Adrenocortical Hormones PDF

Week 3.1 Adrenocortical Hormones Lecture Objectives  At the end of this topic the student should be able to: ◦ ◦ ◦ ◦ ◦ ◦ Describe the anatomy and histology of the adrenal gland List the major hormones produced by the adrenal gland Describe the synthesis and mode of action of the hormones List the p...

Week 3.1 Adrenocortical Hormones Lecture Objectives  At the end of this topic the student should be able to: ◦ ◦ ◦ ◦ ◦ ◦ Describe the anatomy and histology of the adrenal gland List the major hormones produced by the adrenal gland Describe the synthesis and mode of action of the hormones List the physiological effects of adrenocortical hormones Describe the regulation of adrenocortical hormone synthesis Describe the role of adrenocortical hormones in health and wellness ADRENAL MEDULLA AND CORTEX Adrenal Gland  Adrenal Medulla ◦ functionally related to the sympathetic nervous system and secretes mainly epinephrine & some norepinephrine  Adrenal Cortex ◦ forms the bulk of the gland secretes mineralcorticoids, corticosteroids & androgens Adrenal Medulla  The inner zone of the adrenal gland ◦ approximately 20% of the tissue.  The adrenal medulla is of neuroectodermal origin  Specialized ganglion in the sympathetic nervous system ◦ Innervated by the splanchnic nerves ◦ Cell bodies of its preganglionic neurons are located in the thoracic spinal cord. Adrenal Medulla & Chromaffin Cells  Chromaffin cells of the adrenal medulla secrete catecholamines (epinephrine and norepinephrine) into the general circulation.  Adrenal medulla secretes mainly epinephrine (80%) and a small amount of norepinephrine (20%)  (PNMT) phenylethanolamine-N-methyltransferase ◦ PNMT catalyzes the conversion of norepinephrine to epinephrine. CATECHOLAMINES: norepinephrine, and epinephrine. dopamine, enkephalin and enkephalin-containing peptides, and a few other hormones into the blood stream (activated /released when we perceive a threat) Adrenocorticotropic Hormone (ACTH) Corticotropin Release Hormone (CRH) Adrenocorticotropic Hormone (ACTH) Aldosterone Cortisol Androgens Adrenal Cortex  Produces >24 steroid hormones collectively known as corticosteroids Adrenal Cortex Zona Glomerulosa Mineralocorticoids Aldosterone Zona fasciculata Glucocorticoids Cortisol Zona reticularis Androgens Adrenal Cortex  Zona Glomerulosa (outer zone) ◦ Aldosterone ◦ enzyme aldosterone synthase ◦ Renal function  BP  Zona Fasciculata (Middle Zone) ◦ Glucocorticoids ◦ Cortisol and corticosterone  Zona Reticularis (inner zone) ◦ Secretes weak androgens (dehydroepiandrosterone (DHEA) and androstenedione) and some glucocorticoids Adrenal Medulla  Chromaffin cells produce the catecholamines (epinephrine and norepinephrine)  EPI and NE) needed to coordinate the bodily "fight-or-flight" response to fear, stress, exercise, or conflict Adrenal Medulla *Dopamine leads to increased heart rate and blood pressure. Anxiety-inducing stress task is associated with significant dopamine release Corticosteroids  Adrenocortical hormones are synthesized from cholesterol  The rate-limiting step in the synthesis of adrenocortical hormones is the side-chain cleavage of cholesterol to form pregnenolone  All the subsequent steps in the synthesis of adrenocortical hormones occur either in the endoplasmic reticulum or mitochondria First step in each pathway: cholesterol to pregnenolone Corticosteroids secreted by adrenal cortex  Mineralocorticoids (Aldosterone) C21 steroids that have important effects on sodium and potassium balance  Glucocorticoids (Cortisol) C21 steroids that influence carbohydrate, fat, and protein metabolism  Sex hormones C19 steroids that are mostly weak androgens (DHEA [Dehydroepiandrosterone] and androstenedione) and contribute to secondary sex characteristics Corticosteroids  The secretion of mineralocorticoids and glucocorticoids is essential to life. ◦ Only small amounts of sex hormones are normally secreted by the adrenal cortex, and they have little effect on reproductive function - contribute to secondary sex characteristics. Hyperaldosteronism - Conn syndrome Hypoaldosteronism – Addison’s Disease Adrenocortical Hormones & CBG  90% to 95% of the cortisol in the plasma is bound to plasma proteins  Corticosteroid-binding globulin (CBG) ◦ (Transcortin)  Longer half-life  Adrenocortical Hormones are Metabolized in the Liver Regulation of Hormones  The principal regulators of the adrenals are  CRH – Hypothalamus   corticotropin releasing hormone ACTH - Anterior pituitary ◦ adrenocorticotropic hormone Adrenocorticotropic Hormone (ACTH)  Made in the corticotroph cells of the anterior pituitary gland  Secreted in response to CRH  Stimulates the Adrenal Cortex  Release of Aldosterone, Cortisol & Androgens Adrenal Cortex ACTH Family  ACTH family is derived from a single precursor ◦ pro-opiomelanocortin (POMC)  ACTH - Stimulates adrenal cortex  β-lipotropin - lipid-mobilizing functions  β-endorphin - an endogenous opiate  Melanocyte-stimulating hormone (MSH)  pigmentation in lower vertebrates but has little activity in humans. ACTH – Rate limiting enzyme  ACTH stimulates cholesterol desmolase  The synthesis and secretion of steroid hormones by the adrenal cortex depend on the stimulation of cholesterol desmolase. In the absence of ACTH, biosynthesis of adrenocortical steroid hormones ceases Aldosterone  Primary Mineralocorticoid  Aldosterone accounts for approximately 90% of the mineralocorticoid activity  Aldosterone Increases Sodium Reabsorption and Potassium Secretion Aldosterone Aldosterone Secretion  Aldosterone is released from  Zona Glomerulosa of the adrenal Cortex [K+]  ACTH (Minor Stimuli)  Angiotensin II (Major Stimuli) Aldosterone  The zona glomerulosa, which secretes aldosterone depends on ACTH for the first step in steroid biosynthesis  After synthesis, aldosterone it is controlled separately via the reninangiotensin-aldosterone system. (RAAS) Aldosterone  Angiotensin II ◦ major regulator of aldosterone  Angiotensin II increases the synthesis and secretion of aldosterone by stimulating cholesterol desmolase and aldosterone synthase, ◦ the first and last steps in the pathway Renin–Angiotensin II–Aldosterone System  Decrease in ECF volume causes a decrease in renal perfusion pressure  Decrease in renal perfusion pressure stimulates renin secretion by the juxtaglomerular cells of the kidney  Renin catalyzes the conversion of angiotensinogen to angiotensin I  ACE converts Angiotensin I to Angiotensin II  Angiotensin II acts on the zona glomerulosa to stimulate aldosterone synthesis. Aldosterone maintains ECF volume  Aldosterone stimulates Na+ reabsorption by the kidney ◦ Aldosterone increases sodium reabsorption from the tubular epithelial cells of the kidneys back into the blood while simultaneously moving potassium ions from the blood into the kidneys for eventual excretion in urine.  Reabsorption of Na+ promotes reabsorption of filtrate (water)  Restore ECF & Na+ content and ECF volume  BP Aldosterone - Effects  Aldosterone and other mineralocorticoids act on the distal nephron, especially the principal cells of the collecting duct, to increase:  Sodium reabsorption  Potassium secretion Aldosterone Affects Electrolyte Transport in Other Organs  Colon : Aldosterone increases sodium reabsorption from the colon and promotes potassium excretion in the feces.  Sweat and Salivary glands: ◦ increases sodium reabsorption and promotes potassium excretion in sweat and salivary glands Serum K+ & Aldosterone  Aldosterone plays a critical role in eliminating ingested potassium and in feedback regulation of the plasma potassium concentration  Elevated  [K+] levels in blood  Increase Aldosterone Increase in plasma potassium concentration increase aldosterone secretion, which in turn stimulates tubular secretion of potassium  K+ lost in the urine Actions of Mineralocorticoids  Increase Na+ reabsorption  Increase K+ secretion ◦ Increase H+ secretion (Table 9-11) Glucocorticoids Glucocorticoids  95% of glucocorticoid activity exerted by the adrenocortical hormones can be attributed to cortisol The rate-limiting step: sidechain cleavage of cholesterol to form pregnenolone Corticosterone Corticosterone  Corticosterone circulates in blood at 10-20-fold lower levels than cortisol  Corticosterone contributes almost 40% of total active glucocorticoids in the CSF  Corticosterone may play a significant role in human brain function. Cholesterol Desmolase & ACTH  The rate-limiting step in the synthesis of adrenocortical hormones is catalyzed by cholesterol desmolase.  Cholesterol desmolase is stimulated by ACTH Regulation of Glucocorticoid Secretion  The secretion of glucocorticoids by the zonae fasciculata /reticularis is regulated exclusively by the hypothalamic-pituitary axis Effects of ACTH  Stimulate transfer of stored cholesterol to the mitochondria and to activate cholesterol desmolase.  ACTH has a pulsatile and diurnal secretory pattern that drives a parallel pattern of cortisol secretion.  The nocturnal peak of ACTH (i.e., preceding awakening) is driven, in turn, by a burst of CRH secretion. Regulation of Glucocorticoid Secretion  The regulation of cortisol secretion has a pulsatile nature and a diurnal (daily) pattern Regulation of Glucocorticoid Secretion  An average of 10 secretory bursts over 24-hours  The lowest secretory rates occur during the evening hours and just after falling asleep (e.g., midnight)  The highest secretory rates occur just before awakening in the morning (e.g., 8 AM) Hypothalamus - “internal clock”  The “internal clock” - drives the diurnal pattern  The “internal clock” can be shifted by alternating sleepwake cycle (e.g., varying the time of going to sleep and awakening).  The diurnal pattern is altered or abolished by coma, blindness, or constant exposure to either light or dark. Sleep Loss & Glucocorticoids Even partial acute sleep loss delays the recovery of the H-P-A and is likely to involve an alteration in negative glucocorticoid feedback regulation. Sleep loss could thus affect the resiliency of the stress response and may accelerate the development of metabolic and cognitive consequences of glucocorticoid excess. Glucocorticoids - Functions Actions of Glucocorticoids Increase gluconeogenesis  Increase proteolysis (catabolic)  Increase lipolysis  Decrease glucose utilization  Decrease insulin sensitivity  Gastric acid secretion  Overall, the effects of cortisol are Catabolic and Diabetogenic. Inhibit inflammatory response  Suppress immune response  Enhance vascular responsiveness to catecholamines  Inhibit bone formation  Increase GFR  Decrease REM sleep  Fluid retention  Actions of Glucocorticoids  Glucocorticoids are essential for life.  If the adrenal cortex is removed or is not functioning, exogenous glucocorticoids must be administered, or death will ensue  Gluconeogenesis Vascular responsiveness to catecholamines Suppression of inflammatory and immune responses Modulation of CNS function    Stimulation of Gluconeogenesis  Promote gluconeogenesis and storage of glycogen  Cortisol increases protein catabolism in muscle and decreases new protein synthesis, thereby providing additional amino acids to the liver for gluconeogenesis  Cortisol increases lipolysis, which provides additional glycerol to the liver for gluconeogenesis  Cortisol decreases glucose utilization by tissues and decreases the insulin sensitivity of adipose tissue Glucocorticoids & Gluconeogenesis  Glucocorticoids are essential for survival during fasting because they stimulate these gluconeogenic routes.  In Hypocortisolism (e.g. Addison disease)  Hypoglycemia  In Hypercortisolism (e.g., Cushing syndrome),  Hyperglycemia Anti-inflammatory effects  Cortisol induces the synthesis of lipocortin, an inhibitor of the enzyme phospholipase A2 ◦ Phospholipase A2 liberates arachidonic acid from membrane phospholipids and provides the precursor for the prostaglandins and leukotrienes that mediate the inflammatory response. Anti-inflammatory effects  Cortisol inhibits the production of interleukin-2 (IL-2) and the proliferation of T lymphocytes. ◦ Critical for cellular immunity ◦ Exogenous corticosteroids  Cortisol inhibits the release of histamine and serotonin from mast cells and platelets. Maintenance of vascular responsiveness to catecholamines  Cortisol is necessary for the maintenance of normal blood pressure  Cortisol up-regulates α1-adrenergic receptors (NE/Epi) on arterioles  vasoconstrictive response of the arterioles to catecholamines In Hypocortisolism  Hypotension  In Hypercortisolism Hypertension  Effects on CNS  Glucocorticoid receptors are found in the brain, particularly in the limbic system  Cortisol decreases REM sleep, increases slow-wave sleep, and increases awake time.  (Recall that the largest bursts of ACTH cortisol occur just before awakening.) and Pathophysiology of the Adrenal Cortex Pathophysiology of the Adrenal Cortex HIGH CORTISOL LOW CORTISOL  Addisons Disease: Primary Adrenal insufficiency  Primary Hypercortisolism  (Cushing’s Syndrome) ◦ Adrenal gland tumor (30% of cases) ◦ Low ACTH levels - Endogenous ◦ Low Cortisol/ High ACTH levels (Autoimmune or idiopathic) ◦ Adrenal antibodies present +/- ◦ More common in older women   Seconday Hypercortisolism  (Cushing’s Disease) ◦ Pituitary tumor (70% of cases) Secondary Adrenal Insufficiency (Hypopituitarism) ◦ Low ACTH and Low Cortisol (Trauma / benign tumor) ◦ High ACTH  High Cortisol  Iatrogenic Cushing’s Syndrome ◦ High Cortisol / Low ACTH ◦ Stopping Meds vs. Steroid taper Addisons Disease - LOW CORTISOL  Primary Adrenocortical Insufficiency  Autoimmune Disease (Adrenal antibodies present)  Destruction of all zones of the adrenal cortex  Decreased circulating levels of cortisol, aldosterone, and adrenal androgens ◦ Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has been destroyed. Symptoms of Addison Disease  The loss of glucocorticoids (cortisol) ◦ hypoglycemia, anorexia, weight loss, nausea and vomiting, and weakness  The loss of mineralocorticoids (aldosterone) ◦ hyperkalemia, metabolic acidosis, and hypotension due to decreased ECF volume  In women, the loss of the adrenal androgens, ◦ results in decreased pubic and axillary hair and decreased libido Symptoms of Addison Disease Hypoglycemia  Anorexia, Weight loss,  Nausea, vomiting  Weakness  Hypotension (postural)  Hyperkalemia  Metabolic acidosis    Hyperpigmentation (α-MSH fragment) Decreased pubic and axillary hair in females Addison’s Disease  ACTH Levels  Increased  (Decrease cortisol initiates a “feed forward” mechanism)  Cortisol Levels  Decreased ◦ Autoimmune- Disorder  Adrenal antibodies present +/-  More common in older women  Treatment ◦ Replacement of glucocorticoids and mineralocorticoids X Secondary Adrenal Insufficiency  Adrenal insufficiency due to a lack of ACTH ◦ (Low ACTH  Low Cortisol)   Head trauma -pituitary's inability to release ACTH secondary to head trauma Adenomectomy - Surgical removal of ACTH-producing tumors  Low ACTH and Low Cortisol  Stopping Corticosteroid Medication Abruptly! ◦ Failing to comply with a medically prescribed steroid taper X Addisonian Crisis – Medical Emergency  An endocrinologic emergency with a high mortality rate secondary to physiologic derangements from an acute deficiency of the adrenal hormone cortisol ◦ ◦ ◦ ◦ ◦ ◦ Dehydration Low blood pressure Salt craving Loss of consciousness Severe vomiting and diarrhea Sudden penetrating pain in the lower back, abdomen, or legs Cushing's Disease & Cushing Syndrome Cushing's Disease – Pituitary Tumor  Cushing's Disease is the result of hypersecretion of ACTH from a pituitary adenoma.  The elevated ACTH results in the secretion of excess amount of the glucocorticoid cortisol. Cushing Syndrome – Adrenal Tumor  Cushing’s Syndrome is caused excess secretion of cortisol from an adrenal gland tumor (30% of cases)  The signs and symptoms of either Cushing syndrome or Cushing disease can be the same. Both are the result of excessive glucocorticoids / excess cortisol. Symptoms of Cushing's Disease / Syndrome Hyperglycemia  Muscle wasting /Central obesity  Round face /Buffalo hump/  Osteoporosis  Hypertension  Menstrual disorders in females  Striae - dermal scarring associated with  stretching of the dermis, often result from a rapid change in weight Cushing Presntation Associated Symptoms  Hypertension occurs because cortisol has weak mineralocorticoid activity and because cortisol increases the responsiveness of arterioles to catecholamines (by up-regulating α receptors) 1  In biological females - excess androgens cause virilization and menstrual disorders in females Trunkal obesity / Purpal striae Etiology  Cushing’s Disease - ACTH ◦ Primary defect is in the anterior pituitary, which is overproducing ACTH; ACTH levels are elevated  Cushing Syndrome - Cortisol ◦ The primary defect is in the adrenal cortex, which is overproducing cortisol. Accordingly, ACTH levels are low because the high cortisol levels feed back on the anterior pituitary and inhibit ACTH secretion. Adrenal Androgens – In Females / Males  In females, the adrenal cortex is the major source of androgenic compounds.  In females, DHEA and androstenedione are responsible for the development of pubic and axillary hair and for libido.  The adrenal androgens do not have a significant biological effect in males as testosterone is a more potent androgen. Last Major League Baseball pitcher to win 30 or more games during a season (with a record of 31–6) - 1968 79 Prescribed Corticosteroids Stopping Corticosteroid Medication Abruptly!    A course of oral corticosteroid (i.e prednisone) is prescribed as a tapered dose.  Prednisone Withdrawal It is vitally important that a client completes the entire course as prescribed. Severe fatigue Weakness Body aches Joint pain Nausea Loss of appetite Lightheadedness Irritability or mood swings Failing to take the taper as prescribed can result in prednisone withdrawal