Interventions for hirsutism (excluding laser and photoepilation therapy alone): Cochrane systematic review

Abstract

Assessed as up to date: 2014/06/11

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 methods

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.

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.

Author(s)

van Zuuren Esther J, Fedorowicz Zbys, Carter Ben, Pandis Nikolaos

Summary

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.

Reviewer's Conclusions

Implications for practice

Treatment should aim to remove the unwanted hairs, reduce or completely inhibit growth of new hairs, correct hormonal imbalances, and improve the self image, self esteem, and quality of life of the affected woman. To achieve these goals the treatment approach will need to encompass not only pharmacological therapies but also cosmetic procedures and lifestyle modification, as well as methods addressing the psychological support required to enhance individual coping mechanisms (Blume-Peytavi 2011; Blume-Peytavi 2013; Brodell 2010; Martin 2008). Our conclusions are supported by studies with a duration of between six and 12 months.

The effectiveness of oral contraceptives (OCPs), in particular those containing ethinyl estradiol 35 µg combined with cyproterone acetate 2 mg and ethinyl estradiol 30 µg combined with desogestrel 0.15 mg, was supported by low quality evidence. OCPs, preferentially those with antiandrogenic activity, can be considered as a possible first line treatment approach for mild hirsutism.

Among the antiandrogens both flutamide 250 mg twice a day as well as spironolactone 100 mg per day appeared to be effective and safe, although we rated the quality of the evidence as low to very low. Finasteride 5 mg per day showed inconsistent results for its effectiveness in the different comparisons, and therefore no firm conclusion can be made regarding this treatment. In addition, as the side effects of these antiandrogen treatments and finasteride are well known, these should be taken into account in any clinical decision-making.

Although we were unable to pool data for the effects of OCP combined with cyproterone acetate, this combination appeared to be more effective in reducing hirsutism. We were unable to draw conclusions on the effects of other combinations of OCPs, i.e. with flutamide, spironolactone, or finasteride versus OCPs only to see if these additions would result in a more beneficial effect on hirsutism. The inability to pool data was largely due to the wide diversity between treatment arms for these comparisons and because most of the comparisons examined one combination therapy against another different combination therapy. It should be emphasised that all antiandrogens as well as finasteride carry the risk of feminisation of the male foetus and should therefore always be combined with effective contraception. Hirsute women who wish to conceive can only be treated safely with cosmetic procedures.

Out of the insulin sensitisers, there was evidence rated as low quality that metformin was not effective in the treatment of hirsutism, but this does not mean that it has no therapeutic value in the treatment of overweight women with polycystic ovary syndrome (PCOS) and hyperinsulinaemia.

Although the gonadotropin-releasing hormone (GnRH) analogues did not show consistent results in reducing hirsutism they do have significant side effects such as hot flushes, premature menopausal symptoms, and bone loss. Consequently there would appear to be no therapeutic advantage with this category of drugs over OCPs and antiandrogens or finasteride.

Evidence was lacking to support the effect of lifestyle modification on the improvement of hirsutism and we did not identify any randomised controlled trials addressing cosmetic procedures for the treatment of hirsutism.

Clinical decision-making on the choice of treatment for hirsutism should be based on high-level evidence if it is available, but in the absence of such evidence for any other specific intervention, these decisions should continue to be guided by clinical experience and peoples' individual characteristics and preferences until further evidence for these other interventions becomes available. The appropriate monitoring of patients both clinically and biochemically while on therapy is important. Hirsute women are typically otherwise healthy and the risks and benefits of each therapeutic option must be carefully considered and discussed with them. In view of the fact that it may take six to 12 months before any treatment effect can be noticed, alternative and interim measures, including coping strategies and provision of psychological support as well as cosmetic measures, should also be integrated into the decision-making process.

Implications for research

This review covers a wide range of treatments used for the treatment of hirsutism and although we were able to include 157 studies, only very few studies were well designed and rigorously conducted and reported. A minority of the studies addressed patient-reported outcomes such as the participants' assessment of improvement of hirsutism, change in health-related quality of life, and adverse events, but these were frequently inadequately reported.

There is an urgent need for high-quality, well-designed, and rigorously reported studies of head-to-head trials examining OCPs combined with an antiandrogen or a 5α-reductase inhibitor against OCP monotherapy, as well as the different antiandrogens and 5α-reductase inhibitors against each other.

A major area for improvement would be in the standardisation of outcome reporting in any future research. Outcomes collected in future trials should be primarily based on a standardised scale of the participant's assessment of the treatment efficacy, and they should also have a greater emphasis on changes in quality of life as a result of the interventions. The minimal clinically important difference should be established to interpret the outcome data, and to ascertain if a treatment leads to a clinically meaningful and relevant reduction of hirsutism and improvement of quality of life.

Follow-up studies addressing the sustainability of hair reduction after discontinuation of treatment should be taken into account as this constitutes an important outcome for participants.

Since measurable hyperandrogaenemia and body mass index (BMI) do not always correlate with the degree of hirsutism, it may also be that certain forms of treatment have better efficacy in some women compared to others depending upon their baseline characteristics. Therefore, subgroup analyses addressing baseline characteristics might also be appropriate.

Future randomised controlled trials must be well-designed, well-conducted, and adequately delivered, with subsequent reporting including high-quality descriptions of all aspects of methodology. Rigorous reporting needs to conform to the Consolidated Standards of Reporting Trials (CONSORT) statement, and this will enable appraisal and interpretation of results, and accurate judgements to be made about the risk of bias and the overall quality of the evidence. Although it is uncertain whether reported quality mirrors actual study conduct, it is noteworthy that studies with unclear methodology have been shown to produce biased estimates of treatment effects (Schulz 1995). Adherence to guidelines, such as the CONSORT statement, would help ensure complete reporting.

For further research recommendations based on the EPICOT (evidence, population, intervention, comparison, outcomes, and time) format (Brown 2006), see Research recommendations based on a gap in the evidence of the effects of interventions for hirsutism excluding laser and photoepilation therapy.

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