Pharmacology of Adrenal Corticosteroids

Where are the adrenal glands located?

Superior to the kidneys (supra-renal glands)

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What are the layers within a cross-section of the adrenal glands?

Capsule, adrenal cortex, 90% (zona glomerulosa, zona, fasciculata, zona, reticularis), adrenal medulla, 10%

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Describe features of the adrenal gland (1)

Two glands, pyramidal in shape, lie on the anterior of the kidney, average size of 2-3 cm wide, 4-6 cm long, 1 cm thick, mean weight of 4 g (irrespective of age/sex/weight). Autopsy of adrenal gland may weigh 22 g (stress of terminal illness)

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Describe features of the adrenal gland (2)

Serum cortisol can be more than 3x the upper limit of normal at that time. Adrenal medulla makes up about 10% of total weight of adrenal

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Describe the structure of the adrenal gland (1)

Capsule, zona glomerulosa, zona, fasciculata, zona, reticularis, adrenal medulla. Capillaries and venules

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Describe the structure of the adrenal gland (2)

Cortisol cells within zona fasciculata secrete cortisol (made from cholesterol, lipid droplets, made using enzymes from SER, released by mitochondria, conversion of cholesterol to hormones)

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Describe the structure of the adrenal gland (3)

Medulla (modified neurones, sympathetic fibres, secreted granules), chromaffin cells secrete noradrenaline and adrenaline

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Outline the biosynthesis of cortisol (1)

Cholesterol converted to pregnenolone (using demolase enzyme - rate limiting step), converted to corticosterone through pathway. Pregnenolone can also be converted to 17 alpha hydroxy-pregnenolone and to cortisol through pathway

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Outline the biosynthesis of cortisol (2)

17 alpha hydroxy-pregnenolone can be converted to DHEA and to androstenedione through pathway

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Outline the biosynthesis of steroids (1)

ACTH and LH stimulate cholesterol desmolase to convert cholesterol into steroid hormones (e.g. corticosterone or cortisol using 11 beta hydroxylase enzyme). Androstenedione can be converted to testosterone via 17 beta hydroxysteroid dehydrogenase

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Outline the biosynthesis of steroids (2)

Testosterone can be converted to estradiol via FSH stimulating aromatase. Ang II stimulates aldosterone synthase to convert corticosterone to aldosterone (corticosterone made in animals, cortisol made in humans)

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How much adrenaline and noradrenaline is secreted by the medulla?

Adrenaline (80%) and noradrenaline (20%)

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Which steroid hormones are made by the cortex? (1)

Mineralocorticoid - aldosterone (in zona glomerulosa, lacks 17 beta hydroxylase/CYP17). Glucocorticoid - cortisol (zona fasciculata, lacks aldosterone synthase/CYP11B)

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Which steroid hormones are made by the cortex? (2)

Adrenal androgens - androstenedione/DHEA (zona reticularis, lacks aldosterone synthase/CYP11B)

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What is the rate limiting step for the synthesis of steroid hormones?

Transport of cholesterol across mitochondrial membrane

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What does DHEA stand for?

Dehydroepiandrosterone acetate

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Does ACTH have little effect on aldosterone production?

Yes

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Describe the composition of adrenal steroids in plasma

More cortisol than corticosterone in plasma. Low plasma concentration of aldosterone. Main androgen is DHEA-S (has higher concentrations than cortisol)

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Describe the regulation of synthesis of cortisol (1)

Hypothalamus releases CRH (consists of 41 amino acids, acts on CRHR1). CRH stimulates corticotrophs in anterior pituitary to produce ACTH (consists of 39 amino acids). Actions of CRH potentiated by AVP

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Describe the regulation of synthesis of cortisol (2)

ACTH stimulates adrenal cortex to synthesise and release cortisol. Cortisol feeds back on the corticotrophs of the anterior pituitary to decrease ACTH release and on hypothalamus to inhibit release of CRH

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What is the pre-cursor for ACTH?

Pro-opiomelanocortin (POMC). Used in the synthesis of ACTH in the pituitary. Can be used to produce beta endorphins (opioid) and alpha/beta/gamma melanocyte-stimulating hormone (MSH)

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Describe the control of cortisol secretion (1)

Circadian rhythm, drives CRH and ACTH production. Cortisol levels gradually increase during dark phase of sleep and peaks when awake

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Describe the control of cortisol secretion (2)

Circadian rhythm, CRH, ACTH, secretion of cortisol from adrenal glands. In plasma 50% bound and 50% free. Free cortisol acts on tissues and is then excreted by the kidneys (in urine)

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Describe the synthesis of steroid hormones (ACTH interacting with receptor) (1)

ACTH acts on GPCR (melanocortin 2 receptor, MC2R) to activate AC which leads to increased cAMP levels. Activates PKA, activates cholesteryl ester hydrolase (CEH) which liberates cholesterol from lipid droplets

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Describe the synthesis of steroid hormones (ACTH interacting with receptor) (2)

Increased uptake of cholesterol into mitochondria. Stimulation of cholesterol 20,22 hydroxylase (demolase, first enzyme in pathway), rate limiting step). Leads to synthesis of cortisol. ACTH has little effect on aldosterone synthesis

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Describe the synthesis of steroid hormones (ACTH interacting with receptor) (3)

Cholesterol taken up into cell via LDL receptor, contained within lipid droplet. ACTH binds to MC2R (GPCR), activated AC, increase cAMP levels, activate PKA, cholesteryl esters/CEH cause cholesterol to be released. Converted into pregnanolone

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Describe the synthesis of steroid hormones (ACTH interacting with receptor) (4)

Pregnanolone converted to cortisol in mitochondria (using 17-OH preg and 11-deoxycortisol enzymes in SER). Cortisol released into the bloodstream

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Describe features of steroid hormone binding proteins

Cortisol (half life of 90 min, 10% free, 75% CBG/corticosteroid binding globulin, 15% bound to albumin). Aldosterone (half life of 20 min, 40% free, 20% CBG, 40% bound to albumin).

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Describe features of steroid receptors (1)

Steroid hormones interact with nuclear receptors. Steroid hormone enters cell by diffusion and binds to cytoplasmic receptor. Leads to dissociation of Heat Shock Protein (hsp90) from the receptor

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Describe features of steroid receptors (2)

Hormone-receptor complex dimerises and is translocated to nucleus. Complex binds to hormone responsive element (HRE) on DNA which leads to an increase in mRNA production and leads to increased protein synthesis

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Describe features of steroid receptors (3)

Ligand binding domain (in C-terminus), bind to DNA sequences. hsp90 (protein blocks domain/prevent binding of DNA sequences). Steroid hormone causes hsp90 to unbind from domain, transcription activating domain, altered transcription of specific genes

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Describe features of steroid receptors (4)

1 gene codes for glucocorticoid receptors. 2 splice variants hGR alpha and HGR beta. Glucocorticoid regulated genes (50% activated)

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What are the metabolic effects of glucocorticoids - cortisol? (1)

Decrease cell glucose uptake, decrease cell glucose use, increase gluconeogenesis (hyperglycaemia). Decrease protein synthesis, increase protein breakdown (muscle wasting). Decrease Ca absorption in gut, increase Ca excretion in kidney

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What are the metabolic effects of glucocorticoids - cortisol? (2)

Decrease activity of OBs, increase activity of OCs (osteoporosis)

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What are the anti-inflammatory effects of glucocorticoids - cortisol? (1)

Early phase - reduce redness/heat/pain/swelling. Late phase - reduce wound healing/repair/proliferation. Decreases - expression of COX-2, cytokine production (IL-2), complement in plasma, NO production, histamine release, IgG production

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What are the anti-inflammatory effects of glucocorticoids - cortisol? (2)

Increases annexin-1 (lipocortin-1) which inhibits phospholipase A2 (PLA2 - inhibition of arachidonic acid, COX and lipoxygenase enzymes). Water and electrolyte balance (mineralocorticoid receptor) - increase Na retention, increase K excretion

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How is the cortisol activation of mineralocorticoid receptor prevented? (1)

Cortisol has higher affinity for mineralocorticoid receptor than glucocorticoid receptor. Active cortisol can be converted to inactive cortisone via 11 beta hydroxysteroid dehydrogenase

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How is the cortisol activation of mineralocorticoid receptor prevented? (2)

11 beta HSD-2 isoform expressed in aldosterone sensitive tissues (converts cortisol to cortisone). 11 beta HSD-1 isoform expressed in liver, adipose and muscle

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What are the adverse effects of glucocorticoids?

Suppression of response to infection. Suppression of endogenous glucocorticoid production. Metabolic effects. Osteoporosis. Iatrogenic Cushing's syndrome. (High levels of cortisol, suppresses system, less corticosteroid produced)

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What is Cushing's syndrome?

Due to prolonged exposure to elevated levels of cortisol or exogenous glucocorticoid drugs. Other causes - osteoporosis, negative nitrogen balance, increased appetite, obesity, increased susceptibility to infection

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Which is Cushing's disease?

Due to pituitary tumour producing excess ACTH (leads to increased cortisol and androgens)

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What are the clinical features of Cushing's disease of syndrome? (1)

Red cheeks, moon face, buffalo hump, thin skin, high BP, thin arms and legs, bruisability/ecchymoses, red striation, pendulous abdomen, poor wound healing

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What are the clinical features of Cushing's disease of syndrome? (2)

Obesity, hypertension, hirsutism, striae, acne, bruising, neuropsychiatric, menstrual disorders, impotence, glucose intolerance, diabetes

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What would be the treatment for Cushing's disease?

Removal of tumour (not all patients suitable for surgery)

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What is the drug treatment for Cushing's syndrome? (1)

Inhibit steroid biosynthesis - metyrapone (11 beta hydroxylase inhibitor), ketoconazone (17 alpha hydroxylase and 11 beta hydroxylase inhibitor). Inhibit ACTH release - pasireotide/somatostatin analogue (SSTR5 agonist)

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What is the drug treatment for Cushing's syndrome? (2)

Carbergoline (dopamine D2 agonist). Inhibition of glucocorticoid receptor - mifeprestone (also progesterone receptor antagonist)

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What is Addison's disease?

Chronic adrenal insufficiency. Primary adrenal insufficiency due to destruction of adrenal cortex. Secondary adrenal insufficiency due to lack of ACTH

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What are the clinical features of Addison's disease?

Weakness/fatigue/anorexia/weight/loss, hyperpigmentation, hypotension, GI disturbances, salt craving, postural symptoms

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What are the effects of aldosterone on the kidney?

Aldosterone (mineralocorticoid) - increased number of sodium channels in apical membrane (ENaC), increase in Na-K ATPase in basolateral membrane

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What is spironolactone?

Aldosterone antagonist (used as a K+ sparing diuretic)

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Describe the actions of aldosterone in the kidney (1)

Aldosterone enters into principal cell (no cortisol/no 11 beta-HSD2). Binds to mineralocorticoid receptor receptor, hsp protein unbinds, hormone-receptor complex translocates to nucleus, gene expression (protein synthesis)

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Describe the actions of aldosterone in the kidney (2)

Effects on ENac and Na-K ATPase (Sgk, Ki-RasA, CHIF). Na enters into cell, K+ excretion

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Describe features of androgens and oestrogens (1)

Adrenal gland secretes weak androgens dehydroepiandrosterone and its sulphate and androstenedione. In pre-menopausal women, 50% of androstenedione is derived from adrenal and is converted in peripheral tissue to oestrone and testosterone

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Describe features of androgens and oestrogens (2)

Excess secretion of androgens in women can lead to hirsutism and virilisation. In post-menopausal women, regression of ovary (main oestrogen in oestrone)

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Describe features of androgens and oestrogens (3)

(Menopause - reduced oestrogen due to less being produced by the ovaries), oestrogen comes from androgens produced by adrenal glands, conversion in the periphery, post-menopausal symptoms

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Describe features of androgens and oestrogens (4)

Peripheral conversion takes place in adipose tissue, production of oestrone is higher in obese post-menopausal women than in thin wome In males, only 5% testosterone comes from adrenal androgens

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Give examples of synthetic steroids

Hydrocortisone (cortisol), prednisolone, methylprednisolone, dexamethasone, betamethasone, beclometasone dipropionate, budesonide, fludrocortisone, aldosterone

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Pharmacology of Adrenal Corticosteroids

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