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Adrenal Corticosteroids

Outline• Stress response & the adrenal cortex

• Hypothalamic & anterior pituitary stimulation of cortisol synthesis

• Biological role of cortisol

• Pharmacological uses of glucocorticoids

• Cortisol excess

• Cortisol deficiency

• Tests for hypothalamic-pituitary function

DHEA

Affects kidneys to regulate salt metabolism

↑ catabolic rxns, ↑ metabolic fuels,↑ blood glucose

Source of androgens

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Aldosterone Cortisol

DHEA

Biological Actions of Cortisol

What are the effects of excess cortisol?

• Cushing’s syndrome

Glucocorticoid Excess: Cushing’s syndrome

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What are the effects of insufficient cortisol?• Addison’s disease

– Cortisol is required for survival– Carbohydrate imbalance– Tiredness (low blood glucose)– Low blood pressure– ↑ skin pigmentation – (JFK had Addison’s)

• Congenital adrenogenital syndrome

X X

Congenital Adrenogenital Syndrome: deficiency in 21-β-hydroxylase

↑ Androgens

When are glucocorticoids used therapeutically?

Minimize suppression of pituitary & adrenal cortex by administration of glucocorticoid in morning after normal peak of release

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Fig. 28.4 The long negative feedback loop is more important than the short loop (dashed lines). Adrenocorticotrophic hormone (ACTH, corticotrophin) has only a minimal effect on mineralocorticoid production. Drugs are shown in yellow boxes. ADH, antidiuretic hormone (vasopressin); CRF, corticotrophin-releasing factor.

Regulation of synthesis and secretion of adrenal corticosteroids.

Tests of hypothalamic-pituitary-adrenocortical function:

To test for causes of adrenal excess (Cushings’ Syndrome)

Dexamethasone suppression test:

• Administer low dose of dexamethasone (potent glucocorticoid)

• Test for suppression in ACTH and suppression of cortisol secretion due to long feedback inhibition of the hypothalamus & pituitary

DHEA

Dexamethasone suppression test:

Dexamethasone1

ACTH2

Cortisol3

Stimulation of Long Feedback Loop with Dexamethasone

1) Control

2) Pretreat with Dexamethasone

Normal: Dexamethasone causes ↓ ACTH and ↓ cortisol due to negative feedback.

If cortisol doesn’t decrease, may indicate Cushings syndrome, suggesting that there is an ectopic source of ACTH or cortisol (eg: adrenal adenoma) that is not inhibited by the dexamethasone

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Tests of hypothalamic-pituitary-adrenocortical function:

To test for causes of adrenal insufficiency

1) Administer ACTH:

• Does [cortisol] increase?

2) Metyrapone enhancement test:

• Block synthesis of cortisol in the adrenal cortex with metyrapone

• Test for ↑ [ACTH] and ↑ [11-deoxycortisol] due to decreasing long feedback inhibition of the hypothalamus & pituitary

X X cortisol

Metyrapone blocks 11-β-hydroxylase & decreases cortisol synthesis

28.5

11-deoxycortisol

ACTH

Decrease in Long Feedback Loop Inhibition by Metyrapone

Normal: Metyrapone causes ↓ cortisol, ↑ ACTH, ↑ 11-deoxycortisol due to lack of negative feedback.

If ACTH and 11-deoxycortisol don’t increase, may indicate deficiency of hypothalamic-pituitary regulation.

Summary• Cortisol released in response to stress• CRH (hypothalamus) stimulates ACTH secretion (anterior

pituitary), which stimulates cortisol synthesis (adrenal cortex)• Cortisol causes catabolic reactions: increases blood glucose• Cortisol is slow acting (via transcriptional regulation)• Glucocorticoids use therapeutically to decrease inflammation

& immune suppression• Feedback inhibition causes suppression of adrenal; very slow

to recover• Cortisol excess: Cushing’s syndrome• Cortisol deficiency: Addison’s syndrome• Dexamethasone suppression test & metyrapone

enhancement test used to test long feedback inhibition loop