Hirsutism in Women
Effective therapy that is safe for long-term use
Wilma F. Bergfeld, MD

VOL 107 / NO 7 / JUNE 2000 / POSTGRADUATE MEDICINE

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CME learning objectives

To understand how hyperandrogenism can induce hirsutism
To review appropriate laboratory evaluation in a woman with hirsutism
To learn the safest and most effective therapeutic combinations for long-term management of hirsutism

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This is the third of four articles on troublesome skin problems

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Preview: How to manage hirsutism in a woman depends on several factors, including the underlying cause, contraceptive needs, and the patient’s preference. To many patients, appearance is the most important consideration. However, the increased risks conveyed by long-term androgen excess are more significant. In this article, Dr Bergfeld describes, with illustrations, the clinical presentation of hirsutism and how to evaluate patients for androgen excess. In addition, she summarizes the various therapeutic approaches that are available, their advantages and limitations, and combinations that have shown the best success.
Bergfeld WF. Hirsutism in women: effective therapy that is safe for long-term use. Postgrad Med 107(7):93-104

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Hirsutism in women is a common and disturbing disorder defined as excessive male-pattern hair growth. Commonly affected sites are the face (figure 1: not shown), neck, extremities, trunk, breasts, linea alba, lower back, upper pubic triangle, and upper inner thighs (1-3). Unwanted hair is coarse, long and, often, pigmented.

The old classification distinguished among androgen-induced (hyperandrogenism), non-androgen induced (familial and idiopathic), and drug-induced hirsutism. Today, the literature reflects that although use of certain drugs may induce excessive hair growth, most women who have the problem have excess circulating or peripheral androgens (4,5).

Drug-induced hirsutism
Many drugs can induce hirsutism, both generalized and localized. These agents, too, are divided into those that have androgenic activity and those that have nonandrogenic activity (1).

Commonly used drugs that have androgenic activity are testosterone, dehydroepiandrosterone sulfate (DHEAS), danazol (Danocrine), corticotropin, high-dose corticosteroids, metyrapone (Metopirone), phenothiazine derivatives, anabolic steroids, androgenic progestin, and acetazolamide (Dazamide, Diamox).

Common nonandrogenic drugs that can cause hirsutism include cyclosporine (Neoral, Sandimmune, SangCya), phenytoin (Dilantin), diazoxide (Hyperstat IV), triamterene-hydrochlorothiazide (Dyazide, Maxzide), minoxidil (Loniten, Rogaine), hexachlorobenzene, penicillamine (Cuprimine, Depen), and psoralens.

Androgen-excess hirsutism
Androgen receptors are found in the anagen (active) phase in follicles’ dermal papillae and associated sebaceous glands. Circulating androgens arriving at the dermal papillae receptors enter the cell and are metabolized to the final, most potent androgens–testosterone and dihydrotestosterone. The specific androgen and amount, the number and specificity of the receptors, the amount of intermediate or final metabolites, and the presence of enhanced or abnormal androgen metabolism determine localized androgen excess (figure 2: not shown).

This excess induces hirsutism, except on the scalp, where androgenic alopecia is induced. Persistent or transient androgen excess, which can vary from mild to severe, is caused by circulating androgens from the ovary and the adrenal gland, peripheral hair follicle androgen abnormalities, and combined disorders (6-8). Persistent androgen excess has a high association with endometrial cancer, osteopenia, and osteoporosis (9-13).

Clinical presentation (figure 3a and b: not shown) of androgen-excess syndrome has several major features (table 1): seborrhea, acne, hirsutism, alopecia, obesity, and acanthosis nigricans. When hirsutism is associated with obesity and menstrual abnormalities, the source of androgen excess is often ovarian, typically polycystic ovary syndrome. When it is associated with average weight and normal menses, the source is often adrenal and rarely (in <5% of cases) pituitary.

Table 1. Features and risk factors of androgen excess syndrome
Features
Acanthosis nigricans
Acne
Adrenal hyperplasia
Alopecia
Cushing’s disease
Hirsutism
Obesity
Hyperinsulinemia (insulin resistance)
Hyperlipidemia
Menstrual abnormalities
Type 2 diabetes
Seborrhea

Risks
Cardiovascular disease
Endometrial carcinoma
Hypertension
Infertility
Osteoporosis
Pituitary adenoma

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Polycystic ovary syndrome
Polycystic ovary syndrome is the most common cause of hirsutism. Rosenfield (14) loosely defines polycystic ovary syndrome as unexplained hyperandrogenism with variable degrees of cutaneous symptoms, anovulatory symptoms, and obesity. He includes hyperinsulinemia (insulin resistance), familial ovarian hyperplasia, abnormal glucose intolerance, hyperlipidemia, and predisposition to cardiovascular disease. Hypertension may also be a feature.

Persistent hyperinsulinemia increases production of ovarian testosterone and up-regulates androgen receptors. However, it has been successfully treated with antiandrogen agents and the insulin-lowering agent metformin (Glucophage). Hirsutism improves with lowered levels of testosterone (15-18).

Other ovarian disorders
Ovarian hyperthecosis, elevated levels of androgen (namely testosterone), and all the risks of polycystic ovary syndrome have been reported in postmenopausal women with recent onset of hirsutism (19,20). Another recently described ovarian androgen disorder is transient hyperandrogenism, which occurs either in the early follicular phase in ovulatory cycles or in the second phase in delayed or anovulatory cycles (6). Masculinizing ovarian or adrenal tumors are rare but should be considered in sudden onset of severe hirsutism.

Adrenal disorders
Adrenal androgens are elevated in late-onset adrenal hyperplasia, congenital adrenal hyperplasia, Cushing’s syndrome, pituitary adenomas that produce excess corticotropin or prolactin (7), and acromegaly. The specific adrenal androgen-excess marker is DHEAS, which is also a marker for late-onset adrenal hyperplasia. Puberty heralds elevation of DHEAS and is associated with onset of clinical androgen excess (1,7,8,11,13).

Less common abnormalities
A disorder that may occasionally cause androgen-excess hirsutism is 21-hydroxylase deficiency (elevated 17 alpha-hydroxyprogesterone), which is suggested by severe hirsutism and oligomenorrhea. Another uncommon abnormality is 3 beta-, 11-hydroxysteroid dehydrogenase deficiency (elevated 3 beta-, 11-hydroxysteroid), which may result in early- or late-onset congenital adrenal hyperplasia (21). Dexamethasone suppression tests are necessary to identify these two disorders.

Patient evaluation
Because the effects of androgen hormone produce many clinical findings, extensive clinical history taking is essential, including personal history of menstrual periods, pregnancy, infertility, birth control methods, and menopausal symptoms and signs. Drug history and questions regarding family history of androgen excess, thyroid disorders, diabetes, hyperlipidemia, cardiovascular disease, hypertension, and cancer are also important.

Physical examination should include blood pressure and weight measurements and skin examination with specific observations of hirsutism, acne, seborrhea, obesity, and acanthosis nigricans.

Laboratory testing may be divided into simple and extensive evaluation (table 2). Simple evaluation consists of measuring total and free testosterone, DHEAS, and androstenedione (1,10,22), which identifies about half of patients with hyperandrogenism. More extensive testing includes evaluation of follicle-stimulating hormone, luteinizing hormone, sex hormone-binding globulin, testosterone-sex hormone-binding globulin ratio, dihydrotestosterone, estradiol, prolactin, corticotropin, cortisol, and 3 alpha-androstanediol glucuronide (which detects mixed-origin and peripheral-excess hyperandrogenism) (23).

Table 2. Laboratory testing for androgen excess in women with hirsutism
Simple evaluation
Testosterone level (total and free)
Dehydroepiandrosterone sulfate level
Androstenedione level

Extensive evaluation
Follicle-stimulating hormone level
Luteinizing hormone level
Sex hormone-binding globulin level
Testosterone-sex hormone-binding globulin ratio (free testosterone)
Dihydrotestosterone level
Estradiol level
Prolactin level
Corticotropin level
Cortisol level
3 alpha-androstanediol glucuronide level
Dexamethasone suppression testing
Transvaginal ultrasound

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In addition, dexamethasone suppression testing with measurements of the hormones mentioned plus 17 alpha-hydroxyprogesterone and 3 beta-, 11-hydroxy-steroid can further identify uncommon sources of androgen excess. Transvaginal ultrasound has been useful in diagnosing polycystic ovary syndrome (24).

Treatment methods
Treatment of hirsutism involves understanding and consideration of the cause and available cosmetic and antiandrogen approaches (22,24-28). Sources of androgen excess can rarely be permanently removed, so treatment is long term and either continuous or intermittent. Discontinuation of antiandrogen therapy has resulted in recurrence of hirsutism within 6 months (29).

Cosmetic approaches
Among standard treatments of hirsutism in women are camouflaging with heavy makeup, bleaching, and removal with physical methods, such as rubbing, cutting, shaving, plucking, waxing, or “sugaring” (plucking of a large area, similar to waxing but with use of a paste and cloth strips). Chemical depilatories (eg, calcium thioglycolates) are designed to use on specific body locations. Most physical and chemical methods are temporary, with effects lasting hours to days.

Thermodestruction of the hair follicle is possible with electrolysis, which retards regrowth for days to weeks and when repeated can permanently remove hair. However, electrolysis is time-consuming, costly, and uncomfortable.

A new hair-removal method is photothermodestruction with a laser (30). This procedure is costly but offers longer periods between regrowth (weeks to months) and permanent hair loss with repeated sessions. In addition, larger areas can be treated quickly and with minimal discomfort.

All of these methods can induce skin irritation, folliculitis, pigment abnormalities and, rarely, scarring. Education and practice are necessary for self-treatment. Electrolysis and laser hair removal are done by trained professionals who should be certified or licensed.

Weight loss
Obese women with polycystic ovary syndrome and hirsutism can benefit from weight loss. Obesity is associated with excess levels of insulin, androgen, and testosterone. Weight loss can reduce insulin levels, which reduces testosterone levels (31).

Antiandrogen agents
In women of reproductive age, birth control is imperative because antiandrogen therapy is teratogenic to fetuses and has the potential to feminize male fetuses. Antiandrogen agents include drugs that block androgen cytochrome P-450 receptors, resulting in decreased testosterone, dihydrotestosterone, and DHEAS levels, and drugs that inhibit 5-alpha-reductase, which hinders conversion of testosterone to dihydrotestosterone and results in increased testosterone and estradiol levels. However, prescribing the following agents for antiandrogen therapy is considered an off-label use by the US Food and Drug Administration (10,22,23,27,28).

Oral contraceptive agents: Because they compete for the androgen receptor, oral contraceptives can be used as antiandrogen therapy. In addition, they offer birth control protection when used in combination with other antiandrogen or gonadotropin-releasing hormone (GnRH) agonist therapy. Such combinations enhance therapeutic effectiveness and prolong remission (32,33). With oral contraceptives, suppression is greater for ovarian than for adrenal androgens. Estrogen increases sex hormone-binding globulin, which binds androgens, thus reducing circulating levels. Agents containing androgenic progestins (eg, norgestrel, levonorgestrel) should be avoided.

Hormone replacement: In perimenopausal and menopausal women with hirsutism, hormone replacement is useful as both supportive hormone and antiandrogen therapy. In postmenopausal women, hormone-replacement and antiandrogen agents are used to treat ovarian hyperthecosis and hirsutism (20).

Cyproterone acetate: This progestin is an effective antiandrogen and is often combined with the oral contraceptive component ethinyl estradiol. It is the most popular therapeutic agent worldwide for androgen excess, polycystic ovary syndrome, and hirsutism. However, because cyproterone acetate is a potential fetal teratogen, it has not been approved for use in the United States. At least one study (32) indicates that therapies consisting of combinations of non-cyproterone acetate oral contraceptives and antiandrogen and/or GnRH agonist agents are as effective as high-dose cyproterone acetate alone or in combination with antiandrogens.

Glucocorticoid agents: The activity of glucocorticoids is specific for adrenal androgen excess, either late-onset or congenital types. Low-dose dexamethasone (0.125 to 5 mg/day) or prednisone (2.5 to 5 mg/day) given at night reduces androgen excess without impairing immune function, mineral levels, the hypothalamus-pituitary-adrenal axis, or adrenal function. For maintenance therapy, either intermittent or pulse dosing may be used. Combination therapy with antiandrogens and/or oral contraceptives enhances efficacy and extends remission (34).

GnRH agonist: Low-dose monthly GnRH agonist therapy reduces luteinizing hormone, which down-regulates ovarian testosterone and androstenedione but is not effective for adrenal androgen excess (35). When combined with a low-dose oral contraceptive (eg, ethinyl estradiol, 25 micrograms) and a non-androgenic progestin, GnRH agonist therapy reduces ovarian androgen excess and prolongs remission (33). Disadvantages of GnRH agonist therapy are high cost and the need for monthly intramuscular injections.

Spironolactone: In the United States, spironolactone (Aldactone) is the most popular antiandrogen agent for hirsutism. It is often combined with an oral contraceptive agent, which improves effectiveness and reduces menstrual irregularities and the potential for fetal abnormalities. Spironolactone blocks the androgen cytochrome P-450 receptor, reducing testosterone metabolism. Doses range from 100 to 300 mg/day.

Major side effects are abnormal menstrual periods, tender and enlarged breasts (usually temporary), loss of sodium, and retention of potassium. Potassium retention represents a minimal problem if hydration is maintained by increasing water ingestion (eg, 4 glasses per day).

Comparative studies of antiandrogen therapies indicate that spironolactone is more effective than finasteride, and combination with an oral contraceptive agent produces enhanced benefit. Studies have found that finasteride, flutamide, and cyproterone acetate are equal in effectiveness (29,36-38).

Flutamide: An antiandrogen that blocks the androgen cytochrome P-450 receptor, flutamide (Eulexin) has recently been noted to be effective at low doses (125 to 250 mg/day) (39). Liver toxicity has been reported at higher doses. Combination with an oral contraceptive agent enhances effectiveness.

Finasteride: The antiandrogen finasteride (Propecia, Proscar) inhibits 5-alpha-reductase type 2, which reduces dihydrotestosterone and increases testosterone and estradiol levels. Finasteride at a daily dose of 5 mg has been found to be as effective as flutamide and cyproterone acetate. Combined therapies of androgen-receptor blockade, oral contraception, and inhibition of 5-alpha-reductase have enhanced effectiveness and prolonged remissions (37).

Ketoconazole: The antifungal agent ketoconazole (Nizoral) has antiandrogen activity and has been found to be effective at doses of 400 mg/day. However, antiandrogen comparative studies have not been reported, and use of ketoconazole is considered an alternative antiandrogen therapy. Patients should be monitored for possible toxic effects on the liver (39).

Cimetidine: The histamine2 antagonist cimetidine (Tagamet) has weak antiandrogen activity and blocks androgen receptors at doses of 800 to 1,600 mg/day. However, cimetidine has failed to produce any significant benefit in hirsutism (40).

Summary
Hirsutism should be considered part of the androgen-excess syndrome unless another cause (eg, masculinizing tumor, androgenic-drug use) can be established. Medical evaluation for transient or late-onset androgen excess, polycystic ovary syndrome, and insulin resistance is important because of the risks associated with chronic androgen excess. Treatment of insulin resistance with antiandrogen and/or insulin-lowering therapy can reduce ovarian testosterone levels and hirsutism.

Simple laboratory evaluation (ie, measuring total and free testosterone, DHEAS, and androstenedione) identifies about half of patients with hyperandrogenism. More extensive evaluation and testing are required in the remaining half.

Combination therapies, specifically oral contraceptives along with antiandrogen agents, are the most effective. Studies suggest that addition of low-dose GnRH agonist therapy prolongs remission of hirsutism. Most methods produce improvement within 6 months, with continued improvement at 12 months. Successful treatment results in finer hair, decreased rate of growth, decreased need for cosmetic camouflage or removal, and improved appearance. All methods, whether used continuously or intermittently, should be considered long term.

References
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Isik AZ, Gokmen O, Zeyneloglu HB, et al. Low dose ketoconazole is an effective and relatively safe alternative in the treatment of hirsutism. Aust N Z J Obstet Gynaecol 1996;36(4):487-9
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For a helpful guide to electronic and print resources on skin problems for physicians and patients, see the Resource Guide in this issue.

Dr Bergfeld is head of clinical research, department of dermatology, The Cleveland Clinic, Cleveland. Correspondence: Wilma F. Bergfeld, MD, Department of Dermatology, The Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: bergfew@ccf.org.

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Symposium Index
TROUBLESOME SKIN PROBLEMS: Introduction to a four-article symposium by Ken Landow, MD
TREATING THE PATIENT WITH MULTIPLE COSMETIC PRODUCT ALLERGIES: A problem-oriented approach to sensitive skin by Zoe Diana Draelos, MD
ALOPECIA AREATA: A clinical overview by Arthur P. Bertolino, MD, PhD
HIRSUTISM IN WOMEN: Effective therapy that is safe for long-term use by Wilma F. Bergfeld, MD
ACUTE AND CHRONIC HERPES ZOSTER: An ancient scourge yields to timely therapy by Ken Landow, MD

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