Adrenal gland disorders, steroidogenesis, adrenocortical disorders, actions of cortisol, adrenocortical insufficiency, autoimmune polyendocrine disorder (APS), hypercortisolism, pheochromocytoma, multiple endocrine neoplasm (MEN)

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Biomedical Science
BMS 460
D.Rao Veeramachaneni

22 November Adrenal Gland Disorders Hypofunction or insufficiency of adrenal cortex results in Addison’s disease Hyperfunction or tumors in Zona glomerulosa → hyperaldosteronism Zona fasciculata → hypercortisolism (Cushing’s syndrome) Zona reticularis → adrenogenital syndrome Medulla → pheochromocytoma Steroidogenesis All steroids are generated from cholesterol The types of steroids a cell makes depend upon the types and concentrations of enzymes a cell has Cholesterol → pregnenolone Rate-limiting step Mutations affecting enzymes primarily responsible for the production of cortisol and mineralocorticoids can have secondary effects on sex steroid production. 3β-hydroxysteroid dehydrogenase No glucocorticoids, mineralocorticoids, androgens, estrogens Salt excretion in urine Early death 21α-hydroxylase Most common form of CAH Usually a partial deficiency ACTH elevated, causing an increased shift to sex hormones and masculinization 11β-hydroxylase Decreased cortisol, aldosterone, corticosterone Increased deoxycorticosterone leading to fluid retention and hypertension Masculinization Adrenocortical Disorders: Zona Reticularis 21-hydroxylase deficiency impairs the synthesis of both cortisol and aldosterone. The resultant decrease in feedback inhibition causes increased secretion of ACTH, resulting ultimately in adrenal hyperplasia and increased synthesis of testosterone. Congenital adrenal hyperplasia Adrenogenital syndrome Female pseudohermaphorditism Deficiency of 21- or 11β-hydroxylase in adrenals can have secondary effects on sex steroid production Virilization (adrenogenital syndrome; female pseudohermaphorditism) Virilization can be ameliorated by administering oral steroids to the mother Multiple Actions of Cortisol Cortisol has powerful anti-inflammatory effects. Inhibits phospholipase A 2rom converting membrane phospholipids to arachidonic acid Inhibits cyclooxygenase from converting arachidonic acid to prostaglandins Cortisol exerts catabolic actions on most tissues, with the exception of the liver, on which it exerts anabolic effects. Liver Gluconeogenesis ↑ Potentiates actions of epinephrine and glucagon Glycogenesis ↑ Skeletal muscle Glucose uptake ↓ Glycogenesis ↑ Protein catabolism ↑ Adipose Glucose uptake ↓ Lipolysis ↑ Cortisol increases blood pressure in several ways. It facilitates activity of the sympathetic nervous system by increasing the expression of α- and β-adrenergic receptors in multiple tissues. At increased levels, cortisol exerts mineralocorticoid actions on the kidneys because it is similar in structure to aldosterone. This stimulates renal sodium reabsorption and causes plasma volume expansion. At supraphysiologic levels, cortisol weakens bones by stimulating bone-degrading cells (osteoclasts). In addition, cortisol reduces intestinal absorption of calcium, which can precipitate a compensatory increased in parathyroid hormone secretion, causing further bone breakdown. Adrenocortical Insufficiency Etiology and pathogenesis Primary Hyposecretion of adrenal cortex Autoimmune, infections (e.g., TB), injury Addison disease Secondary Inadequate secretion of ACTH (anterior pituitary) Iatrogenic; prolonged exogenous corticosteroid therapy Tertiary Lack of CRH secretion (hypothalamus) Injury, disease Addison disease Neurological symptoms Lethargy Easy fatigability Depression Nausea, vomiting Hyperpigmentation Weight loss Amenorrhea Fat loss Muscle weakness and atrophy Cardiovascular symptoms Arrhythmia Postural hypotension Syncope Gastrointestinal symptoms Abdominal pain Diarrhea/constipation Anorexia Lab ↓ Corticosteroids ↑ ACTH + ↑ K + ↓ Na - ↓ Cl - ↓ HCO 3 ↓ Glucose Signs and symptoms result from the deficiency of glucocorticoids and mineralocorticoids. Adrenal androgens are also missing, but this deficiency is less obvious clinically. Autoimmune Polyendocrine Disorder, APS Autoimmune adrenalitis, by far the most common cause of primary adrenal insufficiency in developed countries, can occur in one of two clinical settings Autoimmune polyendocrine syndrome type 1 (APS1) is also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy. APS1 is characterized by chronic mucocutaneous candidiasis and abnormalities of skin, dental enamel, and nails (ectodermal dystrophy) occurring in association with a combination of organ-specific autoimmune disorders. APS1 is caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22 Autoimmune polyendocrine syndrome type 2 (APS2) usually starts in early adulthood and presents as a combination of adrenal insufficiency and autoimmune thyroiditis or type I diabetes. Unlike in APS1, mucocutaneous candidiasis, ectodermal dysplasia, and autoimmune hypoparathyroidism do not occur. Most common form of the
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