Androgenital Syndromes

ADULT ANDROGENITAL (ADRENOGENITAL) SYNDROMES

Definition

• Adult adrenogenital syndromes: Disorders associated with excess adrenal androgens in adults.
• Causes:
  1. Late-onset (nonclassic) congenital adrenal hyperplasia (CAH)
  2. Familial glucocorticoid resistance
  3. Cushing syndrome (ACTH-dependent)
  4. Androgen-secreting adrenal neoplasms
• Gender Differences:
  • In men, adrenal androgen excess may be clinically silent (because gonadal testosterone dominates).
  • In women, leads to masculinization (virilization), menstrual dysfunction.

Clinical Features in Women

1. Hirsutism
   • Excessive male-pattern hair growth (cheeks, upper lip, chin, midline chest, male-type pubic hair pattern, etc.).
2. Virilization (more severe androgen excess)
   • Musculature: Increased muscle bulk, loss of female body contours.
   • Voice: Deepening.
   • Breasts: Atrophy.
   • Clitoromegaly: Clitoris >10 mm length or >7 mm width = abnormal.
   • Scalp Hair: Temporal balding.
   • Androgenic Flush: Plethoric face, neck, upper chest.

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LATE-ONSET (NONCLASSIC) CONGENITAL ADRENAL HYPERPLASIA

1. Pathophysiology
   • Milder/partial enzymatic blocks in steroidogenesis (3β-HSD, 21-hydroxylase, or 11β-hydroxylase).
   • Present later in life with hirsutism, menstrual irregularities, ± mild virilization.
2. 3β-Hydroxysteroid Dehydrogenase (3β-HSD) Deficiency
   • Laboratory: ↑DHEA-S, low androstenedione.
   • Cosyntropin test: Marked ↑17-hydroxypregnenolone & DHEA, no ↑17-hydroxyprogesterone & androstenedione.
3. 21-Hydroxylase Deficiency
   • Most common cause of CAH (90+%).
   • Laboratory: ↑Progesterone, ↑17-hydroxyprogesterone, ↑androstenedione (all rise further with ACTH stimulation).
   • Clinically presents with hirsutism, oligomenorrhea, ± mild virilization.
4. 11β-Hydroxylase Deficiency
   • Laboratory: ↑11-deoxycortisol, ↑11-deoxycorticosterone, ↑DHEA, ↑androstenedione.
   • May have hypertension, hypokalemia (DOC’s mineralocorticoid effect), androgen excess → hirsutism.
5. Treatment
   • Glucocorticoid replacement to suppress ACTH and reduce adrenal androgen production.
   • Care to avoid iatrogenic Cushing syndrome from overtreatment.

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FAMILIAL GLUCOCORTICOID RESISTANCE

1. Pathophysiology
   • Mutations in the glucocorticoid receptor gene → decreased cortisol action → ↑ACTH → bilateral adrenal hyperplasia → excess androgens & mineralocorticoid-like steroids (11-deoxycorticosterone).
2. Clinical
   • Similar to partial 11β-hydroxylase deficiency: androgen excess plus HTN, hypokalemia.

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ACTH-DEPENDENT CUSHING SYNDROME

1. Mechanism
   • High ACTH → adrenal hyperplasia → overproduction of cortisol and adrenal androgens.
2. Clinical
   • Women: Combined features of Cushing’s (central obesity, striae, etc.) plus hirsutism/virilization.

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ANDROGEN-SECRETING ADRENAL NEOPLASMS

1. Incidence
   • Rare. More frequent in adrenocortical carcinoma than benign adenoma.
2. Hormonal Output
   • Typically DHEA, often androstenedione or testosterone.
3. Imaging
   • Carcinomas: Usually large (>4 cm), inhomogeneous, high CT density.
   • Adenomas: Small (<3 cm), homogeneous, lower CT density.

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THE BIOLOGIC ACTIONS OF ADRENAL ANDROGENS

1. Major Adrenal Androgens: DHEA, DHEA-S, androstenedione, testosterone.
   • Women: Adrenal androgens are the primary source of androgens.
   • Men: Testicular testosterone usually dominates.
2. Physiologic Roles
   • Anabolic effects → muscle mass increase.
   • Male secondary sex traits (facial hair, deep voice, etc.).
   • In women, adrenal androgens are crucial for axillary/pubic hair; deficiency leads to hair loss in these areas.
3. Adrenarche vs. Pubarche
   • Adrenarche: Biochemical event, ↑adrenal androgens at ~6–8 yrs.
   • Pubarche: Phenotypic event, sexual hair growth in pubic & axillary areas.
   • Premature: Pubarche <8 yrs in girls, <9 yrs in boys = advanced hair growth, possibly advanced bone age.
4. Conversion and Metabolism
   • DHEA-S acts as a large reservoir → converted to DHEA → androstenedione → testosterone or estradiol in peripheral tissues.
   • Possibly a neurosteroid role in brain, though no definitive DHEA receptor identified.
5. Anabolic Steroid Use in Athletes
   • Often used illicitly to increase muscle mass, enhance performance.
   • Negative effects: testicular suppression (↓fertility), gynecomastia, liver damage, mood disorders (“roid rage”), dyslipidemia, virilization in women, stunted growth in adolescents.