The overall quality of primary evidence of the relative efficacy of treatments for hirsutism is weak and is based on small studies of short duration that lack quality-of-life outcomes. Recently, however, systematic reviews have amalgamated this evidence, and new guidelines are now available (Table 55–4). It should be explained that hair grows in cycles. Thus it can take months for an individual hair follicle to proceed through catagen, anagen, and telogen phases.
Lifestyle changes that promote weight loss through diet and physical exercise are useful in obese patients. Obesity is present in 60% of patients with PCOS, the most common form of hirsutism and hyperandrogenism. Weight loss in patients with hyperandrogenism, with or without the clinical presence of PCOS, should be the first therapeutic option because it decreases androgen levels, increases SHBG, and may restore ovulation. As little as a 7% reduction in body weight can restore fertility, decrease hirsutism, and improve the response to induction of ovulation. Lifestyle measures that promote weight loss through diet and exercise are of paramount importance because obesity has an adverse effect on the outcome of all systemic treatments.
Eflornithine, a topical agent, is an irreversible inhibitor of ornithine decarboxylase, an enzyme that catalyzes the rate-limiting step for follicular polyamine synthesis, which is necessary for hair growth. Eflornithine hydrochloride cream 13.9% (Vaniqa) is approved in many countries for the treatment of unwanted facial hair in women. Eflornithine does not remove hair but acts to reduce the rate of hair growth.
A large sponsored randomized trial showed a 26% reduction in facial hair after 24 weeks of treatment, with most of the benefit achieved in 8 weeks. Nevertheless, Endocrine Society Clinical Practice Guideline recommends against the use of topical antiandrogen therapy.
Systemic treatment reduces stimulation of the anagen growth phase by testosterone. Thus enough follicles have to pass through anagen before a clinical effect is observed. The goal of treatment is to find the lowest effective dose of treatment that maintains the benefit gained in the first phase of treatment. For all pharmacologic therapies for hirsutism a trial of at least 6 months should be conducted before making changes in dose, changing medication, or adding medication. Medical suppression of hirsutism is detailed in Table 55–5.
Table 55–5. Suppression of Hirsutism over Baseline over 6 Months Compared with Placebo.
The primary driver of ovarian androgen secretion is LH, which can be suppressed using a combined oral contraceptive pill. The effectiveness of oral contraceptives in suppressing hirsutism will depend on the content of ethinylestradiol (20–35 μg) and on the nature of the progestogen. Pills containing progestogens with antiandrogenic properties, such as cyproterone acetate and drospirenone found in Diana and Yasmin, respectively, are effective in hirsutism. Pills containing levonorgestrel and norethisterone are more androgenic and could potentially exacerbate hirsutism. Third-generation progestogens such as desogestrel or gestodene have relatively neutral androgenic effects, and oral contraceptives containing these compounds can usefully be combined with an antiandrogen such as spironolactone. Only 1 small randomized controlled trial has compared different oral contraceptive pills, and current guidelines do not recommend one specific pill for treating hirsutism.
Gonadotropin-Releasing Hormone Agonists
Severe hirsutism of ovarian origin can sometimes be treated by gonadotropin-releasing hormone (GnRH) analogues. GnRH analogs inhibit the secretion of gonadotropins from the pituitary gland, thereby inhibiting the secretion of androgens and estrogens from the ovary. Although GnRH agonists acutely stimulate ovarian production of androgens and estrogens, continued therapy causes a sustained decrease in ovarian steroid production compared with pretreatment levels. This suppression continues for the duration of GnRH agonist therapy. Significant decreases in serum levels of estradiol, testosterone, and androstenedione occur during treatment, although adrenal androgens are usually unaffected.
As a result of the hypoestrogenism associated with ongoing GnRH therapy, a potential risk of osteoporosis and menopausal symptoms exists with long-term therapy. However, concomitant use of estrogen and progesterone replacement therapy may counteract the adverse effects. Newer studies suggest that spironolactone may also simulate this effect.
Most studies have shown greater improvement of hirsutism with the use of GnRH agonists alone or in combination with oral contraceptives as compared with combination oral contraceptives alone; however, some studies show comparable efficacy. Endocrine society guidelines suggest against using GnRH agonists except in women with severe forms of hyperandrogenemia, such as ovarian hyperthecosis, who have a suboptimal response to oral contraceptive pills and antiandrogens.
Androgen Receptor Antagonists
In a proportion of women, ovarian suppression alone may not be sufficient, and antiandrogens will need to be added. Patient-important hirsutism that remains despite ≥6 months of monotherapy with an oral contraceptive justify combination therapy by adding an antiandrogen.
Antiandrogens are efficacious for treating hirsutism. There are 4 androgen receptor antagonists currently being used for the treatment of hirsutism. Despite proven efficacy in numerous clinical trials, none of these drugs has been approved by the US Food and Drug Administration for this indication. Additionally, similar reported efficacy has been reported with all of these medications. Hence the agent of choice should be dictated by the individual's response, reported side effects, and known contraindications. All antiandrogens, and particularly finasteride, are potentially teratogenic, so some clinicians prescribe them only to women using reliable contraception.
This potent agent was the first androgen receptor antagonist used to treat hirsutism and is widely prescribed in Europe to treat hirsutism. Antiandrogenic effects result from competitive displacement of dihydrotestosterone from its receptor and reduction of 5α-reductase activity in the skin. Progestational activity results in gonadotropin suppression with subsequent suppression of ovarian testosterone secretion. Cyclical administration of 50–100 mg on days 1–10 of the menstrual cycle combined with oral estrogen on days 1–21 produces therapeutic levels. More prolonged use tends to induce amenorrhoea because of its progestogenic properties. This method counters hypoestrogenism and irregular bleeding and prevents pregnancy and the potential teratogenic complications that may result. Although effective in 50–75% of hirsute women, significant side effects include decreased libido, mental depression, and hepatotoxicity, which is rarely seen when cyclic administration is performed. Clinical studies have shown efficacy equivalent to that of spironolactone, with the latter showing fewer side effects (see next section). Currently, cyproterone acetate is not available in the United States.
Spironolactone, an aldosterone antagonist traditionally used as a diuretic in the treatment of hypertension, is also used to treat hirsutism. Cochrane review showed that spironolactone can effectively suppress hirsutism. It possesses antiandrogenic properties and exerts its peripheral antiandrogenic effects in the hair follicle by competing for androgenic receptors and displacing dihydrotestosterone at both nuclear and cytosol receptors. It also lowers testosterone levels by inhibiting the cytochrome P450 monooxygenases that are required for biosynthesis of androgens in gonadal and adrenal steroid-producing cells. Serum levels of SHBG, DHEAS, and DHEA are unaltered by treatment with spironolactone. The dosage used for treatment of hirsutism is between 50 and 200 mg/d. Serum androgen levels will drop within a few days of the start of treatment, and a clinical response can usually be seen within 2–5 months. Side effects include fatigue, transient diuresis, polydipsia, menorrhagia or unscheduled menstrual bleeding, gastro-intestinal bleeding and breast tenderness, but no long-term problems have been encountered. Its anti-mineralocorticoid and diuretic properties are rarely prominent in young women. Because spironolactone is a potent antiandrogen, all women using it should use effective contraception. Nevertheless, women taking spironolactone should be sent for periodic screening of potassium level to identify hyperkalemia.
Flutamide is a potent, highly specific, nonsteroidal antiandrogen with no intrinsic hormonal or antigonadotropin activity. Although the exact mechanism of action is unknown, it competitively inhibits target tissue androgen receptor sites. Recent studies suggest that 250 mg 1–3 times daily is a highly effective treatment for moderate to severe hirsutism. Side effects include decreased appetite, amenorrhea, decreased libido, or dry skin. A rare but serious reported side effect is hepatotoxicity. Consequently, flutamide is usually reserved for resistant cases of hirsutism, and liver enzymes should be checked regularly in patients who are taking the drug. Additionally, because of possible teratogenic effects, contraception must be used with this therapy. Endocrine Society Clinical Practice Guideline recommends against flutamide for the treatment of hirsutism.
If additional treatment is needed, then finasteride would be a sensible option because it has a different mode of action. Finasteride is the newest antiandrogenic agent used for hirsutism. It is a selective type 2 5α-reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone. It has proven efficacy in up to 86% of patients with a subjective improvement rate of 21–45% when 5 mg is administered orally over 3 months to 1 year. Side effects at this dosage are usually mild or absent and include headaches, transient gastrointestinal upset, and an unexplained increase in total testosterone.
Dexamethasone is used mainly to treat hirsutism in patients with hyperandrogenism of adrenal origin. Chronic low-dose dexamethasone, 0.5–1 mg orally taken at bedtime, will provide adequate adrenal androgen suppression. Diminution of hair growth is reported in 16–70% of patients. Glucocorticoid therapy has fallen out of favor due to frequent side effects, potential for adrenal suppression, and evidence that these agents are less effective than antiandrogens, even when there is a clear adrenal cause of hyperandrogenism. However, their use may be justified in some patients, as recent data suggest that concomitant use of glucocorticoids with GnRH agonists may prolong the disease-free interval when therapy is discontinued. Moreover, glucocorticoids are the treatment of choice to decrease ACTH levels and thereby decrease formation of androgenic precursors of cortisol for patients with CAH.
Dopamine is a centrally acting inhibitor of prolactin secretion and is frequently used in the treatment of hyperprolactinemia. Recently, hirsutism scores were shown to decrease significantly during dopamine treatment of hyperandrogenic women with hyperprolactinemia.
Insulin, which acts as a co-gonadotrophin and amplifies LH-induced testosterone production, is a secondary driver of ovarian androgen secretion. Troglitazone, an insulin-sensitizing agent of the thiazolidinedione class, results in a decrease in androgen level in patients with polycystic ovarian syndrome. Additionally, it has been shown that the administration of 600 mg/d results in improvement of hirsutism in this population. Endocrine Society Clinical Practice Guideline recommends against the use of insulin-lowering drugs for the treatment of hirsutism.
Conveniently, women for whom suppression of LH is not possible (eg, obese women who should not take the oral contraceptive pill because of the risk of thrombosis) are often the very women for whom suppression of insulin is most effective. Nevertheless, insulin sensitizers are of limited use as sole treatment for hirsutism.
Cimetidine, an H2-receptor antagonist, has weak antiandrogenic properties. Recent studies show minimal or no beneficial effect in hirsutism.
Ketoconazole is a synthetic imidazole derivative that blocks adrenal and gonadal steroidogenesis; it has been advocated by some as a treatment for hirsutism. However, serious side effects result in poor compliance and preclude long-term use. Its use should be avoided because safer therapeutic regimens exist.
The goal of mechanical therapy is to limit new hair growth without affecting existing hair. For this reason, mechanical depilators such as lasers, electrolysis devices, creams, and waxes are often used as supplemental therapy (Table 55–4). Recent technology has made this procedure faster, easier, less painful, and generally free of any serious adverse effects. Many women will be familiar with routine methods of hair removal such as shaving, threading, waxing, and using depilatory creams and can be reassured that these methods do not exacerbate hair growth. Electrolysis and laser epilation or photoepilation are also widely available. A review of 11 trials of laser and light-assisted hair removal in 444 patients showed a 50% reduction in hair over 6 months but noted that the long-term efficacy of these treatments is not well established. Laser treatment is less effective in darker skin because a contrast is needed between skin and hair pigments, but some types of photoepilation can be of benefit patients with for darker skin.
In the minority of hirsute patients in whom a specific cause can be identified, therapy should be directed toward the underlying disorder. For example, ovarian and adrenal tumors should be surgically excised. Additionally, women with Cushing's disease are treated with transsphenoidal pituitary microsurgery. Alternatively, when Cushing's syndrome is caused by an adrenal tumor, simple adrenalectomy is sufficient. Finally, acromegaly can be treated by transsphenoidal hypophysectomy. For persistent disease, bilateral adrenalectomy or pituitary irradiation is appropriate.
Similarly, a minority of older women may fail to respond to medical management for hyperthecosis despite good compliance. For these women, bilateral oophorectomy may be justified as definitive therapy.
Although wedge resection of the ovary has been successfully used to induce ovulation, it is not recommended for the treatment of hirsutism. This surgical procedure exposes patients to the risks of both anesthesia and possible formation of adhesions. More importantly, this procedure results in only a transient decrease in androgen levels and has successfully reduced the rate of hair growth in only 16% of patients. Wedge resection should not be used as a treatment for hirsutism.