Adrenal Endocrinology Anatomy of adrenal gland "Ad" "Renal" = Next to kidneyTwo glands that sit above the kidneys like a hat The adrenal gland is a mixed organ; it contains an outer cortex and an inner medulla Medulla: The center of the adrenal gland consists of a group of cells that embryologically develop as post ganglionic sympathetic neurons. They don’t develop axons but retain synapses from preganglionic sympathetic neurons. They contain an extra enzyme that converts Page 1 of 8BICD 150Sp’14Fortes106/3/141 of 8norepinephrine into epinephrine. It secretes mainly epi and some norepi after stimulation from the sympathetic nervous system. Norepi and epi are the same as noradrenaline and adrenaline Cortex: Contains cells that specialize in taking up cholesterol and synthesizing steroid hormones 3 Layers:Zona Glomerulosa: Outermost layer; synthesizes and secretes aldosterone and mineralocorticoids. Involved in mineral balance; specifically reabsorbing Na and K in the distal tubule of the nephron. This will increase water reabsorption and therefore increase blood pressure Zona: Fasciculata: Secretion of glucocorticoids; named for their ability to increase plasma glucose. Main glucocorticoid is Cortisol Zona: Reticularis: Innermost layer of the cortex. Secretion of weak Androgens; DHEA and Androstenedione The secretions of the two innermost zones of the cortex are under control of ACTH; Aldosterone secretion in the zona glomerulosa is not regulated by ACTH.Secretion of cortisol controlled by HPA axis; CRH->ACTH->Cortisol Steroids: Numbered by # of carbons C21 steroids contain an extra acetyl groupC19 steroids are the sex steroids Steroid Synthesis Page 2 of 8In this diagram the first column of reactions represents synthesis of Aldosterone in the zona glomerulosa. The second column of reactions shows the pathway of cortisol synthesis in the zonafasciculata. The third column shows synthesis of androgens in the zona reticularis. Enzyme 2 in the above diagram represents the enzyme 17a-Hydroxylase. This critical enzyme isnot present in the glomerulosa and only the aldosterone pathway can be followed. The enzyme is present in the zona fasciculata and reticularis, allowing for the synthesis of cortisol or androstenedione respectively.In females 50% of circulating androgens come from the zona reticularis; the rest come from the ovaries . After menopause it becomes the main source of androgens. Androstenedione is more potent than DHEA and is easily converted into T in both males and females Regardless of what steroid is being made, Cholesterol must first be taken up into the mitochondria of cells by the enzyme star STAR and cleaved by P450ssc into Pregnenolone; the precursor to all steroid hormones Secretion of Cortisol and androgens is under control of ACTHCRH-> ACTH-> Cortisol/Androgens Cholesterol comes from LDLs, which are taken up by cells in the adrenal cortex from the circulation via endocytosis of the LDL/LDLR complex. Cholesterol Esters from LDLs and lipid droplets are cleaved into free cholesterol via Cholesterol Esterases ACTH binds to its GPCR Gas to activate AC and PKA. PKA activates both StAR and CEases Page 3 of 8Cholesterol is transported into mitochondria via star and converted to pregnenolone. It is then turned into hydroxypregnenolone via 17a-hydroxylase. It can then enter the pathway to be turnedinto Cortisol Steroids are permeable to bilayers; their secretion is regulated by controlling their synthesis Stimuli for Cortisol secretion:-Circadian Rhythm generated by hypothalamus; Highest levels in the early morning -Stress; physical/psychological -Hypoglycemia Cortisol has negative feedback to inhibit CRH and ACTH Cortisol binds to receptors called glucocorticoid receptors that translocate to the nucleus and bind DNA to alter gene expression. Mineralocorticoids respond to aldosterone and bind mineralocorticoid receptors. MCRs are not specific, and recognize cortisol as well as aldosterone. This would cause a problem as cortisol could affect the pathway that affects blood pressure. In the kidney cortisol is inactivated by being converted into cortisone. Hydroxysteroid dehydrogenase 2 (11b-HSD2) oxidizes cortisol in the kidney into cortisone; which is inactive to the mineralocorticoid receptor. This enzyme is also present in the colon and sweat glands. Normal function of MCRs is to increase Na reabsorption as well as water. Sweat glands want to reabsorb salts just like the kidneys so you don’t lose them during exercise 11b-HSD1 reduces cortisone into cortisol in the liver, adipose tissue, and CNS. Cortisol will bindthe GCR. Glucocorticoids are essential for life. Animals cannot survive w/out the adrenal glands. Syntheticanalogs of cortisol are very potent and exert the same negative feedback effects; eg Prednisone Page 4 of 8Patients who are given these drugs cannot suddenly stop taking them. They've inhibited their body’s endogenous CRH and ACTH production via this negative feedback and it takes some time to start releasing them again. Patients must be slowly tapered off the drugs. Effects of Glucocorticoids/ cortisol: Metabolic effects: Increase plasma glucose-increase gluconeogenesis -Increase protein breakdown providing AAs -Increase lipolysis providing FAs-Decrease in insulin secretion Required for proper response of adrenergic receptors-A1 (vasoconstriction) receptors in blood vessels and B1(HR/Contractility) receptors in the heart need cortisol-Lack of cortisol causes a decrease in BP; lowers vasoconstriction and contraction of heart Anti-inflammatory-Remember NSAIDS inhibit synthesis of prostaglandins and leukotrienes by inhibiting theenzyme COX-Steroids inhibit PLA2; which converts precursor lipids into Arachadonic acid; the substrate of COX -Steroids also decrease expression of COX2 in the joints; prevents formation of prostaglandins that contribute to arthritis -Decrease in immune system at many levels; decrease in immunoglobulin (antibody) production, decrease in interleukins and cytokines, decrease in white blood cell migration. -Steroids given for autoimmune diseases/transplants/ etc Adipose Tissue-Increase lipolysis-Stimulation of fat deposition in central part of body. Abdomen/face/shoulders-Buffalo hump and moon face and central obesity in Cushing's syndrome (excess cortisol) -Increase apatite: Cortisol or drug analogs will inhibit CRH. CRH is an appetite inhibitor; results in polyphagia and