Hirsutism & Virilization

Essentials of Diagnosis

• Hirsutism: increased hair, acne, menstrual disorders

• Virilization: increased muscularity, androgenic alopecia, deepening of the voice, clitoromegaly; rarely, a palpable pelvic tumor

• Serum dehydroepiandrosterone sulfate (DHEAS) and androstenedione elevated in adrenal disorders, variable in others

• Serum testosterone often elevated

General Considerations

• Hirsutism is defined as cosmetically unacceptable terminal hair growth that appears in women in a male pattern

• The amount of hair growth deemed unacceptable depends on a woman's ethnicity and familial and cultural norms

• The Ferriman-Gallwey score is used to grade hirsutism

  • Grades range from 0 (none) to 4 (severe) in nine areas of the body

  • Scores below 8 are considered mild hirsutism and normal variants

  • Scores 8-15 indicate moderate hirsutism

  • Scores over 15 indicate severe hirsutism

• Virilization is defined as the development of male physical characteristics in women, such as

  • Pronounced muscle development

  • Deep voice

  • Male pattern baldness

  • More severe hirsutism

Causes of hirsutism

• Idiopathic or familial—often hirsutism may be normal for genetic background

• Polycystic ovary syndrome

  • Accounts for at least 50% of all cases of hirsutism associated with elevated serum testosterone levels

  • Must meet three criteria

    • Androgen excess with clinical hyperandrogenism and/or elevated serum free or total testosterone

    • Ovarian dysfunction with oligoanovulation and/or polycystic ovary morphology

    • Absence of other causes of testosterone excess or anovulation such as pregnancy, thyroid dysfunction, 21-hydroxylase deficiency, neoplastic testosterone secretion, Cushing syndrome, or hyperprolactinemia

• Ovarian tumor (uncommon) and adrenal carcinoma (rare)

• Steroidogenic enzyme defects

  • ~2% of adult-onset hirsutism is due to partial defect in adrenal 21-hydroxylase

  • Rare patients with hyperandrogenism and hypertension have 11-hydroxylase deficiency

  • Patients with XY karyotype and deficiency of 17α-hydroxysteroid dehydrogenase-3 or 5α-reductase-2 may present as phenotypic girls in whom virilization develops at puberty

• Other rare causes of hirsutism and virilization

  • Acromegaly

  • ACTH-induced Cushing syndrome

  • Adrenal carcinoma

  • Genetic cortisol resistance

  • Porphyria cutanea tarda

  • Maternal virilization during pregnancy due to luteoma of pregnancy

  • Hyperreactio luteinalis

  • Diffuse stromal Leydig cell hyperplasia in postmenopausal women

  • Acquired hypertrichosis lanuginosa (diffuse fine hair growth on face and body in association with malignancy, especially colorectal cancer)

  • Pharmacologic causes

    • Minoxidil

    • Cyclosporine

    • Phenytoin

    • Anabolic steroids

    • Interferon

    • Cetuximab

    • Diazoxide

    • Certain progestins

Symptoms and Signs

• Increased sexual hair (chin, upper lip, abdomen, and chest)

• Acne due to increased sebaceous gland activity

• Menstrual irregularities, anovulation, and amenorrhea common

• Defeminization

  • Breast size decrease

  • Loss of feminine adipose tissue

• Virilization implicates presence of testosterone-producing neoplasm

  • Frontal balding

  • Muscularity

  • Clitoromegaly

  • Deepening of voice

• Hypertension is seen in rare conditions with Cushing syndrome, adrenal 11-hydroxylase deficiency, or cortisol resistance syndrome

• Ovarian enlargement may be cystic or neoplastic

• Polycystic ovary syndrome is associated with hypertension and hyperlipidemia

Laboratory Tests

• Serum androgens are mainly useful to screen for rare occult adrenal or ovarian neoplasms

  • Serum testosterone > 200 ng/dL (6.9 nmol/L) or free testosterone > 40 ng/dL (> 140 pmol/L) indicates need for pelvic examination and ultrasound. If normal, perform adrenal CT scan

  • Free testosterone is best measured by calculation, using accurate assays for testosterone and sex hormone binding globulin (SHBG)

  • Serum androstenedione > 1000 ng/dL (> 34.9 nmol/L) implicates ovarian or adrenal neoplasm

  • Milder elevations of testosterone or androstenedione are usually treated with oral contraceptives

  • Markedly elevated serum DHEAS (> 700 mcg/dL [> 35 nmol/L]) implies adrenal source of androgen, usually adrenal hyperplasia and rarely adrenal carcinoma. Perform adrenal CT scan

• Unclear which patients (if any) with hyperandrogenism should be screened for "late-onset" 21-hydroxylase deficiency, where baseline 17-hydroxyprogesterone is usually > 300 ng/dL (> 9.1 nmol/L) or stimulated level is > 1000 ng/dL (> 30.3 nmol/L) (30–60 min after 0.25 mg intramuscular cosyntropin)

• Signs of Cushing syndrome should prompt screening

• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) elevated if amenorrhea is due to ovarian failure

• LH:FSH ratio < 2.0, hyperglycemia, and elevated fasting insulin level are common in polycystic ovary syndrome

• Selective venous sampling for testosterone may be required to diagnose small virilizing ovarian tumors not detected on ultrasound, MRI, or CT

Imaging Studies

• Adrenal CT as described above

• Pelvic ultrasound or MRI to detect virilizing tumors of ovary

• Ultrasound shows polycystic ovaries in ~25–30% of normal young women, so test is not helpful in diagnosis of polycystic ovary syndrome

Medications

• Spironolactone

  • 100–200 mg orally daily (taken as a single dose or in two divided doses) on days 5–25 of the menstrual cycle or daily if used concomitantly with an oral contraceptive

  • Hyperkalemia or hyponatremia occur uncommonly

• Flutamide

  • 250 mg once or twice daily for the first year, then 125–250 mg/day for maintenance

  • Used with oral contraceptive, likely more effective than spironolactone in improving hirsutism, acne, and male pattern baldness

  • Rarely hepatotoxic

  • Women must be counseled to take strict contraceptive measures, since antiandrogen drug use during pregnancy causes malformations and disorders of sexual development (pseudohermaphroditism) in male infants

• Bicalutamide

  • Dosage: 50 mg once daily

  • May be more effective than spironolactone in improving hirsutism, acne, and male pattern baldness

  • Women must be counseled to take strict contraceptive measures, since antiandrogen drug use during pregnancy causes malformations and disorders of sexual development (pseudohermaphroditism) in male infants

• Finasteride: 5 mg once daily orally provides inconsistent reduction of hirsutism and androgenic alopecia over 6 months in women

• Combined oral contraceptives

  • Stimulate menses

  • Combinations that contain antiandrogenic progestins such as desogestrel, drospirenone, norgestimate, or cyproterone acetate reduce hirsutism and acne

  • Combinations that contain norethindrone, norgestrel, or levonorgestrel are relatively ineffective for hirsutism and acne

• Metformin

  • Started at 500 mg/day with breakfast for 1 week, then 500 mg with breakfast and dinner for 1 week, then 500 mg with breakfast and 1000 mg with dinner for 1 week, then 850–1000 mg with breakfast and dinner

  • Contraindicated in severe kidney and liver disease

  • Does not cause hypoglycemia in nondiabetics

• Simvastatin

  • Can reduce hirsutism in women with polycystic ovary syndrome

  • In one study, 20 mg orally daily was given to women receiving an oral contraceptive for polycystic ovary syndrome

  • Besides improving their serum lipid profiles, women receiving simvastatin had greater decreases in hirsutism and serum free testosterone levels than the women receiving an oral contraceptive alone

• Steroids

  • Women with congenital adrenal hyperplasia (21-hydroxylase deficiency) require glucocorticoid and mineralocorticoid replacement

  • However, women with partial "late onset" 21-hydroxylase deficiency do not require hormone replacement

  • Treating such women with dexamethasone risks iatrogenic Cushing syndrome and is not more effective than the other treatments listed above

• Minoxidil

  • Topical minoxidil 2% solution twice daily chronically to dry scalp is used for androgenic alopecia

  • Hypertrichosis occurs in 3–5% (eg, on forehead, cheeks, upper lip, chin); usually resolves 1–6 months after drug stopped

Surgery

• Resection of any testosterone-secreting ovarian or adrenal tumor

• Laparoscopic bilateral oophorectomy (if CT scan of adrenals and ovaries is normal) is indicated in postmenopausal women with severe hyperandrogenism, since small hilar cell tumors of ovary may not be visible on scans

Therapeutic Procedures

• Discontinue any potentially offending drugs

• Encourage shaving, depilatories, waxing, electrolysis, or bleaching, and laser therapy for hirsutism

Follow-Up

• Check serum potassium and creatinine 1 month after starting spironolactone

• If serum testosterone elevated, follow testosterone during therapy or after surgery

Prognosis

• Polycystic ovary syndrome: women frequently regain normal menstrual cycles with aging