Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 48Slide 49Slide 50Slide 51Slide 52Slide 531PITUITARY HORMONESYulia Komarova, [email protected] Hypothalamic-Pituitary-Endocrine Axis3Anterior Pituitary Hormone Hypothalamic Hormone Target Organ Primary Target Organ Hormone or MediatorGrowth hormone (GH, somatotropin)Growth hormone-releasing hormone (GHRH) (+) Somatostatin (–)Liver, muscle, bone, kidney, and othersInsulin-like growth factor-1 (IGF-1)Thyroid-stimulating hormone (TSH)Thyrotropin-releasing hormone (TRH) (+)Thyroid Thyroxine, triiodothyronineAdrenocorticotropin (ACTH) Corticotropin-releasing hormone (CRH) (+)Adrenal cortex Glucocorticoids, mineralocorticoids, androgensFollicle-stimulating hormone (FSH) Luteinizing hormone (LH)Gonadotropin-releasing hormone (GnRH) (+)2 Gonads Estrogen, progesterone, testosteroneProlactin (PRL) Dopamine (–) Breast —Hormones that Integrate the Hypothalamic-Anterior Pituitary-Endocrine Axis4Hypothalamic Hormone Clinical UsesGrowth hormone-releasing hormone (GHRH) Used rarely as a diagnostic test for GH responsivenessThyrotropin-releasing hormone (TRH, protirelin) Used rarely to diagnose hyper- or hypothyroidismCorticotropin-releasing hormone (CRH) Used rarely to distinguish Cushing's disease from ectopic ACTH secretionGonadotropin-releasing hormone (GnRH) Used rarely in pulses to treat infertility caused by hypothalamic dysfunction Analogs used in long-acting formulations to inhibit gonadal function in men with prostate cancer and women undergoing assisted reproductive technology (ART) or women who require ovarian suppression for a gynecologic disorderDopamine Dopamine agonists used for treatment of hyperprolactinemiaClinical Uses of Hypothalamic Hormones and Their Analogs5HORMONE MASS (daltons)PEPTIDE CHAINSAMINO ACID RESIDUESCHROMOSOMAL LOCATIONSomatotropic hormones Growth hormone (GH) 22,000 1 191 17q22-24Prolactin (PRL) 23,000 1 199 6p22.2-21.3Placental lactogen (PL) 22,125 1 190 17q22-24Glycoprotein hormones Luteinizing hormone (LH) 29,400 2 α-92β-1216q12.q2119q13.3Follicle-stimulating hormone (FSH)32,600 2 α-92β-1116q12.q2111p13Human chorionic gonadotropin (hCG)38,600 2 α-92β-1456q12.q2119q13.3Thyroid-stimulating hormone (TSH), thyrotropin28,000 2 α-92β-1186q12.q211p13POMC-derived hormones* Adrenocorticotropic hormone (ACTH)4500 1 39 2p22.3α-Melanocyte-stimulating (α-MSH)1650 1 13 Classification of Anterior Pituitary Hormones6Somatotropic Hormone Family: Growth HormoneStructure and Pharmacokinetics1. GH, a single polypeptide chain of 22 kDa and 20kDa, is secreted by the pituitary cells somatotropes as a heterogeneous mixture of peptides2. Daily GH secretion varies throughout life; high in children, peaks during puberty, and then decreases in an age-related manner in adulthood. 3. GH is secreted in discrete but irregular pulses. The amplitude of secretory pulses is greatest at night, and the most consistent period of GH secretion is shortly after the onset of deep sleep.4. GH has a half-life of 20–25 minutes and is predominantly cleared by the liver.7Molecular and Cellular Bases of GH ActionhGH receptor contains 620 amino acids, approximately 250 of which are extracellular, 24 of which are transmembrane, and 350 of which are cytoplasmic.JAK2, a cytoplasmic tyrosine kinase of the Janus kinase family; STAT (Signal Transducers and Activators of Transcription), Shc (an adapter protein that regulates the Ras/MAPK signaling pathway), and IRS-1 and IRS-2 (insulin-receptor substrate proteins that activate the PI3K pathway).8Somatotropic Hormone Family: Growth HormoneDevelopmental Actions: GH is required during childhood and adolescence for attainment of normal adult size and body composition; GH increases the production of IGF-1 in the liver, bone, cartilage, muscle, and the kidney. GH stimulates longitudinal bone growthMetabolic Effects: GH controls lipid and carbohydrate metabolism, and lean body mass. GH has anabolic effects in muscle and catabolic effects in lipid cells adipocytes. GH reduces insulin sensitivity, which results in mild hyperinsulinemia.9Positive Regulators of GHGH-RH, produced by hypothalamic neurons found predominantly in the arcuate nucleus, binds to and activates specific GPCR on somatotropes; GH-RH receptor → Gs activation → cAMP and Ca2+→ GH secretion and release Ghrelin, a 28-amino acid peptide that is octanoylated at Ser3. Ghrelin is synthesized in endocrine cells in the fundus of the stomach. Ghrelin activates the GH secretagogue receptor and directly stimulates GH release. Both fasting and hypoglycemia stimulate circulating ghrelin levels. Regulation of GH Biosynthesis and Secretion10Negative Regulators of GHInsulin-like growth factor 1 (IGF-1), acts in a negative feedback loop. IGF-1 inhibits GH by effecting GH release from the anterior pituitary gland. Somatostatin (SST) is synthesized in widely distributed neuronsas as a 92–amino acid precursor; proteolytic cleavage products are: SST-28 and SST-14. SST binds to and activates a family of five related GPCRs that signal through Gi to inhibit cyclic AMP accumulation and to activate K+ channels and protein phosphotyrosine phosphatases.11Regulation of GH Biosynthesis and Secretion12Growth Hormone DeficiencyGH deficiency is a result of a genetic mutations or damage to the pituitary or hypothalamus by a tumor, infection, surgery, or radiation therapy. In most patients, the deficiency is idiopathic, with normal production of other pituitary hormones and no obvious structural abnormalities.Children with GH deficiency present with short stature, delayed bone age, a low age-adjusted growth velocity, hypoglycemia and adiposity.Criteria for diagnosis are: (1) a growth rate below 4 cm per year and (2) the absence of a serum GH response to two GH secretagogues.13Growth Hormone TreatmentPrimary Therapeutic Objective Clinical ConditionGrowth Growth failure in pediatric patients associated with: Growth hormone deficiency
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