Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22ENDOCRINE CONTROL OF GROWTH & METABOLISM [Ch. 23]Hypothalamo-pituitary axis [Review Ch. 7, pp.219-23]Pituitary glandbrainanteriorposteriorStandard anatomic view of HP axis Endocrinologist’s view of HP axis In tribute to Gary Moberg, 1941-1999[See: Ch. 7, pp.219-223]•Anterior pituitary is an epithelial-derived, true endocrine organ•Releasing Hormones from hypothalamus Trophic Hormones from anterior pituitary  Effector Hormones from peripheral endocrine organs  Target tissuesHypothalamusAnt. PituitaryAdrenalCRHACTHTarget tissuesCortisollong-loopfeedback inhibitionACTHshort-loopfeedback inhibitionACTH—one of several bioactive peptides produced from a single precursorAdrenal Gland[Fig. 23.1, p.778]catecholaminesMineralocorticoidsGlucocorticoidsSex steroidsAdrenal Gland—Zona fasciculata of cortex synthesizes and releases glucocorticoidsGlucocorticoids Mineralocorticoids Sex steroidsCholesterol is the precursor to all steroid hormonesCortisol secretion—stimuli [Fig. 23.2, p. 779]CircadianrhythmMetabolic system is diurnally active,mainly entrained by daily cycles of lightand dark—our evolutionary legacy. Conditions of human entrainment havechanged over last 150 yearsForced adaptation to altered rhythmscan promote metabolic dysfunction &diseasePrecise mechanisms unknown… --Conflict between biological signals vs. social demands? (shift work) --Asynchrony between brain and periphery? (influx of calories at night)StressEffects of cortisol– [p. 780] --promotes catabolism (similar to glucagon)—protection against hypoglycemia at expense of body protein and fat oxidation --promotes negative calcium balance (decreased absorption, increased excretion, increased bone breakdown) --depresses immune function (inhbitory effects on leukocytes of both innate and adaptive immune systems)1) Necessary for full glucagon effect2) Suppresses immune fxn/inflammation3) Negative Ca2+ balance1233Cortisol—mechanism of action [Review Fig. 7.5b, p. 215]Intracellular (cytoplasmic) receptor—ligand-dependent transcription factordiffusion into cellbinding to receptortranslocation into nucleus stimulation of gene expressionvia binding to GRE’s in gene’s promoterinhibition of geneexpression via blocking activity of transcription factorsCortisol as therapeutic drug— [p.780]•Anti-inflammatory•Suppresses B-cell antibody production•Use of NSAIDs has replaced that of corticoids for minor inflammatory disorders—avoids corticoids’ metabolic effectsinflammatory/rheumatoid diseases & allergiesCortisol pathologies— [p. 781]•Hypercortisolism (most common)—Cushing’s syndrome— 1) adrenal tumor (1° hypercortisolism), 2) pituitary tumor (secretes xs ACTH, 2° hypercortisolism, aka “Cushing’s disease”), 3) iatrogenic (complication of therapeutic use --Excess gluconeogenesis, muscle/fat breakdown (mimicking diabetes) --Increased appetite/food intake --Behavioral/mood alterations—manic depression, defects in memory, learning•Hypocortisolism—1) Addison’s Disease—hyposecretion of all adrenal steroids due to autoimmune destruction of cortex, 2) other inherited disorders involving defects in specific enzymes in synthetic pathway—may show xs androgen production as side effectThyroid Hormone—long-term metabolic actions [pp. 782-7]Thyroid hormone synthesis occurs in the colloid of the thyroid follicleHypothalamusAnt. PituitaryThyroidTRHTSHTarget tissuesT3, T4negativefeedbackT4 T3 IRegulation of TH production& release[Fig. 23.5, p. 785]--T3 is major physiologically active formT3 (but not T4) shows a circadian rhythm which follows that for TSH;Physiological significance of this rhythm is unknownRussell W et al. J. Clin. Endocrinol. Metab.93:2300-2306, 2008Thyroid hormone synthesis– occurs in follicular colloid, 2-3 months supply of TH stored in colloid [Fig. 23.4c, p. 783]76532114TH transport/processing in plasma/target cells—T3, T4 carried by T4 converted to T3 by deiodinases in Thyroid-binding globulin target tissues; T3 has most activityThyroid hormone mechanism of action and effects-- increasedmetabolism, metabolic rate, heat production, necessary for neuraldevelopment, bone growthTH pathologies– can be due to problems with thyroid gland itself or in the control pathway [pp. 784-7]•Goiter: enlargement of thyroid gland due to hypertrophy of follicular cells—trophic effect of excess stimulation of thyroid—can result from either hyper- or hypothyroidism [photo: Fig. 23.6a, p. 786]Hyperthyroidism: ↑↑↑TH – hypermetabolic(i.e. catabolic) state, ↑ CNS excitability, ↑ cardiac activity (HR, contraction), goiter,exophthalmosthyroid-stimulatingImmunoglobulinsGraves’ Disease:Here, excess stimulation of the thyroid occurs even without TSHPrimary hyper-thy: thyroid tumorsHypothalamusAnt. PituitaryThyroidTRHTSHTarget tissuesT3, T4HYPERnegativefeedbackT4 T3 I[Fig. 23.7a, p. 787]Secondary hyper-thy: pituitary tumors—hypersecreton of TSH, TH does not InhibitHere, excess TSH release causesexcess stimulation of the thyroidTreatment: surgical removal of gland,radio-iodine, or drugs to block TH synth.or T4 T3 conversionHypothalamusAnt. PituitaryThyroidTRHTSHTarget tissuesT3, T4T4 T3 IHyperthyroidism (cont.)Hypothyroidism: ↓↓↓ TH–hypo- metabolic state, ↓ prot. synth., myxedema, ↓ bone growth, CNSdepression, cretinism, bradycardia, goiterPrimary hypo-thy: dietary iodine deficiencyTreatment: oral T4 (& T3)HypothalamusAnt. PituitaryThyroidTRHTSHT3, T4NOnegativefeedback↓↓↓ I-↓↓↓[Fig. 23.7b, p.