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Anterior Pituitary Growth Hormone and Prolactin Matthew L. Fowler, Ph.D., OMS-II Class of 2015 Cell Biology and Physiology Block 6 Renal and Reproduction Learning Objectives • Anterior Pituitary Structure and Function – Cell types, vascular supply, development, anatomical function • Anterior Pituitary Hormones • Hypothalamic Control – – • • • Roles hypothalamic factors, glucose and IGF-1 Target cells/organs for IGF’s and Longitudinal growth Actions of GH – – • Releasing and inhibitory factors and transport to pituitary Negative Feedback Mechanisms of Anterior Pituitary Hormone Secretion Relationship Between GH and IGF’s Regulation of GH secretion – – • Three major families, biosynthetic, structural relationships Metabolic Growth-promoting Prolactin Regulation and Effects - Abnormal conditions Hormonal Action Hormones act through sensors to effect physiological change. 1. 2. 3. Hormones circulate in blood bound to a carrier protein (inactive form) Hormones bind to a specific receptor on a target organ yielding a selective physiological response Physiological effects or results can involve: A. 2nd messenger systems • B. Resulting in amplification of the signal Nuclear gene transcription • Resulting in a protein synthesis response Hypothalamus and Anterior Pituitary Functional Anatomy and Origins Anterior Pituitary (adenohypophysis) • Rathke’s pouch – Pharyngeal epithelium cells Posterior pituitary (neurohypophysis) • Neural tissue outgrowths from hypothalamus Hypothalamus Functions • • Collects physiological and neural inputs from all parts of the body – Pain, olfactory, emotions, water, and electrolytes – Senses internal well-being or distress Pituitary secretions controlled by hypothalamus – Hormonal input – Neural input Anterior Pituitary Functions • • • Highly vascular Hypothalamic releasing hormones/factors (HRFs) Hypothalamic inhibiting hormone/factors – Specialized neurons secrete – Hypothalamic-hypophysial portal system • Located in the median eminence – Act on the glandular cells • Control secretion of hormone. Hypothalamic Stimulatory and Inhibitory Hormones Hormone Chemical Composition Primary Action on Anterior Pituitary Thyrotropin-Releasing Hormone (TRH) Tripeptide Stimulates secretion of TSH by thyrotropes Gonadotropin-Releasing Hormone (GnRH) Peptide Stimulates secretion of FSH and LH by gonadotropes Cortiocotropin-Releasing Hormone (CRH) Peptide Stimulates secretion of ACTH by corticotropes Growth Hormone-Releasing Hormone (GHRH) Peptide Stimulates secretion of growth hormone by somatotropes Growth Hormone-Inhibitory Hormone (Somatostatin) Peptide Inhibits secretion of growth hormone by somatotropes Prolactin-Inhibiting Hormone (PIH) Dopamine Inhibits synthesis and secretion of prolactin by lactotropes Major Hormones of the Anterior Pituitary • Glycoprotein Hormones (LFTs) – LH, FSH, TSH – Same a chain (hCG as well) – Different b-chains (confer specificity) • Glycosylation increases t½ • Polypeptide Hormones (GAP) • Corticotropic hormones are derived from Pro-opiomelanocortin, long peptide chain precursor – GH, ACTH, PRL Actions of Anterior Pituitary Hormones • • • • • Growth Hormone – Promotes growth of the entire body by affecting protein formation, cell multiplication, and cell differentiation. Adrenocorticotropic Hormone – Controls the secretion of some of the adrenocortical hormones, which affect the metabolism of glucose, proteins, and fats. Thyroid-stimulating Hormone – Controls the rate of secretion of thyroxine and triiodothyronine by the thyroid gland, and these hormones control the rates of most intracellular chemical reactions in the body. Prolactin – Promotes mammary gland development and milk production. Follicle-stimulating Hormone and Luteinizing Hormone – Control growth of the ovaries and testes, as well as their hormonal and reproductive activities. Anterior Pituitary Hormones Summary Table Cell Type Hormone Chemical Composition Physiological Action Somatotropes Growth Hormone (GH) Polypeptide Stimulates body growth; stimulates secretion of IGF-1; stimulates lipolysis; inhibits actions of insulin on carbohydrate and lipid metabolism; acts as a PRL receptor agonist Corticotropes Adrenocorticotropic Hormone (ACTH) Polypeptide Stimulates production of glucocorticoids and androgens by the adrenal cortex; maintains size of zona fasciculata and zona reticularis of cortex Thyrotropes Thyroid Stimulating Hormone (TSH) Glycoprotein Stimulates production of thyroid hormones by thyroid follicular cells; maintains size of follicular cells Gonadotropes Follicle-stimulating Hormone (FSH) Glycoprotein Luteinizing Hormone (LH) Glycoprotein Stimulates development of ovarian follicles; regulates spermatogenesis in the testis Causes ovulation and formation of the corpus luteum in the ovary; stimulates production of estrogen and progesterone by the ovary; stimulates testosterone production by the testis Prolactin (PRL) Polypeptide Lactotropes (Mammotropes) Stimulates milk secretion and production Tissue Targets Important Note • All of the hormones of the anterior pituitary have specific target tissues Exception • GH has numerous target tissues GH Circulation • Multiple forms circulate • Degraded in liver and kidney • 40-50% circulates bound to GH Binding Protein which is the GH Receptor (GHR) • GHR is a member of the cytokine/GH/PRL/erythropoietin receptor subfamily – Increases GH t½ – Actions mediated through JAK/STAT pathways Regulation of GH Secretion • Pathways from the hypothalamus: 1. Stimulatory • 2. Inhibitory • • • GHRH GHIH (Somatostatin) Also inhibits TSH Tertiary pathway: 3. Ghrelin • • • From stomach and hypothalamic neurons Increases appetite Possible growth/nutrient supply coordination? GH Receptor Once GH is secreted it circulates freely in the plasma -about 40% is bound to HG-binding protein formed from cleavage of extracellular domain of GH receptor high affinity binding increases the half-life of GH (25 min) GH binds to s specific receptor in tissues > 620 AA protein with a single membrane spanning segment > excessively glycosylated > tyrosine kinase associated protein (no intrinsic activity)/related to cytokine receptors > can form a dimer when GH binds and bridges to another receptor > increases the activity of JAK2 family binding triggers a series of protein phosphyrlations that modulate GH and JAK2 activity JAK (Janus kinase) is the associated tyrosine kinase activity for GH (and cytokines) STAT (signal transducer and activator of transcription) >auto-phosphorylated (remember the insulin receptor) >dimerizes > accumulates in the nucleus where it stimulates gene transcription GH-Regulation by Feedback Loops Short loop feedback Long loop feedback Daily Variations in GH Secretion • Secreted in pulsatile pattern – Similar to ACTH • Highest in morning • Lowest in day/afternoon • Secretion increases during: – First 2 hours of deep (slow-wave) sleep – Strenuous exercise (stressor) GH Patterns and Measurement • • Anabolic Secretion increases through puberty – Decreased urea production during synthesis • • Due to AA utilization Declines with age – May account for muscle wasting • Measured via IGF-1 – [GH] variable – IGF-1 has longer t½ Biological Activities of GH • Know the actions on this summary diagram • Lipolysis – Adipose tissue – Due to GH-induced enzymatic activity of hormone sensitive lipase (HSL) Synergism with other hormones GH is one of the Stress Hormones increased by emotional and physical distress increases lipolysis and protein synthesis inhibits insulin action to reduce blood glucose GH is secreted in response acute hypoglycemia Obesity inhibits GH secretion Other hormones that interplay with GH T3-enhances IGF-1 and GH release and bone maturation estrogens GH is a diabetogenic hormone GH opposes insulin action to decrease glucose levels in blood in skeletal muscle and adipose tissue (not liver) produces insulin insensitivity When GH is secreted in excess, GH can cause diabetes. Insulin levels rise in response to excess GH and damage to pancreatic β cells may occur. The absence of excess GH results in secretion declines. Normal levels of GH help maintain normal pancreatic function and normal insulin levels. Diabetogenic effects of GH Target Tissue Effect Muscle Decreased glucose uptake Adipose Increased lipolysis Liver Increased gluconeogenesis Muscle, Fat and liver Insulin resistance These are short –term actions—minutes to hours GH increases skeletal growth Distinct from short term effect –growth is a long term effect • GH increases visceral growth • GH promotes long-bone length • GH promotes cartilage and periosteal growth • Most of these effects are mediated by Insulin like Growth Factors (IGFs) that are made in the liver in response to GH • IGFs are multi-functional hormones regulate cellular differentiation, proliferation and metabolism Diseases/Syndromes-- GH Deficiency Predictably, over or under expression of GH can results in syndrome With results on organ growth, linear growth and carbohydrate and lipid metabolism. In children with growth failure: Can be treated with GH injections short stature mild obesity delayed puberty Causes can be found at every step of the hypothalamic-pituitary-target organ axis. GH Deficiency • • • • • Laron Dwarfism Psychosocial Dwarfism Combined Pituitary Hormone Deficiency Panhypopituitary dwarfism African pigmy Laron Dwarfism • • • • • Reported in 1966—severe resistance to GH Autosomal recessive Mutations in GH receptor LOW levels of IGF-1 and IGFBP Dwarfs have a striking resistance to cancer and diabetes (village in Ecuador 2011) • Seen in Israel and people with Sephardic roots • Treatment by synthetic IGF-1 Psychosocial Dwarfism Kaspar Hauser Syndrome • Failure to thrive / short stature and intellect • Abusive and neglectful environment -Kaspar Hauser was abandoned at the Nuremburg gate in 1828 after 17 years of neglect and isolation in a dungeon • Very short stature, immature sexual deveopment • Very low GH Combined Pituitary Hormone deficiency • • • • Decreased pituitary hormone secretion Delayed or absent puberty, hypothryoidism, Infertility Mostly sporadic , incidence 1/8000 worldwide If familial, can be autosomal dominant or recessive • Most common mutation found • PROP1 (prophet of pit) gene---affects transcription factors that direct pituitary cellular development Combined Pituitary Hormone Deficiency CPHD Panhypopituitary Dwarfism GH Deficiency—from birth, brain injury Proportionate stature treated by injections of GH African Pygmy Height in West Central African tribes---maybe a “hot spot” on chromosome 3 Short height may also have selected for stronger immunity and other advantageous factors ---Science Now (online 2012) Excessive GH-Gigantism • Increased linear bone growth due to intense hormonal stimulation before the the long bone epiphyses close. • Frequently, pituitary adenoma is the cause • Treated with somatostatin analogues inhibit GH secretion. World’s tallest man at 8’11” with his father. Excessive GH-Acromegaly Before After Excessive bone growth after epiphyseal closure at puberty. Because of its pathogenesis and slow progression, the disease is hard to diagnose in the early stages and is frequently missed for many years, until changes in Goal for the treatment of acromegaly is to reduce external features, especially of the face, become noticeable. the production of growth hormone and to alleviate pressure on surrounding tissues. The common treatment for managing acromegaly is transsphenoidal surgery to remove the pituitary adenoma. extract the tumor through a small incision in the back wall of the nasal cavity. Therapeutic Interventions in GH conditions IGFs IGFs IGFs Complimentary regulation of GH and insulin coordinates nutrient availability Insulin Like Growth Factors “Somatomedins” IGFs resemble insulin in structure and function Two family members: IGF-1 major form in adults IGF-2 major form in the fetus They cross-react with insulin receptor Produced in many tissues and have autocrine, paracrine and Endocrine roles Both act through Type 1 IGF receptors (insulin/EGF family) have an Insulin Like Growth Factors “Somatomedins” • Liver may be main source of circulating IGFs but they are known to be made in other tissues • IGFs circulate in blood complexed with IGF Binding Proteins • IGFBP increase half-life of IGFs ---binding proteins degraded by protease that releases active IGFs locally -possible role in prostate cancer • Serum IGF levels correlate with growth in children • GH stimulates IGF in liver (IGF measure of GH in serum) • PTH and estradiol stimulate osteoblastic IGF-1 production • IGFs are mitogenic and stimulate all metabolism of chondrocyte. Prolactin • Lactotrope cells in anterior pituitary produce prolactin (PRL) hormone • 199 aa single chain protein structurally related to GH and hPL • PRL receptor also acts through JAK/STAT signaling pathways • Major functions in breast development and lactation will be covered in Reproduction Prolactin • In context of other pituitary hormones it should be appreciated that PRL is not part of a pituitary feedback loop. • PRL acts directly on non-endocrine cells (breast) to induce physiological changes • PRL is regulated by inhibition of secretion (mediated via dopamine neurons) (Drugs that block dopamine increase PRL) • There may also be a Prolactin Releasing Factor (PRF) • TRH and hormones of the glucagon family (glucagon, secretin, VIP, Gastric Inhibitory Peptide (GIP) can release PRL. Pathophysiology of PRL • Overproduction PRL galatorrhea (excessive milk secretion) and/or infertility • Causes— -Disruption of hypothalamic axis – Destruction of the hypothalamus – Prolactinomas Increased PRL secretion results from removal of inhibition normally regulating PRL—that is a “loss of tonic inhibition by dopamine” Treatment is by a dopamine agonist=bromocriptine