Adrenal Glands PDF Notes

MY1 Repro/Endo - LEFF Adrenal glands Page 1 of 18 The Adrenal Gland Session Learning Objectives: 1. Describe the anatomical structure of the adrenal gland and the hormonal output of each layer of the...

MY1 Repro/Endo - LEFF Adrenal glands Page 1 of 18 The Adrenal Gland Session Learning Objectives: 1. Describe the anatomical structure of the adrenal gland and the hormonal output of each layer of the cortex and of the medulla. 2. Outline the biosynthetic pathways that produce each of the cortical hormones and medullary hormones. 3. Describe the regulation of cortisol production by ACTH. This should include the cell biology of ACTH action as well as the feedback regulatory pathways that control cortisol production. 4. Describe the cellular actions and physiological effects of cortisol and aldosterone in their primary target tissues. 5. The receptors and signaling pathways used by each of the cortical and medullary hormones. 6. Describe the functional relationship between the adrenal medulla and the sympa- thetic nervous system and the regulation of hormone production. 7. Describe the cellular and physiological effects of epinephrine action on the liver. 8. Describe the physiological characteristics of Cushing's syndrome and Addison's disease. Session Outline: 1. Overview of the adrenal gland 2. Biosynthesis of adrenal cortical hormones 3. Corticoid steroid action 4. Biosynthesis and regulation of catecholamines from the adrenal medulla 5. Epinephrine action MY1 Repro/Endo - LEFF Adrenal glands Page 2 of 18 Overview of the Adrenal Gland The adrenal glands produce three classes of steroid hormones (mineralocorticoids, glucocorticoids and adrenal androgens), and two catecholamine hormones (epinephrine and norepinephrine). Although it is difficult to assign a single specific physiological func- tion to the adrenal gland, many of the adrenal hormones are involved in some aspect of the body's response to stress. The glucocorticoids, primarily cortisol, play important roles in the regulation of car- bohydrate and protein metabolism and have a multitude of additional effects on many physiological systems and organs in the body. The mineralocorticoid, aldosterone, is vital in maintaining salt and water balance. Although the adrenal androgens DHEA and androstenedione are quite weak androgens compared to testosterone, they may have effects on the establishment and maintenance of secondary sex characteristics. The main catecholamine produced in by the adrenal gland is epinephrine (adrenaline), which mediates the primary physio- Capsule logical responses to 'flight-or- Adrenal gland Zona glomerulosa fight' situations and other physiological stresses. Zona fasciculata Cortex The adrenal gland is Zona reticularis composed of essentially two Medulla functionally and develop- Capsular mentally distinct endocrine artery organs: the cortex (outer HORMONES layer), and the medulla (in- Capsule ner core). Embryologically, Zona Mineralocorticoid the cortex is derived from glomerulosa (aldosterone) mesoderm while the medulla is derived from neural crest cells that migrate into the Glucocorticoids developing cortex. The cor- Zona (e.g., cortisol) tex and medulla synthesize fasciculata different chemical classes of and hormones. The cortex pro- duces cholesterol-derived, Androgens lipid soluble steroid hor- Zona (DHEA and mones, while the medulla reticularis androstenedione) produces water soluble Preganglionic amine hormones derived sympathetic terminal from tyrosine. Medulla Epinephrine The cortex is composed of three discreet layers, each of which makes a distinct set Medullary of cortical hormones. The vein Figure 50-1 Anatomy of the adrenal gland. An adrenal gland sits on each kidney. The adrenal gland is actually two glands—the cortex and the medulla. The adrenal cortex comprises three layers that surround the medulla. The outermost layer contains the glomerulosa cells that secrete MY1 Repro/Endo - LEFF Adrenal glands Page 3 of 18 specific set of hormones produced from each layer is determined by the set of enzymes present in the cells in that layer. ! Biosynthesis of Adrenal Cortical Hormones Biosynthesis of all of the cortical steroids is initiated by the enzymatic removal of the cholesterol side-chain, by the side chain cleavage (SSC) enzyme. The product (preg- nenolone) is converted, in multiple enzymatic steps, to either cortisol, aldosterone, or an androgen. A representation of the full set of cortical hormone biosynthetic pathways is shown below where the enzymes are shown in the horizontal and vertical boxes. The chemical groups modified by each enzyme are highlighted in the reaction product. Loss-of-function mutation in any of these enzymes reduces the amount of the down- stream products and may cause overproduction of other hormones. For example, re- duced activity of 21α-hydroxylase diminishes production of both cortisol and aldosterone and increases production of the sex steroids.! MY1 Repro/Endo - LEFF Adrenal glands Page 4 of 18 Regulation of Corticosteroid Production The secretion of cortisol is directly controlled by the pituitary hormone ACTH (Adre- nocorticotropic hormone). In the absence of ACTH cortisol secretion is greatly reduced and factors that increase ACTH production increases cortisol's production. Production of ACTH is under hypothalamic control, and there are a number of fac- tors that feed into the hypothalamus that ultimately result in an increase in ACTH pro- duction. When stimulated, small-bodied neurons in the hypothalamus secrete cortico- trophin releasing hormone (CRH), which is transported in the portal vessels to the ante- rior pituitary where it stimulates corticotrophs to release ACTH into the blood stream. ACTH binds to receptors on cells of the zona fasciculata and stimulates the production of cortisol. The production of cortisol is regulated by multiple negative feedback loops. Gluco- corticoids negatively affect their own synthesis primarily by suppression ACTH produc- tion via a direct effect on pituitary corticotrophs. In addition, cortisol acts at the hypotha- lamic level to inhibit CRH secretion. ACTH also exerts a short-term negative feedback on hypothalamic CRF release.  MY1 Repro/Endo - LEFF Adrenal glands Page 5 of 18 Cortisol is secreted into the circulation in an episodic fashion that follows a 24 hour, or circadian, cycle. This cycle is entrained, to circadian rhythms of ACTH secretion. ACTH is secreted by the pituitary in a highly pulsatile manner throughout the day, but with a higher overall rate of secretion in the early morning hours. 20 Sleep Awake 16 Cortisol 12 Cortisol (mg/dL) 8 50 ACTH 4 25 ACTH (pg/mL) 0 0 12 4 8 12 4 8 12 Midnight Noon Midnight Time elapsed (hr) Figure 50-5 Rhythm of ACTH and cortisol. The corticotrophs release ACTH in a circadian rhythm, greater in the early morning hours and less late in the afternoon and early evening. Superimposed on the circadian rhythm is the effect on the corticotrophs of the pulsatile secretion of CRH by the hypothalamus. Thus, ACTH levels exhibit both circadian and pulsatile behavior. Although both ACTH and cortisol are secreted ACTH is generated from proteolytic digestion of the POMC precursor peptide episodically, the duration of the ACTH bursts is briefer, reflecting the shorter half-life of ACTH in plasma. In the adult, POMC (Data (proopiomelanocortin) from Young produced JB, Landsberg L: Catecholamines andinthecorticotrophs adrenal medulla.is processed to In Wilson JD, Foster DW, Kronenberg HM, Larsen PR yield several peptides and ACTH. In the fetus, some corticotrophs (eds): Williams Textbook produce a different of Endocrinology, 9th ed, pp 665-728. Philadelphia: WB Saunders, 1998.) set of peptides, including the melanocyte stimulating hormones γ-MSH and α-MSH. When ACTH is pathologically overproduced (as in Addison’s), some POMC is pro- cessed in the fetal pattern, producing the MSHs and causing a hyperpigmentation of skin. Signal peptide POMC N N N-terminal peptide J-Peptide ACTH (1–39) β-LPH (1–89) C Anterior lobe of N-terminal peptide (1–76) J-Peptide ACTH (1–39) β-LPH (1–89) pituitary (1–30) POMC γ-MSH J-Peptide CLIP γ-LPH (51–76) (1–30) (18–39) Intermediate α-MSH (1–56) β-Endorphin lobe of the (1–13) (59–89) pituitary (fetal life and γ-MSH J-Peptide CLIP γ-LPH pregnancy) (51–76) (1–30) α-MSH (18–39) (1–56) β-Endorphin (1–13) (59–89) Figure 50-4 The primary gene transcript is the preprohormone POMC. The processing of POMC yields a variety of peptide hormones. This processing is different in the anterior and intermediate lobes of the pituitary. In the anterior pituitary, POMC yields a long N-terminal peptide, a joining (J) peptide, ACTH, and β-LPH. In the intermediate pituitary, the same POMC yields a short N-terminal peptide, γ-MSH, J peptide, α-MSH, CLIP, γ-LPH, and β-endorphin. Metabolism by the intermediate lobe is only important during fetal life and pregnancy. (Data from Young JB, Landsberg L: Catecholamines and the adrenal medulla. In Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds): Williams Textbook of Endocrinology, 9th ed, pp 665-728. Philadelphia: WB Saunders, 1998.) MY1 Repro/Endo - LEFF Adrenal glands Page 6 of 18 ACTH action in the adrenal cortex ACTH exerts its action on adrenal cortex cells through a specific GPCR (the ACTH receptor) on the cell membrane that activates the PKA (protein kinase A) signaling pathway. Activation of this pathway in cortical cells stimulates hormone production by multiple mechanisms. 1) Stimulation of the rate-limiting step catalyzed by the side-chain cleavage en- zyme (also known as SSC, CYP11A1 and 20,22-desmolase) 2) Stimulation of 11β-Hydroxylase and the other enzymes required for cortico- steroid synthesis 3) Stimulation of cholesterol uptake from plasma (by increasing Low density lip- oprotein (LDL) receptor levels) 4) Stimulation of cholesterol ester hydrolysis, which acts to generate free choles- terol for steroid biosynthesis If ACTH levels are chronically elevated (as opposed to the normal periodic eleva- tions), hyperplasia of adrenal cortex can occurs. While the production of cortisol is very strongly stimulated by ACTH, this is not the case for the other cortical hormones. Although ACTH does influence aldosterone pro- duction, the primary stimuli for aldosterone biosynthesis are increased blood potassium levels, low blood pressure, and angiotensin II. ! MY1 Repro/Endo - LEFF Adrenal glands Page 7 of 18 Corticosteroid Action Like all steroid hormones, the physiologic action of cortisol is exerted through a spe- cific intracellular receptor within target cells. The cortisol receptor, known as the gluco- corticoid receptor (or GR), is found in virtually all cells in the body. As with many steroid hormone receptors, In the absence of hormone, the receptor is located in the cyto- plasm. Binding of hormone indices the receptor to translocate to the nucleus where it binds to hormone response elements (HREs) in the regulatory regions (promoters) of target genes and stimulates (or suppress) transcription of these genes. In the case of cortisol, its target genes are different in each tissue, so that the set of genes activated by the hormone in the liver is not identical to the cortisol-responsive genes in the brain. The wide range of tissue-specific responses to cortisol, combined with the widespread distribution of GR, generates an enormous complexity in how the body responds to cortisol. MY1 Repro/Endo - LEFF Adrenal glands Page 8 of 18 Physiological effects of cortisol Carbohydrate metabolism. One of the primary effects of cortisol, and the basis of its classification as a glucocorticoid, is to increase blood glucose levels. This is accom- plished by stimulating hepatic gluconeogenesis and glucose production and inhibiting peripheral glucose utilization (via antagonism of insulin action). Protein metabolism. Cortisol inhibits protein synthesis and increases protein break- down especially in muscle and liver. The liberated amino acids are used by the liver for gluconeogenesis, a process that is strongly stimulated by glucocorticoids. These nega- tive effects on protein metabolism, may contribute to the reduction of connective tissue integrity that is seen in syndromes of chronically elevated glucocorticoids (Cushing’s). Lipid metabolism. Cortisol increases lipolysis in peripheral adipose beds and raises circulating fatty acid levels. A large portion of the fat liberated from adipose is absorbed and stored in the liver, producing fatty liver. Importantly, the lipid-releasing activity of cortisol does not occur equally in all adi- pose tissue depots. In conditions of chronically elevated cortisol, many peripheral adi- pose beds are reduced in size while others, mainly in the face and trunk, actually ex- pand. MY1 Repro/Endo - LEFF Adrenal glands Page 9 of 18 Inflammation and the immunity. The effects of cortisol on inflammation are complex and not fully understood. Although cortisol plays a role in all stages of a normal inflam- matory response, from initiation to resolution, it is most commonly associated with im- mune suppression. The anti-inflammatory effect of cortisol is due, in part, to suppres- sion of prostaglandin production, mainly via inhibition of phospholipase-A2. Among many other effects, cortisol can also suppress act lymphoid tissues, to suppress the conversion of T-cells to antibody forming cells. The immunosuppressive and anti-inflammatory actions of the glucocorticoids are exploited clinically for the inhibition of transplant rejection and for the treatment of aller- gic and autoimmune syndromes. The risks associated with this therapy are increased susceptibility to infection and the induction of Cushing's syndrome, similar to Cushing’s disease, which is caused by ACTH-secreting pituitary adenoma. MY1 Repro/Endo - LEFF Adrenal glands Page 10 of 18 Effects of cortisol on insulin signaling The metabolic effects of cortisol conspire to increase insulin resistance and promote a ‘pro-diabetic’ state. Cortisol inhibits insulin action in both the liver and muscle (see insulin dose response curves on below). This effect of cortisol is evident in conditions of chronic hypercortisolemia, as in Cushing’s, which are often accompanied by diabetes. Global actions of Cortisol MY1 Repro/Endo - LEFF Adrenal glands Page 11 of 18 Aldosterone The primary action of al- Brain CRH Anterior and pituitary ACTH dosterone is to increase AVP blood pressure by promoting Na+ and water retention and lowering plasma K+ concen- trations. Aldosterone acts on Three pathways stimulate the glomerulosa its own nuclear receptor cells to synthesize aldosterone. termed the mineralocorticoid Renin-angiotensin ACTH Increased receptor. The mineralocorti- plasma cascade (green) (blue) coid receptor is present in the [K+] (red) principal cells of the distal tu- bule and the collecting duct of Angiotensin II Adrenal cortex the kidney nephron, it up- regulates a Na+/K+ exchanger ACE in lung that pumps three sodium ions out of the cell, into the inter- + stitial fluid and two potassium Plasma [K ] ions into the cell from the in- terstitial fluid. This results in Aldosterone reabsorption of sodium (Na+) Angiotensin I ions and water (which follows sodium) into the blood, and a Kidney net loss of plasma K+ ions Renin into the urine. Angiotensinogen Liver Na+ excretion H2O excretion + [K ] excretion Plasma [K+] Effective circulating volume Extracellular fluid volume Blood pressure Figure 50-6 Control of aldosterone secretion. Three pathways, shown in three different colors, stimulate the glomerulosa cells of the adrenal cortex to secrete aldosterone. Copyright © 2009 by Saunders, an imprint of Elsevier Inc. All rights reserved. MY1 Repro/Endo - LEFF Adrenal glands Page 12 of 18 Corticosteroid ‘Cross-Talk’ at the molecular level A peculiarity of the corticosteroid family of hormones is the molecular similarity of the glucocorticoid cortisol and mineralocorticoid aldosterone. This chemical similarity leads to the possibility of cortisol interacting with, and activating, the mineralocorticoid recep- tor. The fact that cortisol frequently circulates at much higher concentrations than al- dosterone presents the possibility of this receptor ‘cross-talk’ in many tissues. This po- tential problem is managed by the expression of 11-beta-dehydogenase-2 (11βHSD2) in tissues where the mineralocorticoid receptor is present, such as the kidney. 11βHSD2 converts the active cortisol into the inactive cortisone. ! MY1 Repro/Endo - LEFF Adrenal glands Page 13 of 18 Biosynthesis and regulation of catecholamine production The adrenal medulla comprises approximately 25% of the adrenal gland mass and produces catecholamine hormones: norepinephrine, epinephrine (and a small amount of dopamine). While most of the norepinephrine found in circulation is from sympathetic nerve endings rather than from the adrenals, nearly all the epinephrine found in circula- tion is derived from the adrenal gland. Because the autonomic nervous system exerts direct control over the hormone producing chromaffin cells in the medulla, hormone re- lease occurs quickly in response to stressors such as imminent danger, and is the main mediator of the ‘flight-fight’ response. In many ways, the adrenal medulla is analogous to post ganglionic sympathetic neu- rons. Both cell types are derived from neural precursors during development. In addi- tion, both release catecholamines in response to sympathetic signals (acetylcholine). They differ in that the adrenal medulla makes the distant acting hormone epinephrine, while post ganglionic sympathetic neurons secrete norepinephrine which acts specifical- ly on target cells at the point of release. ! ! MY1 Repro/Endo - LEFF Adrenal glands Page 14 of 18 Synthesis of catecholamines The catecholamines are synthesized in the chromaffin cells of the adrenal medulla. Tyrosine hydroxylase is the rate limiting enzyme in the pathway and is stimulated by sympathetic nerve action and is subject to auto-regulatory negative feedback inhibition by norepinephrine. Norepinephrine is converted to epinephrine by, phenylethanolamine N-methyltransferase (PNMT). This enzyme is stimulated by cortisol, which occurs since the medulla is directly downstream from the circulation draining the adrenal cortex. ! MY1 Repro/Endo - LEFF Adrenal glands Page 15 of 18 Factors that stimulate catecholamine release Catecholamine release from the adrenal medulla is mediated by the sympathetic nervous system that transmits signals from the CNS to the adrenal gland when certain stress situations are present. Among these stresses are: 1. Fight/Flight stimuli 2. Anxiety 3. Pain 4. Increased sympathetic nervous system tone 5. Trauma, hypovolemia, anoxia 6. Hypoglycemia 7. Exercise 8. Extreme temperatures Catecholamine Action The effects of norepinephrine and epinephrine are mediated by the actions of two classes of adrenergic receptors: alpha (α) and beta (β). Both alpha and beta recep- tors have multiple family members - e.g. α1, α2, β1 and β2. Although many hor- mones have their biological effects by in- teracting with a single highly specific re- ceptor (e.g. insulin), the situation with the catecholamines is more complex. Both hormones can bind to and activate all of the adrenergic receptors - albeit with dif- ferent affinities. Depending on the amount of each receptor on a given cell type, and the relative concentration of the two hor- mones, the biological effects of the cate- cholamines can vary substantially from one tissue to the next. General actions of catecholamines 1. Cardiovascular/Circulatory Sys- tem: Increased rate and force of cardiac contraction. Constriction or dilation of arterioles causing a shift in blood flow patterns. 2. Nervous System: Increased alertness, and nerve activity in general. 3. Metabolism: Increased blood glucose, FA, ketone bodies. Increased metabolic rate. 4. Digestive System: Decreases GI motility and secretion. MY1 Repro/Endo - LEFF Adrenal glands Page 16 of 18 Metabolic effects of adrenergic receptor activation In effects of epinephrine on carbohydrate metabolism are mediated mainly by the liver. The primary direct effect of epinephrine is the stimulation of hepatic glucose pro- duction and release. This is brought about by the combined effects of increased of gly- cogenolysis and gluconeogenesis. Both effects are mediated by the beta-adrenergic receptor, which signals through cAMP/PKA pathways. Additional epinephrine-mediated effects in muscle, adipose and the pancreas contribute to the overall metabolic outcome of rapidly increasing energy availability. ! MY1 Repro/Endo - LEFF Adrenal glands Page 17 of 18 Rapid degradation of catecholamines The biological actions of catecholamines are very brief, lasting only ∼10 seconds in the case of epinephrine. Circulating catecholamines are degraded first by the enzyme catecholamine-O-methyltransferase (COMT), which is present in high concentrations in endothelial cells and the heart, liver, and kidneys. COMT converts epinephrine to metanephrine. A second enzyme, monoamine oxidase, converts these metabolites to vanillylmandelic acid (VMA). Direct measurement of epinephrine is difficult, but the concentration of metanephrines, and VMA in the urine is a useful indicator of the total adrenal catecholamine production. Adrenal Gland Pathologies Glucocorticoid excess is most commonly seen in individuals receiving corticosteroids for treatment of chronic inflammatory. Less commonly, individuals overproduce cortisol either because of a primary cortisol-producing adrenal tumor or secondary to a pituitary adenoma that produces ACTH. In either case, the cortisol excess causes a constellation of symptoms including truncal adiposity (abdomen, neck, face), hypertension, loss of subcutaneous adipose and connective tissue in the extremities, reduced bone density & mineralization, muscle weakness and wasting, and hyperglycemia. This constellation is referred to as Cush- ing's syndrome. The term Cushing's disease is used for the subset of cases caused by an ACTH-secreting pituitary tumor. MY1 Repro/Endo - LEFF Adrenal glands Page 18 of 18 Glucocorticoid deficiency - or more accurately adrenal insufficiency (which includes both glucocorticoid and mineralocorticoid) – also produces a wide array of symptoms. Conditions leading to glucocorticoid insufficiency, no matter the origin, are referred to as Addison's disease. Although tuberculosis was once a common cause of primary ad- renal insufficiency, today autoimmune adrenal disease is the most common cause. Failure of adrenal cortical hormone secretion leads to increases in circulating concentrations of ACTH as well 3º as other products of POMC including α-MSH and γ- MSH, which cause skin hyperpigmentation. The com- bined absence of glucocorticoid and mineralocorticoid 2º leads to hypotension and hypoglycemia and hyperkale- mia. Addison’s is classified as either: primary, secondary 1º or tertiary depending on where the defect resides; the adrenals, the pituitary or the hypothalamus respectively.