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2002 Selected Articles

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Hirsutism: Etiology and Treatment

Richard S. Legro, MD

Hirsutism is defined as excess body hair in undesirable locations, a subjective description that complicates both diagnosis and therapy. The condition is common, but as its etiology is poorly understood, a variety of pharmacologic, mechanical, and folk remedies have been tried. It is estimated from an epidemiologic perspective that 6% to 7% of reproductive aged women in the United States are affected by hirsutism and that women in the United States spend an estimated $1.5 billion a year treating hirsutism.¹ This article focuses on androgen-dependent hirsutism.

THE ROLE OF Androgens

Most hirsutism is androgen-dependent, ie, associated with androgen excess, although this concept may be too simplistic to explain pathologic states of the pilosebaceous unit (PSU) such as hirsutism, acne, and androgenic alopecia. Androgens can be viewed as growth factors that stimulate the PSU, but they are just one group among many substances that may contribute to the PSU life cycle (Figure 1). Paradoxically, androgens can exert opposite effects on the hair follicles of the scalp, causing conversion of terminal follicles to vellus-like follicles. This leads to male-pattern baldness, which is characterized by frontal and temporal hair loss (Figure 2). Androgens can also cause increased sebum production and abnormal keratinization in the PSU, resulting in acne. The mechanism by which androgens stimulate the PSU is largely unknown, but they can increase the activity of ornithine decarboxylase, promoting polyamine production and thereby cellular division and differentiation.

Figure 1. Role of androgen in the development of the pilosebaceous unit. Solid lines indicate effects of androgens; dotted lines indicate effects of antiandrogens. Hairs are depicted only in the anagen (growing) phase of the growth cycle. In balding scalp (bracketed area), terminal hairs not previously dependent on androgen regress to vellus hairs under the influence of androgen. [Reprinted with permission from R. L. Rosenfield and D. Deplewski: Am J Med 98:80S-88S, 1995 (1A ) (c) Excerpta Medica Inc.]

Figure 2. Androgenic Alopecia in Women Ludwig Scale

The PSU is the skin structure that gives rise to both hair follicles and sebaceous glands, covering the body with the exception of the palms and soles. The number of PSUs (about 5 million) does not increase after birth, but they can become more prominent through activation and differentiation. Before puberty, body hair is primarily of the fine, unpigmented, vellus type. Puberty and the accompanying androgen stimulation transforms some of these hairs into coarser, pigmented, terminal hairs, mainly along the midline. A similar mechanism may explain the onset of acne with puberty due to increased sebum production by the sebaceous glands. After such a period of active growth (anagen), the hair follicle enters a resting phase (telogen) that varies in length.

Assessment

Androgen-dependent midline hair grows primarily on the upper lip, chin, cheeks, intermammary area, escutcheon, inner thighs, lower back, and intergluteal area. The assessment of hirsutism is notoriously subjective. One common method of assessing hirsutism, the modified Ferriman-Gallway score, also considers nonmidline, nonandrogen-dependent body hair in the diagnosis (Figure 3).² The best discrimination between control and hirsute populations uses the sum of scores from four regions: upper lip, chin, lower abdomen, and thighs.³ Another confounder of hirsutism evaluation is the robust mechanical hair removal employed by some women, decreasing the degree of hirsutism viewed by a subjective observer.


Figure 3.

Differential Diagnosis

The differential diagnosis of hirsutism must include causes of androgen excess, especially polycystic ovary syndrome (PCOS), which is the most common cause of androgen-dependent hirsutism. Other possible etiologies are an androgen-secreting tumor, Cushing's syndrome, nonclassical congenital adrenal hyperplasia (NC-CAH), and exogenous androgens. Nonclassical congenital adrenal hyperplasia, often termed late-onset congenital adrenal hyperplasia, can present in adult women with anovulation and hirsutism, and is due almost exclusively to genetic defects in the steroidogenic enzyme 21-hydroxylase (CYP21). Rare causes of hirsutism include hyperthecosis (a severe form of PCOS), acromegaly, and extreme androgen excess with insulin resistance due to genetic mutations in the insulin receptors (eg, Rabson-Mendenhall syndrome, leprechaunism/Donohue syndrome). Androgen excess in adult women from exogenous androgens may be due to anabolic steroid use or androgen overdose in postmenopausal patients.

Virilization in adult women is rare. It includes the common signs of acne and hirsutism, but also is accompanied by peripheral effects such as temporal balding, clitoromegaly, deepening of the voice, breast atrophy, and changes in body contour. Amenorrhea may occur in a premenopausal woman. Virilization is never idiopathic, and all cases must be investigated. Coexisting signs of Cushing's syndrome, including "moon" facies, "buffalo hump," abdominal striae, centripetal fat distribution, and hypertension, should be documented and evaluated. As Cushing's syndrome has an extremely low prevalence (1 per 1 million) and screening tests lack 100% sensitivity/specificity, routine screening is not indicated in all women with hirsutism.

Androgen-independent hirsutism, which tends to have a diffuse distribution (hypertrichosis), may be a familial tendency (familial hypertrichosis) or may be due to medications such as cyclosporine, diazoxide, and minoxidil. The term "idiopathic hirsutism" is often used to describe hirsutism in eumenorrheic women with normal circulating androgen levels, but this may reflect the limited ability to assess androgen activity in the peripheral compartment. When thoroughly investigated, these "idiopathic" cases usually prove to have some component of androgen excess.

Laboratory Studies

Appropriate laboratory tests for hirsutism are listed in Table 1. The circulating androgen most closely associated with unexplained androgen excess has yet to be determined. Testosterone and/or bioavailable/free testosterone levels are useful for documenting ovarian hyperandrogenism. A dehydroepiandrosterone sulfate (DHEAS) test may be useful in cases of rapid virilization as a marker of adrenal origin, but its utility in common hirsutism assessments is questionable.

Androgen-secreting tumors of ovarian or adrenal origin are invariably accompanied by elevated circulating androgen levels. However, there is no absolute level that is pathognomonic for a tumor, just as there is no minimum androgen level that excludes a tumor. In the past, testosterone levels exceeding 2 ng/mL and DHEAS levels exceeding 700 mg/dL have been regarded as suspicious for a tumor of ovarian or adrenal etiology, respectively, but these cutoffs have poor sensitivity and specificity. In one study, fewer than 10% of women with a total testosterone value of more than 250 ng/dL had a tumor.⁴ Nonetheless, these cutoffs are useful for quantifying circulating androgen excess and its potential source.

A prolactin test can identify prolactinomas, which secrete massive amounts of prolactin that may stimulate ovarian androgen production, but this is an extremely rare cause of hyperandrogenic chronic anovulation. A serum thyroid-stimulating hormone (TSH) test is also useful, given the protean manifestations and frequency of thyroid disease in women with menstrual disorders.

 

Table 1. Potential Evaluation for Hirsutism Total testosterone and/or bioavailable/free testosterone (documentation of biochemical hyperandrogenemia). TSH (exclusion of other causes of hyperandrogenism, including thyroid dysfunction). Prolactin (hyperprolactinemia). 17-OHP (Nonclassical congenital adrenal hyperplasia due to 21 hydroxylase deficiency). Normal ≤ 4 ng/mL (random) or ≤ 2 ng/mL (fasting am); consider screening for Cushing's syndrome and other rare disorders such as acromegaly Oral glucose tolerance test (metabolic abnormalities). 2-hr fasting glucose < 110 mg/dL = normal, 110-125 mg/dL = impaired fasting glucose, >126 mg/dL = type 2 diabetes; 2-hr glucose level after 75-g oral glucose load < 140 mg/dL = normal, 140-199 mg/dL = impaired glucose tolerance, > 200 mg/dL = type 2 diabetes. Fasting lipid and lipoprotein levels, including total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and low-density lipoprotein cholesterol (LDL-C) calculated by Friedewald equation.

Women with NC-CAH due to CYP21 mutations can be identified by obtaining a fasting 17a-hydroxyprogesterone (17-OHP) level in the morning. A value of less than 2 ng/mL is normal, and cutoffs as high as 4 ng/mL have been proposed for tests in the morning and during the follicular phase.⁵ Values above this cutoff, or values above 2 ng/mL obtained at a random time, should be investigated with an adrenocorticotropic hormone (ACTH) stimulation test. This is performed in the early morning by giving 250 mg of cosyntropin, a synthetic form of ACTH, intravenously (IV) after baseline 17-OHP analysis and then obtaining a 1-hour value. Results may be interpreted according to nomograms, but a cutoff 1-hour 17-OHP value of less than 10 mg/mL excludes NC-CAH.⁶

Although the yield is low, all patients with hirsutism should be screened for NC-CAH due to the possibility of CYP21 mutations, as this diagnosis has a different prognosis and treatment regimen, and requires genetic counseling. Cortisol excess can be detected with a 24-hour urine test for free cortisol, which better quantifies excess cortisol production than random blood testing. Urinary free-cortisol values greater than 300 mg/d are virtually diagnostic for Cushing's syndrome. Intermediate elevations require further testing.

Currently, the American Diabetes Association (ADA) does not recommend screening for insulin resistance by measuring insulin or other markers for insulin resistance syndrome due to the variability of insulin assays, the poor predictive value of fasting insulin levels, and the unclear association between hyperinsulinemia and other metabolic sequelae (primarily cardiovascular disease). However, insulin levels may be useful in cases of severe insulin resistance with marked acanthosis nigricans (HAIR-AN syndromes). In obese hirsute women, assessment for diabetes and related metabolic abnormalities should be strongly considered. This may consist of a glycosylated hemoglobin and a fasting lipoprotein profile, or alternatively, a 2-hour glucose value after a 75-g glucose load to assess for glucose intolerance.

Treatment

Although they can improve hirsutism, most medical therapies do not produce the significant reduction in hair growth that most women desire, and treatment is often palliative rather than curative. Trials have been hampered by both methodology concerns and the small number of subjects. In general, combination therapies appear to produce better results than single-agent approaches^7-9; however, randomized trials have not established a preferred primary treatment for hirsutism. There are few adequately powered randomized trials of acne and fewer still of androgenic alopecia, so treatment of hirsutism is extrapolated from the treatment of other signs of hyperandrogenism at the PSU. In terms of ameliorating the effects of androgen excess on the PSU, there are three important goals: decreasing androgen production, decreasing androgen bioavailability, and opposing androgen activity (Figure 4).

Figure 4.

Eflornithine

Eflornithine hydrochloride cream (Vaniqa) is the only agent that directly affects the cell cycle in the PSU. This is a potent, irreversible inhibitor of the enzyme ornithine decarboxylase, which is necessary for production of the polyamines that mediate cell migration, proliferation, and differentiation. Inhibition of this enzyme limits cell division and function. This compound was originally used as a parenteral treatment for Trypanosomoa brucei gambiense, which causes African sleeping sickness. After hair loss was observed as one of the side effects of this treatment, a topical preparation was subsequently developed and tested for inhibition of hair growth.¹⁰

Eflornithine hydrochloride (13.9% cream) is applied to the upper lip twice a day for a minimum of 4 hours for each application. Two randomized, double-blind, placebo-controlled trials have been conducted involving 594 women (both pre- and postmenopausal; 60% white, 30% black, and 7% Latino). These studies lasted 24 weeks, plus an 8-week follow-up phase with no treatment. In these clinical trials, 32% of women showed marked improvement after 24 weeks compared with 8% in the placebo group. Benefit was first noted at 8 weeks. A total of 58% of subjects had some overall improvement.¹¹ Improvement was assessed using the Physicians' Global Assessment, a 4-point scale for evaluating response. Assessments by the treating physician (including the use of photographs) occurred 48 hours after shaving at several points during the study. Additionally, video analysis and patient self-assessment were performed, both of which supported the Physicians' Global Assessment.

This agent is generally well tolerated. The most common side effects are stinging of the skin (8.5% in the treatment group versus 2.5% in the placebo group) and skin rash (2.8% versus 1.5%). The drug is rated pregnancy category C, although such an antimitotic, antiproliferative, and antidifferentiation agent should theoretically be avoided during pregnancy and used cautiously in a population of reproductive-aged women. However, systemic absorption appears to be minimal.¹² While eflornithine has not been studied specifically on areas other than the upper lip, it should be effective for other midline terminal hair growth.

Oral Contraceptives

No oral contraceptive (OC) has a US Food and Drug Administration (FDA)-approved indication for the treatment of hirsutism. In addition, there are no studies of adequate power to confirm their benefit in PCOS-related hirsutism despite the theoretical possibility of decreasing hyperandrogenemia and androgenic stigmata and increasing sex-hormone-binding globulin (SHBG) levels through their estrogen effects. Nonetheless, a number of observational and nonrandomized studies have noted improvement in hirsutism during OC use.^13-15 Few studies have compared different types of OCs, and no pill has been shown to be superior in treating hirsutism in PCOS.¹⁶ A number of studies have found additive benefit when an OC is combined with other treatment modalities, such as flutamide.⁷ Onset of action may be prolonged; one observational study of long-term effects noted that mild to moderate hirsutism took 36 to 60 cycles to resolve and was still present in about 33% of women, although severe cases were ameliorated after 60 cycles.¹⁴ Acne may respond in a shorter time (12 to 24 months), and may show a higher remission rate.¹⁴

The best OC for treating women with PCOS is unknown, but a pill containing a progestin that also functions as an antiandrogen, such as cyproterone acetate or drospirenone may be theoretically preferable.¹⁷ An example of a pill in the United States with this formulation is Yasmin, a combination agent containing drospirenone, which differs from other progestins used in OCs in that it is derived from 17-a spironolactone rather than norethindrone or levonorgestrel.¹⁸ Drospirenone increases SHBG levels 3- to 4-fold and works as an antimineralocorticoid, and its use may favor weight maintenance or even weight loss. These antimineralocorticoid effects preclude its use in women with renal disease or hyperkalemia, Additional benefits in terms of hirsutism are obtained from its antagonistic properties at the level of the androgen receptor (much like spironolactone). Thus, this combination OC may address all three goals for treating androgen excess. However, studies confirming the utility of this agent in the treatment of hirsutism are not yet available.

GnRH Analogs

No gonadotropin-releasing hormone (GnRH) agonist is FDA-approved to treat hirsutism. A GnRH agonist given alone may improve hirsutism, but results in unacceptable bone loss. Combining a GnRH agonist with an add-back regimen may further decrease circulating androgen levels, but there is little additive benefit for hirsutism.^8,19 Currently, the utility of GnRH agonists in the long-term management of hirsutism is limited.

Antiandrogen Overview

None of these agents are FDA-approved specifically to treat hyperandrogenism in women, and they are used empirically in women with hirsutism. These compounds antagonize the binding of testosterone and other androgens to the androgen receptor. Therefore, they are teratogenic as a class, and pose a risk of feminization of the external genitalia in a male fetus if the patient conceives. These agents may have additional benefits, including direct inhibition of steroidogenesis, and androgen antagonism may improve other metabolic variables such as insulin sensitivity and circulating lipid levels. All appear to offer some benefit, although the best choice for hirsutism has not been established. Randomized trials have found that spironolactone, flutamide, and finasteride all have similar efficacy in improving hirsutism.^20-22

Spironolactone. - Spironolactone has a long history as an antiandrogen and multiple clinical trials have been published showing a benefit, but the overall quality of the trials and small numbers enrolled have limited the ability of a meta-analysis to document its benefit in the treatment of hirsutism.²³ Spironolactone, a diuretic and aldosterone antagonist, also binds to androgen receptors with 67% of the affinity of dihydrotestosterone. It has other mechanisms of action, including inhibition of ovarian and adrenal steroidogenesis, competition for androgen receptors in hair follicles, and direct inhibition of 5-a-reductase activity. The usual dose is 25 to 100 mg twice a day orally, and the dose is titrated to maximize efficacy while minimizing side effects. There is a dose-response effect, and it may take 6 months for benefits to appear. About 20% of women experience increased menstrual frequency, which is why this agent is often combined with an OC. Because it can cause and/or exacerbate hyperkalemia, it should be used cautiously in women with renal impairment. The medication also has potential teratogenicity as an antiandrogen, although exposure has rarely resulted in ambiguous genitalia in male infants.²⁴ Acne has also been successfully treated with spironolactone. Thus, despite extensive published experience with spironolactone, much of the treatment rationale for hirsutism is empiric.

Flutamide.—Flutamide is another nonsteroidal antiandrogen shown to be effective against hirsutism in observational trials.^25-27 The most common side effect is dry skin, but in rare cases its use has been associated with hepatitis. The dosage is 250 mg/d. There is a significant risk of teratogenicity with this compound, and contraception should be used. Its mechanism is unclear, as there is evidence to suggest that antiandrogens may also improve insulin sensitivity in hyperandrogenic women.²⁸

Finasteride.—There are two forms of the enzyme 5-a-reductase; type 1 is predominantly found in the skin, and type 2 in the prostate and reproductive tissues. Finasteride inhibits both forms, and is available as a 5-mg tablet for the treatment of prostate cancer and a 1-mg tablet for the treatment of male alopecia. It has been found to be effective for the treatment of hirsutism at a dosage of 5 mg.^29,30 Finasteride is better tolerated than other antiandrogens, with minimal hepatic and renal toxicity, but has the highest risk for teratogenicity in a male fetus and adequate contraception must be used.

Glucocorticoids

Glucocorticoid suppression of the adrenal glands also offers theoretical benefits, but deterioration in glucose tolerance and induction of dyslipidemia are problematic for women with PCOS or other metabolic abnormalities. Long-term effects such as osteoporosis are a significant concern. Dexamethasone has been shown to slow hair growth rates in women who are already using a GnRH agonist.³¹ The use of glucocorticoids to treat hirsutism is largely empiric.

Insulin Sensitizing Agents

Figure 5.

Insulin sensitizing agents have been adapted from the treatment of type 2 diabetes, and improve ambient hyperinsulinemia by increasing insulin sensitivity. It is difficult to separate the effects of raising insulin sensitivity from those of lowering serum androgens, as any "pure" improvement in insulin sensitivity can raise SHBG levels and thus lower bioavailable androgen levels. Given the long onset of action for reducing hirsutism, longer periods of observation are needed. In the largest and longest randomized trial to date of these agents, troglitazone at the highest dose of 600 mg a day was found to significantly improve hirsutism in women with PCOS.³² The mean percentage of improvement was only 17% (Figure 5). In small studies with metformin, hirsutism was unchanged^33,34 or improved slightly.^35,36 Further study is needed to detect differences between classes of insulin sensitizing agents and establish prolonged benefit over a longer duration of study.

Mechanical and Chemical Depilatory Methods

Mechanical hair removal (shaving, plucking, waxing, depilatory creams, electrolysis, and laser vaporization) can control hirsutism, and is becoming front-line treatment for many women. Shaving may be the most common temporary method. There is no evidence that shaving can increase hair follicle density or hair shaft size.³⁷ Judicious plucking can be helpful if tolerated, but care must be taken to avoid folliculitis, pigmentation, and scarring. Waxing and depilatories are used less commonly, and have potential adverse side effects such as skin burning or rash.³⁸

Electrolysis.—There are three electrolysis modalities.³⁹ In galvanic electrolysis, a direct current is passed down a needle inserted into the hair follicle, destroying the follicle. In thermolysis, a high-frequency alternating current is passed down the needle to produce destructive heat. The third modality combines galvanic electrolysis and thermolysis. Electrolysis satisfactorily removes hair from women and men with hypertrichosis, but women with hirsutism require concomitant hormonal management. Shaving 1 to 5 days before electrolysis greatly increases efficacy because it ensures that only growing anagen hairs are epilated. Electrolysis is tedious, highly operator-dependent, and may be impractical for the treatment of large areas of hair growth. Electrologists are supervised to varying degrees in different states.

Laser Hair Removal.—Laser- and light-assisted hair removal is based on the principle of selective photothermolysis.⁴⁰ Ruby, alexandrite, diode, and neodymium:yttrium-aluminum-garnet (Nd:YAG) lasers and a broad-band intense pulsed light have been used. Hair is damaged with wavelengths of light that are well absorbed by follicular melanin and pulse durations that selectively damage the target thermally while sparing surrounding tissue. Women with dark hair and light skin are ideal candidates, and treatment appears to be most effective during the anagen phase. Due to the presence of hair follicles in various stages of the hair growth cycle, multiple treatments may be necessary. The majority of studies have been observational and nonrandomized, with no specific focus on women with PCOS. Randomized studies have demonstrated a benefit over control areas,⁴¹ but no specific laser type or method has been found to be superior.⁴² The role of lasers in the treatment of hirsutism has not yet been clearly defined.

CONCLUSION

A number of modalities are available to treat hirsutism. Most are empirical and not approved for this indication by the FDA. In general, multiagent treatment has been preferred with a variety of mechanisms. Typically, OCs offer relief through a number of mechanisms, as well as conferring a variety of other health benefits. Avoiding unwanted pregnancy and potential unrecognized fetal exposure to teratogenicity are important considerations when antiandrogens are used alone. Onset of action with medical treatments can last several months, with years required to obtain the full benefit. Physical removal methods including electrolysis and lasers are often used as adjuvant therapies after adequate medical suppression has been achieved. The future promises continued development and utilization of agents such as eflornithine that directly inhibit the cell cycle or cellular differentiation in the PSU.

Richard S. Legro, MD, is an associate professor, Hershey Medical Center, Department of Obstetrics and Gynecology, Pa.

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