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ADRENAL CORTEX Introduction • Adrenal Location – Superior Pole of each Kidney – Retroperitoneal – Embedded in the Perirenal fat pad. – Left gland sits slightly more superior than right gland Adrenal Gland • Adrenal Cortex • Adrenal Medulla/ Chromaffin Tissue • Different embryological origins • Not together below birds Adrenal Cortex • Embryology – Intermediate Mesoderm • Zones – Zona Glomerulosa – Zona Fasciculata – Zona Reticularis Medulla Adrenal Cortex Cytology • Lipid Inclusions • Well Developed SER • Mitochondria with Tubular Cristae • Capillary Adjacent to each Cell Cholesterol Side Chain • LDL • De Novo Synthesis Mineralocorticoids Side-Chain Cleavage 3-OH dehydrogenase Steroid Pathways GlucoAndrogens corticoids Estrogen Aromatase 21-hydroxylase 11-hydroxylase 18-hydroxylase 18-OH steroid dehydrog. 17-OH Steroid Dehydrogenase 17-OHase C17-20 Lyase 16-OHase Mineralocorticoids Mineralocorticoids Side-Chain Cleavage 3-OH dehydrogenase Z. Glomerulosa GlucoAndrogens corticoids Estrogen Aromatase 21-hydroxylase 11-hydroxylase 18-hydroxylase 18-OH steroid dehydrog. 17-OH Steroid Dehydrogenase 17-OHase C17-20 Lyase 16-OHase Mineralocorticoids • C-21 Steroids • Primarily produced by zona glomerulosa • Principal mineralocorticoid is aldosterone • Aldosterone actions – Promote Na+ reabsorption – Inhibit K+ reabsorption – Antidiuretic – Acts primarily on the cortical collecting duct & DCT Regulation of Aldosterone Secretion Na+ K+ Na+ K+ Z. Glomerulosa Aldosterone Na+ Reabsorption Kidney K+ Reabsorption Regulation of Aldosterone Secretion Angiotensinogen Kidney Juxtaglomerular Renin Cells Blood Pressure Angiotensin-I Blood Volume Water Reabsorption Na+ Reabsorption Kidney Lung Converting Enzyme Angiotensin-II Aldosterone Z. Glomerulosa Regulation of Aldosterone Secretion Hypothalamus CRH Anterior Pituitary ACTH Z. Glomerulosa Aldosterone Atrial Natriuretic Hormone • 28 amino acid peptide • Similar peptides produced in other organs • Actions – cGMP is second messenger – Increases GFR – Inhibits Na+ and water reabsorption Regulation of ANH Venous Return Venous Return Atrial Stretch Receptors ANH Blood Volume Kidney Water Reabsorption Na+ Reabsorption Glucocorticoids Mineralocorticoids Side-Chain Cleavage 3-OH dehydrogenase Z. Fasiculata GlucoAndrogens corticoids Estrogen Aromatase 21-hydroxylase 11-hydroxylase 18-hydroxylase 18-OH steroid dehydrog. 17-OH Steroid Dehydrogenase 17-OHase C17-20 Lyase 16-OHase Which ones are glucocorticoids? • • • • Cortisol 11-deoxycorticosterone 17-hydroxyprogesterone 17-hydroxypregnenolone • Cortisol Most Potent • 11-deoxycorticosterone, very weak, but does act as feedback effector and has potent mineralocorticoid activity. • Remainder are inactive Serum binding proteins • Corticosteroid binding globulin (CBG) – 75% of Cortisol bound to CBG – 10% of Aldosterone bound to CBG • Albumin – 15% of Cortisol bound to Albumin – 50% of Aldosterone bound to Albumin • Free – 10 % of Cortisol – 40 % of Aldosterone Actions of the Glucocorticoids Anti-inflammatory • Inhibit Prostaglandin production – Inhibit phospholipase A2 • Inhibit secretion of Interleukin-I • Prevents movement of PMNs, lymphocytes, & monocytes from blood into areas of injury. • Decrease lymphocyte production Intermediary Metabolism • • • • • Stimulates gluconeogenesis Protein catabolic Decrease glucose catabolism Increase lipolysis Inhibit DNA synthesis. Growth • Glucocorticoids inhibit mitosis • Inhibit bone formation and mineralization – Decrease intestinal absorption of Ca++ – Stimulates PTH (secondarily) Connective Tissues • Inhibit collagen formation • Decreased bone deposition Blood • Increased intravascular levels of neutrophils • Decreased intravascular levels of lymphocytes, monocytes, & eosinophils • Diminished immune response Cardiovascular • Increase blood pressure – Increased cardiac output – Increased vascular tone – Possibly augmenting action of catecholamines – Increasing number of adrenergic receptors Effects on CNS • Easily enter Brain • Neurons have glucocorticoid receptors • Physiologic effect unknown • Excess or deficiency of glucocorticoids known to profoundly alter behavior and cognitive function. Effects on Other Hormones • Inhibit TSH production • Inhibit GnRH production Ulcer formation • Inhibit Prostaglandin production • Immunosuppression ACTH Side-Chain Cleavage 3-OH dehydrogenase Mineralocorticoids Z. Fasiculata GlucoAndrogens corticoids Estrogen Aromatase 21-hydroxylase 11-hydroxylase 18-hydroxylase 18-OH steroid dehydrog. 17-OH Steroid Dehydrogenase 17-OHase C17-20 Lyase 16-OHase Regulation of Glucocorticoid Secretion STRESS Circadian Rhythm Hypothalamus CRH Anterior Pituitary ACTH Z. Fasciculata & Reticularis Cortisol General Adaptation Syndrome (Selye) Cortisol STRESS • Alarm • Resistance • Exhaustion---Death Time Adrenal Androgens • Dehydroepiandrosterone (DHEA) – DHEA-S • Androstenedione Fetal Adrenal Cortex • Develops first in fetal adrenal gland • Produces androgens (DHEA) • Replaced by definitive cortex Pathologies of the Adrenal Cortex Adrenocortical Insufficiency (Addison’s Disease) • Signs & symptoms – Weakness, Fatigue – Anorexia, Weight loss – Hyperpigmentation (primary only) – Hypotension – G-I disturbances – Salt craving • Crisis • Treatment Hypersecretion (Cushing’s Disease) • Primary, secondary, or tertiary • Ectopic ACTH production • Signs and symptoms – Obesity – Thinning of the skin – Striae – Hirsutism – Hypertension Hypersecretion (Cushing’s Disease) – Weakness – Gonadal dysfunction – Glucose intolerance • Treatment Androgenital syndrome • Excess adrenal androgen production. • Maybe due to tumor Enzyme Deficiencies Side-Chain Cleavage 3-OH dehydrogenase 21-Hydroxylase Deficiency 21-hydroxylase 17-OHase C17-20 Lyase Enzyme Deficiencies Side-Chain Cleavage 3-OH dehydrogenase 11-Hydroxylase Deficiency 21-hydroxylase 11-hydroxylase 17-OHase C17-20 Lyase Enzyme Deficiencies Side-Chain Cleavage 3-OH dehydrogenase 3-Hydroxysteroid Dehydrogenase Deficiency 17-OHase C17-20 Lyase