Shobaloju A.G. OUTLINE: Intro Morphology Adrenal medulla and function of its hormones Regulation of adrenal medulla secretion Biosynthesis of adrenal medullary hormones Adrenal cortex hormones biosynthesis. Effects of adrenal androgens and estrogens Regulation of glucocorticoid and mineralocorticoid secretion Physiologic effect of glucocorticoids and mineralocorticoids Effects of adrenal cortex hyper or hypo function. ADRENAL GLAND INTRODUCTION 2 endocrine organs-adrenal medulla and adrenal cortex Adr. medullary hormones...epinephrine, norepinephrine and dopamine, are not essential for life, for emergencies. Adr.cortex hormones are essential for life-secretes glucocorticoids(cortisol) -- CHO and protein metabolism.Also mineralocorticoids(aldosterone) -- Na reabsorption and increase ECF volume, Sex hormones (androgens and estrogens) -- minimal effect on reproduction Adrenocortical secretion is under control of ACTH but mineralocorticoids secretion also under independent control by circulating angiotensin II. ADRENAL MORPHOLOGY Adrenal cortex--forms majority of the ad.gland. Divided into 3 zones: 1) Zona glomerulosa(ZG)-15% of gland (outer) 2) Zona fasciculata(ZF)-50% of gland (middle) 3) Zona Reticularis(ZR)-7% of gland. (inner) The active enzymatic mechanism for aldosterone synthesis is in the ZG and that of the sex hormones is present in the ZR while ZF is for cortisol. ADRENAL MORPHOLOGY. Adrenal medulla—28% of the adrenal gland. Interlacing cords of cells that contains granules. These cell types secrete—epinephrine and norepinephrine Dopamine is also secreted by the adrenal medulla but the cell type is not identifiable. Adrenal medullary hormones are also known as catecholamines. BIOSYNTHESIS OF CATECHOLAMINES EFFECTS OF EPINEPHRINE AND NOREPINEPHRINE. •Their effect is brought about by the action on two types of receptors and •They mimic the effect of noradrenergic nervous discharge. •Norepinephrine/epinephrine exert metabolic effects e.g. glycogenolysis in the liver and skeletal muscle. • plasma lactate, metabolic rate EFFECTS OF EPINEPHRINE AND NOREPINEPHRINE (CTD) •Nor epinephrine causes vasoconstriction of vessels via 1 receptors •Nor epinephrine/epinephrine the force of contraction and rate of contraction by action of the 1 receptors •Epinephrine dilates the blood vessels in skeletal muscles and liver via the 2 receptors. EFFECTS OF DOPAMINE. The physiologic function of dopamine in circulation is not known Has a positive inotropic effect on the heart. The net effect of moderate doses of dopamine is an ↑ in systolic pressure and no change in diastolic pressure. Catecholamines generally ↑alertness and myocardial excitability. ADRENAL CORTEX Hormones of adrenal cortex are derivatives of cholesterol Hormones of Adrenal cortex are known as steroids. Include-mineralocorticoids, glucocorticoids and sex steroids. BIOSYNTHESIS OF STEROIDS. Androgen and Estrogen EFFECTS OF ANDROGENS Androgens exert masculinizing effects. ↑ protein metab and growth. Testosterone from the testes is the most active androgen. Secretion of adrenal androgen is controlled by ACTH. In adult males,excess adrenal androgens only accentuate existing characteristics. In pubertal boys cause precocious puberty. In females they cause pseudohermaphroditism. PHYSIOLOGIC EFFECTS OF GLUCOCORTICOIDS Cortisol: ↑ protein catabolism ↑ hepatic gluconeogenesis ↑ G-6-Phosphate activity. ↑ glucose activity ↑ ketone body formation antagonizes insulin secretion. permissive action:calorigenic effects of glucagon and catecholamines, also for the bronchodilatory effects of catecholamines. ↑ RBC,WBC helps to cope with stress and also ↑concentration TRANSPORT AND METABOLISM OF GLUCOCORTICOIDS Cortisol is bound to a protein called transcortin or corticosteroid-binding globulin. minor degree of binding to albumin. Bound steroids are physiologically inactive. Because of the binding to protein, there is little free cortisol in the urine. CBG is synthesized in the liver and its production is stimulated by estrogen. TRANSPORT AND METABOLISM OF GLUCOCORTICOIDS When CBG levels↑, more cortisol is bound and there's reduced free cortisol which stimulates ACTH and more cortisol is produced until a new equilibrium is struck. CBG levels are increased in pregnancy, reduced in cirrhosis and nephrosis. Metab of cortisol is in the liver, where most of the cortisol→ dihydrocortisol →tetrahydro cortisol which is conjugated to glucoronic acid by glucoronyl transferase. PATHOLOGIC EFFECTS OF GLUCOCORTICOIDS(CORTISOL) Excess Cushing's synd production of cortisol. 2 types-Acth-dependent and Acthindependent. Acth- independent is caused by glucocorticoid secreting adrenal tumors Acth-dependent is caused by Acth-secreting tumors of anterior pituitary usually called Cushing's ds and tumors of lungs secreting Acth. PRESENTATION OF CUSHINGS SYND Physiology of the stress response Catecholamine hormones facilitate immediate physical reactions associated with a preparation for violent muscular action. These include the following: •Acceleration of heart and lung action •Paling or flushing, or alternating between both Inhibition of stomach and upper-intestinal action (digestion slows down or stops) •General effect on the sphincters of the body •Constriction of blood vessels in many parts of the body •Liberation of nutrients (particularly fat and glucose) for muscular action •Dilation of blood vessels for muscles •Inhibition of the lacrimal gland (responsible for tear production) and salivation •Dilation of pupil (mydriasis) •Relaxation of bladder •Evacuation of colon •Inhibition of erection •Auditory exclusion (loss of hearing) •Tunnel vision (loss of peripheral vision) •Acceleration of instantaneous reflexes •Shaking Anti-Inflammatory & Anti-Allergic Effects of Glucocorticoids•Glucocorticoids inhibit the inflammatory response to tissue injury. •The glucocorticoids also suppress manifestations of allergic disease that are due to the release of histamine from tissues. •Both of these effects require high levels of circulating glucocorticoids and cannot be produced by administering steroids without producing the other manifestations of glucocorticoid excess.(cushings syndrome like effects) •Large doses of exogenous glucocorticoids inhibit ACTH secretion to the point that severe adrenal insufficiency can be a dangerous problem when therapy is stopped. •However, local administration of glucocorticoids, for example, by injection into an inflamed joint or near an irritated nerve, produces a high local concentration of the steroid, often without enough systemic absorption to cause serious side effects. The actions of glucocorticoids in patients with bacterial infections are dramatic but dangerous. For example, in pneumococcal pneumonia or active tuberculosis, the febrile reaction, the toxicity, and the lung symptoms disappear, but unless antibiotics are given at the same time, the bacteria spread throughout the body. It is important to remember that the symptoms are the warning that disease is present, when these symptoms are masked by treatment with glucocorticoids, there may be serious and even fatal delays in diagnosis and the institution of treatment with antimicrobial drugs. Moral of the story-Don’t use steroids just to relieve symptoms. EFFECTS OF MINERALOCORTICOIDS (ALDOSTERONE) Aldosterone and other steroids with mineralocorticoid activity ↑ reabsorption of Na from the kidneys, expanding the ECF vol. Primarily act on P cells of collecting tubule in kidney. Na exchanges for K and H in the renal tubules producing K diuresis and increased urine acidity. STIMULI FOR ALDOSTERONE SECRETION Glucocorticoid secretion Surgery Anxiety Physical trauma Hemorrhage Glucocorticoid secretion unaffected↑ K Na intake Standing Constriction of the IVC, Secondary hyperaldosteronism(ccf,cirrhosis) REGULATION OF ALDOSTERONE SECRETIONRENIN- ANGIOTENSIN SYSTEM. ADDISON’S DISEASE Adrenal gland not producing enough cortisol May also involve aldosterone Also known as adrenal insufficiency or hypocortisolism Causes…Disorder of the adrenal glandPrimary adrenal insufficiency /Addisons disease. Disorder of ACTH secretion– Secondary adrenal insufficiency. Disorder of CRH from hypothalamus Tertiary adrenal insufficiency. SYMPTOMS Chronic worsening fatigue Muscle weakness Loss of appetite Wt loss Decreased BP-if persists Addisonian crisis. Skin changes…usually areas of hyperpigmentation over pressure points Irritability Depression PIGMENTATION IN ADDISON'S DISEASE DIAGNOSIS ACTH stimulation test.. Most specific Addisonian crisis….. Rx … Hormone replacement.. Steroid tablets.. CONN’S SYNDROME Is characterized by overproduction of mineralocorticoid aldosterone Caused by Aldosterone-secreting adrenal adenoma and also Hyperplasia of the adrenal gland Aldosterone causes Na and H20 retention Also causes K excretion in the kidneys Leading to hypertension Also known as primary hyperaldosteronism SECONDARY ALDOSTERONISM Secondary aldosteronism due to increase in Renin levels E.g. Decreased bld flow to the kidneys Decreased blood pressure Renal artery stenosis CCF Cirrhosis CONN’S SYNDROME CTD Symptoms include hypertension Tetany(Hypocalcemia) hypokalemic alkalosis Polyuria Diagnosis Adrenal Adenoma – CT scan QUIZ a) b) c) d) Which of the following is expected in a patient with a gunshot injury to the leg and who has been bleeding profusely for about an hour Decreased aldosterone level Increased aldosterone level Arteriolar vasodilatation All of the above QUIZ State the layers of the adrenal glands What is the effect of cortisol on glucose Cushing’s syndrome ..Define State 5 clinical presentation of cushing’s syndrome. Conns syndrome.. Define Pigmentation in addisons disease Androgens are produced in the adrenal medulla T/F 17 alpha hydroxylase is contained in the zona glomerulosa T/F CONGENITAL ADRENAL HYPERPLASIA Any of the severe autosomal recessive conditions resulting in abnormal steroid production Most involve greater or lesser production of sex steroids Can alter the dev of primary and secondary sex characteristics in infants, children Can be due to 21 hydroxylase deficiency (commonest cause) Can also be due to 17 alpha hydroxylase deficiency Or 11 hydroxylase deficiency EFFECTS OF ADRENOCORTICAL HYPER OR HYPO FUNCTION (CTD) Primary hyperaldosteronism e.g. Conn’s synd-Excess mineralocorticoid - K, Na, weakness, HTN, polyuria.—Adenoma of ZG. Sec hyperaldosteronism—plasma renin increased e.g. cirrhosis, heart failure. Primary Adrenal insufficiency—destroys the adrenal cortex called Addison's ds-due to autoimmune ds. Patients lose wt, are tired and develop severe hypotension. Secondary adrenal insufficiency—caused by pituitary disease that Acth secretion Tertiary adrenal insufficiency is caused by hypothalamic disorders ( CRH) EFFECTS OF ADRENAL CORTEX HYPER OR HYPO FUNCTION..