Treatment of Hirsutism

Almost all patients presenting with hirsutism represent excess androgen production in association with the steady state of persistent anovulation. Treatment is directed toward interruption of the steady state. In those patients who wish to become pregnant, ovulation can be induced as discussed in Chapter 30. In patients who do not want to become pregnant, the steady state can be interrupted by suppression of ovarian steroidogenesis by utilizing the potent inhibitory action on LH of progestational agents.

Androgen production in hirsute women is usually an LH-dependent process. Suppression of ovarian steroidogenesis depends upon adequate LH suppression. In addition to the inhibitory action of the progestational component, oral contraceptives provide a further benefit because of the increase in SHBG levels induced by the estrogen component. The increase in SHBG results in a greater androgen-binding capacity with a decrease in free testosterone levels. The progestins in oral contraceptives also inhibit 5a-reductase activity in skin, further contributing to the clinical impact of oral contraceptives on hirsutism.

The low-dose oral contraceptives are effective in treating acne and hirsutism. Suppression of free testosterone levels is comparable with that achieved with higher dosage.  The beneficial clinical effect is the same with low-dose preparations containing levonorgestrel, previously recognized to cause acne at high dosage. Formulations with desogestrel, gestodene, and norgestimate are associated with greater increases in sex hormone-binding globulin and significant decreases in free testosterone levels. Comparison studies with oral contraceptives containing these progestins can detect no differences in effects on various androgen measurements among the various products.116 Theoretically, these products would be more effective in the treatment of acne and hirsutism; however, this is not documented by clinical studies. It is likely that all low-dose formulations through the combined effects of an increase in sex hormone-binding globulin and a decrease in testosterone production produce an overall similar clinical response, especially over time (a year or more).

Even in women being treated with antiandrogens, oral contraceptives are important and useful to provide both cycle control and contraception.

In the patient in whom oral contraceptives are contraindicated or unwanted, good results can be achieved with the use of medroxyprogesterone acetate, either 150 mg intramuscularly every 3 months or 10–20 mg orally per day. The mechanism of action of medroxyprogesterone acetate is slightly different from that of the combination oral contraceptive. Suppression of gonadotropins is less intense; hence, ovarian follicular activity continues. LH suppression is significant, however, and testosterone production is decreased, although to a lesser degree than with combined oral contraceptives. In addition, testosterone clearance from the circulation is increased. This latter effect is due to an induction of liver enzyme activity. Medroxyprogesterone acetate decreases SHBG so that less testosterone is bound; however, suppression of total testosterone production is so great that the actual amount of free testosterone decreases. The overall effect yields a clinical result comparable with that achieved with the combination oral contraceptive.

A noteworthy feature of hirsutism is the slow response to treatment. Because of the hair growth cycle, change takes time. The patient should be cautioned that treatment with hormonal suppression will be necessary for at least 6 months before an observable diminution in hair growth occurs. Combined treatment with electrolysis is not recommended, therefore, until hormonal suppression has been used at least 6 months.

New hair follicles will no longer be stimulated to grow, but hair growth that has been previously established will not disappear with hormone treatment alone. This can be affected temporarily by shaving, tweezing, waxing, or the use of depilatories. Contrary to a common belief, these methods do not stimulate growth or increase the rate of growth of hair. None of these tactics alters the inherent growth of the hair; therefore, they must be reapplied at frequent intervals. Permanent removal of hair can be accomplished only by electrocoagulation of dermal papillae. Patients should be counseled to make sure their electrologists use disposable needles.

Some patients return after a period of treatment expressing disappointment because hair is still present. The effect of the treatment (prevention of new hair growth) may not be apparent unless the previously established hair is removed. The combination of ovarian suppression preventing new hair growth and electrolysis removing the old hair yields the most complete and effective treatment of hirsutism.

How long should treatment be continued? After 1–2 years, it is worthwhile to stop the medication and observe the patient for a return of ovulatory cycles. Even in those patients who continue to be anovulatory, testosterone suppression continues for 6 months to 2 years after discontinuing treatment. Of course, if anovulation is still present, one can expect the eventual return of hirsutism.

The really resistant patient deserves further consideration. Combination therapy with one of the methods discussed below is worthwhile, preferably an oral contraceptive combined with either spironolactone or finasteride.

In most patients, DHAS levels are suppressed by progestational treatment.The mechanism is not definitely known, but there are several possible explanations. If the original stimulus for the increased DHAS secretion is the steady estrogen state of anovulation, then the change in the endocrine milieu of the adrenal gland brought about by the suppression of ovarian steroidogenesis will restore a normal adrenal secretory pattern. Oral contraceptives may also produce subtle but significant alterations in ACTH secretion or response in the adrenal gland.

The effectiveness of adrenal suppression in inducing ovulatory cycles in some anovulatory patients can be attributed to a lowering of circulating androgen levels due to a decrease in the adrenal contribution as well as a reduction in the amount of DHAS available for conversion to testosterone within the ovarian follicle. The intraovarian androgen level is decreased, therefore lowering the inhibitory action of androgens on follicular growth and development. In terms of ovulation, the frequency of successful response with this type of treatment does not match that of the first drug of choice, clomiphene. In terms of treatment of hirsutism, progestin suppression of ovarian steroidogenesis is more effective and should remain the first therapeutic approach. Adrenal suppression should be reserved for patients with a clearly established diagnosis of an adrenal enzyme deficiency.

In an older woman who has no further desire for fertility, and in the woman for whom continued use of steroid medication is disturbing because of increasing risks with increasing age, serious consideration should be given to a surgical solution. A persistent problem of hirsutism, especially if it is progressive in severity, is a reasonable indication for hysterectomy and bilateral salpingo-oophorectomy. Patients with hyperthecosis respond poorly to suppression and are usually older. Surgical treatment for these patients is often very appropriate. Of course, an estrogen regimen is recommended for these patients postoperatively.

Keep in mind the strong association between hyperandrogenism and hyperinsulinemia. Treating the problem of hirsutism by suppression of androgen production and action will not restore glucose metabolism to normal; these patients will continue to demonstrate insulin resistance. In overweight, hyperandrogenic patients, a weight control program is essential to reduce the risks of diabetes mellitus and cardiovascular disease, and consideration should be given to the preventive health benefits expected from long-term treatment with metformin or troglitazone. Nevertheless, hirsutism in hyperandrogenic women with hyperinsulinemia will respond favorably to treatment with oral contraceptives.

Spironolactone

Spironolactone is an aldosterone-antagonist diuretic. In the treatment of hirsutism, spironolactone has multiple actions, inhibiting the ovarian and adrenal biosynthesis of androgens, competing for the androgen receptor in the hair follicle, and directly inhibiting 5a-reductase activity. The inhibition of steroidogenesis is achieved through an effect on the cytochrome p450 system, but the steroid suppressive effects are so variable that the receptor-blocking action is the most important mechanism. It is probably for this reason that cortisol, DHA, and DHAS levels are not significantly changed with spironolactone treatment, even though androstenedione levels are decreased.

The impact of spironolactone treatment on hirsutism is related to dosage, and a better effect is seen with a dose of 200 mg daily.125, 126 and 127 After a period of time, one can usually lower the dose of spironolactone to a maintenance dose of 25–50 mg daily. As with progestational agents, the response is relatively slow, and a maximal effect can be demonstrated only after 6 months of treatment. Side effects are minimal, including diuresis in the first few days of use, occasional complaints of fatigue, ad dysfunctional uterine bleeding. Remember that the anovulatory state requires progestational management in order to avoid abnormal uterine bleeding (and endometrial hyperplasia). Because of the possibility of hyperkalemia, spironolactone should be used with caution in women who are elderly, diabetic, or using drugs that raise the potassium level.

We use spironolactone when patients find oral contraceptives unacceptable or the response is disappointing. Indeed, it makes sense to combine the peripheral tissue action of spironolactone with oral contraceptives to achieve a more dramatic result; however, the results with combined treatment regimens have not been impressively better than single agent therapy. Acne has been effectively treated with the local application of a cream containing 2–5% spironolactone. Systemic absorption does not occur, and there are no side effects.

One word of caution: with inhibition of androgen secretion, ovulation can occur, and effective contraception is important. Theoretically, spironolactone interference with testosterone action could result in the feminization of a male fetus; however, a disrupting effect on the external genitalia has not occurred, despite fetal exposure to high doses.131 Combined treatment with an oral contraceptive may produce a better clinical effect and, at the same time, prevent menstrual irregularity and provide contraception.

Cyproterone Acetate

Cyproterone is a potent progestational agent that both inhibits gonadotropin secretion and blocks androgen action by binding to the androgen receptor. In many parts of the world, it has been used in an oral contraceptive agent called “Diane” (2 mg cyproterone acetate and 50 µg ethinyl estradiol). “Dianette” or “Diane 35” contains 2 mg cyproterone acetate and 35 µg ethinyl estradiol. In a method for the treatment of hirsutism called the reversed sequential regimen, cyproterone acetate is given in a dose of 50 or 100 mg daily on days 5–14, with 30 or 50 µg of ethinyl estradiol daily on days 5–25.132 In a comparison of Diane with the high dose (100 mg) cyproterone acetate treatment, the therapeutic effect was greater (but probably not of clinical significance) with the higher dose, and there was a similar incidence of side effects with both treatments.133 In a comparison of Dianette with higher doses of cyproterone acetate (20 and 100 mg), the clinical response with the 2 mg dose of cyproterone in Dianette was equal to that of the higher doses.134 The most common reactions include fatigue, edema, loss of libido, weight gain, and mastalgia. Significant improvement in facial hirsutism is seen by the 3rd month of treatment. In comparisons of spironolactone and cyproterone acetate, a monophasic low-dose oral contraceptive combined with spironolactone 100 mg daily was as effective as the reversed sequential regimen of 50 or 100 mg cyproterone and estrogen.135, 136 and 137

Dexamethasone

Dexamethasone suppression of endogenous ACTH secretion is used in women who have an adrenal enzyme deficiency. Dexamethasone is given nightly (to achieve maximal suppression of the central nervous system-adrenal axis that peaks during sleep) in a dose of 0.5 mg. An equivalent dose of prednisone is 5–7.5 mg. If this treatment suppresses the morning plasma cortisol level below 2.0 µg/dL, the dose should be reduced to avoid an inability to react to stress. Fortunately, adrenal androgen secretion is more sensitive to suppression by dexamethasone than is cortisol secretion.138 Patients with adrenal hyperplasia may require higher doses to normalize the steroid blood levels. With higher doses, alternate day therapy can still accomplish significant adrenal androgen suppression without affecting cortisol secretion.139 It should be emphasized that moderate elevations of DHAS do not indicate patients who will benefit from dexamethasone treatment.140 Maximal effectiveness against hirsutism in patients with an adrenal enzyme deficiency may require treatment besides glucocorticoid supplementation.141, 142 The addition of an oral contraceptive or antiandrogen should be considered.

Treatment With GnRH Agonists

Because ovarian androgen production is LH-dependent, suppression of the pituitary with chronic GnRH agonist treatment improves hirsutism. However, inconsistent results in the literature attest to the fact that sufficient dosage must be administered to achieve effective suppression and clinical response. Therefore, monitoring dosage and response is recommended. A greater dose of GnRH agonist is required to suppress ovarian androgen secretion compared with estradiol secretion.143 We recommend the use of depot administration of a GnRh agonist with monitoring treatment by measuring testosterone levels (the goal being less than 40 ng/dL). To avoid the problems associated with estrogen deficiency, estrogen-progestin add-back should be initiated after the maintenance dose of a long-acting GnRH agonist has been established. We recommend the daily administration of 0.625 mg conjugated estrogens or 1.0 mg estradiol combined with 2.5 mg medroxyprogesterone acetate or 0.35 mg norethindrone, or, even better, an oral contraceptive.

Although a combination of a GnRH agonist and an oral contraceptive produces a greater reduction in free testosterone levels, improvement of hirsutism is similar, comparing the combination to treatment with only an agonist; however, treatment with an agonist has been reported to be more effective than oral contraceptives alone. In one clinical trial, the improved response associated with agonist treatment was observed only in the first 3 months of treatment; by 6 months the combination of oral contraceptives and a GnRH agonist was no more effective than oral contraceptives. The addition of a long-acting agonist to Dianette (2 mg cyproterone acetate and 35 µg ethinyl estradiol) did not significantly improve clinical results.148 After one year, a comparison of GnRH agonist treatment with the high dose cyproterone acetate regimen indicated equal efficacy, although agonist treatment was followed by a more prolonged remission.149 These mixed results reflect variability in the severity of the condition and the degree in androgen suppression. The impact of a GnRH agonist-oral contraceptive combination is maximal when testosterone levels are suppressed below 40 ng/dL and in patients who are overweight with severe hirsutism.

This method of treatment is relatively complicated and expensive and should be reserved for the severe case of ovarian hyperandrogenism, which is usually due to significant hyperthecosis and marked hyperinsulinemia (a condition that responds less well to the usual methods of treatment). An alternative that deserves consideration is treatment of the hyperinsulinemia with metformin or troglitazone. Once maximal response has been obtained with one of these more expensive methods, long-term suppression of hair growth can be maintained with an oral contraceptive or an antiandrogen.

Flutamide

Flutamide (Eulexin) is a nonsteroidal antiandrogen at the receptor level.150 Flutamide directly inhibits hair growth without many side effects (dry skin is the most common); however, hepatotoxicity is possible.Because of the uncommon but severe toxic effect on the liver, a low-dose approach is recommended. A dose of 250 mg daily can have a marked beneficial impact on hirsutism within 6 months.Despite the use of lower doses, however, it is prudent to monitor liver enzymes. In a comparison study, flutamide (250 mg bid) was not more effective than spironolactone (100 mg/day). Treatment with flutamide should be combined with a method of contraception; blockage of androgen receptors in a male fetus could interfere with normal male development. In our view, the potential for hepatotoxicity makes flutamide an unsatisfactory choice for treatment of hirsutism.

Finasteride

Finasteride inhibits 5a-reductase activity, thus blocking conversion of testosterone into dihydrotestosterone. The 5a-reductase enzyme exists in two forms, type I and II, each encoded by a separate gene, with the type I enzyme found in skin and the type II reductase predominately expressed in reproductive tissues. Finasteride (Proscar), used to treat prostate cancer, effectively inhibits both isoenzymes, and, therefore, can be used to treat hirsutism. A dose of 5 mg per day decreases hirsutism without side effects.155 A lower dose is probably as effective. Finasteride has been available only as a 5 mg unscored tablet, but it can with care be cut into quarters. A smaller dose, 1 mg (Propecia), has now been approved for the treatment of hair loss in men. In a randomized, clinical trial finasteride and spironolactone (100 mg daily) were equally effective. In another randomized clinical trial, spironolactone in a dose of 100 mg daily was more effective than finasteride.  The main advantage of finasteride is the lack of side effects. Because the development of the urogenital sinus and urogenital tubercle into the male external genitalia, urethra, and prostate requires the action of dihydrotestosterone, patients being treated with finasteride should be cautioned regarding this possible risk during pregnancy, and an effective method of contraception must be used.

Other Agents

Cimetidine (300 mg qid) has been used to treat hirsutism, but it is the least potent of the androgen receptor blockers, and the clinical response is disappointing. The use of a skin cream containing progesterone is effective, but it must be applied frequently (because of rapid metabolic clearance) and its action is very concentrated at the point of application.  Minoxidil in a topical application produces a moderate increase in hair growth in women with alopecia; however, indefinite, on-going treatment is necessary, and a return to the previous hair pattern cannot be achieved. Ketoconazole in a dose of 400 mg daily blocks androgen synthesis by inhibiting the cytochrome P450 system. Although the impact on hirsutism is significant, there is a high incidence of side effects as well as changes in liver enzymes.  Ketoconazole, at best, should be a last resort, requiring frequent monitoring of liver function. In addition, chronic treatment with ketoconazole may suppress adrenal corticosteroid production.

Clinical Gynecologic Endocrinology and Infertility 6th ed: Leon Speroff, Robert H. Glass, Nathan G. Kase, 1999 Lippincott Williams & Wilkins