Anterior pituitary hormones

Five secretory cells producing 6 different hormones Cortocotroph ACTH Gonadotroph LH and FSH Somatotroph GH Lactotroph Prolactin Thyrotroph TSH

ACTH Part of larger protein Pro-opiomelanocortin One gene (8kb, three exons and two introns) Codes for one large protein Transcription of gene Activated by CRH, arginine vasopressin, cytokines Inhibted by glucocorticoids

Transcription of POMC gene CRH type 1 receptor Production of cAMP and activation of protein kinase A pathway Activation of CREB transcription factor Activation of MAP-Kinase pathway Cytokine receptor (LIF) Activation of JAK/Stat pathway Interaction with CRH signaling pathway

Pro-opiomelanocortin 266 amino acids Proteolytically cleaved to produce corticotrophic, opioid, and melanotrophic peptides

Secretion of ACTH Complex regulation through HPA (hypothalamus-pituitary-adrenal) axis Circadian and ultradian rhythm Hypothalamic control (CRH) Activity of nuclei regulated by glucocorticoids Pulse amplitude rather than frequency determines circadian rhythm

Regulation of ACTH secretion Exercise (short and exhausting) Increased secretion of ACTH Hypercortisolism in athletes Stress Increased production of cortisol Integration of information received by the CNS Constrain the inflammation

Action of ACTH Primary function Proper maintenance of adrenal gland Adrenal steroidogenesis Cholesterol transport Conversion to pregnenolone Inhibited by glucocorticoids

Gonadotropins Two hormones from one type of cells LH and FSH Glycoprotein hormones Two subunits Alpha Universal among all glycoprotein hormones Beta Hormone specific Combination of alpha and beta subunits Essential for biological activity

Synthesis of gonadotropins Alpha subunit Generated from different gene Chromosome 6 Increased synthesis by GnRH and TRH Beta subunits Determinant of biological activity LH beta on chromosome 19 FSH beta on chromosome 11

Transcription of LH beta subunit mRNA GnRH SF-1 Estrogen Transcription of FSH beta Role of GnRH and steroids Unclear Different promoter structure from LH

Regulation of gonadotropin secretion Pulsatile secretion Mirror image of GnRH pulses Frequency and amplitude LH more sensitive to changes in GnRH Gonadal steroid hormones Testosterone Inhibits secretion Enhances FSH beta subunit mRNA transcription Estrogens Dual function (stimulatory/inhibitory) Cyclic changes in female during reproductive cycle

Gonadal peptides Inhibins Activins Follistatin Inhibits secretion of FSH Activins Stimulates FSH secretion and action Follistatin Inhibits FSH secretion and action

Function of gonadotropins Receptors for LH and FSH Highly homologous 50 % of extracellular domain 80 % of transmembrane domain Steroidogenesis in male and female cAMP production Increased cholesterol availability via increased production of steroidogenic acute regular protein (StAR) Increased enzyme activity

Function of gonadotropins Receptors for LH and FSH Steroidogenesis in male and female cAMP production Increased cholesterol availability via increased production of steroidogenic acute regular protein (StAR) Increased enzyme activity Development and function of gonadal cells and gametes FSH

Growth hormone Human GH gene Located in chromosome 17 66 kb in length Cluster of genes that encode closely related genes GH-V Placental lactogen/chorionic somatotropins Transcription of GH mRNA POUF1 transcription factor Pituitary specificity Interacts with protein kinase A pathway

Large polypeptide hormone 191 amino acids Four alpha helices looped together Interacts with binding protein (GHBP) Extends half-life of GH Found in rodents, rabbits, and humans Extracellular domain of GH receptor in human and rabbit Product of alternative transcription in rodents

Regulation of GH secretion Major GH pulses (70 % of total daily output) Slow sleep (deep sleep) Age-related loss of GH Decrease quality of sleep Obesity and diabetes Decreased GH release Nutritional status One of the major regulatory factor of GH secretion

Hormones Steroids Thyroid hormones Acute elevation in glucocorticoids (+) Chronic elevation in glucocorticoids (-) Gonadal steroids (+) Thyroid hormones Inhibitory

Action of GH Growth and metabolism Action mediated by IGF-I Mediation of growth Endocrine IGF-I Liver Local (autocrine/paracrine) IGF-I

Gender-specific pattern of GH secretion Affects amount of steroidogenic enzymes Gender-specific pattern of steroidogenesis Gender-specific pattern of liver enzyme expression Gender-specific action of GH Mediated by STAT 5b activity

TSH Glycoprotein hormone Alpha and beta subunits Alpha is identical to that of gonadotropins Thyrotroph-specific expression Different region of gene promoter Gene for TSH beta subunit Located on chromosome 1 Transcription regulated by Pit-1

Post-translational modification Glycosylation Affects proper molecular folding Combination of alpha and beta subunits Regulated by TRH (+) and T3 (-)

Secretion of TSH Bioactivity of TSH Pulsatile secretion Glycosylation Clearance rate Pulsatile secretion Not as pronoused as gonadotropins or GH Low variation in concentrations Circadian pattern Increased secretion during night Independent of sleep

Hormonal regulation Major factor of TSH secretion Thyroid hormone concentrations Extremely important TRH Dopamine (-) Glucocorticoids (-) SS (-)

Action of TSH Thyroid hormone production G-protein coupled receptor Thyroid cell integrity maintenance

Prolactin Structurally similar to GH Prolactin gene expression Common ancestry Chromosome 6 Prolactin gene expression Estrogen Dopamine TRH Thyroid hormones

Exits as monomer or polymer in circulation 23 kDa (monomer) Most bioactive 48-56 kDa (dimer) > 100 kDa (polymer) Glycosylated Less active Binds to prolactin binding protein

Regulation of prolactin secretion Inhibitory Hypothalamic Dopamine Calcitonin Paracrine factors Endothelin-1 TGF-beta 1

Stimulatory Growth factors bFGF EGF Gut hormone VIP Estrogen

Function of prolactin Essential for survival Lactation Immune function Prolactin surge during labor Essential for initiation of lactation Not required for maintenance of lactation Immune function Stimulates lymphocyte development Reproduction Essential for rodents