HIRSUTISM AND VIRILIZATION

Definitions

• Hirsutism: Excessive male-pattern terminal hair growth in women (e.g., on face, midline chest/abdomen, back).
• Virilization: A more severe androgen excess in women, manifested by masculinizing signs (deepening voice, clitoromegaly, temporal balding, increased muscle mass, breast atrophy).
• Hypertrichosis: Diffuse increased total body hair (not male-pattern), which may be drug-induced (e.g., minoxidil) or associated with anorexia nervosa, malnutrition, etc.

HAIR GROWTH CYCLE AND ANDROGEN EFFECTS

• Hair Growth Phases:
  1. Anagen (growth)
  2. Catagen (involution)
  3. Telogen (rest)
• Hair Follicles:
  • Two main types: Vellus hair (fine, unpigmented) vs. Terminal hair (coarse, pigmented).
  • Androgens → enlarge follicle, increase hair diameter, prolong anagen phase in androgen-sensitive areas.
  • At the scalp, androgens can reduce anagen duration → hair thinning (male-pattern baldness).

CLINICAL ASSESSMENT OF HIRSUTISM

• Modified Ferriman-Gallwey Score:
  • Grades terminal hair growth (0–4) at 9 body sites: upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, upper arms, thighs.
  • Scores <8 are generally normal; >8 suggests hirsutism.
• Ethnic Variation:
  • Same androgen levels can manifest differently (e.g., Asian and American Indian women have minimal body hair, Mediterranean women have more).

PATHOPHYSIOLOGY: ANDROGEN PRODUCTION AND ACTION

1. Androgens and 5α-Reductase
   • Testosterone → Dihydrotestosterone (DHT) (more potent) via 5α-reductase in hair follicles.
   • Local tissue 5α-reductase activity + androgen receptors → net androgen effect (hair growth or thinning).
2. Adrenal Androgens
   • DHEA and androstenedione from adrenal cortex.
   • DHEA is weakly androgenic, mainly a substrate for peripheral conversion to androstenedione → testosterone.
3. Ovarian Androgens
   • The ovary secretes ~1/3 of total testosterone in premenopausal women.
   • The rest (2/3) from peripheral conversion of androstenedione in adipose/skin.
   • High Testosterone usually reflects ovarian source; High DHEA-S usually reflects adrenal source.
   • Excess androstenedione may come from either adrenal or ovarian origin.

COMMON CAUSES OF HIRSUTISM AND VIRILIZATION

1. Polycystic Ovary Syndrome (PCOS)
   • Most frequent cause of androgen excess.
   • Associated with obesity, anovulatory cycles, oligomenorrhea/amenorrhea, infertility, and signs of hyperandrogenism (hirsutism, acne).
   • Typically starts soon after menarche; progresses gradually.
2. Other Causes
   • Idiopathic/Constitutional Hirsutism (familial, ethnic disposition).
   • Nonclassic congenital adrenal hyperplasia (late-onset CAH).
   • Androgen-secreting tumors (ovary or adrenal).
   • Medications (e.g., anabolic steroids, certain progestins).

Virilization-Related Causes

• Markedly increased androgens: ovarian/adrenal tumors, severe CAH, exogenous androgens → clitoromegaly, voice deepening, male body habitus changes.

Hyperthecosis

• Definition: A severe variant of PCOS caused by increased ovarian stromal tissue with luteinized theca cells distributed among sheets of fibroblast-like cells.
• Pathophysiology:
  • Positive correlation between degree of hyperthecosis and insulin resistance.
  • Hyperinsulinism → stimulates proliferation of thecal interstitial cells.
• Clinical Note: Some patients develop virilization due to markedly increased serum testosterone levels.

Idiopathic Hirsutism

• Second most common diagnosis in women with hirsutism.
• Clinical Features:
  • Normal menstrual cycles.
  • Normal blood androgen levels.
  • No identifiable cause of hirsutism after evaluation.
• Possible Mechanism: Increased cutaneous 5α-reductase activity.

Congenital Causes of Virilization in Female Neonates

• Congenital Adrenal Hyperplasia (CAH):
  • Enzymatic defect in cortisol synthesis.
  • ACTH not suppressed normally → adrenal glands produce DHEA + androgenic precursors.
  • Newborn may show clitoral hypertrophy, hirsutism.
• Maternal Androgen Excess:
  • Exogenous androgenic hormones (pills/injections) in early pregnancy.
  • Secretory ovarian or adrenal tumor in pregnant mother → androgens cross placenta → fetal virilization.
• Late-Onset (Nonclassic) CAH:
  • Partial 21-hydroxylase deficiency.
  • Typically presents after puberty with hirsutism + oligomenorrhea (similar to PCOS).
  • More common in certain ethnic groups (e.g., Ashkenazi Jewish, central European, Hispanic).

Androgen-Secreting Tumors

1. Ovarian Tumors
   • Sertoli-Leydig cell (arrhenoblastoma)
   • Granulosa-theca cell tumors
   • Hilum-cell tumors
   • Clinical presentation:
     • Rapidly progressive androgen excess.
     • Markedly elevated serum testosterone.
   • Sertoli-Leydig: Usually large.
   • Hilum-cell: Often small, can evade detection on imaging.
2. Adrenal Androgen-Secreting Tumors
   • Typically adrenocortical carcinoma producing excess DHEA.
   • Rarely, a benign adenoma or carcinoma hypersecreting testosterone.

Other Situations

• Post-Menopausal Facial Hair:
  • Related to adrenal androgens unopposed by estrogen after ovarian failure.
• Medication-Induced:
  • Anabolic steroids, other androgenic drugs.
• Rare Causes:
  • Cushing syndrome
  • Glucocorticoid resistance syndrome

EVALUATION OF WOMEN WITH HIRSUTISM

Testosterone Circulation

• Testosterone Forms:
  1. Tightly bound to sex hormone–binding globulin (SHBG).
  2. Loosely bound to albumin.
  3. Unbound (free).
• Bioavailable Testosterone = Loosely bound + Free fractions.
• SHBG Reduction (e.g., obesity, hypothyroidism, liver disease) → increased bioavailable T.

Common Causes of Elevated Testosterone in Hirsute Women

1. Polycystic Ovary Syndrome (PCOS)
2. Nonclassic CAH
3. Hyperthecosis
4. Hypothyroidism
5. Androgen-Secreting Tumor (ovarian or adrenal)

• Tumor Suspicion: If serum testosterone is >3× upper limit of normal.

Additional Diagnostic Tests

• Serum DHEA-S, Androstenedione:
  • Elevated in adrenal tumors, some CAH.
• Serum TSH: To exclude hypothyroidism.
• 8 AM 17-Hydroxyprogesterone (baseline + post-cosyntropin):
  • Abnormal in most CAH patients.
• LH, FSH:
  • Increased ratio (LH>FSH) consistent with PCOS.
• 24-Hour Urinary-Free Cortisol:
  • To exclude Cushing syndrome.
• Imaging:
  • Transvaginal ultrasound (ovarian masses).
  • CT scan (adrenal masses).