BICD 150 Sp 14 Fortes 10 6 3 14 1 of 8 Adrenal Endocrinology Anatomy of adrenal gland Ad Renal Next to kidney Two 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 8 norepinephrine 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 group C19 steroids are the sex steroids Steroid Synthesis Page 2 of 8 In 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 zona fasciculata 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 is not 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 ACTH CRH 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 8 Cholesterol 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 turned into 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 bind the GCR Glucocorticoids are essential for life Animals cannot survive w out the adrenal glands Synthetic analogs of cortisol are very potent and exert the same negative feedback effects eg Prednisone Page 4 of 8 Patients 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 the enzyme 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 obesity Nervous system Cortisol or its analogs can cause euphoria perhaps to deal with stress but high levels can cause psychosis and depression Bones Decrease