Cyproterone acetate for hirsutism

Hyperandrogenism (elevation of masculinizing hormones) is probably the commonest endocrine disturbance in women. The clinical manifestations of hyperandrogenism vary from mild skin changes (increased oiliness), acne, excess facial and body hair through to voice changes, enlargement of the clitoris and change in body habitus.

Hirsutism is the growth of terminal hair in sites at which it is usually considered a male secondary sexual characteristic e.g. chest and beard area. About one third of women in the reproductive years have some hair on their face, abdomen or chest (McKnight 1984).

Among older women, up to 75% may have slightly increased facial hair, because the main product of the postmenopausal ovaries is androstenedione which is converted to testosterone in the peripheral tissue.

The three main naturally occurring steroids responsible for androgen action are testosterone, dehydroepiandrosterone (DHEA) and androstenedione. Testosterone is the most important androgen and conversion by five alpha-reductase to the more potent dihydrotestosterone is necessary for its biological action (Franks 1989). Androstenedione and DHEA may be regarded as pre hormones which are converted in peripheral tissue to testosterone before they exert any androgenic influence. Production, peripheral conversion and protein binding are important determinants of androgenic effect. Total testosterone measurements, which reflect bound and free hormone do not accurately reflect tissue exposure to androgens. The derived free androgen index (testosterone x 100 divided by sex hormone binding globulin levels) may be used to give an indirect estimation of the free testosterone levels.

The distribution and quality of the hair and the concentration of androgen receptors in the skin are genetically determined, and hence the clinical effects of hyperandrogenaemia are influenced by genetic predisposition (Flamigni 1971; Mowszowicz 1981). Once five alpha-reductase activity has been induced in a hair follicle, it remains sensitive to androgen stimulation for the rest of its life cycle. The hair cycle varies in different parts of the body - from three-six months on the face to five+ years on the scalp (Saitoh 1970; Seago 1985). As a result, therapeutic interventions result in gradual changes in the clinical presentation and the development of hirsutism itself reflects prolonged androgen stimulation.

Androgens also increase the rate of mitosis and epithelial proliferation of sebaceous gland acini and cause enhanced sebum production - both these factors contribute to the development of acne (Ashton 1987; Nurnberger 1987).

Hyperandrogenism may result from ovarian and/or adrenal overproduction of androgens and/or altered peripheral metabolism and/or altered end organ sensitivity. The diagnosis in the majority of women who present with hirsutism will be the polycystic ovary syndrome which is characterised by a typical ultrasound appearance of the ovaries and a variable endocrine and clinical picture (Conway 1989; Adams 1986; Bunker 1989).

Objective scoring systems to assess hirsutism have been used in clinical practice, but these may be difficult to reproduce as there may be considerable inter-observer variation (Ferriman 1961). Other methods of assessing hair growth include measuring the rate of hair growth with a trichometer or shaving and weighing the hair (Jones 1981). Sebum production is affected by androgens and is sometimes used as a surrogate marker for the effect of therapy on the skin. Many of these methods are impractical in current clinical practice.

Therapeutic options for the management of hirsutism have increased considerably over the past few decades.

Cyproterone acetate is an anti-androgen with potent progestational action and in combination with ethinyl estradiol it inhibits five alpha-reductase activity in the skin of hirsute women, increases SHBG levels and has a significant anti-gonadotrophin effect (Neumann 1987). Cyproterone acetate is stored in adipose tissue which causes a marked depot effect when high doses are used. It has now been an accepted treatment of hirsutism for almost two decades with a reported good clinical response in sixty to eighty percent of patients (Mowszowicz 1983; Kuttenn 1980; Hammerstein 1975; Hammerstein 1983). The documented effects of cyproterone acetate on serum androgen concentrations are somewhat varied (Reed 1988; Rubens1984). Side effects of weight gain, depression, fatigue, breast symptoms and sexual dysfunction have been reported during cyproterone acetate therapy (Lunnell 1982; Appelt 1984).

Other therapeutic agents for hirsutism include spironolactone (which inhibits steroidogenesis, blocks the androgen receptor and inhibits five alpha reductase, ketoconazole (a powerful enzyme inhibitor), flutamide (a receptor blocker), finasteride (a five alpha reductase inhibitor) and GnRH agonist analogues (which cause pituitary down regulation) (van der spuy 1992).

The effectiveness of cyproterone acetate with or without estrogen therapy has not been confirmed by systematic review.

The objective of this review was to investigate the effectiveness of cyproterone acetate alone, or in combination with ethinyl estradiol, in reducing hair growth in women with hirsutism secondary to ovarian hyperandrogenism.

Search strategy
The Cochrane Menstrual Disorders and Subfertility Group trials register was searched (last search - 4 June 2002). The Cochrane Menstrual Disorders and Subfertility Group register is based on regular searches of MEDLINE (1966 to 2002), EMBASE (1980 to 2002), CINAHL (1982 to 2002), PsycINFO (1987 to 2002) and CENTRAL (Issue 2, 2002 of the Cochrane Library) the handsearching of several journals and conference proceedings, and searches of several key grey literature sources. All publications of randomised controlled trials of cyproterone acetate with or without estrogen versus placebo or other drug therapies for hirsutism were identified.

Selection criteria
All randomised controlled studies comparing:
- cyproterone acetate to placebo
- cyproterone acetate with ethinyl estradiol to placebo
- cyproterone acetate with ethinyl estradiol to cyproterone acetate alone
- cyproterone acetate (with or without estradiol) to other medical therapies for treatment of hirsutism.

Data collection and analysis
Eleven studies were identified which fulfilled the inclusion criteria. Nine randomised studies were included in the review, and two were excluded because of insufficient information. Only one study had more than 100 women included in the analysis. The major outcomes included: subjective improvement in hirsutism, changes in Ferriman Gallwey scores, changes in linear hair growth and hair shaft diameter, alterations in endocrine parameters, side effects to treatment, withdrawals during therapy

Main results
There were no clinical trials comparing cyproterone acetate alone with placebo. There was one small study comparing cyproterone acetate in combination with ethinyl estradiol to placebo. In this study there was a significant subjective reduction in hair growth with cyproterone acetate therapy, although the confidence limits were large. There were no studies comparing cyproterone acetate alone with cyproterone acetate in combination with ethinyl estradiol to treat hirsutism. In studies where cyproterone acetate was compared to other drug modalities (ketoconazole, spironolactone, flutamide, finasteride, GnRH analogues) no difference in clinical outcome was noted. There were, however, endocrinological differences in androgen and estrogen levels between different drug therapies. There were insufficient data to assess differences in side effects between women treated with cyproterone acetate and other medical therapy.

Authors’ conclusions
Cyproterone acetate combined with estradiol results in a subjective improvement in hirsutism compared to placebo. Clinical differences in outcome between cyproterone acetate and other medical therapies were not demonstrated in the studies included in this review. This may be because of the small size of the studies, lack of standardized assessment and lack of objective determinants of improvement in hirsutism. The endocrinological effects of the different drug therapies reflect the mode of action. Larger carefully designed studies are needed to compare efficacy and safety profiles between drug therapies for hirsutism.

ZM Van der Spuy, PA le Roux

Cochrane Database of Systematic Reviews 2007 Issue 3

DOI: 10.1002/14651858.CD001125   This version first published online: 20 October 2003 in Issue 4, 2003
Date of Most Recent Substantive Amendment: 17 July 2003

Van der Spuy ZM, le Roux PA. Cyproterone acetate for hirsutism. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD001125. DOI: 10.1002/14651858.CD001125.

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