Adrenocortical hormones Cairo University Faculty of Pharmacy Department of Pharmacology & Toxicology Pharmacology III Practical Sessions Adrenocortical hormones

Mineralocorticoids The adrenal cortex secretes 3 types of hormones: Pharma-III Practical The adrenal cortex secretes 3 types of hormones: Mineralocorticoids (mainly aldosterone) Glucocorticoids (mainly cortisol = hydrocortisol) Androgens

- Regulation of secretion: Hormones Pharma-III Practical - Regulation of secretion: - Hypothalamus CRF Anterior Pituitary ACTH = Corticotropin Adrenal cortex Glucocorticoids

Very important Hormones Pharma-III Practical Very important Long-term administration of exogenous GCs  -ve feedback on ACTH & CRH  Suppression of Adrenal cortices Too rapid withdrawal of GCs  acute adrenal insufficiency  may lead to death!!! Hence, GCs should be GRADUALLY withdrawn

1- Glucocorticoids Diurnal (circadian rhythm) Hormones Pharma-III Practical 1- Glucocorticoids Diurnal (circadian rhythm) ACTH is secreted in irregular bursts through out the day Plasma cortisol tends to rise and fall in response to these bursts These bursts are most frequent in early morning and least frequent in the evening

Actions of GCs: Hormones 1. Metabolism: Pharma-III Practical Actions of GCs: 1. Metabolism: CHO metabolism: maintains an adequate glucose supply within a normal range. Similar to growth hormone (GH),  GC has anti-insulin activity  utilization of glucose by peripheral tissues  GC also  gluconeogenesis   hepatic glucose output Both hyperglycemia   insulin secretion (hyperinsulinemia)

Hormones Pharma-III Practical Protein metabolism: pharmacological or therapeutic dose of GC has catabolic effect on protein. Fat metabolism: pharmacological or therapeutic dose of GC causes peculiar redistribution of fats  thin extremities & central obesity (↑ fat deposition in abdominal area & in face & back of neck & shoulders  moon-face & buffalo hump)

Hormones Pharma-III Practical 2. Electrolyte balance: hydrocortisone has a weak mineralocorticoid-like activity   Na+& H2O reabsorption &  K+ & H+ secretion. 3. CVS:  blood Pressure. 4. CNS: behavioral changes. GIT:  PGs   HCl &  mucus formation  predispose to peptic ulcer. 6. Skeletal muscles: GCs are essential for normal muscle work ( GC  muscle weakness due to  protein catabolism and electrolyte imbalance) 7. Anti-inflammatory effect 8. Immunosuppressive effect

Clinical disorders Hormones Hypercorticism: Cushing`s syndrome Pharma-III Practical Clinical disorders Hypercorticism: Cushing`s syndrome Hypocorticism: Addison`s disease

Clinical state of excess free GCs occurs due to: Hormones Pharma-III Practical Cushing’s syndrome Clinical state of excess free GCs occurs due to: Therapeutic administration of ACTH or GCs for long periods (Iatrogenic CS) Endocrine disorder (Pituitary ACTH dependent   ACTH secretion), Known as cushing disease (Pituitary ACTH independent  adrenal tumor) Tumor outside  the normal pituitary-adrenal system, which produces ACTH (ectopic Cushing’s syndrome) (small cell lung cancer).

The dexamethasone suppression test Hormones Pharma-III Practical The dexamethasone suppression test  is designed to diagnose and differentiate among the various types of Cushing's syndrome  Dexamethasone is given at night & plasma cortisol is measured next morning Cortisol Interpretation Not suppressed Adrenal CS Ectopic CS Suppressed Pituitary CS

Features of Cushing`s syndrome : Hormones Pharma-III Practical Features of Cushing`s syndrome : Hyperglycemia . Thinning of skin. Myopathy & muscle weakness Uneven fat redistribution. Buffalo hump. Moon face.  abdominal fat.

Features of Cushing`s syndrome….. contd. Hormones Pharma-III Practical Features of Cushing`s syndrome….. contd.

Hormones Pharma-III Practical Hypertension. Poor wound healing. Features of Cushing`s syndrome…… contd. Hypertension. Poor wound healing.  susceptibility to infection.  in hair growth. Osteoporosis. (Why?) Euphoria, psychosis or depression.

Hormones Pharma-III Practical Features of Cushing`s syndrome …… contd. Purple or red stria (the weight gain in Cushing's syndrome stretches the skin, which is thin and weakened, causing it to hemorrhage)

☺ Treatment of Cushing’s syndrome: Hormones Pharma-III Practical ☺ Treatment of Cushing’s syndrome:  or stop exogenous GC gradually (risk vs benefit) Surgical removal of the tumor Using inhibitors of biosynthesis, e.g.: Aminoglutethimide (inhibit the 1st step in steroid hormones synthesis from cholesterol). Trilostane (3β- dehydrogenase inhibitor), Metyraponore. (11β-hydroxylase inhibitor) Using GCs receptor antagonists , e.g.: Mifepristone

Addison’s disease Hormones This clinical state occurs due to: Pharma-III Practical Addison’s disease This clinical state occurs due to: 1ry adrenal insufficiency: Adrenal cortex dysfunction ( GCs  ACTH) 2ry adrenal insufficiency: pituitary disorder ( ACTH  GCs) 3ry adrenal insufficiency: hypothalamic disorder ( CRF  ACTH  GCs)

Features of Addison`s disease : Hormones Pharma-III Practical Features of Addison`s disease : Weakness & fatigue. Hypotension. Anorexia & , weight loss. Hyperpigmentation (bronzing of skin) Why? Due to ↑ ACTH, which has structural similarity with MSH  ↑ melanin production by melanocytes also MSH is a by product of ACTH synthesis from common precursor.

☺ Treatment of Addison’s disease: Hormones Pharma-III Practical ☺ Treatment of Addison’s disease: Replacement therapy with: GCs as prednisolone & Mineralocorticoids as fludrocortisone N.B. Immune mediated destruction of the adrenal glands often occurs in conjunction with other autoimmune endocrine diseases such as thyroiditis (hypothyroidism), diabetes mellitus or hypoparathyroidism or non endocrine disease as vitiligo (autoimmune polyendocrine syndrome )

Physical examination Diagnosis: Hormones Laboratory tests: Pharma-III Practical Diagnosis: Physical examination Laboratory tests: Laboratory tests Cushing’s syndrome Addison’s disease Serum cortisol (190-680 mmol/l) ↑ ↓ Serum ACTH (10-47 ng/l) ↑ or ↓ Na+ K+ Fasting BGL (70-120 mg/dl)

2- Mineralocorticoids Actions: Hormones Pharma-III Practical 2- Mineralocorticoids Actions: - ↑ Na+ & H2O reabsorption and ↑ K+ & H+ secretion. - Regulation of aldosterone secretion: ↓ plasma Na+ , ↑ K+  ↑ aldosterone. ↓ Na+ , ↓ BP  ↑ renin  ↑ Ang II  ↑ aldosterone. ACTH also stimulates secretion but to a much smaller extent.

1ry hyperaldosteronism Hormones Pharma-III Practical Clinical disorders Hyperfunction: 1ry hyperaldosteronism (CONN`s disease) Hypofunction: Hypoaldosteronism Hypotension Hyponatremia Hyperkalemia Acidosis Hypertension Hypernatremia Hypokalemia Alkalosis ttt: Aldosterone antagonist e.g. Spironolactone ttt: RT with fludorocortisone

2ry hyperaldosteronism Hormones Pharma-III Practical Hyperfunction: 2ry hyperaldosteronism (hyperreninism, or hyperreninemic hyperaldosteronism) due to overactivity of the renin-angiotensin system. As in Juxtaglomerular cell tumor. Renal artery stenosis. Hyporeabsorption of sodium from kidney tubulues (as seen in Bartter and Gitelman syndromes).

Assessment Chrousos syndrome

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