Adrenal Physiology Page 1

Adrenocorticosteroids and Adrenocortical Antagonists

Overview
- Natural adrenocortical hormones:
  - steroid molecules synthesized in released by the adrenal cortex
  - Clinical Uses:
    1. diagnosis of adrenal function
    2. treatment of adrenal function disorders
    3. treatment of inflammatory/immunological disorders (at higher doses)
  - Control over adrenocorticosteroid secretion:
    - pituitary corticotropin (ACTH) release
    - Angiotensin modulation of aldosterone secretion
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- Adrenocorticosteroids
  - Major categories of action:
    - Glucocorticoids: affecting intermediary metabolism
    - Mineralocorticoids: regulation of salt retention
    - Corticosteroids with:
      1. androgenic activity
      2. estrogenic activity
  - Major glucocorticoid: cortisol
  - Major mineralocorticoid: aldosterone
  - Major androgen: dehydroepiandrosterone (DHEA)
    - quantitatively -- DHEA
    - DHEA and androstenedione }very weak androgens
    - small amount of testosterone, secreted by the adrenals, maybe more important
  - Adrenal estrogens secretion?:
    - adrenal androgens: testosterone and androstenedione may be converted to estrone by non-endocrine tissue:
      - Major endogenous estrogen source in women after menopause

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Glucocorticoids (naturally occurring; cortisol -- hydrocortisone)

Pharmacokinetics:
- Synthesis:
  - major glucocorticoid: cortisol
  - precursor: cholesterol
  - site of adrenal cortisol synthesis:
    1. zona fasciculata
    2. zona reticularis
  - cortisol release modulated by ACTH
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- Characteristics:
  - Release rate of cortisol controlled by circadian rhythm affected by ACTH pulses
  - 75% of cortisol bound to plasma proteins
    - corticosteroid-binding globulin (CBG) -- alpha₂ globulin;
    - cortisol also bound to serum albumin
    - free cortisol plasma concentrations rise rapidly if CBG binding capacity is exceeded.
    - Factors that change plasma CBG concentration
      - pregnancy
      - estrogen administration (increased hepatic synthesis)
      - hyperthyroidism
      - hypothyroidism
      - protein deficiency
      - diminished synthetic capability (genetics)
    - cortisol half-life: about 60-90 minutes
    - Factors that increase cortisol half-life
      1. stress
      2. hypothyroidism
      3. liver disease
      4. large dosage of hydrocortisone administration
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  - Cortisol metabolism:
    - 20% converted to cortisone (by renal/other tissues with mineralocorticoid receptors) -- catalyzed by 11-hydroxysteroid dehydrogenase
    - Cortisol and cortisone inactivated in the liver by conversion (3-hydroxysteroid dehydrogenase catalyzed) to:
      1. tetrahydrocortisol
      2. tetrahydrocortisone
    - Other metabolites: cortol, cortolone
    - Some metabolites ultimately excreted in the urine as 11-oxy, 17-ketosteroids
    - Some metabolites undergo hepatic conjugation to form glucuronic acid or sulfate derivatives
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Pharmacodynamics
- Mechanism of Action:
  - Glucocorticoid action through glucocorticoid receptors
  - Receptor Properties:
    - member of receptor superfamily that includes:
      - steroid receptors
      - thyroid receptors
      - other receptors (many with unknown function -- "orphan receptors"
    - Receptors bound to heat shock proteins (Hsp/hsp90)
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  - Sequence of activation:
    1. Free glucocorticoid hormone enters the cell
    2. binds to the receptor, inducing a conformational change
    3. receptor dissociates from heat shock proteins
    4. hormone-receptor complex associate to form homodimers
    5. homodimers actively transported to the nucleus
    6. homodimers mind to glucocorticoid receptor elements (GREs) of target genes
    7. Genomic effects -- protein synthesized; Indirect mediation of some genomic effects by paracrine influences of hormone-regulated cytokines on nearby cells
  - Some physiological effects occur to rapidly to be accounted for by gene transcription/ protein synthesis:
    - feedback suppression of pituitary ACTH (unknown mechanism)

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Physiological effects of glucocorticoids:
- Major metabolic effects: due to direct cellular action
  - Some effects:secondary to homeostatic insulin and glucagon responses
- Physiological responses modulated by glucocorticoids ("permissive" effects)
  1. catecholamine vascular/bronchial smooth muscle response:
    - diminished in the absence of cortisol
    - restored by physiological amounts of cortisol
  2. catecholamine-induced lipolytic adipocytes response:
    - reduced in the absence of glucocorticoids (unknown mechanism)

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