Hirsutism and Virilism

Hirsutism is defined as the excessive growth of thick dark hair in an androgen-dependent pattern where hair growth in women is usually minimal or absent, e.g. face, chest, and areolae. It occurs as a result of increased androgen production, increased skin sensitivity to androgens, or both.¹

When hirsutism in women is accompanied by other signs of virilism, it may be a manifestation of a more serious underlying disorder causing hyperandrogenism, such as an ovarian tumour or adrenal neoplasm.² The most common causes of clinical hyperandrogenism are polycystic ovary syndrome (PCOS), idiopathic (no other clinical or biochemical abnormalities) hyperandrogenism, non-classic (late onset) adrenal hyperplasia, and androgen-secreting tumours.¹

• Hirsutism is a common disorder affecting between 5% and 10% of women.³ It is uncommon in sub-Saharan and East Asian people.
• Familial hirsutism is most often seen in Southern European and South Asian countries.
• Dark-haired and dark-skinned whites tend to be more hirsute than blond or fair-skinned people.
• Obesity is associated with increased hirsutism.

• Idiopathic hirsutism:
  • Common and often familial.
  • Is a diagnosis of exclusion and thought to be related to disorders in peripheral androgen activity.
  • Onset occurs shortly after puberty with slow progression.
  • There are no other signs of virilism, normal menstrual function and normal investigations.
• Drug-induced hirsutism, e.g. anabolic steroids, danazol, minoxidil, metoclopramide, methyldopa, phenothiazines, progestogens and reserpine.
• Ovarian causes:
  • PCOS: Virilisation is minimal, and hirsutism is often prominent.
  • Menopause.
  • Androgen-producing ovarian tumours, e.g. luteoma of pregnancy, arrhenoblastomas, Leydig cell tumours, hilar cell tumours, thecal cell tumours.
• Adrenal causes:
  • Androgen-producing adrenal tumour.
  • Congenital adrenal hyperplasia (CAH).
  • Cushing's syndrome.
• Other causes include severe insulin resistance, anorexia nervosa, prolactinoma, acromegaly, hypothyroidism and porphyria.

Hirsutism in children

• Familial or ethnic hirsutism usually begins during puberty. Therefore hirsutism in prepubertal children may be a sign of precocious puberty, and may signify a serious underlying disease (all relevant conditions listed above should be considered).
• Hirsutism resulting from congenital adrenal hyperplasia begins early in childhood, while late-onset CAH presents with hirsutism after puberty.

• Excess terminal hair in a masculine pattern: Face (particularly moustache, beard and temple areas), chest, areolae, linea alba, upper and lower back, buttocks, inner thighs, external genitalia.
• Other signs of virilism include:
  • Acne
  • Alopecia, temporal hair recession
  • Male pattern (truncal) obesity
  • Clitoromegaly
  • Deepening of voice
  • Increased libido
  • Increased muscle mass (primarily shoulder girdle)
  • Loss of breast tissue or normal female body contour
  • Malodorous perspiration
  • Infertility
  • Menstrual dysfunction
• Other abnormalities associated with excessive levels of androgen are cardiovascular disease, dyslipidaemia, glucose intolerance/insulin resistance and hypertension. Acanthosis nigricans, a marker for insulin resistance, may also be present.
• Pelvic mass: Ovarian (bimanual vaginal examination) or adrenal tumour.

Hypertrichosis: Androgen-independent and causes uniform growth of vellus hair over the body, especially in non-sexual areas. The aetiology of hypertrichosis includes:¹

• Familial
• Related to drugs, e.g. phenytoin, ciclosporin
• Non-endocrine causes such as anorexia nervosa

Initial investigations include:¹

• Thyroid function tests: Thyroid dysfunction can affect menstruation and hypothyroidism is associated with changes in hair.
• Testosterone:
  • A high total testosterone concentration indicates that hyperandrogenaemia may be caused by an ovarian or adrenal tumour.
  • If the total testosterone is normal or only slightly raised, an androgen-secreting tumour can be excluded.
  • Testosterone concentrations more than 1.5-2 times the upper limit of normal or a history of rapid virilisation are likely to be associated with tumour-associated hyperandrogenism.
  • Dehydroepiandrosterone sulphate and androstenedione should then be measured to identify an adrenal or ovarian source of the hyperandrogenaemia.
• Free androgen index:
  • Total testosterone is often normal in PCOS but the free androgen index is raised because sex hormone-binding globulin is suppressed.
  • The free androgen index is calculated by also measuring sex hormone-binding globulin (free androgen index is total testosterone concentration divided by sex hormone-binding globulin concentration multiplied by 100).
• Follicle stimulating hormone (FSH), luteinising hormone (LH): Women with PCOS have an increased LH/FSH ratio (>2 is common).
• Prolactin:
  • Prolactin affects the menstrual cycle and hyperprolactinaemia can be associated with hirsutism.
  • If prolactin concentrations are more than 1.5-2 times the upper limit of normal, other causes of hyperprolactinaemia should be considered.
• 17-hydroxyprogesterone:
  • Blood should be taken at about 9 a.m. in the first half of the menstrual cycle.
  • A 17-hydroxyprogesterone value of 5 nmol/l has a sensitivity of 100% and specificity of 88.6% for diagnosing non-classic congenital adrenal hyperplasia.
• 24-hour urine cortisol (to rule out Cushing’s syndrome if suspected):
  • Cushing’s disease is a rare cause of hirsutism and exclusion is not necessary unless the patient has cushingoid features.
• Pregnancy should be ruled out in women with irregular or absent menstrual cycles.
• Ultrasound: Patients with either menstrual disturbances or clinical or biochemical evidence of hyperandrogenism alone should have transvaginal ultrasound imaging of the ovaries.

Further investigations as indicated:

• Glucose tolerance test with serial growth hormone measurements.
• Abdominal ultrasound, CT, MRI: If suspected PCOS, adrenal or ovarian tumour. MRI brain scan: If suspected pituitary tumour.

• Treatment for hirsutism is unnecessary if no abnormal aetiology can be diagnosed and if the patient is not concerned about the cosmetic appearance. Management is mainly directed at any underlying cause if present.
• Encourage weight loss if overweight:
  • Weight loss increases steroid hormone-binding globulin levels and decreases insulin resistance and the levels of serum androgens and luteinising hormones.
  • Obesity has an adverse effect on the outcome of all systemic treatments.⁵
  • Women who are overweight, hyperandrogenic or hyperinsulinaemic are at increased risk of diabetes mellitus and cardiovascular disease.
• Because of the cyclical nature of hair growth, any systemic treatment may take up to 6 months to be effective

Topical cosmetic therapies²

Shaving, threading, waxing, using depilatory creams, electrolysis and laser epilation or photo-epilation do not exacerbate hair growth and are effective, at least in the short-term.⁵

• Shaving: Removes all hairs superficially but regrowth produces a rough stubble. Most women prefer not to shave facial hair.
• Chemical depilation may be suited to treatment of large hairy areas in patients unable to afford more expensive treatments such as electrolysis and laser epilation.
• Temporary epilation:
  • Plucking: May result in irritation, damage to the hair follicle, folliculitis, hyperpigmentation, and scarring.
  • Waxing: Painful and sometimes results in folliculitis. With repeated treatments it may reduce the number of hairs permanently.
  • Home epilating devices that remove hair by rotation or friction: May produce traumatic folliculitis.
• Permanent epilation:
  • Electrolysis and thermolysis:
    • Thermolysis (diathermy) is much faster than the traditional electrolysis method.
    • Electrolysis and thermolysis can be used on all skin and hair colours, but they require multiple treatments.
    • Results depend on the skill of the operator.
    • Electrolysis and thermolysis can be uncomfortable and may produce folliculitis and post-inflammatory pigmentary changes in the skin.
  • Laser epilation:
    • Can treat larger areas faster than electrolysis and thermolysis.
    • Most effective on dark hairs in fair-skinned people.
    • Multiple treatments may be necessary for long-term hair destruction.
    • Folliculitis, discomfort and pigmentary changes may occur.

Drug therapy

A systematic review of randomised trials of systemic treatments for hirsutism found that the following drugs were effective: metformin, finasteride, oral contraceptive pills, thiazolidinediones, cyproterone acetate and ethinylestradiol in combination, spironolactone, and flutamide. However a systematic review of trials of insulin sensitisers concluded that this group of drugs is of limited use as sole treatment for hirsutism.

• Combined oral contraceptives:⁵
  • Pills containing progestogens with anti-androgenic properties, e.g. Dianette® or Yasmin®, are effective but those containing levonorgestrel and norethisterone are more androgenic and could potentially exacerbate hirsutism.
  • Third generation progestogens, e.g. desogestrel or gestodene, have relatively neutral androgenic effects and oral contraceptives containing these progestogens can be combined with an anti-androgen such as spironolactone.
  • Only one small randomised controlled trial has compared different oral contraceptive pills, and current guidelines do not recommend one specific pill for treating hirsutism.
• Anti-androgens:
  • May be combined with oral contraceptives for the treatment of hirsutism.³ Cyproterone acetate can be added to the first 10 days of each calendar pack of the oral contraceptive.⁵
  • In most patients, low doses of anti-androgens (e.g. flutamide, spironolactone) are used with few adverse effects and good results.⁶
  • However, although there is some evidence to show that spironolactone is an effective treatment to decrease the degree of hirsutism, there is no evidence for effectiveness for the treatment of acne vulgaris and there are only a few small studies in this area.⁷
  • Patients with severe hyperandrogenic hirsutism may require larger doses of anti-androgens.⁶
  • Response to anti-androgens is slow and may take up to 18 months. Stopping treatment is usually followed by recurrent hair growth.
  • Finasteride, which inhibits 5 alpha-reductase activity, can be used as a single agent or combined with an oral contraceptive or a competitive anti-androgen.⁵
• Dexamethasone: May be used at low doses with an anti-androgen to prolong the length of the remission.⁶
• Gn-RH agonists:
  • Leuprolide should be reserved for use in women who do not respond to combination hormonal therapy or those who cannot tolerate oral contraceptives.
  • Long-term adverse effects include hot flushes, bone demineralisation, atrophic vaginitis.
• Insulin-sensitising agents: Metformin has been shown to improve insulin sensitivity and decrease testosterone levels in patients with PCOS.
• Eflornithine, a topical hair growth retardant, inhibits the enzyme ornithine decarboxylase. A large sponsored randomised trial showed a 26% reduction in facial hair after 24 weeks of treatment, with most of the benefit achieved in 8 weeks.⁵
  • Must be used indefinitely to prevent regrowth.
  • Continuous use for 8 weeks is required before benefit is seen.
  • Should be discontinued in the absence of improvement after treatment for 4 months.
• Co-cyprindiol may be effective when hirsutism co-exists with acne (e.g. in PCOS).

• Hirsutism may have a detrimental impact on a woman's body image and quality of life.
• Facial hirsutism may cause considerable emotional distress and social embarrassment to women; hirsutism exceeding culturally normal levels can be very distressing.⁴