PITUITARY HORMONES Yulia Komarova Ph D ykomarov uic edu 1 The Hypothalamic Pituitary Endocrine Axis 2 Hormones that Integrate the Hypothalamic Anterior PituitaryEndocrine Axis Anterior Pituitary Hormone Hypothalamic Hormone Target Organ Primary Target Organ Hormone or Mediator Growth hormone GH somatotropin Growth hormone releasing hormone GHRH Somatostatin Liver muscle bone kidney and others Insulin like growth factor 1 IGF 1 Thyroid stimulating hormone TSH Thyrotropin releasing hormone Thyroid TRH Thyroxine triiodothyronine Adrenocorticotropin ACTH Corticotropin releasing hormone CRH Adrenal cortex Glucocorticoids mineralocorticoids androgens Follicle stimulating hormone FSH Luteinizing hormone LH Gonadotropin releasing hormone GnRH 2 Gonads Estrogen progesterone testosterone Prolactin PRL Dopamine Breast 3 Clinical Uses of Hypothalamic Hormones and Their Analogs Hypothalamic Hormone Clinical Uses Growth hormone releasing hormone GHRH Used rarely as a diagnostic test for GH responsiveness Thyrotropin releasing hormone TRH protirelin Used rarely to diagnose hyper or hypothyroidism Corticotropin releasing hormone CRH Used rarely to distinguish Cushing s disease from ectopic ACTH secretion Gonadotropin 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 disorder Dopamine Dopamine agonists used for treatment of hyperprolactinemia 4 Classification of Anterior Pituitary Hormones HORMONE Somatotropic hormones Growth hormone GH Prolactin PRL Placental lactogen PL Glycoprotein hormones Luteinizing hormone LH MASS daltons PEPTIDE CHAINS 22 000 23 000 22 125 1 1 1 191 199 190 17q22 24 6p22 2 21 3 17q22 24 29 400 2 92 6q12 q21 2 121 92 19q13 3 6q12 q21 2 111 92 11p13 6q12 q21 2 145 92 19q13 3 6q12 q21 118 1p13 2p22 3 Follicle stimulating hormone FSH 32 600 Human chorionic gonadotropin hCG 38 600 Thyroid stimulating hormone TSH thyrotropin POMC derived hormones Adrenocorticotropic hormone ACTH Melanocyte stimulating MSH 28 000 AMINO ACID CHROMOSOM RESIDUES AL LOCATION 4500 1 39 1650 1 13 5 Somatotropic Hormone Family Growth Hormone Structure and Pharmacokinetics 1 GH a single polypeptide chain of 22 kDa and 20kDa is secreted by the pituitary cells somatotropes as a heterogeneous mixture of peptides 2 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 6 Molecular and Cellular Bases of GH Action hGH 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 7 activate the PI3K pathway Somatotropic Hormone Family Growth Hormone Developmental 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 growth Metabolic 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 8 Regulation of GH Biosynthesis and Secretion Positive Regulators of GH GH 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 9 Negative Regulators of GH Insulin 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 SST28 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 10 Regulation of GH Biosynthesis and Secretion 11 Growth Hormone Deficiency GH 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 12 Growth Hormone Treatment Primary Therapeutic Objective Clinical Condition Growth Growth failure in pediatric patients associated with Growth hormone deficiency Chronic renal failure Noonan syndrome Prader Willi syndrome Short stature homeobox containing gene deficiency Turner syndrome Small for gestational age with failure to catch up by age 2 Idiopathic short stature in pediatric patients Improved metabolic state increased lean body mass sense of well being Growth hormone deficiency in adults Increased lean body mass weight and physical endurance Wasting in patients with HIV infection Improved gastrointestinal function Short bowel syndrome in patients who are also receiving specialized nutritional support malabsorption syndrome 13 Indications for Growth Hormone Treatment rhGH Treatment of children with short stature Children with Turner syndrome Noonan s syndrome Prader Willi syndrome or chronic renal insufficiency children born small for gestational age and children with idiopathic short stature In
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