Treatments for unwanted male pattern hair growth in women

Background
Up to 5% to 10% of women are hirsute (hair in areas where normally only men have hairs such as moustache, beard area, chest, belly, back etc). The most common cause is polycystic ovary syndrome. Hirsutism can lead to psychological distress, low self esteem, decreased self image, depression, feelings of shame and social difficulties.

Review question
Which treatments (except laser and light-based therapies alone) work best for hirsutism?

Study characteristics
We included 157 studies published up to June 2014, which examined 10,550 people. Participants included women with a mean age of 25 years. There was considerable variation in the quality of how the studies were conducted; more than half were not blinded and this may have had an impact on the reporting of the outcomes. Most studies were carried out in single centres in Europe and lasted six to 12 months. A range of treatments were evaluated, mostly in single studies. These included a few topical treatments, lifestyle modification, oral contraceptive pills (OCPs), medication to inhibit the effect of hormones that are responsible for male traits, and combination therapies. Participant-assessed improvement and impact on quality of life were evaluated in a minority of the studies, whilst the majority of the studies measured physician-assessed reduction in hirsutism, as well as androgen levels in the blood. Half of the studies reported adverse events and around one-third other signs and symptoms, e.g. oily skin and menstrual irregularities that might be due to an increase of androgen levels in the blood.

Key results
Oral contraceptive pills reduced the amount of hairs, but the reduction was not consistent across the studies, although two OCPs (ethinyl estradiol 35 µg + cyproterone acetate 2 mg compared to ethinyl estradiol 30 µg + desogestrel 0.15 mg) appeared to be effective in a way that can be considered important for women with hirsutism.

Of the antiandrogen drugs, flutamide was considered to be more effective than placebo by both the women and the doctors. Spironolactone was also effective, but data were only available for the physicians' assessments. Finasteride did not show convincing effectiveness based on the evaluations of the hirsute women and those made by the investigators. The addition of cyproterone acetate (an antiandrogen) to OCP seemed to enhance the beneficial effect of OCPs on hair reduction.

Insulin sensitisers (antidiabetic drugs) and lifestyle modification did not have any demonstrable benefit in terms of the severity of hirsutism. Unfortunately, the self assessments by the women, as well as the impact of hirsutism on their quality of life, were outcomes that were insufficiently addressed in the studies.

The adverse events reported with the different drugs are well known, i.e. pain in the stomach and intestines, breast tenderness, reduced libido and dry skin with flutamide and finasteride; irregular bleeding with spironolactone; nausea, diarrhoea and abdominal bloating with metformin; and hot flushes, decreased libido, vaginal dryness, breast tenderness and headaches with the GnRH analogues.

There were no important differences in blood androgen levels between the different treatment groups, OCPs had a positive effect on acne, and similarly insulin sensitisers improved the menstrual pattern.

We were expecting to find evidence that combined therapies of an OCP with an antiandrogen were more effective than, for example, OCPs alone, but the lack of studies did not allow us to draw these conclusions.

Overall we concluded that OCPs (especially with antiandrogenic activity), OCPs combined with cyproterone acetate, flutamide and spironolactone are effective in treating hirsutism. However, additional cosmetic measures (epilating, waxing, bleaching, electrolysis, laser and photoepilation) are generally required because all treatments need at least six to 12 months to reach the optimum effect. In addition, because of the distress associated with hirsutism and its impact on quality of life psychological support should be part of the treatment approach.

Quality of the evidence
The overall quality of the evidence for the different outcomes was on average rated as moderate to very low. Important reasons for this were that studies were not blinded, or had a small sample size.

Authors' conclusions: 

Treatments may need to incorporate pharmacological therapies, cosmetic procedures, and psychological support. For mild hirsutism there is evidence of limited quality that OCPs are effective. Flutamide 250 mg twice daily and spironolactone 100 mg daily appeared to be effective and safe, albeit the evidence was low to very low quality. Finasteride 5 mg daily showed inconsistent results in different comparisons, therefore no firm conclusions can be made. As the side effects of antiandrogens and finasteride are well known, these should be accounted for in any clinical decision-making. There was low quality evidence that metformin was ineffective for hirsutism and although GnRH analogues showed inconsistent results in reducing hirsutism they do have significant side effects.

Further research should consist of well-designed, rigorously reported, head-to-head trials examining OCPs combined with antiandrogens or 5α-reductase inhibitor against OCP monotherapy, as well as the different antiandrogens and 5α-reductase inhibitors against each other. Outcomes should be based on standardised scales of participants' assessment of treatment efficacy, with a greater emphasis on change in quality of life as a result of treatment.

Read the full abstract...
Background: 

Hirsutism occurs in 5% to 10% of women of reproductive age when there is excessive terminal hair growth in androgen-sensitive areas (male pattern). It is a distressing disorder with a major impact on quality of life. The most common cause is polycystic ovary syndrome. There are many treatment options, but it is not clear which are most effective.

Objectives: 

To assess the effects of interventions (except laser and light-based therapies alone) for hirsutism.

Search strategy: 

We searched the Cochrane Skin Group Specialised Register, CENTRAL (2014, Issue 6), MEDLINE (from 1946), EMBASE (from 1974), and five trials registers, and checked reference lists of included studies for additional trials. The last search was in June 2014.

Selection criteria: 

Randomised controlled trials (RCTs) in hirsute women with polycystic ovary syndrome, idiopathic hirsutism, or idiopathic hyperandrogenism.

Data collection and analysis: 

Two independent authors carried out study selection, data extraction, 'Risk of bias' assessment, and analyses.

Main results: 

We included 157 studies (sample size 30 to 80) comprising 10,550 women (mean age 25 years). The majority of studies (123/157) were 'high', 30 'unclear', and four 'low' risk of bias. Lack of blinding was the most frequent source of bias. Treatment duration was six to 12 months. Forty-eight studies provided no usable or retrievable data, i.e. lack of separate data for hirsute women, conference proceedings, and losses to follow-up above 40%.

Primary outcomes, 'participant-reported improvement of hirsutism' and 'change in health-related quality of life', were addressed in few studies, and adverse events in only half. In most comparisons there was insufficient evidence to determine if the number of reported adverse events differed. These included known adverse events: gastrointestinal discomfort, breast tenderness, reduced libido, dry skin (flutamide and finasteride); irregular bleeding (spironolactone); nausea, diarrhoea, bloating (metformin); hot flushes, decreased libido, vaginal dryness, headaches (gonadotropin-releasing hormone (GnRH) analogues)).

Clinician's evaluation of hirsutism and change in androgen levels were addressed in most comparisons, change in body mass index (BMI) and improvement of other clinical signs of hyperandrogenism in one-third of studies.

The quality of evidence was moderate to very low for most outcomes.

There was low quality evidence for the effect of two oral contraceptive pills (OCPs) (ethinyl estradiol + cyproterone acetate versus ethinyl estradiol + desogestrel) on change from baseline of Ferriman-Gallwey scores. The mean difference (MD) was -1.84 (95% confidence interval (CI) -3.86 to 0.18).

There was very low quality evidence that flutamide 250 mg, twice daily, reduced Ferriman-Gallwey scores more effectively than placebo (MD -7.60, 95% CI -10.53 to -4.67 and MD -7.20, 95% CI -10.15 to -4.25). Participants' evaluations in one study with 20 participants confirmed these results (risk ratio (RR) 17.00, 95% CI 1.11 to 259.87).

Spironolactone 100 mg daily was more effective than placebo in reducing Ferriman-Gallwey scores (MD -7.69, 95% CI -10.12 to -5.26) (low quality evidence). It showed similar effectiveness to flutamide in two studies (MD -1.90, 95% CI -5.01 to 1.21 and MD 0.49, 95% CI -1.99 to 2.97) (very low quality evidence), as well as to finasteride in two studies (MD 1.49, 95% CI -0.58 to 3.56 and MD 0.40, 95% CI -1.18 to 1.98) (low quality evidence).

Although there was very low quality evidence of a difference in reduction of Ferriman-Gallwey scores for finasteride 5 mg to 7.5 mg daily versus placebo (MD -5.73, 95% CI -6.87 to -4.58), it was unlikely it was clinically meaningful. These results were reinforced by participants' assessments (RR 2.06, 95% CI 0.99 to 4.29 and RR 11.00, 95% CI 0.69 to 175.86). However, finasteride showed inconsistent results in comparisons with other treatments, and no firm conclusions could be reached.

Metformin demonstrated no benefit over placebo in reduction of Ferriman-Gallwey scores (MD 0.05, 95% CI -1.02 to 1.12), but the quality of evidence was low. Results regarding the effectiveness of GnRH analogues were inconsistent, varying from minimal to important improvements.

We were unable to pool data for OCPs with cyproterone acetate 20 mg to 100 mg due to clinical and methodological heterogeneity between studies. However, addition of cyproterone acetate to OCPs provided greater reductions in Ferriman-Gallwey scores.

Two studies, comparing finasteride 5 mg and spironolactone 100 mg, did not show differences in participant assessments and reduction of Ferriman-Gallwey scores (low quality evidence). Ferriman-Gallwey scores from three studies comparing flutamide versus metformin could not be pooled (I² = 62%). One study comparing flutamide 250 mg twice daily with metformin 850 mg twice daily for 12 months, which reached a higher cumulative dosage than two other studies evaluating this comparison, showed flutamide to be more effective (MD -6.30, 95% CI -9.83 to -2.77) (very low quality evidence). Data showing reductions in Ferriman-Gallwey scores could not be pooled for four studies comparing finasteride with flutamide as the results were inconsistent (I² = 67%).

Studies examining effects of hypocaloric diets reported reductions in BMI, but which did not result in reductions in Ferriman-Gallwey scores. Although certain cosmetic measures are commonly used, we did not identify any relevant RCTs.