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Hirsutism

Chapter 406 | Part 12: Endocrinology · Part 12 – Endocrinology & Metabolism · Chapter 406

Key Clinical Points

  1. Hirsutism is defined by the presence of excessive terminal hair growth in a woman.
  2. Approximately 10% of reproductive-age women have hirsutism.
  3. A Ferriman-Gallwey score >8 suggests excess androgen-mediated hair growth.
  4. Baseline plasma total testosterone >12 nmol/L (>3.5 ng/mL) usually indicates an androgen-producing tumor; >7 nmol/L (>2 ng/mL) is suggestive of a tumor or hyperthecosis.
  5. Basal DHEAS >18.5 μmol/L (>7000 μg/L) suggests an adrenal tumor.
  6. Combination estrogen-progestin therapy is the first-line endocrine treatment for hirsutism.
  7. Spironolactone (100–200 mg daily) is an effective antiandrogen but requires contraception.
  8. Cyproterone acetate is widely used in Canada, Mexico, and Europe but not available in the United States.
  9. Virilization (deepening voice, clitoromegaly) suggests a virilizing tumor and requires urgent evaluation.
  10. Attenuation of hair growth is typically not evident until 4–6 months after initiation of medical treatment.

1. DEFINITION & OVERVIEW

• Hair Morphology: ◦ Vellus: Fine, soft, and not pigmented. ◦ Terminal: Long, coarse, and pigmented. • Definition: Hirsutism is defined by the presence of excessive terminal hair growth in a woman. • Epidemiology: ◦ Approximately 10% of reproductive-age women have hirsutism. ◦ Ethnic factors: Dark-haired individuals tend to be more hirsute; Asian and Native American women are less likely to manifest hirsutism (often only showing pustular acne or thinning scalp hair). • Clinical Progression: ◦ Typically first noted in the second and third decades of life. ◦ Growth is usually slow but progressive. ◦ Red Flag: Sudden development and rapid progression suggest an androgen-secreting neoplasm.

2. ETIOLOGY & PATHOPHYSIOLOGY

• Androgen Dynamics: ◦ Testosterone is the primary circulating steroid in hirsutism; androstenedione, DHEA, and DHEAS also contribute. ◦ Conversion: Testosterone is converted to dihydrotestosterone (DHT) by 5α-reductase. ◦ Potency: DHT has a higher affinity for and slower dissociation from the androgen receptor than testosterone. ◦ Enzymes: Type 2 5α-reductase is found in the prostate and hair follicles; Type 1 is found primarily in sebaceous glands. • Impact of Hormonal Environment: ◦ Hyperinsulinemia and androgen excess decrease hepatic production of SHBG, increasing the proportion of unbound (biologically active) testosterone. ◦ Post-menopause: Estrogen levels drop significantly, further reducing SHBG and increasing the relative proportion of unbound testosterone.

2.1 Causes of Hirsutism

• Table 406-1: Causes of Hirsutism ◦ Gonadal hyperandrogenism: Ovarian hyperandrogenism, Polycystic ovary syndrome (PCOS)/functional ovarian hyperandrogenism, Ovarian steroidogenic blocks, Hyperthecosis. ◦ Adrenal hyperandrogenism: Premature adrenarche, Functional adrenal hyperandrogenism, Congenital adrenal hyperplasia (nonclassic and classic), Adrenal neoplasms. ◦ Other endocrine disorders: Cushing's syndrome, Hyperprolactinemia, Acromegaly. ◦ Peripheral androgen overproduction: Obesity. ◦ Pregnancy-related: Hyperreactio luteinalis, Thecoma of pregnancy. ◦ Drug-induced: Androgens, Oral contraceptives containing androgenic progestins, Minoxidil, Phenytoin, Diazoxide, Cyclosporine, Valproic acid. ◦ Other: Idiopathic, Ovotesticular disorders of sex development.

3. CLINICAL FEATURES

• Clinical Assessment: ◦ Age at onset and rate of progression are critical for identifying potential neoplasms. ◦ Associated symptoms: ◦ Oligomenorrhea (<8 cycles/year) suggests an ovarian source. ◦ Galactorrhea suggests hyperprolactinemia or hypothyroidism. ◦ Hypertension, striae, easy bruising, and centripetal weight gain suggest Cushing's syndrome. ◦ Acanthosis nigricans and skin tags indicate insulin resistance. • Scoring System: ◦ Ferriman-Gallwey Scale: Nine androgen-sensitive sites are graded from 0 (no hair) to 4 (frankly virile). ◦ Threshold: A score <8 is considered normal; a score ≥ 8 suggests excess androgen-mediated growth requiring hormonal evaluation. • Signs of Virilization: ◦ Red Flags: Deepening of the voice, clitoromegaly, increased muscle bulk, and increased libido suggest a virilizing tumor and require urgent evaluation. ◦ Cutaneous Signs: Acne and androgenic alopecia (thinning scalp hair).

4. DIFFERENTIAL DIAGNOSIS

• Gonadal Hyperandrogenism: PCOS, Ovarian steroidogenic blocks, Hyperthecosis. ◦ Adrenal Hyperandrogenism: CAH (classic/nonclassic), Adrenal neoplasms, Premature adrenarche. ◦ Systemic Disorders: Cushing's syndrome, Hyperprolactinemia, Acromegaly. ◦ Peripheral & Other: Obesity, Idiopathic hirsutism, Ovotesticular disorders of sex development. ◦ Pregnancy-related: Hyperreactio luteinalis, Thecoma of pregnancy. ◦ Drug-induced: Minoxidil, Phenytoin, Diazoxide, Cyclosporine, Valproic acid.

5. INVESTIGATIONS & DIAGNOSIS

• Laboratory Thresholds: ◦ Total Testosterone: ◦ >12 nmol/L (>3.5 ng/mL) → suggests an androgen-producing tumor. ◦ >7 nmol/L (>2 ng/mL) → suggestive of tumor or hyperthecosis. ◦ DHEAS: ◦ >18.5 μmol/L (>7000 μg/L) → suggests an adrenal tumor. ◦ Free Testosterone: Measured via LC/MS or calculated from total testosterone and SHBG to determine the biologically active fraction. • Diagnostic Approach: 1. Initial Assessment: Evaluate for localized terminal hair, abnormal Ferriman-Gallwey score, or clinical evidence of hyperandrogenic disorder. 2. Dermatologic Trial: If growth is localized, initiate dermatologic therapy. 3. Assessment of Progress: ◦ If stable/improving → Normal variant. ◦ If progression occurs → Proceed to laboratory evaluation (Total Testosterone). 4. Interpretation of Total Testosterone: ◦ If Normal → Hirsutism is mild and isolated; initiate dermatologic or oral contraceptive therapy. If stable → Idiopathic hirsutism. ◦ If Elevated → Hyperandrogenism. 5. Advanced Evaluation (if T is elevated): ◦ Assess for specific conditions: PCOS, Nonclassic CAH, Cushing's syndrome, Virilizing tumor, Hyperprolactinemia. ◦ If Free Testosterone is elevated → Re-evaluation of underlying pathology. 6. Medication Review: Identify and discontinue offending agents (e.g., Minoxidil, Phenytoin) if applicable.

Diagnostic Algorithm

  1. Initial Presentation ◦ Localized terminal hair → Trial of dermatologic therapy. ◦ Abnormal score/growth + clinical evidence → Total testosterone blood level. ◦ Medication-related growth → Discontinue if possible.
  2. Dermatologic Response ◦ Course stable or improving → Normal variant. ◦ Hair growth progresses → Proceed to laboratory assessment.
  3. Laboratory Assessment (Total Testosterone) ◦ Total testosterone normal → Hirsutism mild and isolated → Trial of dermatologic or oral contraceptive therapy → If stable/improving → Idiopathic hirsutism. ◦ Total testosterone elevated → Hyperandrogenism.
  4. Hyperandrogenism Pathway ◦ Identify major hyperandrogenic endocrine disorder (e.g., PCOS, Nonclassic CAH). ◦ If hirsutism is moderate-severe or other evidence exists → Free testosterone blood level. ◦ If free testosterone elevated → Re-evaluation.

6. MANAGEMENT & TREATMENT

• Nonpharmacologic Treatment: ◦ Options include bleaching, shaving (does not increase density), chemical depilatory, waxing, electrolysis, and laser/IPL. ◦ Laser/IPL is effective for large areas of pigmented terminal hair via photothermolysis. • Pharmacologic Treatment: 1. First-line Therapy: Combination estrogen-progestin therapy (oral contraceptives). ◦ Mechanism: Suppresses LH → reduces ovarian androgens; increases SHBG → lowers unbound testosterone; direct effect on sebaceous cells. 2. Antiandrogens: ◦ Spironolactone: 100–200 mg daily. Effective but requires contraception due to risk of feminizing a male fetus.\ ◦ Cyproterone acetate: Widely used in Canada, Mexico, and Europe; not available in the United States. 3. Clinical Expectations: ◦ Treatment effects typically not evident until 4–6 months after initiation. ◦ Maximum effect may require 9–12 months due to hair growth cycles. ◦ Improvement in hirsutism is typically ~20%; acne improvement is often ~50% with OCPs.

Reference Tables

TABLE 406-1 Causes of Hirsutism Gonadal hyperandrogenism

Harrison's 22e, p.3138

  • Gonadal hyperandrogenism
    Ovarian hyperandrogenism
    Polycystic ovary syndrome/functional ovarian hyperandrogenism
    Ovarian steroidogenic blocks
    Syndromes of extreme insulin resistance
    Ovarian neoplasms
    Hyperthecosis
    Adrenal hyperandrogenism
    Premature adrenarche
    Functional adrenal hyperandrogenism
    Congenital adrenal hyperplasia (nonclassic and classic)
    Abnormal cortisol action/metabolism
    Adrenal neoplasms
    Other endocrine disorders
    Cushing’s syndrome
    Hyperprolactinemia
    Acromegaly
    Peripheral androgen overproduction
    Obesity
    Idiopathic
    Pregnancy-related hyperandrogenism
    Hyperreactio luteinalis
    Thecoma of pregnancy
    Drugs
    Androgens
    Oral contraceptives containing androgenic progestins
    Minoxidil
    Phenytoin
    Diazoxide
    Cyclosporine
    Valproic acid
    Ovotesticular disorders of sex development