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00019616-200711000-00010ReviewThe EndocrinologistThe Endocrinologist© 2007 Lippincott Williams & Wilkins, Inc.17November 2007 p 335-340HirsutismInvestigation and ManagementCME Review Article #32Smith, D MD*; Tan, C Y. MRCPI†; McKenna, T J. MD‡*Consultant Endocrinologist, Beaumont Hospital, Dublin, Ireland; and †Specialist Registrar in Endocrinology and ‡Professor of Investigative Endocrinology, St. Vincent’s University Hospital, Dublin, Ireland.The authors have disclosed that they have no significant relationships with or financial interests in any commercial company that pertains to this educational activity.Lippincott Continuing Medical Education Institute, Inc. has identified and resolved all faculty conflicts of interest regarding this educational activity.Reprints: T. J. McKenna, Department of Investigative Endocrinology, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. E-mail: [email protected] Editor’s Note: This article is the 32nd of 35 that will be published in 2007 for which a total of up to 35 AMA PRA Category 1 Credits™ can be earned. Instructions for how credits can be earned precede the CME Examination at the back of this issue.AbstractHirsutism is a common disorder, which can present either to the primary care or hospital specialist. The appropriate management of the hirsute patient depends on the mode of presentation, the severity, and the psychologic and social distress often associated with hirsutism. This article seeks to outline an effective clinical approach to patients with hirsutism, plan investigations to ensure a sinister cause of hirsutism is not missed, and optimise treatment.Learning ObjectivesIdentify mechanisms of hirsutism, a manifestation of hyperandrogenism, in patients with no apparent cause (idiopathic hirsutism, IH) and those with polycystic ovary syndrome (PCOS)—who together comprise the vast majority of hirsute women.Describe the clinical presentation of patients having IH or PCOS, and those clinical features that may suggest a tumor or other serious underlying condition.Appraise and compare the cosmetic and endocrinological options available for treating IH and hirsutism associated with PCOS.Hirsutism is a common disorder and affects approximately 8% of the general female population.1 However, physicians are often uncertain on how to manage the hirsute patient. The uncertainty arises from a lack of understanding of the pathogenesis of the common causes of hirsutism and the fear that the hirsutism may reflect a sinister pathology such as an underlying malignant tumor. This article seeks to outline an effective clinical approach to patients with hirsutism, help plan investigations, and optimize treatment.How to Diagnose HirsutismHirsutism is the growth of male-type hair in a male distribution in a woman. Androgen-dependent terminal hair (male-type hair) is coarse, tends to curl, grows away from the skin, and is distributed on the face, particularly the upper lip and chin, chest, back, abdomen, upper arm, and thigh. Nonandrogen-dependent hair is fine, straight, and tends to lie on the skin. Unwanted nonandrogen-dependent hair, vellus hair, does not constitute hirsutism. Some ethnic groups, such as the Mediterranean races, tend to have more vellus-type hair than other ethnic groups. This trait may constitute a cosmetic embarrassment but is not a medical disorder and does not respond to medical treatments for hirsutism.1Causes of Hirsutism (Table 1):JOURNAL/endst/04.03/00019616-200711000-00010/table1-10/v/2021-02-17T201839Z/r/image-tiff Causes of HirsutismThe term idiopathic hirsutism, IH, is variously defined as hirsutism associated with regular menstruation or hirsutism associated with normal androgen levels or hirsutism associated with regular menstrual pattern and normal circulating androgens. This accounts for approximately 50% of hirsute patients. Approximately 50% of hirsute patients have oligomenorrhoea and carry the diagnosis of polycystic ovary syndrome, PCOS.2 The criteria used for PCOS diagnosis are controversial.3 Currently, the recommended diagnostic criteria for PCOS are based on the presence of hyperandrogenism with or without skin manifestation hirsutism and/or acne and ovulatory dysfunction in the absence of other specific causes of androgen excess, such as nonclassic adrenal 21-hydroxylase deficiency, Cushing syndrome, and androgen-producing tumors.4 Polycystic ovary morphology on pelvic ultrasound is consistent with but not essential for the diagnosis of PCOS. The Rotterdam criteria recommend 2 of the following 3: (a) evidence of hyperandrogenism (hormonal or clinical); (b) oligomenorrhea; and (c) polycystic ovaries on ultrasound examination.3 IH and PCOS probably represent extremes in the spectrum of the same disorder. While patients with IH by definition may have normal menstruation, greater than 80% of these patients will demonstrate polycystic ovaries, PCO, on ultrasound examination. The spectrum of presentation associated with PCO extends from absolute normality through IH to full-blown PCOS.5 Less than 5% of hirsute patients have an alternative more sinister diagnosis (Table 1).6Hyperandrogenism and HirsutismHirsutism is a manifestation of hyperandrogenism. Hirsutism can result either from an excess of androgens arising from the ovaries and/or adrenals7,8 or increased sensitivity of the hair follicles to androgens.9In IH or PCOS an excess of androgens may be derived from polycystic ovaries (75%–100%) and/or from the adrenal glands (25%–35%).10 The etiology of adrenal androgen excess has not been defined. Possible mechanisms include a relative excess of a pro-opiomelanocortin (POMC)-derived fragment other than ACTH.11 When this happens, there may be a shift in the balance of steroid secretion from the adrenal so that there is an increase in the ratio of androgens to cortisol. Other mechanisms include increased metabolic clearance of cortisol associated with a compensatory increase in ACTH secretion.12,13 This causes increased secretion of androgens from the adrenal and as, unlike that of cortisol, metabolism of androgens is not increased, androgen levels will increase in plasma.PCOS is associated with abnormalities in gonadotropin secretion, with increased luteinizing hormone (LH) pulse frequency and amplitude resulting in an elevated LH-to-follicle-stimulating-hormone ratio, which favors androgen secretion.14 In addition, insulin resistance frequently associated with PCOS causes hyperinsulinemia.15 The concept of insulin resistance is confined to the glucose-lowering action of insulin but does not affect the androgen secretion from ovarian theca cells in response to insulin. Insulin appears to stimulate androgen production through a number of different mechanisms. Insulin enhances the androgen stimulating effect of LH on the polycystic ovaries16 and increases the activity of cytochrome p450c 17a hydroxylase, a key regulatory enzyme in stimulating ovarian and adrenal androgen production.17,18 Insulin also lowers sex hormone binding globulin (SHBG) levels and thus increases the biologically important level of nonprotein bound or the “free” fraction of testosterone. It has been suggested that oligo-ovulation as a characteristic of PCOS is associated with more insulin resistance than is seen in patients with IH who continue to ovulate regularly.19 Insulin resistance in POCS may underlie the frequently associated characteristics of obesity, acanthosis nigricans, and dyslipidemia. Recent studies suggest that approximately 45% of women with PCOS meet the criteria for metabolic syndrome as defined by the Adult Treatment Panel III.20 Insulin resistance is also likely to lead to the development of impaired glucose tolerance and diabetes in approximately 5%–10% of young women with PCOS.21When testosterone gains access to cells of androgen-dependent tissue, the enzyme 5α-reductase facilitates its conversion to 5α-dihydrotestosterone (5DHT). 5DHT is a more potent androgen than testosterone and binds readily to the androgen receptor.9 This complex makes its way into the nucleus and is responsible for directing the production of a characteristic protein profile in the androgen target tissue. Therefore, the androgen effect depends upon the level of androgen available to androgen-dependent tissue and the sensitivity of the cells to androgen, eg, the rate of 5α-reductase activity.22 Between individuals, there is a wide normal range of activity of the enzyme 5α-reductase in the hair follicle. In most endocrine systems, a negative-feedback system ensures that the highest normal levels of circulating hormone occur in those individuals where the target tissue is least sensitive to the hormone. However, almost unique within endocrine systems, androgen production in women from either the ovaries or the adrenals is not under negative-feedback control. The coincidence of high normal androgen levels and high normal androgen sensitivity may result in excess androgen expression in the absence of a hormonal or receptor abnormality.In our experience, hirsutism associated with hyperandrogenemia is much more frequently encountered than are normal androgen levels. However, this will depend on the investigations used to identify hyperandrogenemia. This includes testosterone level, measurement of sex-hormone-binding globulin to derive an index of free testosterone level, and measurement of additional androgens, eg, androstenedione and dehydroepiandrosterone sulfate (DHEA-S).Clinical Presentation of Patients With IH/PCOSMost patients with IH or PCOS note the gradual development of hirsutism over 1 or more years before it is sufficiently severe to be brought to medical attention. Hirsutism is usually first noted in the decade between 15 and 25 years and is frequently accompanied by acne. Approximately 50% of hirsute women experience oligomenorrhoea. It is useful to use a hirsutism score to record the extent of hair growth at presentation. The Ferriman-Gallwey score is widely used and is helpful in gauging the response to treatment, but it is less useful in establishing the diagnosis of hirsutism. Patients with IH or PCOS do not have any evidence of virilization. Features of virilization such as temporal recession of the scalp hair, male-pattern balding, male-type musculature, deepening of the voice, and clitoromegaly suggest a more sinister pathology as the cause of the hirsutism and warrant intensive investigation (Table 1).Identifying Patients With Other Causes of HirsutismA clinical presentation of gradually developing hirsutism, ie, history of greater than 1 year, in the decade 15 to 25 years, with or without associated menstrual disturbances and in the absence of virilization, may be sufficient to establish a clinical diagnosis of IH/PCOS5 (Table 2). Measurement of testosterone and particularly a free testosterone index is useful for most patients (Table 3). This provides a means of checking for the unsuspected very high value and to track the early response to treatment. A total testosterone level greater than twice the upper limit of normal for total testosterone or a free testosterone index 5 times above the upper limit of normal should prompt additional investigation for more sinister causes of hirsutism (Table 1). Where patients present with rapidly progressive hirsutism or outside the decade 15–25 years of age or with evidence of virilization, extensive investigation is warranted, as set out in Table 4. Investigations should include a 1-mg overnight dexamethasone suppression test as a screening test for Cushing syndrome, early-morning 17-hydroxyprogesterone level, and imaging of the ovaries and/or adrenal glands as appropriate. When the patient is of an ethnic background where late-onset congenital adrenal hyperplasia occurs with a relatively high frequency, eg, Ashkenazi Jews, Eskimos, Hispanic peoples, routine specific screening for 21-hydroxylase deficiency is warranted.JOURNAL/endst/04.03/00019616-200711000-00010/table2-10/v/2021-02-17T201839Z/r/image-tiff Clinical Features Suggestive of IH/PCOS in a Hirsute PatientJOURNAL/endst/04.03/00019616-200711000-00010/table3-10/v/2021-02-17T201839Z/r/image-tiff Optional Testing of Hirsute Patients With Clinically Diagnosed PCOSJOURNAL/endst/04.03/00019616-200711000-00010/table4-10/v/2021-02-17T201839Z/r/image-tiff Evaluation for Patients With Clinical Features Unusual for IH/PCOSHow Is Hirsutism Treated?The treatment options available for hirsute patients with IH/PCOS are outlined in Table 5. Less than 5% of patients will have an alternative diagnosis, and treatment should be targeted at the source of androgen excess, eg, resection of an androgen-secreting tumor.JOURNAL/endst/04.03/00019616-200711000-00010/table5-10/v/2021-02-17T201839Z/r/image-tiff Hirsutism: Treatment Options for Patients With PCOS/IHGeneral AdviceSince a significant proportion of hirsute patients are obese and obesity results in elevated insulin levels, which drive ovarian androgen production, weight loss is important. Indeed, weight loss has been associated with resumption of regular ovulation and a fall in testosterone levels in PCOS.23 Similarly, there is evidence that mild adrenal androgen excess may occur in patients who smoke.7 Since estrogen is a widely used and effective agent in the management of hirsutism and associated side effects are more likely to occur in obese patients and in patients who smoke, advice to lose weight and discontinue smoking is important.Cosmetic MeasuresUse of local measures, including plucking, bleaching, waxing, shaving, electrolysis, or laser treatment, should all be encouraged so that the patient achieves the optimum response rapidly. There is little evidence to support popular notions that the use of plucking, shaving, and depilatory creams will cause worsening of hirsutism.24 These forms of treatment are associated with the return of hair growth. However, subsequent growth does not result in coarser hair, increased density of hair growth, or faster hair growth. Only electrolysis or laser treatment can be associated with destruction of a hair follicle. Other hairs will replace these unless the underlying abnormality is also treated. Patients should seek advice within the local community as the success of these treatments is entirely operator dependent. Regulation of those providing electrolysis and laser treatment services varies around the world.AnovulantsTreatment with estrogen and a nonandrogenic progestogen in a combination anovulant is widely used as the basic hormonal treatment for hirsutism. Estrogen suppresses gonadotropin secretion from the pituitary, which in turn reduces the stimulus to the ovaries to produce androgen. SHBG levels in blood also rise. Thus, free testosterone levels fall. Third-generation combination anovulants contain nonandrogenic progestogens. Concern has been expressed about their slightly higher rate of thromboembolic disease than occurred with previous-generation anovulants.25A combination of ethinyl estradiol, 35 μg, and cyproterone acetate, 2 mg, EE/CA, daily for 21 days followed by a 7-day treatment-free phase (Dianette) has been widely used successfully in the cyclical treatment of hirsutism.26 Cyproterone acetate was one of the first available nonandrogenic progestogens. Indeed, in higher doses it is a potent antiandrogen and competes with dihydrotestosterone for binding to the androgen receptor. Approximately 90% of patients demonstrate a satisfactory response gradually over a period of 2 years. However, withdrawal of treatment is associated with relapse in approximately 80% of patients after 2 years. The relapse rate is significantly retarded when drug treatment is maintained for 4–5 years.26 Drospirenone, a novel 17-α spironolactone derivative with both antiandrogenic and antimineralocorticoid activity, has been shown recently to be an effective agent in treating hirsutism, with a similar efficacy to Dianette.27 Hirsute women with and without PCOS treated with 3 mg of drospirenone plus 30 μg of ethinyl-estradiol (Yasmin) for 12 months showed a decline in Ferriman-Gallwey scores of between 60% and 70%. Improvement was most prominent on the chest and abdomen, followed by the upper lip and chin.28,29AntiandrogensIn some cases, specific antiandrogen treatment is used in addition to a combined anovulant. The use of the anovulant brings about suppression of androgen level and also provides contraception necessary to preclude the possibility of exposure of a male fetus to the antiandrogen, giving rise to feminization of the genitalia. Since treatment with combination anovulants is associated with the development of very low testosterone levels, the additional high-dose antiandrogen may provide little extra benefit. Antiandrogens include cyproterone acetate, 50–100 mg, which because of its slow metabolic clearance is used daily only for the first 10 days of the anovulant treatment cycle to ensure regular withdrawal bleeding. Spironolactone, 100–200 mg daily, has both antiandrogenic and antimineralocorticoid effects and is widely used in the United States where cyproterone acetate is not available. Spironolactone is also useful in the treatment of patients who tend to develop hypertension while on an anovulant. Side effects include irregular menstrual bleeding and breast tenderness. Because of the potential of spironolactone to cause abnormalities in fetal development during pregnancy, it should only be used in women of a reproductive age in conjunction with a combined oral contraceptive. The nonsteroidal preparation flutamide is a useful alternative and may reduce visceral fat and improve the lipid profile in PCOS women,30 but its use has been limited because of hepatotoxicity and deaths associated with its use.31An important effect of estrogen-progestogen treatment in combination with an antiandrogen is reduction of the androgen level. When Barth et al32 compared the effectiveness of cyproterone acetate 2 mg, 20 mg, and 100 mg given in combination with ethinyl estradiol 35 μg per day in a cyclical manner, the impact on hair growth in hirsute patients was similar. An explanation for this observation is that since estrogen brings about lowering of testosterone to subphysiologic levels, the role of the antiandrogen is limited. When cyproterone acetate was introduced, it was noted to have improved efficacy when compared with other available agents, which at the time were generally androgenic, reflecting its role as a nonandrogenic progestogen rather than an antiandrogen.Adrenal SuppressionUse of near-physiologic doses of glucocorticoid with slow clearance prior to sleep results in suppression of the early-morning ACTH surge and lowering of cortisol and androgen levels. This has been associated with both resumption of regular ovulation in previously oligomenorrheic patients and with an improvement in hirsutism over a 6-month period.33,34 However, the lowering of androgen levels and the hirsutism response is less than that seen in patients treated with anovulants. In obese patients, even replacement doses of glucocorticoid tend to be associated with appetite stimulation. However, glucocorticoids have the characteristic desirable for some patients of facilitating ovulation. Clearly this treatment has a particular role in patients found to have congenital adrenal hyperplasia. However, even in these patients the optimum hirsutism response will probably be gained by the combination treatment with glucocorticoid and a suitable anovulant.5α-Reductase InhibitorSince testosterone becomes biologically active in the target organ only when converted to 5DHT facilitated by the enzyme 5α-reductase, there is a rationale to the use of an inhibitor of this enzyme, finasteride.35 Data on the efficacy of finasteride compared with other antiandrogens are conflicting; some studies suggest a similar response rate of hair growth when compared with spironolactone,36 while other studies show it to be less effective.37 In general, it would appear to have no additional advantage over other antiandrogens except when their use is specifically contraindicated, but it may have a synergistic effect when combined with spironolactone in the treatment of hirsutism.38Insulin SensitizersMuch interest is centered around the use of insulin sensitizers in the treatment of type 2 diabetes mellitus, including metformin and members of the thiazolidinedione family.38,39 Insulin sensitizers have been demonstrated to be effective in lowering testosterone levels. The extent to which testosterone is lowered is less than that seen with the estrogen-progestogen combination anovulants and is unlikely to be as effective as an anovulant in the suppression of hirsutism. However, similar reduction in hair growth using metformin and an anovulant has been reported in some studies,40,41 but this is not our anecdotal experience. In the broader context, use of insulin sensitizers in the treatment of PCOS has shown a variety of significant beneficial effects, including increased frequency of ovulation,39 increased frequency of pregnancy,42 decreased frequency of miscarriage,43 and decreased frequency of gestational diabetes without adverse impact on fetal or maternal outcome.44,45Gonadotropin-Releasing Hormone Analogues (GnRH)Long-acting GnRH agonists, which suppress gonadotropin secretion and ovarian androgens, have also been used in the management of hirsutism. There is no reason to believe that these relatively expensive agents will be more effective than anovulants. Furthermore, GnRH agonists will cause hypogonadotropic hypogonadism and estrogen deficiency, which may be associated with rapid bone loss. This can be prevented by the addition of estrogen replacement.46 It is likely that this combination is no more effective than a conventional anovulant.Ornithine Decarboxylase Inhibitor (Topical)Eflornithine 15% cream applied twice daily has been reported to be associated with reduced hair growth in some women. By 24 weeks, 32% of patients receiving the active drug demonstrated “marked improvement” in hirsutism compared with 8% of patients receiving placebo. Hair growth had returned to pretreatment rates within 8 weeks of discontinuing the drug.47The Choice of TreatmentsThe choice of pharmacologic intervention is determined by the balance of the side effects of treatment, the patient’s desire to start a family, and the perceived severity of hirsutism. None of the pharmacologic treatments address the underlying cause of hyperandrogenism in IH/PCOS as it has not been clearly defined. It is likely that relapse will occur with all drug treatments, similar to that described on the withdrawal of anovulants. If anovulants are considered, the risk and benefits should be explained clearly to the patient. Patients should be advised that only the mildest forms of hirsutism are likely to respond fully within 2 years and that the likelihood of long-term remission would be significantly greater with treatment lasting 4–5 years. Long-term treatment may not only bring about a temporary lowering of androgen levels but there have been several suggestions that with time androgen levels tend to fall; a reduction in hirsutism may be part of the natural history of IH/PCOS. If alternative treatments are required, specialist advice should be sought. Without an anovulant, pregnancy during treatment can occur. The risk and benefit should be explained to the patient.Because of the associated problems of obesity, insulin resistance, and hypertension associated with IH/PCOS, patients should be given advice on a healthy lifestyle, including weight reduction and increased exercise. There may be some reassurance to be gained from observations that while risk factors for coronary artery disease are common among patients with IH and PCOS, long-term follow-up and assessment of mortality of women with PCOS has not indicated an unfavorable outcome.48REFERENCES1. Azziz R, Carmina E, Sawaya ME. Idiopathic hirsutism. 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