CRD summary

This review compared combination therapy with monotherapy (clomiphene citrate or metformin) for treatment of infertility in women with polycystic ovary syndrome (PCOS). The authors' conclusion that combination therapy offered no advantage and monotherapies were similarly effective reflected most of the data presented. Limitations in the review process and paucity of data mean that the conclusions should be viewed with caution.

Authors' objectives

To compare the effectiveness of clomiphene citrate alone, metformin alone and clomiphene citrate combined with metformin as a first line treatment of anovulatory infertility in patients with polycystic ovary syndrome.

Searching

MEDLINE, EMBASE, Biological Abstracts, Cochrane Database of Systematic Reviews and Cochrane Controlled Trials Register were searched from inception to March 2008. Search terms were reported. No language restrictions or study methodology filters were applied. The bibliographies of text books, reviews and retrieved articles were scanned for additional studies.

Study selection

Randomised controlled trials (RCTs) of head-to-head comparisons of any combination of clomiphene citrate, metformin or clomiphene citrate and metformin combined for first-line treatment of anovulatory infertility in patients with polycystic ovary syndrome were eligible for inclusion. All doses and schedules for clomiphene citrate and metformin were eligible for inclusion.

The primary outcome measure for the review was live birth rate; studies that did not report this outcome were excluded. Secondary outcome measures were rates of ovulation, pregnancy, abortion and adverse events leading to discontinuation.

Most (three out of four) included studies were restricted to women under 40 years of age. Polycystic ovary syndrome was diagnosed by a variety of criteria (reported in the article). All studies were conducted over six months.

Two reviewers independently assessed studies for inclusion. Disagreements were resolved by discussion and the final decision of the first author.

Assessment of study quality

The methodological quality of included studies was assessed using Cochrane Collaboration guidelines with criteria that assessed allocation concealment, blinding, use of intention-to-treat analysis and follow up.

The authors did not state how many reviewers performed the quality assessment.

Data extraction

Data were extracted on treatment regimens and follow-up period, inclusion/exclusion criteria (such as body mass index, insulin resistance, previous treatment) and the event rates for each outcome measure.

Results were presented as odds ratios with 95% confidence intervals (CIs).

The authors stated neither how data were extracted for the review nor how many reviewers performed the data extraction.

Methods of synthesis

Between-study heterogeneity was assessed using the Cochran Q-test (p=0.5 was considered to represent statistical homogeneity).

For statistically homogeneous data, a fixed-effect (Mantel-Haenszel) model was used to calculate a weighted summary odds ratio; a random-effects model was used where statistical heterogeneity was identified.

The analysis of treatment effect was performed on both an intention-to-treat and per-protocol basis.

Results of the review

Four RCTs, with a total of 1,066 participants (sample size 100 to 626) were included in the review. Allocation concealment was adequately explained in all studies and both patients and investigators were blinded to treatment in three out of four studies (neither were blinded in the remaining study). Only one study analysed data on an intention-to-treat basis.

No difference was seen between the intention-to-treat and per-protocol analyses; meta-analyses were, therefore, reported per-protocol only.

Clomiphene citrate versus metformin (three studies, 841 participants):

No significant differences between clomiphene citrate and metformin were observed for any outcome measure. The odds ratios were 1.17 (95% CI: 0.16 to 8.61) for live birth, 1.22 (95% CI: 0.23 to 6.55) for pregnancy rate and 1.55 (95% CI: 0.40 to 5.99) for cumulative ovulation rate. Significant heterogeneity was detected for all three outcomes. The odds ratios were 1.58 (95% CI: 0.77 to 3.25) for abortion and 0.71 (95% CI: 0.22 to 2.25) for adverse events leading to discontinuation. No significant heterogeneity was observed for either outcome.

Metformin plus clomiphene citrate versus clomiphene citrate (three RCTs, 966 participants):

No significant differences between metformin plus clomiphene citrate and clomiphene citrate alone were observed for any outcome measure. The odds ratios were 0.99 (95% CI: 0.70 to 1.40) for live birth, 0.85 (95% CI: 0.62 to 1.15) for pregnancy and 0.84 (95% CI: 0.60 to 1.18) for cumulative ovulation rate. No significant heterogeneity was detected for any of these outcomes. The odds ratios were 0.74 (95% CI: 0.43 to 1.26) for abortion and 0.23 (95% CI: 0.04 to 1.24) for adverse events leading to discontinuation. Significant heterogeneity was observed for adverse events.

Metformin plus clomiphene citrate versus metformin (two RCTs, 741 participants):

Combination therapy was more effective than metformin alone with respect to live births (odds ratio 0.23, 95% CI: 0.13 to 0.40), pregnancy rates (odds ratio 0.23, 95% CI: 0.14 to 0.37) and ovulation rates (odds ratio 0.23, 95% CI: 0.15 to 0.34). No significant heterogeneity was observed for any outcome. There was no significant difference between metformin and combination therapy in either abortion rate (odds ratio 0.47, 95% CI: 0.22 to 1.0) or adverse events leading to discontinuation (odds ratio 0.86, 95% CI: 0.23 to 3.04). No significant heterogeneity was detected for either outcome.

Authors' conclusions

Combination therapy with metformin plus clomiphene citrate was no better than monotherapy (metformin or clomiphene citrate alone) for first-line treatment of anovulatory infertility in patients with polycystic ovary syndrome. No recommendation could be given on the choice of metformin or clomiphene citrate as the best first step to induce ovulation in these patients.

CRD commentary

The review addressed a clearly stated research question and defined appropriate inclusion criteria. A thorough search of the literature was conducted to identify relevant studies and no language restrictions were applied. No searches for unpublished studies were reported. Measures to reduce error and bias in the study selection process were reported, but it was unclear whether similar measures were applied to the data extraction and quality assessment of the included studies. The methodological quality of included studies was assessed using relevant criteria and the findings of this assessment were incorporated in the results of the review. Relevant details of the included studies were reported and the meta-analytic methods used were appropriate. Although there was limited evidence that combination therapy may be more effective than metformin alone, these data were sparse and the authors' conclusions accurately reflected the generality of the data presented. However, the findings of this review should be treated with some caution given the limitations in reporting of the review process and small number of included studies.

Implications of the review for practice and research

Practice: The authors stated that combination therapy offered no benefits over monotherapy with either clomiphene citrate or metformin. The choice between metformin and clomiphene citrate as the best first-step to induce ovulation remaineds unclear and, therefore, likely to depend upon patient preference.

Research: The authors made no recommendations for future research.

Funding

Not reported.

Bibliographic details

Palomba S, Pasquali R, Orio F, Nestler J E. Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis Clinical Endocrinology 2009; 70(2): 311-321. [PubMed: 18691273]

Original Paper URL

http://onlinelibrary.wiley.com/journal/121372515/abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Anovulation /drug therapy /etiology; Clomiphene /therapeutic use; Drug Therapy, Combination; Female; Humans; Infertility, Female /drug therapy /etiology; Metformin /therapeutic use; Polycystic Ovary Syndrome /complications /drug therapy; Randomized Controlled Trials as Topic

AccessionNumber

12009103224

Database entry date

16/09/2009

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.