Page%1%of%8%%Lecture 7: TRH is the smallest peptide hormone; 3amino acids long * Main effect is stimulation of thyrotrophs in ant pituitary * Can also stimulate prolactin release in high concentrations TSH, LH, and FSH are all protein dimers with the same alpha subunit and different beta subunits TSH Receptor • GPCR • Both Gas and Gaq coupled; will increase both[Ca] and [cAMP] in follicular cells • Can be targeted by antibodies of the immune system (Ab) o TSH-R-Stimulating antibody; binds to receptor and acts as if it is TSH; seen Graves Disease (hyperthyroidism) o TSH-R-Blocking Ab; Hashimoto’s Thyroiditis (hypothyroidism) o TPO (thyroid peroxidase)-Ab; hypothyroidism o TGB (thyroglobulin)-Ab; hypothyroidism Effects of TSH • Increased growth of thyroid cells including volume and vascularity; cause the growth of a Goiter • Increased Iodide uptake and transport; Increase NIS and Pendrin transporter protein synthesis BICD 150 Sp’14 Fortes 4 4/22/14 1 of 8Page%2%of%8%%• Stimulate TPO synthesis and activity (iodination and coupling of tyrosine) • Stimulate synthesis and secretion of TGB • Stimulate pinocytosis of iodinated TGB back into the follicle from the colloid • Increase number of lysosomes; increase TGB digestion; increase in T3/T4 release Thyroid receptors (TR) mainly bind T3 are in the nucleus and are inactive; bound to co-repressors, not HSPs T3/T4 diffuses into cells and are transported into the nucleus T3 binds to TR; T4 is converted into T3 before binding TR will dissociate from its co-repressor and bind co-activator TR-complex will bind DNA and will affect transcription Physiological effects of thyroid hormones • Essential for development of the fetus; both growth and development of CNS o Deficiency of thyroid hormones in a developing baby will have permanent problems; Cretinism o Cretinism: Mental retardation, lack of growth/dwarfism o If identified early (babies are now tested for TSH levels after birth) babies can be supplemented to prevent the disease • Metabolic effects o Increase metabolism o Increase O2 consumption o Increase heat generation; biochemical reactions are exothermic and release heat o Increase Na/K ATPase activity; transporters located in all cells and are the main consumers of ATP and therefore O2 o Increase Ca ATPase activity o Increase Lipolysis o Increase # of mitochondria; Increase O2 consumption o T3/T4 can uncouple oxidative metabolism; thyroid hormones were prescribed to lose weight (bad idea).Page%3%of%8%%• Cardiovascular effects o Increase fast myosin o Increase B1 adrenergic receptors which are Gas coupled (increase hear rate and Contractility); complaint of hyperthyroidism is heart palpitation/increase HR • Intestinal Effects o Increase motility particularly in the colon; hyper defecation 2 or 3x a day in hyperthyroid. Opposite in hypothyroid • Hematopoietic effects o Increase red blood cell and hemoglobin production; hypothyroid is often anemic o Increase growth of bone and Ca deposition o Increase resorption of bone/bone turnover • Muscular Effects o Increase in fast myosins; hyperthyroid tend to have faster reflexes/jitter or tremor • Pulmonary Effects o Maintain ventilation; hypothyroid tend to have hypoventilation • Increased Sympathetic responses in general Lack of dietary iodine can cause hypothyroidism; problem solved in the US by adding it to table salt • Decreased T3/T4 synthesis; increased TRH and TSH • High TSH will stimulate growth of thyroid; goiter; can scavenge the blood for iodide more effectively and can even bring hormonal levels back to normal Hyperthyroid • Either an excess of TRH/TSH or excessive function of thyroid gland itself (high T3/T4) • Primary hyperthyroidism = Thyroid gland overproduces T3/T4 • Secondary hyperthyroidism = Pituitary Gland overproduces TSH Hyperthyroidism Symptoms: • Weight lossPage%4%of%8%%• Heat intolerance • Nervous/increased reflexes/tremors • Tachycardia • Hyper defecation • Goiter • Exophthalmos (in the case of Graves disease); antibody reacts with some antigens around the muscles behind the eyes causing them to bulge out of their sockets Treatment of hyperthyroidism • Inhibit TPO with drugs • Radioactive iodine to destroy the thyroid; patients would have to be supplemented for life afterwards Hypothyroidism: Hashimoto's Thyroiditis is the most common cause • Constipation • Weight gain • LethargyPage%5%of%8%% Lecture 8 Hypothyroidism: • Dry skin • Weight gain; rarely more than 50lbs • Swelling • Malaise No such thing as giving "little bit of thyroid hormone" as a treatment The dose you give will shut down endogenous (the body’s normal) production via negative feedback. Given dose needs to be large enough for them to live normally on for their lifetime Subclinical hypothyroidism: * Normal T4 levels but elevated TSH * Sign of a failing thyroid gland * Decision to treat may be difficult; depends on severity of symptoms Estrogen or birth control pill can raise Thyroid binding globulin (TBG) levels. Will look like levels of free T4 are low because more of it is bound to TBG Hyperthyroidism: Graves disease most common BICD 150 Sp’14 Fortes 4 4/24/14 5 of 8Page%6%of%8%%-lose weight • Sweaty • Nervous • Tired; too active too much of the time • Goiter; Eye bulging; Exophtalmus • Treated by • Anti-thyroid drugs that decrease thyroid hormone made • Radioactive iodine Goiters can be caused by either hyper or hypothyroidism * Iodide deficiency can cause the growth of the thyroid as it scavenges the blood for iodide as discussed earlier * Overstimulation of thyroid gland by antibodies seen in Graves disease can also cause the growth of a goiter Male endocrinology • Penis: Contains erectile tissues; corpus cavernosum and corpus spongeosum fill with blood when there is vasodilation causing erection • Urethra extends from urinary bladder. It will pass through the prostate gland Accessory structures: • Seminiferous tubules where sperm cells divide and develop • Epididymis is where sperm are stored • Vas deferens transport sperm where it will form the ejaculatory duct which joins into the urethra • Seminal vesicles provide fluid and substrates like fructose to the sperm cells • Prostate gland also secretes things like buffers to the semenPage%7%of%8%%• The penis and prostate both require dihydrotestosterone DHT (a very potent