Hypothalamic & Pituitary Hormones
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- How are hypothalamic hormones released and regulated?
- released in a rhythmic/circadian pattern and regulated in a negative feedback loop.
- What are the hormones released from the hypothalamus?
- TRH; CRH; GnRH; GHRH; somatostatin; dopamine
- What are the hormones released from the anterior pituitary that are stimulated by the hypothalamus?
- TSH; ACTH; FSH/LH; GH
- What target organs and hormones are stimulated by the anterior pituitary?
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Thyroxine & T3 from thyroid
glucocorticoid from adrenals
androgens, estrogens & progestins from gonads
IGF-1 from liver - what is the function of somatostatin?
- To inhibit GH release from the anterior pituitary.
- what is the function of dopamine?
- Inhibits prolactin release.
- Growth Hormone production
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most abundant hormone in AP.
1 gene produces a heterogenous mix of peptides, leads to several GH's of different AA combos. - Growth Hormone control and release
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controlled Somatostatin and GHRH
Released by nurons in hypothalamus in pulsatile fashion therfore pulsatile stimulation of somatrophs in AP which release GH. - Somatostatin receptors
- there are up to 5 SS receptors: SSTR2 and SSTR5 are the most important
- Somatostatin
- Decapeptide, inhibits GH, made in hypothalamus and pancreatic islets, also inhibits TSH, gonadotropins, insulin and glucagon release
- GH Regulation
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Negative Feedback loop
short loop- GH feedback to neurons of GnRH, inhibits GHRH's release
classic loop- end hormone (IGF-1)inhibits GH release of GHRH release - What influences GH secretion?
- sleep, hypoglucemia, physical exertion, emotional excitement, drugs: increased by alpha agonists, L-dopa and amphetamines; decreased by Beta agonists and phenothiazines
- What is the insulin tolerance test?
- hypoclycemia increases GH release. Test: infuse insulin, blood gluc should dec, GH should inc, and cortisol should inc.
- pharmocodynamics of GH
- GH binds to cell surface receptors, and also circulates bound to extracellular protein domain of GH receptors
- Function of GH alone
- GH directly increases lipolysis and gluconeogenesis
- Function of GH through IGF-1
- anabolic and growth promoting effects (metab of proteins, fat, carbs, Ca) results in growth(increased cell number not size)
- Function of IGF's
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mediate most GH effects
IGF-2 activates intracellular mannose-6-phosphate receptor
IGF-1 binds receptors similar to insulin receptor - Diseases of hypo GH secretion.
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dwarfism- in children
endocrinopathies in adults (including increased cardiovascular mortalities) - Diseases of hyper GH secretion.
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Gigantism- in kids before epiphyseal plates close
acromegaly- after plates close - symptoms of acromegaly
- visual problems from pituitary adenomas, bone overegrowth in hands, feet and face, headaches, sweating, diabetes, joint problems, colon cancer, cardiovascular disease
- prolactin
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structurally related to GH
secretion influenced by same factors as GH plus estrogen
role= lactation
receptors on other cells have unknown functions - hyperprolactemia
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suppresses HPG-axis through actions on hypothalamus and gonads
Treatment= dopamine, bromocriptine, pergolide, cabergoline - Octreotide
- SS analog,treats acromegaly, preferred because most specific for GH system, has modified Amino acid therefore longer t1/2 & greater selectivity,also used for metastatic carcinoid cancers, VIP secreting tumors, AIDS related diarrhea; SIDE EFFECTS: hypothyroidism, GI symptoms (loose stool, malabsorption, nausea and flatulence)
- Pegvisomant
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GH receptor antagonist, genetically engineered analog of human GH conjugated to polyethylene glycol= pegylation (reduces renal clearance and gives longer t1/2)
mech: blocks GH binding to receptor therefore decreases serum IGF-1 secretion but increases GH in serum
most effective for acromegegaly
SE: can develop auto GH Ab's leads to CV probs - Bromocriptine
- dopamine agonist, treats acromegaly, hyperprolactinemia, amenorrhea, galactoffhea, infertility, hypogonadism, parkinson's; SE= HA, dizziness, nausea, HTN, postural hypotension, contraindicated in pts with sensitivity to ergot alkaloids
- Growth Hormone as a drug
- for dwarfism, chronic renal insufficiency, Turner's syndrome; can be prepared as hGH (somatropin)(encapsulated for monthly IM injections)or synthetic hGH with methionine removed (somatotrem)
- Dopamine
- inhibits prolactin release
- pergolide
- for hyperprolactinemia,
- cabergoline
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longer t1/2, more potent D2 selective, used once or twice a week
preferred over bromcriptine in acromegaly