Page%1%of%9%%%Lecture 5: Hypothalamus Pituitary Axis continued: Stress hormones; cortisol Several stimuli feed into the hypothalamus to increase secretion of CRH • Circadian Rhythm • Physical stress; injury/exercise/pain • Emotional stress; psychological • chemical stress; hypoglycemia/malnutrition/starvation CRH will enter the portal vessels and reach the corticotrophs in the ant pit and cause them to release ACTH ACTH will stimulate the adrenal cortex to release Cortisol Negative Feedback- Short loop: ACTH inhibits the hypothalamus Long loop: Cortisol inhibits the ant pit and hypothalamus Secretion of ACTH (and therefore cortisol) decreases during the day and increases to its highest levels at late night/early morning We'll cover the specific effects of Cortisol later in the course • Anti-inflammatory • Metabolism • Immune system ACTH is made as a protein hormone as part of a large precursor protein called POMC • POMC contains several other hormones in it before it is cleaved/processed • Pro Opio Melano Cortin (POMC) o Opioid hormones (Enkephalins and Endorphins) o Melanocyte stimulating hormones (MSH) o ACTH • POMC is made in the corticotrophs of the ant pit BICD 150 Sp’14 Fortes 3 4/15/14 1 of 9Page%2%of%9%%• Hormones in the appetite regulatory center of the hypothalamus also secrete some portions of POMC The ACTH portion of POMC also contains the hormone a-MSH • Melanocytes are cells that create pigment in skin and are stimulated by MSH • In the regulatory center of the hypothalamus; MSH inhibits appetite Unusual increases in ACTH: • Low levels of cortisol; primary adrenocortical insufficiency. "Addison's Disease" o Student diagnosed himself after his skin became unusually dark/tan. Excess ACTH (due to low cortisol) would contain a-MSH and stimulate pigment production o Failure of adrenal cortex was often associated w/ TB o Now main cause is usually autoimmune • Direct increase of ACTH caused by a pituitary tumor of the corticotrophs. "Cushing's Disease" o Excess ACTH overstimulates the adrenal cortex causing Hypercortisolism aka "Cushing's Syndrome" o This increase in Cortisol would also have negative feedback on the tumor itself. You'd get the symptoms of Hypercortisolism but not the pigment change o Early treatment of these tumors was difficult from a surgical standpoint; instead the adrenal glands were removed to remove excess cortisol. Doing this removed the negative feedback of cortisol on the pituitary; ACTH was secreted even more! Hyperpigmentation was then seen though it treated the high cortisol Symptoms of Hypercortisolism • Accumulation of fat/swelling in the face. "Full moon face" • Accumulation of fat in the back "buffalo hump" • Central obesity confined to the trunk/face/abdomen • Development of stretch marks due to rapid weight gain and the thinning of the skin via cortisol's inhibition of fibroblasts and collagen deposition HP-Liver: Growth hormone pathway • GHRH (+) and Somatostatin (-) from hypothalamus regulate the release of GH from the pituitary GH stimulates growth and is a "storage hormone" Stimuli for GH release • GHRH • Hypoglycemia; an administered overdose of insulin can lead to hypoglycemia as a test to see if there is a deficiency in GH release • Increase amino acids in the circulation, especially Arginine; can be given in solution to measure the increase in secreted GH (probably safer than insulin shock test) • GH release decreases with agePage%3%of%9%%• Ghrelin: hormone secreted from the stomach that increases GH secretion as well as appetite. Secreted when the stomach is empty. Ghrelin secretion is inhibited by eating • Exercise • Circadian rhythm; first few hours after sleep Inhibition of GH release • Somatostatin • Hyperglycemia; a test for GH excess is a high glucose drink also used for a glucose tolerance test. Measure GH levels before and after. GH levels should decrease to almost 0 after drinking. If it doesn't there may be the presence of a small tumor over secreting GH The majority of GH's growth effects are via IGF-1 from the liver. GH has other effects on organs • GH uses cytokine receptors • IGF-1 uses growth factor receptors GHRH->GH->IGF-1 Hypothalamus->Ant Pit->Liver Metabolic Effects of GH: • Increase Lipolysis • Increase FA/Lipid metabolism • Increase Glycogen synthesis • Decrease Glucose metabolism • Increase in Insulin Resistance; excess GH can cause diabetic symptoms • Increase AA uptake • Increase protein synthesis • Inhibits protein breakdown Overall GH shifts the metabolism away from using protein and carbs for energy towards breaking down Fat By conserving protein and increasing AA uptake it promotes the growth of muscle Growth of bone via IGF-1: • Bones contain growth cartilage aka "epiphyseal plate" • Cartilage cells divide and secrete material that can be calcified to increase bone length • Growth spurt during puberty caused by GH and sex hormones • Sex hormones will also convert all of this growth cartilage into bone itself • We all stop growing after puberty • Growth of bone mainly caused by IGF-1 and some GH • Genetics and nutrition affect growth; "nature vs nurture" Abnormal GH/IGF-1 • Too little GH gives rise to dwarfism; "pituitary dwarves" Munchkins in wizard of oz • Nonfunctional GH Receptors: Laron Dwarfism • Lack of GH can be treated with exogenous recombinant GH, assuming the GHR's are functionalPage%4%of%9%%• Laron Dwarfism can be treated w/ IGF-1 instead • Non functional IGF-1R's or low levels of IGF-1 seen in pygmies • Increased in GH almost always caused by tumors in the somatotrophs of the ant pit • Increased growth during childhood/puberty aka Gigantism • Increased growth after puberty aka Acromegaly o Bones cannot grow in length, but thickness o Enlarged forehead/nose/jaw o "Jaws" from 007 or "Frankenstein" are good examples Hormones of the Hypothalamic/Posterior Pituitary axis • Oxytocin • ADH/Vasopressin: o Secreted when the plasma osmolarity rises. ~1%change can stimulate or inhibit ADH secretion. Osmoreceptors are in the hypothalamus itself. o Weaker stimuli are low BP and BV via baroreceptors from the medulla o Pressure = (Volume Contents)/(Volume Container) o Blood Loss and dehydration increases Osm and decreases BP/BV and will stimulate ADH release o ADH reabsorbs more water from kidney and cause vasoconstriction = Increase