Stress and the Adrenal Axis: Nuclear Hormones and Steroidogenesis PDF

Andrea C. Gore, PhD Professor, Division of Pharmacology and Toxicology [email protected] 1 By the end of this lecture you will understand: ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ Anatomy of the adrenal medulla & cortex Adrenocortical hormones (mineralocorticoid, glucocorticoid, sex hormones) Introduction to Ste...

Andrea C. Gore, PhD Professor, Division of Pharmacology and Toxicology [email protected] 1 By the end of this lecture you will understand: ¡ ¡ ¡ ¡ ¡ ¡ ¡ ¡ Anatomy of the adrenal medulla & cortex Adrenocortical hormones (mineralocorticoid, glucocorticoid, sex hormones) Introduction to Steroid Hormones Steroidogenesis Steroid hormone receptors Stress response Hypothalamic-pituitary-adrenal axis & hormones Pathophysiology of adrenocortical disorders 2 ¡ Above kidney, in fat pad § Adrenal cortex (mesodermal origin) § Adrenal medulla (neural crest origin) Glomerulosa Fasciculata Reticularis Courtesy of Dr. Keith Parker, UTSouthwestern Medulla 3 4 Zone Controlled by Effect Mineralocorticoids (Aldosterone) Glomerulosa ReninAngiotensin Na+, K+ balance, fluid volume Glucocorticoids (corticosteroids, especially cortisol) Fasciculata + Reticularis Hormone Stress response, related metabolic changes Cortex Androgens (mainly DHEA) Medulla Catecholamines (Epi, Norepi) ACTH Androgendependent processes in females; muscle mass, energy balance Preganglionic fibers of SNS Rapid stress response Fasciculata + Reticularis No zone; internal to cortex 5 ¡ ¡ ¡ ¡ ¡ Derive from cholesterol precursor Are synthesized via a series of enzymatic reactions beginning with cholesterol side-chain cleavage Enzymes are expressed in a tissue-specific manner (e.g. in layers of the adrenal; in gonads; in fat; in brain; etc) Include mineralocorticoids, glucocorticoids, sex steroids (estrogens, androgens, progestins), vitamin D, others Lipophilic 6 Steroids and steroidogenesis: overview C D A Cholesterol B Estradiol Cortisol Yellow box: Key hormones Purple box: Key enzymes (drug targets) DHT 7 7 CYP11A1: P450 Sidechain cleavage (rate-limiting) ¡ ¡ Orange: zona glomerulosa (mineralocorticoids – aldosterone) Gray: zona fasciculata and reticularis (glucocorticoids) CYP21 (necessary for both cortisol and aldosterone) CYP11B1 (unique to cortisol) CYP11B2 (unique to aldosterone) 8 ¡ Receptors are proteins in the steroid hormone family, which is a subset of the nuclear hormone superfamily ¡ Receptors are abundant and heterogeneously expressed in many tissues. ¡ Steroids circulate in association with binding proteins (often called binding globulins) § In the case of glucocorticoids, that is corticosteroid-binding globulin (CBG) and albumin (the latter binds to all steroids). 9 Corticosteroid binding globulin ¡ ¡ ¡ ¡ GR gene is Nr3c1 As nuclear hormone superfamily members, steroid receptors (proteins) are in cytosol/nucleus when unbound, and translocate to nucleus when bound. The receptor-ligand complex acts as a transcription factor. Binding of receptor-ligand dimers modulate gene expression and governs protein synthesis. Some proteins are involved in sequestration & transport, and others are transcriptional regulators. ¡ ¡ ¡ Cortisol in humans and other primates (corticosterone in rats) is the major glucocorticoid Binding to plasma proteins (CBG) controls distribution and delivery to target tissues Binding also delays metabolic clearance and prevents marked fluctuations § 96% bound to Corticosteroid-binding globulin (CBG; also called transcortin) – which is synthesized in liver. Half-life of cortisol is 60-90 min. § 4% bound to albumin ¡ Metabolized in liver by conjugation to glucuronide or sulfate groups, which inactivates them, and secreted in urine and stool. 11 Hypothalamus – Corticotropin-releasing hormone (CRH) - 41 amino acid peptide; signals via GPCR on pituitary target cells. Pituitary – Adrenocorticotropic hormone (ACTH) – 39 aa tropic peptide, made in corticotropes half life of 10 min. Cleaved from Pro-opiomelanocortin (POMC) gene – one of many peptides [Note: POMC is also a precursor to melanocortins; see energy balance unit] ACTH receptor is a GPCR. Adrenal – ACTH binds to GPCRs to stimulate cortisol, DHEA release. Negative feedback: from cortisol to CRH neurons/corticotropes 12 Mediate stress response. Traditional feed-forward (from hypothalamus to pituitary to adrenal). Negative feedback (from adrenal glucocorticoids). Diurnal rhythm (peak in AM). Stress overcomes negative feedback, stimulates steroidogenesis. Suppress inflammation. Exogenous glucocorticoids are used for replacement therapy when endogenous production is impaired. These drugs have substantial side effects so risk-benefits must be considered. 13 ACG: The point of this slide is to show the diurnal rhythm, as well as association with food (glucose) intake. 14 ¡ Stress: Perturbation of physiological or psychological homeostasis ¡ Stressor: Any noxious stimulus that brings about the stress response § Emotional stressors – fear, anxiety § Bodily injury – surgery § Hypoglycemia § Volume depletion (also triggers vasopressin release) 15 § Glucocorticoids are anti-inflammatory & immunosuppressive § Profound effects on immune responses of lymphocytes. § Anti-inflammatory actions make glucocorticoids among the most prescribed drugs. § Therapeutically, they used for diseases with undesirable immune reactions including transplantation rejection. § Glucocorticoids can reduce expression of proinflammatory cytokines, and diminish inflammatory responses. 16 § Carbohydrate and protein metabolism § Overall goal is protection of brain/heart from glucose starvation. § Lipid metabolism Glucocorticoids stimulate gluconeogenesis in the liver. § Needed for normal lipid metabolism. Body fat is redistributed in hypercortisolism (Cushing’s). § Skeletal Muscle § Normal corticoid levels are needed for skeletal muscle function. § CNS – Mood, behavior, neural excitability § Blood § Decrease lymphocyte numbers, increase leukocyte numbers. 17 ¡ Excessive glucocorticoid secretion – Cushing’s syndrome § Moon-face, truncal obesity, hypertension, osteoporosis, glucose intolerance/diabetes mellitus, protein depletion, mental symptoms ¡ Excessive mineralocorticoid secretion in hyperaldosteronism § Na+ retention (usually without edema), K+ depletion, leading to hypertension, muscle weakness, polyuria, hypokalemia, metabolic alkalosis (elevated serum bicarbonate) ¡ Excessive adrenal androgen secretion § Virilization, hirsutism, precocious puberty, or disorder of sexual development 18 ¡ Cushing’s syndrome – excess cortisol. § ¡ ¡ ¡ Over-secreting tumor is most common cause 2-4 per million population Much more common in women Excessive gluconeogenesis leads to lipid excess, hyperglycemia 19 ¡ Deficient adrenal hormone secretion § Glucocorticoid deficiency: Weakness, fatigue, malaise, anorexia and GI symptoms, weight loss, hypotension, hypoglycemia, stress intolerance, hyperpigmentation, behavioral changes. § Mineralocorticoid deficiency: renal Na+ wasting, K+ retention, severe dehydration, hypotension, hyponatremia, hyperkalemia, metabolic acidosis. ¡ Can be due to primary (adrenal) or secondary (pituitary) cause § Primary adrenocortical insufficiency (Addison’s disease) - undersecretion by all three adrenal cortical layers and hormones – usually autoimmune § Secondary - Occurs because of pituitary abnormality leading to insufficient ACTH - Only cortisol and DHEA (but not aldosterone) are deficient 20 ¡ Made in zona fasciculata and reticularis § Primarily Dehydroepiandrosterone (DHEA) and its sulfated metabolite, DHEAS § Has anabolic and masculinizing effects ▪ About 100X weaker in activating the androgen receptor (AR) than testosterone ▪ In blood, binds mainly to albumin ▪ Physiologically significant in females where it governs: ▪ Growth of pubic and axillary hair ▪ Enhancement of pubertal growth spurt ▪ Development and maintenance of female sex drive § ACTH is the stimulus for DHEA synthesis 21 Congenital adrenal hyperplasia (CAH) – excessive secretion of adrenal androgens due to an enzyme defect in cortisol steroidogenesis and loss of normal negative feedback from cortisol. § The increased CRH-ACTH drives the adrenal, and DHEA synthesis is sensitive to ACTH. § DHEA, while a weak androgen, can masculinize an affected individual, especially females who normally have low androgen concentrations. § Leading cause of ambiguous genitalia: 1 in 1000 births (mild form) or 1 in 15,000 births (severe form). May be more common in certain ethnic groups. § Treatment: lifelong glucocorticoid therapy (hydrocortisone) 22 By the end of this lecture you will understand: ¡ Anatomy of the adrenal medulla & cortex ¡ Adrenocortical hormones (mineralocorticoid, glucocorticoid, sex hormones) ¡ Introduction to Steroid Hormones ¡ Steroidogenesis ¡ Steroid hormone receptors ¡ Stress response ¡ Hypothalamic-pituitary-adrenal axis & hormones ¡ Pathophysiology of adrenocortical disorders 23