diploma Students Faculty of Science Cairo University Classical definition of a hormone 1. 2. 3. 4. 5. 6. 7. 8. 9. Chemical messengers Synthesized by living cells and Secreted by a specific gland Secreted directly into the blood stream Carried by the blood Acts on a specific target At a site distant from site of secretion Secreted in minute quantities Acts via specific receptors to exert specific actions New Definition of a Hormone "Any substance released by a cell and which acts on another cell, near or far, regardless of the means of conveyance" The seven principal glands and their hormones Gland Hypothalamu s Hormone Thyrotrophin-releasing (TRH) Type hormone Somatostatin (SS) Major physiological role(s) Neurohormone Protein ↑ TSH secretion Neurohormone Protein ↓ GH secretion Gonadotrophin-releasing (GnRH) hormone Neurohormone Protein ↑ FSH & LH secretion Corticotrophin-releasing (CRH) hormone Neurohormone Protein ↑ ACTH secretion Growth hormone-releasing hormone (GHRH) Neurohormone Protein ↑ GH secretion Prolactin releasing hormone Neurohormone Unknour ↑ Prolactin secretion Neurohormone Tyrosinederived ↓ Prolactin secretion Thyroid stimulating hormone (TSH) Endocrine Glycoprotein ↑ Thyroid hormones (T4 & T3) synthesis and secretion Luteinizing hormone (LH) Endocrine Glycoprotein ↑ Follicle-stimulating hormone (FSH) Endocrine Glycoprotein ↑ Female: ovarian follicle growth; estradiol synthesis ↑ Male: spermatogenesis Prolactin Endocrine Protein ↑ Milk synthesis; Growth hormone (GH) Endocrine Protein ↑ Hepatic somatomedin (IGF-I,II) biosynthesis Adrenocorticotrophin (ACTH) Endocrine Protein ↑ Adrenal steroidogenesis Prolactin-inhibiting Dopamine (PIH) Anterior Pituitary Chemical Group hormone, Female: ovulation;ovarian estradiol progesterone synthesis ↑ Male: testicular androgen synthesis & Vasopressin, antidiuretic hormone (VP, ADH) Endocrine Protein ↑ Renal water absorption; vasoconstriction Oxytocin (OT) Endocrine Protein ↑ Milk secretion; uterine contraction Thyroxine (T4) & Tri-iodothyronine (T3) Endocrine Tyrosinederi ved ↑ Growth; differentiation; calorigenesis (↑ metabolic rate & oxygen consumption) Calcitonin (CT) Endocrine Protein ↓ Blood Ca2+ Parathyro id Parathyroid hormone (PTH) Endocrine Protein ↑ Blood calcium (Ca2+), ↓ Blood phosphate (PO4-3) Adrenal Cortex Aldosterone Endocrine Steroid ↑ Sodium retention Cortisol Endocrine Steroid ↑ Carbohydrate metabolism; Adrenal Med ulla Adrenaline, Epinephrine (E) Endocrine Tyrosinederi ved Multiple effects on nerves, muscles, cellular secretions & metabolism; cardiovascular function; response to stress Noradrenaline, Norepinephrine (NE) Endocrine Tyrosinederi ved Response to stress Insulin Endocrine Protein ↓ Blood sugar; ↑ protein, glycogen & fat synthesis Glucagon Endocrine Protein ↑ Blood glucose; gluconeogenesis; glycogenolysis Somatostatin Paracrine Protein ↓ Secretion of pancreatic islets hormones Pancreatic polypeptide (PP) Paracrine Protein ↓ Secretion of pancreatic islets hormones & bile Oestrogen Endocrine Steroid ↑ Female development, breasts, growth & behavior Progesterone Endocrine Steroid ↑ Uterine & mammary gland growth Testosterone Endocrine Steroid ↑ Male development & growth of reproductive system Inhibin Endocrine Peptide ↓ FSH secretion Posterior Pituitary Thyroid Pancreatic Islets Gonads Ovary Testis Some hormones secreted from tissues Source Hormone Type Chemical group Major role Stomach Gastrin Paracrine & autocrin e Protein ↑ gastric HCl secretion Small Intestin e Secretin Paracrine & Protein ↑ pancreatic bicarbonate secretion Cholecystokinin (CCK) autocrine Protein ↑ gall bladder contraction & secretion of pancreatic enzymes Gastric inhibitory hormone (GIP) Endocrine ↓ Gastric secretion, ↑ intestinal secretion, insulinotropic, anabolic hormone Vasoactive intestinal peptide (VIP) Endocrine ↑ Intestinal secretion of water & electrolytes; relaxation of circulatory smooth muscles (vasodilator, hypotensive) Motilin ↑ Contraction of stomach & small intestine, stimulate gastric motor activity Neurotensin (NT) Inhibits gastric acid secretion & emptying of stomach Substance P (SP) Contraction of gut smooth muscles, vasodilation Gastrin releasing peptide (GRP) ↑ release gastrin Heart Atrial Natriuretic peptide (ANP) Endocrine Protein ↑ renal salt excretion, GFR & urine volume; lowering of blood pressure Kidney Vitamin D3 Endocrine Steroid ↑ calcium absorption by the intestine Most Tissues Prostaglandins(PGs) Prostacyclins Thromboxanes Leukotrienes Autocrine & paracrin e Eicosanoid ↑ Second messenger formation. They have multiple effects; blood clotting, muscle contraction, defense mechanism etc Gastrointestinal (luminal) Hormones Hormone Location Major Action Gastrin gastric antrum, duodenum gastric acid and pepsin secretion Cholecystokinin (CCK) duodenum, jejunum pancreatic amylase secretion Secretin duodenum, jejunum pancreatic bicarbonate secretion Gastric inhibitory peptide (GIP) small bowel enhances glucose-mediated insulin relaese; inhibits gastric acid secretion Vasoactive intestinal peptide (VIP) pancreas smooth muscle relaxation; stimulates pancreatic bicarbonate secretion Motilin small bowel initiates interdigestive intestinal motility Pancreatic polypeptide (PP) pancreas inhibits pancreatic bicarbonate and protein secretion Enkephalins stomach, duodenum, gallbladder opiate-like actions Substance P entire gastrointestinal tract physiological actions uncertain Bombesin-like immunoreactivity (BLI) stomach, duodenum stimulates release of gastrin and CCK Neurotensin ileum physiological actions unknown Enteroglucagon pancreas, small intestine physiological actions unknown General functions of hormones Control Reproductive processes: differentiation, maturation, gametogenesis. Growth and development: stimulate or inhibit cellular proliferation Homeostasis: Maintenance of healthy internal environment in a continuously changing external and internal environments Metabolism: anabolic and catabolic processes, muscular activity, excretion, reabsorption of ions Energy production, utilization and storage Animal behavior: sexual, aggressive and maternal Other hormones (synthesis, secretion, permissive action) Classification of hormones according to mode of their delivery 1. 2. 3. 4. 5. 6. Endocrine: Neuroendocrine: Paracrine: Autocrine: Luminal: Pheromone Classification according to Chemical classes of hormones 1. 2. 3. 4. 5. 6. Protein and polypeptides Steroids Tyrosine-derived Eicosanoids Vitamins Miscellaneous group: Gaseous molecules (NO, CO), metabolic substances (glucose, lactic acid), chalones, lumones, pheromones Polypeptide Hormone Peptides S S Cys Try Ile Gln Asn Cys Pro Leu Gly Steroid Hormones Testosterone Aldosterone Estradiol Pregnenolone: Cortisol Progesterone Tyrosine-derived hormones Eicosanoids Vitamin D Synthesis of Protein Hormones Transcription of a gene in the nucleus mRNA 2. Translation of mRNA by ribosomes on RER pre-prohormone in ER 3. Post-translational modification: I. Pre-prohormone in ER prohormone by losing signal peptide sequence II. Prohormone migrates to Golgi complex incorporated into a vesicle III.prohormone in vesicle + protease enzymes hormone 1. Synthesis of Steroid Hormones Activation of specific enzymes: acetate cholesterol pregnenolone to the diff hormones. The SER, mitochondria and cytoplasm contain the enzymes required for the transformations Steroids of the Adrenal Cortex Synthesis of the male sex hormones Synthesis of Vitamin D They are sterol hormones and have much in common to other steroid hormones Its precursor, cholecalciferol, is obtained from diet or synthesized by the ultraviolet irradiation of provitamin D in the skin Cholecalciferol, by a series of enzymes in the liver and kidney, is hydroxylated to the active hormone, calcitriol Vitamin D Synthesis of Tyrosine-derived hormones I.Thyroid hormones: is a unique process 1. Thyroid cells concentrate iodine 2. Thyroid cells synthesize a glycoprotein, thyroglobulin 3. Iodine is oxidized 4. Iodine is oxidized, then coupled to iodotyrosine within thyroglobulin (organification process) by thyroid peroxidase enzyme 5. Reuptake of thyroglobulin by endocytosis 6. Proteolytic digestion by lysosomal enzymes (hydrolyases) T3+ T4 (iodothyronines) and MIT+ DIT (iodotyrosines) II. Catecholamines: They are synthesized from tyrosine by a number of enzymes in the cytoplasm and chromaffin granules Synthesis of Catecholamines Thyroid Hormone Synthesis Synthesis of Eicosanoids From fatty acid (arachidonic acid) released from phospholipids in cell membrane by means of a number of enzymes. Pathways of Eicosanoids Synthesis Storage Protein hormones: In secretory granules within the cytoplasm Steroid hormones: Are not stored. The hormones precursor, cholesterol esters, is the storage form Tyrosine-derived hormones Thyroid hormones: in the thyroglobulin Catecholamines: in secretory chromaffin granules in the cytoplasm + ATP + chromogranin • Eicosanoids: Are not stored. Vitamin D: Cholecalciferol is stored in adipose tissue. Liver stores its metabolite Release Protein hormones: By exocytosis Steroid hormones: by diffusion immediately upon synthesis Vitamin D: by diffusion immediately upon synthesis Tyrosine – derived hormones: Thyroid hormones: fusion of lysosomes with colloid droplets, the hormones are released by exocytosis from the basement membrane Catecholamines: stimulus-secretion coupling requiring Ca, vesicular exocytosis Eicosanoids: by diffusion Transport Protein hormones: mostly unbound, free in the blood Steroid hormones: Bound to a plasma protein (high- affinity binding to globulin and low-affinity to albumin). Cortisol to transcortin, sex hormones to sex-hormone-binding globulin (SHBG). Vitamin D: Bound to a globulin (transcalciferin) Tyrosine-derived hormone: • Thyroid hormones: Mostly bound to thyronine-binding globulin (TBG) or prealbumin (transthyretin) • Catecholamines: Bound to albumin. Eicosanoids: Are not transported. They act as autocrine or paracrine hormones Purpose of binding of hormones to proteins: 1. 2. 3. The hormone is protected from the inactivating systems present in the blood. The hormone is maintained in a “stored” circulating form to be readily available to its target tissues. Ensure ubiquitous distribution of the water-insoluble hormones. Relation between bound and unbound hormone A dynamic equilibrium exists between the concentrations of free (unbound) hormone, plasma protein, and the hormone-protein complex: [H]x[P] [HP] [H]x[P] = K [HP] Where K is the dissociation constant Peripheral Conversion Some biologically active hormones are converted to other equally active hormones in peripheral tissues such as liver, breast adipose tissue, brain etc Example: Testosterone dihydrotestosterone Thyroxine (T4) triiodothyronine (T3) Single hormone, different effects. Example: Estradiol acts on ovarian follicles to promote granulosa cell differentiation, on uterus to stimulate its growth and maintain the cyclic change of uterine mucosa, on mammary gland to stimulate ductal growth, on bone to promote linear growth and closure of epiphyseal plates, on HPA to regulate secretion of gonadotropins and prolactin, on metabolic processes to affect adipose tissue distribution, volume of ECF, etc Several hormones, single function. Example: Release of fatty acids (lipolysis) from adipose tissue stimulated by catecholamines, glucagon, secretin, prolactin and B-lipotropin Permissive effect of Hormones It is the effect that some hormones exhibit, these hormones have little effect by themselves, but when they are present they affect other hormones to become fully manifested. Example: Development of mammary gland, under infleunce of prolactin, estradiol & progesterone and the permissive influence of glucocorticoids, thyroid hormones and insulin