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CLINICAL REVIEW |
Knowledge and Encounter Research Unit (B.A.S., M.C., D.N.F., D.M.K., M.L.L., R.J.M., P.J.E., V.M.M.) and Division of Endocrinology, Diabetes, Metabolism, and Nutrition (B.A.S., M.C., V.M.M.), Department of Medicine, and Mayo Clinic Libraries (P.J.E.), Mayo Clinic College of Medicine, Rochester, Minnesota 55905; and State University of New York at Geneseo (M.L.L.), Geneseo, New York 14454
Address all correspondence and requests for reprints to: Victor M. Montori, M.D., M.Sc., Mayo Clinic, W18A, 200 First Street SW, Rochester, Minnesota 55905. E-mail: montori.victor{at}mayo.edu.
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Abstract |
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Objective: We performed a systematic review and metaanalyses of randomized controlled trials (RCTs) evaluating the effect of antiandrogens on hirsutism.
Data Sources: We used librarian-designed search strategies for MEDLINE, EMBASE, and Cochrane CENTRAL (up to May 2006), review of reference lists, and contact with hirsutism experts to identify eligible RCTs.
Study Selection: Eligible studies were RCTs of at least 6 months of antiandrogen use in women with hirsutism. Reviewers, with acceptable chance-adjusted agreement (
= 0.72), independently assessed eligibility.
Data Extraction: Reviewers used structured forms to assess and collect methodological quality (allocation concealment, blinding, and loss to follow-up) and study data.
Data Synthesis: Of 348 candidate studies, 12 were eligible (18 comparisons). Their methodological quality was low. Random-effects metaanalyses showed that compared with placebo, antiandrogens reduce Ferriman-Gallwey scores by 3.9 [95% confidence interval (CI), 2.3–5.4; inconsistency (I2) = 0%]. When compared with metformin, spironolactone reduced hirsutism scores by 1.3 (CI, 0.03–2.6) and flutamide by 5.0 (CI, 3.0–7.0; I2 = 0%). For these interventions, two to five women need to receive treatment for one to notice improvement. Spironolactone or finasteride in combination with contraceptives (1.7; CI, 0.1–3.3; I2 = 0%) or flutamide with metformin (4.6; CI, 1.3–7.9; I2 = 40%) appear superior to monotherapy with contraceptives and metformin, respectively. Only three RCTs reported patient self-assessments of hirsutism.
Conclusions: Weak evidence suggests antiandrogens are mildly effective agents for the treatment of hirsutism.
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Introduction |
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Some experts consider hirsutism the result of an atypical relationship between levels of circulating androgens and the sensitivity of androgen receptors in hair follicles to circulating androgens (5, 6). Commonly used therapies capitalize on this concept. For instance, oral contraceptive pills (OCPs) can increase estrogens and reduce androgens by suppression of circulating LH and stimulation of SHBG.
Antiandrogens more directly address this concept by competitively inhibiting androgen binding to the androgen receptor or by inhibiting 5
-reductase (6). Four antiandrogens have been evaluated in randomized controlled trials (RCTs) and used by clinicians in managing hirsute patients: spironolactone, cyproterone acetate, flutamide, and finasteride.
Spironolactone is an aldosterone antagonist structurally similar to progestins. It competes with dihydrotestosterone (DHT) for binding to the androgen receptor, has inhibitory effects on 5-reductase, competes for binding to SHBG, and inhibits enzymes involved in androgen biosynthesis (1).
Cyproterone acetate (CPA) is a 17-hydroxyprogesterone acetate derivative that competes with DHT for binding to the androgen receptor and reduces LH levels which decrease testosterone and androstenedione levels (1).
Flutamide is a nonsteroidal androgen receptor blocker. It also may reduce the synthesis of androgens or increase their metabolism (1).
Finasteride is usually considered an antiandrogen because it competitively inhibits 5-reductase, which inhibits the conversion of testosterone to DHT (1).
In general, these agents are contraindicated in pregnancy (may lead to pseudohermaphroditism in the fetus) and in liver disease (flutamide may cause fatal hepatotoxicity). All but CPA are available in the United States.
As described here, several small RCTs have evaluated the efficacy of antiandrogens in women with hirsutism with varied results, limited precision, and uncertain applicability in practice. Limitations in statistical precision and applicability could be overcome through rigorous systematic review and metaanalyses of the available evidence (7).
We set out to determine the extent to which antiandrogens, alone or in combination with other therapies (OCPs or insulin sensitizers), improve hirsutism. To achieve this goal, we conducted a systematic review and metaanalyses of RCTs. The Endocrine Society Task Force on Hirsutism, assembled to produce clinical practice guidelines, commissioned these metaanalyses to support the formulation of evidence-based recommendations.
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Materials and Methods |
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Eligibility criteria
Eligible studies were fully published RCTs in any language that randomly allocated women at least 12 yr old with varying degrees of hirsutism to antiandrogens, either alone or in combination with OCPs or insulin sensitizers, or to placebo or active control (OCPs or insulin sensitizers). For this review, OCPs included single-pill preparations, some of which contained a low dose of CPA (2 mg). We considered higher CPA doses separately as antiandrogens.
Eligible RCTs treated women for at least 6 months and measured hirsutism as an outcome by patient self-assessment, clinician assessment, or laboratory assessment of hair (e.g. hair diameter, hair length, or rate of hair growth). We excluded RCTs that enrolled women who received GnRH, clomiphene, or glucocorticoids, and women in whom hirsutism was secondary to etiologies other than idiopathic hirsutism, polycystic ovary syndrome, or presumed late-onset congenital adrenal hyperplasia.
Study identification
An expert reference librarian (P.J.E.) designed and conducted the electronic search strategy with input from an endocrinologist (V.M.M.) with expertise in conducting systematic reviews. To identify eligible studies, our systematic search included electronic databases (MEDLINE, EMBASE, and CENTRAL) from their inception until May 2006. The detailed strategy is available upon request. Review of the reference sections of each of the eligible primary studies and of narrative and systematic reviews, and contact with expert members of the Task Force identified additional candidate studies.
Study selection
Reviewers working independently (B.A.S., M.C., D.M.K., and V.M.M.) and in duplicate screened all abstracts and titles. All apparently eligible studies were obtained for evaluation in full text. Again, reviewers working independently and in duplicate with acceptable chance-adjusted agreement ( statistic = 0.72) determined the eligibility of full text reports. Disagreements were resolved by consensus or arbitration (by V.M.M.).
Data collection
Working in duplicate using a computerized extraction form, B.A.S., M.C., and V.M.M. abstracted from every study data describing the patient population and treatments studied.
We also abstracted specific hirsutism outcomes. Outcomes were either self-assessed, when patients reported on their hirsutism, assessed by a health care professional (e.g. Ferriman-Gallwey score) (9), or assessed through laboratory measurements (e.g. hair diameter measurement). We collected end-of-study hirsutism scores or, when these were not reported, change-from-baseline scores. Outcomes collected were at the longest point of complete follow-up while patients were still exposed to the interventions. We contacted authors when data were missing.
Quality assessment
To ascertain the reported methodological quality of eligible RCTs, pairs of reviewers (B.A.S., M.C., D.M.K., M.L.L., R.J.M., and V.M.M.) working independently and with adequate reliability (corresponding chance-adjusted inter-reviewer reliability, , reported where appropriate) determined the adequacy of allocation concealment ( = 0.56); the blinding of patients ( = 0.69), health care providers ( = 0.63), and outcome assessors ( = 0.88); and the extent of loss to follow-up (i.e. the proportion of patients in whom the investigators were unable to ascertain outcomes).
Statistical analyses
Metaanalyses Given the paucity of trials reporting patient self-assessment of hirsutism, we focused our quantitative analyses on subjective assessments by healthcare professionals. We determined the pooled weighted mean difference between intervention and control groups and the associated 95% confidence interval (CI) using a DerSimonian and Laird (10) random-effects metaanalysis as implemented in RevMan 4.2 (Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) and in StatsDirect statistical software (StatsDirect Ltd., Altrincham, UK; http://www.statsdirect.com).
To conduct metaanalyses across trials that measured the subjective assessment of hirsutism using different tools, we estimated the standardized mean difference using the Hedges’ g approach implemented in RevMan 4.2 (Cochrane Collaboration). Hedges’ g divides the mean difference between groups by the pooled SD with adjustment for small samples.
When reports quantified only the proportion of responders, we converted the corresponding odds ratios to effect sizes (11) and then pooled these data using the inverse variance method. To facilitate the interpretation of effect sizes in this report, we have expressed the results in Ferriman-Gallwey terms by multiplying the effect size by 3.5, the mean SD for the Ferriman-Gallwey score in the antiandrogen vs. placebo trials, the only metaanalysis where this conversion was necessary.
We quantified inconsistency using the I2 statistic, which describes the proportion of the observed overall between-study variability not due to chance, thus describing the extent of true inconsistency in results across trials (12). I2 less than 25% conventionally reflects small inconsistency, and I2 more than 50% reflects large inconsistency.
Because the relationship between the magnitude of change in the hirsutism score and patient judgment of the magnitude of improvement is not clear, we estimated the proportion of patients who would benefit from an intervention based on the methods described by Norman et al. (13). For each metaanalysis, effect sizes were considered along with an estimate of the minimally detectable change, which is the smallest difference in scores (e.g. Ferriman-Gallwey scores) that individuals can detect. Because, to our knowledge, a minimally important difference has not been determined for hirsutism scores, we chose 0.5 SD as an acceptable difference because this is a reproducible estimate, across different instruments and conditions, of the minimally detectable change (14). Under these assumptions, we estimated the proportion of patients who would benefit from an intervention (i.e. the absolute difference in the likelihood of benefit between groups, considering benefit as an improvement of at least 0.5 SD). We then calculated its inverse, the number needed to treat (NNT), which in this situation is the number of women who need to be treated for one of these women to notice any improvement in her hirsutism.
Subgroup analyses Our a priori hypotheses to explain potential heterogeneity across studies included study quality (loss to follow-up and blinding status), patient population characteristics (etiology of hirsutism, degree of hirsutism at baseline, and age), treatment interventions (antiandrogen type, alone or in combination, and dose), control interventions (placebo vs. active control), and outcomes (length of follow-up). To explore these hypotheses, we estimated the differences in treatment effects between subgroups or treatment-subgroup interactions (15).
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Results |
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Figure 1
describes the flow of candidate and eligible articles. There were 12 eligible RCTs from which we abstracted 18 comparisons. One RCT reported results for patients with idiopathic hirsutism and polycystic ovary syndrome separately (16). Three trials evaluated multiple interventions, so we abstracted a separate comparison for each intervention of interest (17, 18, 19) while avoiding duplicate counting of the control group within the same metaanalysis.
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Overall, the included trials had limited reporting of methodological features that protect against bias (Table 1). Blinding was uncommon, with only half of the trials clearly blinding the outcome assessors. The median loss to follow-up across trials was 4%, with two trials reporting more than 20% loss to follow-up.
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Table 2 describes trial characteristics and demonstrates considerable heterogeneity in terms of participants, baseline hirsutism scores, interventions, and length of treatment. Overall, enrolled women were young (median age = 23). Researchers used Ferriman-Gallwey (with or without modification) to quantify hirsutism. Hirsutism was an explicit enrollment criterion for nine of the 12 RCTs, five of which specified a minimal Ferriman-Gallwey score required for enrollment. Across the comparisons, baseline mean Ferriman-Gallwey scores ranged from 11.4–25.1.
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The eligible trials assessed four antiandrogens (50–100 mg spironolactone, 100 mg CPA, 250–500 mg flutamide, and 5–7.5 mg finasteride per day). Metformin (1000–1700 mg per day) was the only insulin sensitizer these trials evaluated. OCPs were administered as either 35 µg ethinyl estradiol with 2 mg CPA or 30 µg ethinyl estradiol with 150 µg desogestrel. Patients received treatments for 6–12 months.
Metaanalyses: effect of antiandrogens on hirsutism
Figure 2 summarizes the results of the metaanalyses described in detail below. The supplemental data (published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org) includes additional figures, the metaanalytic plots, for the separate analyses listed below.
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There were seven comparisons of antiandrogens vs. placebo, of which three came from the same study (19) (i.e. shared the same placebo group), thus precluding pooling all seven to estimate a class effect vs. placebo. To present a class effect of antiandrogens vs. placebo, we excluded two of the three comparisons that came from the same study (19) (selecting the comparison with the median point estimate to remain), allowing us to appropriately pool five comparisons. Metaanalysis of these five comparisons showed the antiandrogen group had significantly lower hirsutism scores than the placebo group (–3.9; CI, –5.4 to –2.3) with no inconsistency across studies (I2 = 0%, supplemental Fig. S1). Using this result to estimate the NNT, three women need to be treated with spironolactone, flutamide, or finasteride for one of these women to notice any improvement. Considering the seven comparisons, pooled Ferriman-Gallwey scores of studies grouped by antiandrogen type also showed each of the antiandrogen types was superior to placebo (supplemental Fig. S2). There were no significant type-treatment interactions (spironolactone vs. finasteride, P = 0.29; spironolactone vs. flutamide, P > 0.99; finasteride vs. flutamide, P = 0.25). None of the other planned subgroup analyses yielded significant treatment-subgroup interactions.
Antiandrogens vs. OCPs
Only one RCT (20) reported on the comparison of antiandrogens to OCPs. After 9 months; there was no significant difference in hirsutism score between the finasteride group and the group receiving combination ethinyl estradiol and low-dose CPA (2 mg) (2.5; CI, –0.4 to 5.4).
Antiandrogens vs. metformin
Three trials compared antiandrogens vs. metformin: one tested spironolactone (21) and two flutamide (17, 18). Metaanalysis of these three comparisons showed the antiandrogen group had significantly lower hirsutism scores than the metformin group (–3.7; CI, –6.8 to –0.6) but with large inconsistency across studies (I2 = 80%).
A significant type-treatment interaction partly explains this inconsistency (test of interaction, P = 0.002); the flutamide trials reported a greater treatment effect (–5.0; CI, –7.0 to –3.0; I2 = 0%; NNT = 2; supplemental Fig. S3) than the spironolactone trial (–1.3; CI, –2.6 to –0.03; NNT = 5). All other planned subgroup analyses were noncontributory.
Antiandrogens as add-on therapy to OCPs (antiandrogens and OCPs vs. OCPs)
There were five comparisons of antiandrogens combined with OCPs vs. OCPs alone. A metaanalysis of these comparisons showed no significant difference in end-of-study hirsutism scores between treatment groups (–0.8; CI, –2.3 to 0.7, I2 = 32%).
Subgroup analyses by type of antiandrogen showed subgroup-treatment interactions between trials that measured the effect of spironolactone or finasteride vs. the trial measuring the effect of high-dose CPA (test of interaction, P = 0.02), with no difference between the spironolactone and finasteride comparisons (test of interaction, P = 0.57). Pooling of the spironolactone and finasteride comparisons revealed a significant effect compared with OCPs alone (–1.7; CI, –3.3 to –0.1; I2 = 0%; NNT = 6; supplemental Fig. S4). All other planned subgroup analyses were noncontributory.
Antiandrogens as add-on to metformin
Meta-analysis of the two eligible trials showed the patients receiving the combination flutamide and metformin had significantly lower hirsutism scores than patients receiving metformin alone (–4.6; CI, –7.9 to –1.3; I2 = 40%; NNT = 2; supplemental Fig. S5). We found no significant subgroup-treatment interactions to account for the moderate inconsistency.
Patient self-assessments of hirsutism
Two RCTs reported both provider assessments and patient self-assessments of hirsutism (19, 22) and found them congruent. For example, in Lakryc’s study (22), the estimated effect size of hirsutism score improvements (–1.4; CI, –2.3 to –0.5) was of a similar magnitude to that of patient-assessed improvements (–1.3; CI, –2.6 to –0.3). Another study (23) reported a trend toward improved patient self-assessments with eight of 11 patients reporting improvements in the spironolactone group compared with three of 11 in the placebo group (P = 0.09); however, they did not present hirsutism scores assigned by health professionals.
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Discussion |
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This systematic review and the metaanalyses found that antiandrogens are effective agents for the treatment of hirsutism. Further exploration including planned subgroup analyses suggests that antiandrogens are superior to placebo and metformin, and when spironolactone or finasteride are combined with OCPs, or when flutamide is combined with metformin, these regimens are superior to monotherapy with OCPs and metformin, respectively.
Weaknesses and strengths
Given our focus on published RCTs and that most RCTs in this field are small, the potential for publication bias cannot be confidently excluded in this metaanalysis. As in any metaanalysis, pooling from low-quality studies reduces confidence in the results. In this review, the majority of RCTs had important methodological shortcomings (e.g. no blinding). Also, several studies had group differences in baseline hirsutism scores (see Table 2
) that may not have averaged out in the metaanalyses given the paucity of trials. The small number of studies and their small sizes further limit the precision of our results. Therefore, the overall quality of the evidence supporting the use of antiandrogens for the treatment of hirsutism is low, and these methodological shortcomings weaken the resulting inferences toward making clinical recommendations.
Although the primary literature has limitations, our work itself has several important strengths. The focused review questions; comprehensive and systematic literature search; collaboration of a multidisciplinary team of endocrinologists, internists, and researchers; explicit and reproducible eligibility criteria; and focused protocol-driven analyses contribute to the validity of our findings. The extent of agreement between abstractors increases our confidence in our assessments of quality and data extraction. Planned subgroup analyses often provided a plausible explanation to the observed inconsistencies (namely, small differences between agents).
Comparison with previous studies
Antiandrogens vs. placebo Overall, each antiandrogen type appears effective at improving hirsutism. One trial (19) reported comparisons against placebo but also found no significant differences between agents in head-to-head comparisons. Our results are consistent with two other systematic reviews. First, Van der Spuy and le Roux (24) evaluated the effects of CPA on hirsutism and found no RCTs of CPA vs. placebo. Also, Farquhar et al. (25) evaluated the effects of spironolactone vs. placebo, alone or in combination with steroids, for hirsutism or acne. Farquhar’s review and our analyses share two studies in common (19, 23) and concur that spironolactone is associated with improvements in hirsutism when compared with placebo.
Antiandrogens vs. OCPs Only one eligible RCT contributed to the metaanalysis of antiandrogens vs. OCPs (20). This small trial had no report of allocation concealment and limited blinding. The Ferriman-Gallwey scores were different at baseline (i.e. the OCP group mean score was 2.0 points lower than that of the antiandrogen group), whereas the absolute change in Ferriman-Gallwey scores was similar between groups. The trial compared finasteride with OCPs containing low-dose CPA, limiting inferences about the efficacy of antiandrogens vs. OCPs in general. Van der Spuy and le Roux’s review (24) and this review found no studies comparing CPA alone with OCPs, and no other systematic reviews have addressed this question.
Antiandrogens vs. metformin In the metaanalysis of antiandrogens vs. metformin, the RCTs had no reported allocation concealment and had limited or no blinding. Also, baseline hirsutism scores were different between groups with the metformin groups having higher scores in both studies (17, 18). This limits the inference that the antiandrogen flutamide is more efficacious than metformin. No other systematic reviews have addressed this question.
Antiandrogens as add-on therapy These comparisons involve trials with low methodological quality. Subgroup analyses suggest that antiandrogens add significantly to OCPs, but inconsistency (partly explained by androgen type) weakens this inference. These results are consistent with those of Van der Spuy and le Roux’s review (24) in that the addition of a higher dose of CPA (100 mg) to OCPs (containing 2 mg CPA) provided no additional benefit (26). No additional systematic reviews addressing this question are available.
Comparison with recent trials
Since the completion of our review, some relevant trials have appeared in the literature (27, 28, 29). In all, these studies support the efficacy of antiandrogens compared with placebo or metformin and as additive therapy to contraceptives or metformin, as demonstrated in our review, and they do not substantially alter our findings and conclusions.
Implications for clinical policy and research
This review summarizes the best available evidence informing the use of antiandrogens for the treatment of hirsutism. The overall quality of evidence across all comparisons is low to very low using the GRADE system of classification (30). Furthermore, there is extremely poor reporting of side effects in these trials. This makes the explicit tradeoff between benefits and downsides unclear, a clinical situation in which patient preferences may play an important role in the decision. The accompanying clinical practice guidelines, based on the evidence summarized here, along with the values, preferences, and expertise of the Task Force members, provide additional guidance to clinicians and patients. Whether our findings can be applied with confidence across ethnic and cultural groups remains unclear. Variations in androgen levels and receptors, within and across ethnic groups, can influence the expression of hirsutism as well as its response to therapy (6). This may explain why one patient may respond better or worse than the results may suggest. Furthermore, the interpretation of what is considered to be normal hair growth varies across ethnic and cultural groups. This needs to be considered when applying study results to individual patients.
Very few trials have examined patient-reported outcomes. However, when examined, they generally report improvements with antiandrogens that are congruent with reductions in Ferriman-Gallwey scores. This suggests that perhaps this score captures, at least partially, patient satisfaction with treatment. To provide clinically helpful estimates of effect, we estimated the NNT for interventions that proved beneficial in improving hirsutism. In general, two to six women need to receive antiandrogens for one to experience any detectable benefit. Future trials should make patient-reported outcomes (e.g. satisfaction with changes in hair growth and quality and with the burden and cost of treatment) central to their assessment of the efficacy of interventions.
Unanswered questions
The low methodological quality of the evidence summarized here highlights the research needs in this field. Funded by nonprofit agencies, investigators should conduct large, rigorous randomized trials in women with different etiologies of hirsutism, using the various types and doses of antiandrogens alone and in combination with other interventions (mainly OCPs in fertile women not seeking pregnancy) for longer periods of follow-up and measuring blinded patient self-assessments of hirsutism as the primary outcome. Furthermore, researchers should determine the smallest change in hirsutism burden that is important to patients and design appropriately large trials with sufficient power to detect this effect size. Also needed are trials comparing antiandrogens with biological modifiers of hair growth (e.g. eflornithine) and with mechanical modifiers (e.g. shaving, depilation, electrolysis, and laser epilation).
Conclusion
Antiandrogens appear to be mildly effective agents for the treatment of hirsutism. They appear more efficacious than placebo and metformin, and some antiandrogens appear to demonstrate additional improvements when added to OCPs or metformin regimens. However, the currently available evidence is of low to very low quality and offers weak inferences regarding the clinical efficacy of antiandrogens on hirsutism scores and patient-reported outcomes. Large randomized trials of antiandrogens, alone and in combination with other interventions, reporting on important patient outcomes would provide the necessary high quality evidence required to strengthen clinical recommendations.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: B.A.S., M.C., D.N.F., D.M.K., M.L.L., R.J.M., P.J.E., and V.M.M. have nothing to declare.
First Published Online February 5, 2008
Abbreviations: CI, Confidence interval; CPA, cyproterone acetate; DHT, dihydrotestosterone; NNT, number needed to treat; OCP, oral contraceptive pill; RCT, randomized controlled trial.
Received November 2, 2007.
Accepted January 25, 2008.
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References |
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-reductase inhibitor, in women with idiopathic hirsutism. Fertil Steril 64:299–306[Medline]This article has been cited by other articles:
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  O. Koulouri and G. S Conway Management of hirsutism BMJ, March 27, 2009; 338(mar27_1): b847 - b847. [Full Text]
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 K. A. Martin, R. J. Chang, D. A. Ehrmann, L. Ibanez, R. A. Lobo, R. L. Rosenfield, J. Shapiro, V. M. Montori, and B. A. Swiglo Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1105 - 1120. [Abstract] [Full Text] [PDF]
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