Xiaoli Sun, Dan Zhang & Wei Zhang

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1 Effect of metformin on ovulation and reproductive outcomes in women with polycystic ovary syndrome: a meta-analysis of randomized controlled trials Xiaoli Sun, Dan Zhang & Wei Zhang Archives of Gynecology and Obstetrics ISSN DOI /s

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3 DOI /s REPRODUCTIVE MEDICINE Effect of metformin on ovulation and reproductive outcomes in women with polycystic ovary syndrome: a meta-analysis of randomized controlled trials Xiaoli Sun Dan Zhang Wei Zhang Received: 8 November 2012 / Accepted: 4 February 2013 Ó Springer-Verlag Berlin Heidelberg 2013 Abstract Purpose To evaluate the effect of MET on ovulation and reproductive outcomes in patients with polycystic ovary syndrome. Methods Meta-analysis of available data from randomized controlled trials that examined the ovulation, pregnancy and live birth rate after the administration of clomiphene citrate (CC) or MET alone or combined. Results The ovulation rate was found to be higher in the group treated with MET combined with clomiphene citrate (CC) than only with CC, odds ratio (OR): 1.27, 95 % confidence interval (95 % CI) ( ), while the pregnancy and live birth rate showed no significant difference between the two groups, OR: 1.19, 95 % CI ( ) and OR: 0.99, 95 % CI ( ), respectively. The MET? CC group produced a higher ovulation and pregnancy rate than MET group, OR: 2.10, 95 % CI ( ) and OR: 2.08, 95 % CI ( ), respectively, while between two groups the live birth rate showed no significant difference, OR: 1.50, 95 % CI ( ). The ovulation rate was lower in MET than in CC group, OR: 0.65, 95 % CI ( ), while between the two groups the pregnancy and live birth rate showed no X. Sun D. Zhang W. Zhang (&) Institute of Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China zhang.wei.fudan@gmail.com D. Zhang zd_loy@163.com X. Sun Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China zymsxl@126.com significant difference, OR: 0.86, 95 % CI ( ) and OR: 0.89, 95 % CI ( ). Conclusion The current study indicated that combination of MET and CC could gain advantage over a single administration in the ovulation induction and pregnancy rate. Keywords Polycystic ovary syndrome Metformin Clomiphene meta-analysis Ovulation rate Pregnancy rate Live birth rate Introduction Polycystic ovary syndrome (PCOS) is a common condition affecting women of reproductive age by 5 10 % [1]. Irregular or absent ovulation is one of the characteristic symptoms of PCOS patients [2], 91 % of anovulation women were PCOS patients [3]; therefore, inducing ovulation is needed for them. Clomiphene citrate (CC) has been regarded as the first line drug for ovulation induction in PCOS patients; however, % of women may fail to ovulate and are considered to be CC resistant [4]. Recently, it was reported that insulin resistance was a significant contributor to the pathogenesis of PCOS [5], and % of PCOS women developed insulin resistance, which caused compensatory hyperinsulinemia bringing out many phenotypic features of PCOS [6]. Because of the insulin resistance in the pathogenesis of PCOS, MET was applied to the treatment of infertile women with PCOS before or during the ovulation induction with CC [7]. Although the liver is the primary target organ, MET acts on a variety of tissues, such as skeletal muscles, adipose tissue, endothelium, and the ovary [8].

4 Table 1 Characteristic of the included trials References Comparisons Protocol Duration Outcomes 1 Nestler [9] P\MET MET: 500 mg tid 4 8 weeks Ovulation 2 Nestler [10] P\MET\P? CC\P? MET MET: 500 mg tid 53 days Ovulation CC: 50 mg qd 3 Ernest Hung P\MET\P? CC\P? MET MET: 500 mg tid 3 months Ovulation\pregnancy YU Ng et al. [11] CC: 100 mg qd 4 Sturrock et al. P? CC\MET? CC MET: 850 mg bid 6 months Ovulation\pregnancy [12] CC: mg qd 5 David T et al. P? CC\MET? CC MET: 500 mg tid 6 months Ovulation\pregnancy [13] CC: mg qd 6 Muberra P? CC\MET? CC MET: 850 mg bid 2 months Ovulation\pregnancy Kocak et al. [14] CC: 100 mg qd 7 Fleming [15] P\MET MET: 850 mg bid 3.5 months Ovulation\pregnancy 8 Kathleen et al. [16] 9 Yilmaz Sahina et al. [17] 10 Stefano Palomba et al. [18] 11 Moll et al. [19] 12 Lord et al. [20] 13 Legro et al. [21] 14 Murizah Mohd Zain et al. [22] 15 Siebert TI et al. [23] 16 Talieh Kazerooni, et al. [24] 17 Johnson et al. [25] 18 Mohammad Ali Karimzadeh et al. [26] P\MET\lifestyle modification plus placebo \lifestyle modification plus metformin MET: 850 mg bid; lifestyle modification plus metformin 850 mg bid; lifestyle modification plus placebo, or placebo alone. 12 months Ovulation CC \MET? CC MET: 500 mg tid 9 months Ovulation\pregnancy CC: 100 mg qd P? CC\MET? P MET: 850 mg bid 6 months Ovulation\pregnancy\abortion CC: mg qd \live birth CC? P\MET? CC MET: no description 6 months Ovulation\pregnancy\abortion CC: mg qd P\MET MET: 500 mg tid 3 months Ovulation\pregnancy CC: 100 mg qd P? CC\MET? P\MET? CC MET: 1,000 mg bid 6 months Ovulation\pregnancy\live birth CC: 50 mg qd CC\ MET\MET? CC MET: 500 mg tid 6 months Ovulation\pregnancy\live CC: mg qd birth. CC\MET? CC MET: 850 mg bid 3 months Ovulation CC: mg qd P? CC\MET? CC MET: 500 mg tid 2 months Ovulation\pregnancy CC: 100 mg qd MET\MET? CC\CC MET: 500 mg tid 6 months Pregnancy\live birth CC: mg qd CC\ MET \MET?CC \lifestyle modification Metformin: 1,500 mg/day 6 months Pregnancy CC: 100 mg/day CC clomiphene citrate, MET metformin, p placebo, qd once a day, bid twice a day, tid three times a day MET, firstly administrated in obese PCOS women in 1994, reduced serum levels of insulin and androgen and regularized the cycle of menses [27]. Furthermore, previous researches showed that MET could diminish ovarian 17, 20-lyase activity and ovarian androgen secretion while lowering insulin level in PCOS women [9], and it could increase the ovulation rate, cervical scores and pregnancy rates in them [14, 28]. Kjotrod et al. [29] found that MET treatment that lasted 12 weeks before and during IVF or ICSI in non-obese PCOS women significantly increased

5 Fig. 1 Comparison of ovulation rate between MET? CC and CC group Fig. 2 Comparison of pregnancy rate between MET? CC and CC group pregnancy and live birth rate when compared with placebo. Weerakiet et al. [30] showed that MET of 1,000 mg produced the same efficacy as that of 1,700 mg on the induction of ovulation and pregnancy in PCOS women. However, there have been still controversies over the effect of MET on reproductive function in PCOS patients [19, 21, 22, 31, 32]. Thus, its role in the treatment of PCOS remains to be further proved. Therefore, we searched the randomized controlled trails (RCTs) about PCOS treated with MET or CC alone, or with a combination of both, and then we conducted a systematic review and meta-analysis to evaluate the effect of MET on ovulation and pregnant outcomes in PCOS patients. Materials and methods In the current study, the key words for search were as follows: PCOS, polycystic ovary syndrome, metformin, clomiphene citrate, ovulation induction, pregnancy,

6 Fig. 3 Comparison of live birth rate between MET? CC and CC Fig. 4 Comparison of ovulation rate between MET? CC and MET Fig. 5 Comparison of pregnancy rate between MET? CC and MET abortion, randomized controlled trial. The search was performed at such bibliographic databases as Medline from 1966 to 2012, Embase from 1980 to 2012, and Science Direct from 1966 to The titles and abstracts were screened to get relevant articles in English, which were reviewed through inclusion and exclusion criteria by two independent reviewers. The criteria in terms of PCOS diagnosis had to be consistent with those as follows: oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism and polycystic ovaries visible with ultrasound. The inclusion criteria applied to those of RCTs, which compared ovulation, pregnant, and live birth rates upon the administration of MET or CC, or the combination of both (MET? CC) in PCOS women. Any conflict between the two reviewers was resolved by the third one in consultation.

7 Statistical analysis Meta-analysis was performed usingstatase11software, the fixed-effects model applied to the analysis of the statistical homogeneity trials, and the random-effects model used when no statistical heterogeneity was apparent. Results Included trials Seventy-two RCTs were identified and screened; consequently, 54 were excluded for reasons as follows: not being really randomized, not being relevant to the patient population, and not being relevant to the treatment invention, and the rest were enrolled for potential meta-analysis (Table 1). Comparison between MET? CC and CC A total of ten RCTs were settled, where the effect on ovulation induction was compared between MET? CC and CC group. Four reports showed a significant difference between MET? CC and CC group, but the rest failed to do so. Meta-analysis results showed that ovulation rate was higher in MET? CC than in CC group, OR: 1.27, 95 % CI: ( ) (Fig. 1). As to pregnancy rate, 11 RCTs were settled, 10 of which showed no significant difference between MET? CC and CC group, as indicated by meta-analysis, OR: 1.19, 95 % CI ( ) (Fig. 2). In the case of live birth rate, meta-analysis of three RCTs showed no significant difference between MET? CC and CC group, OR: 0.99, 95 % CI ( ) (Fig. 3). Comparison between MET? CC and MET Based on two RCTs, a higher ovulation rate was found in MET? CC than in MET group, OR: 2.10, 95 % CI ( ) (Fig. 4); and on four RCTs, a higher pregnancy rate was found in MET? CC than in MET group, OR: 2.08, 95 % CI ( ) (Fig. 5), while on three RCTs, no significant difference was found between the two groups, OR: 1.50, 95 % CI ( ) (Fig. 6). Comparison between MET and CC From three RCTs, the ovulation rate was found to be statistically significant between MET and CC group, OR: 0.65, 95 % CI ( ) (Fig. 7), while from five RCTs, the pregnancy rate was found to show no significant difference between the two groups, OR: 0.86, 95 % CI ( ) (Fig. 8), and from four RCTs, the live birth rate was found to show the same results, OR: 0.89, 95 % CI ( ) (Fig. 9). Discussion Ovulation rate As the first line ovulation inductor, CC is a partially selective estrogen (E) receptor modulator having an antiestrogenic effect on the hypothalamus, causing an increased level of FSH, which results in follicular development and E 2 production [33]. It was reported that the ovulation rate induced by CC was about % of patients [34]. Because of the insulin resistance in the pathogenesis of PCOS, MET was applied to the treatment of infertile women with PCOS before or during the ovulation induction with CC [7]. Fig. 6 Comparison of live birth rate between MET? CC and MET

8 Fig. 7 Comparison of ovulation rate between MET and CC Fig. 8 Comparison of pregnancy rate between MET and CC Fig. 9 Comparison of live birth rate between MET and CC In our meta-analysis, the ovulation rate was slightly higher MET? CC than in CC or MET group alone, but it was lower in MET than in CC group, suggesting that the combined therapy could enhance the ovulation induction effect. Our data also showed that the effect of CC was stronger than MET in terms of ovulation induction. It could

9 be concluded that MET could increase the sensitivity of ovaries of PCOS patients to CC. Pregnancy rate Our meta-analysis data showed that the pregnancy rate was higher in MET? CC than in CC group, even though there was no statistically significant difference; and the pregnancy rate showed a significant difference between MET? CC and MET group, suggesting that the combined therapy could increase the pregnancy rate; and the pregnancy rate produced no significant difference between MET and CC group. It was reported that the ovulation rate of CC was about % of infertile PCOS patients [35], while the pregnancy rate was approximately % [34]. The discrepancy between ovulation and pregnancy was probably related to the anti-estrogenic effect of CC on the cervix and endometrium, leading to the thickening of the cervical mucus so that the sperm was obstructed from moving to the uterine cavity, and the thinning of the endometrium, being unsuitable for implantation [36]. Metformin is a biguanide oral antihyperglycemic agent. There have been preliminary data indicating that metformin may directly decrease ovarian androgen production [37]. However, no evidence shows that MET has an adverse effect on the endometrial and cervical mucus, which could explain why the ovulation rate of CC was higher than that of MET, while the pregnancy rate was similar between two groups, and why the combined therapy showed a higher pregnancy rate than the monotherapy of CC in the current study. Live birth rate PCOS women may be at greater risk of such outcomes as spontaneous abortion or stillbirth [38 40]; therefore, the evaluation of live birth can be particularly appropriate to the population. Some studies reported that the first trimester abortion rate was % in PCOS women [41], who accounted for % of those with recurrent early pregnancy loss [42]. Hyperinsulinemia has been regarded as the risk factor for early pregnancy loss [43]. MET was reported to decrease the risk of the first trimester spontaneous abortion [44]. Therefore, we speculated that the administration of metformin could increase the rate of live birth. But our meta-analysis showed that it presented no statistically significant difference in the comparisons. This could be ascribed to the limited number of samples, which suggests that further investigations are needed. In summary, the administration of MET? CC could gain advantage over the monotherapy of MET or CC in PCOS patients with anovulatory infertility for ovulation induction and pregnancy, and it is necessary to conduct multicenter, well-designed trials to verify our conclusion. Acknowledgments We would like to thank Chen Hanyi for her help in the application of Stata SE 11 software. This work was supported by grants from the Shanghai Action Plan for Science and Technology Innovation (No ), and the Bootstrap of Shanghai Medical Project (No ). 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3. Metformin therapy for PCOS

3. Metformin therapy for PCOS 1. Introduction The key clinical features of polycystic ovary syndrome (PCOS) are hyperandrogenism (hirsutism, acne, alopecia) and menstrual irregularity with associated anovulatory infertility. 1 The