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Twenty years of ovulation induction with metformin for PCOS; what is the best available evidence?
Reproductive BioMedicine Online, Volume 32, Issue 1, January 2016, Pages 44 - 53
Editorial Comment from Bruce Dunphy: There is controversy over whether metformin has a role in ovulation induction for women with PCOS. This article critically appraises and summarizes randomized controlled trials (RCTs) and meta-analyses of RCTs, and provides helpful recommendations regarding the management of women with PCOS
The potential reproductive benefits of metformin, a drug endowed with the capacity to ameliorate insulin resistance in polycystic ovary syndrome (PCOS), has garnered much interest over the past 2 decades. In this review, randomized-controlled trials (RCT) and meta-analyses of RCT comparing metformin are critically appraised and summarized. PubMed and CENTRAL databases were consulted. Evidence is insufficient to favour the use of metformin or metformin plus clomiphene citrate instead of clomiphene citrate for ovulation induction in women with newly diagnosed PCOS. Evidence is also insufficient to recommend metformin as a primary treatment for non-obese women with PCOS. Metformin plus clomiphene citrate should be considered as an effective option in clomiphene citrate-resistant PCOS. In women with PCOS undergoing gonadotrophin ovulation induction, metformin significantly increased pregnancy and live birth rates (P < 0.0001 and P = 0.020, respectively) with reduced risk of cancelled cycles. A beneficial effect of metformin co-treatment in increasing clinical pregnancy rates and reducing the risk of OHSS in PCOS patients undergoing assisted reproduction techniques has been shown. No evidence was found of reduced risk of spontaneous abortion or increased risk of major anomalies in women with PCOS taking metformin during the first trimester.
Keywords: clomiphene citrate, infertility, metformin, polycystic ovary disease, polycystic ovary syndrome, pregnancy rate.
Since its discovery 80 years ago (Stein and Leventhal, 1935), polycystic ovary syndrome (PCOS) remains a challenging metabolic disorder for gynaecologists and endocrinologists. It is the leading cause of World Health Organization type 2 anovulatory infertility, and is by far the most common endocrinopathy of women in their reproductive age (ESE PCOS Special Interest Group, 2014 and ESHRE Capri Workshop Group, 2012). Over the past 12 years, great efforts have been made by the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine to resolve three consensuses to diagnose the syndrome, its infertility management as well as addressing various aspects of women's health (ESHRE/ASRM, 2004, ESHRE/ASRM, 2008, and ESHRE/ASRM, 2012). The Rotterdam diagnostic consensus for PCOS requires at least two of the following three criteria to be met: oligo- or anovulation; clinical, biochemical signs of hyperandrogenism, or both, and polycystic ovaries on ultrasound; and absence of other causes (ESHRE/ASRM, 2004). Recently, a prevalence rate of around 20% has been reported based on the Rotterdam criteria compared with 6–10% according to the US National Institute of Health criteria (March et al, 2010 and Yildiz et al, 2012).
An Australian study found that women with PCOS were more proactive in seeking out treatment for infertility than normal women (Herbert et al., 2009). Ovulation induction remains a milestone in managing anovulatory infertile women with PCOS, and clomiphene citrate is first-line pharmacological treatment for ovulation induction in women with PCOS (Abu Hashim, 2012, Brown et al, 2009, and ESHRE/ASRM, 2008). Resistance to clomiphene citrate has been shown in 15–40% of women with PCOS who did do not ovulate with a daily treatment dose of 150 mg of clomiphene citrate for 5 days in three successive cycles (Abu Hashim, 2012 and Brown et al, 2009).
Polycystic ovary syndrome is not merely an ovarian disease, but rather a disorder of intermediary metabolism often characterized by insulin resistance and hyperandrogenism. Insulin-sensitizing agents, especially metformin, have therefore been used as a treatment option in women with PCOS (Diamanti-Kandarakis, Dunaif, 2012 and Fox, Ryan, 2002). In fact, insulin resistance is a significant contributor to the widely accepted Rotterdam criteria for diagnosing PCOS by virtue of its direct and indirect effects (Figure 1). The use of metformin as a treatment option for PCOS was first reported in a pilot study of 26 women with PCOS by Velazquez et al. (1994). Reduction of insulin resistance and hyperandrogenism resulted in improvements of hormonal and metabolic patterns, as well as reproductive function. This appealing aspect of metformin opened up a window of opportunity for extensive research, spanning 2 decades, on its potential for inducing ovulation in women with PCOS. Within this context, and given that this is a clinically important area to address, this review was conducted to critically appraise and summarize current research on the effect of metformin on reproductive outcomes in women with PCOS on the basis of the best available evidence from randomized controlled trials (RCT) and meta-analyses of RCT.
Materials and methods
A litereature search of English-language studies was conducted on PubMed (from January 1994 to January 2015) and CENTRAL (Cochrane Central Register of Controlled Trials, Issue 1, 2015) using the terms ‘metformin’, ‘PCOS’, ‘polycystic ovary syndrome‘, and ‘polycystic ovary disease’. The search was limited to high-quality evidence from randomized trials, systematic reviews and meta-analyses of RCT in which reproductive outcomes were reported, including ovulation, clinical pregnancy, live birth and spontaneous abortion rates. A population, intervention, comparison, outcome (PICO) framework was established a priori to select the articles for the question posed for each section in the review. RCT not addressing the specified outcomes to this evidence review, non-randomized studies, editorials, letters to the editor, narrative reviews, case series, reports as well as old versions of Cochrane systematic reviews, were excluded. For each comparison, individual RCT were excluded if their results were previously included in a subsequent meta-analysis of RCT. Those RCT published after the most recent meta-analysis addressing a specific comparison were included. Pertinent full texts were selected and reviewed, and its reference lists were manually searched to identify other important articles. A search update to 20 May 2015 was carried out to identify newly relevant citations. Overall, this search produced 947 articles, 18 of which met the selection criteria (four RCT and 14 meta-analyses of RCT) (Abu Hashim et al, 2015, Cassina et al, 2014, Costello et al, 2006, Creanga et al, 2008, Hamed et al, 2010, Hosseini et al, 2013, Johnson, 2011, Karimzadeh, Javedani, 2010, Misso et al, 2013, Palomba et al, 2004, Palomba et al, 2009a, Palomba et al, 2009b, Palomba et al, 2013, Palomba et al, 2014, Siebert et al, 2006, Siebert et al, 2012, Tang et al, 2012, and Tso et al, 2014). A flow diagram of the study is presented in Figure 2. Examples of excluded studies and reasons for their exclusion are presented in Supplementary Table S1.
Metformin versus lifestyle intervention as first-line treatment in women with anovulatory PCOS
Optimization of body weight should be the first line of treatment in all obese infertile women with PCOS (body mass index [BMI] ≥ 30 kg/m2) before considering any further treatment. Weight loss alone through lifestyle management improves hyperandrogenism and insulin resistance. It may, therefore, restore ovulation, improve response to ovulatory drugs, in addition to successful pregnancy outcomes (Moran et al, 2011 and NCC-WCH/NICE, 2013). In a large randomized double-blind study including 343 overweight infertile women with PCOS, Karimzadeh and Javedani (2010) compared lifestyle modification (diet plus exercise) with three ovulation-induction protocols, including clomiphene citrate, metformin and clomiphene citrate plus metformin. They reported a higher, albeit non-significant clinical pregnancy rate in the lifestyle modification group (20%) compared with metformin (14.4%), clomiphene citrate (12.2%) or combined treatment (14.4%). No data were available on live birth rate. Consequently, the authors highlighted the importance of lifestyle modification as first-line treatment of infertile women with PCOS before resorting to pharmacological ovulation induction (Table 1).
|Comparison/references||Study design||Ovulation rate||Clinical pregnancy rate||Live birth rate|
|Metformin versus lifestyle intervention|
|Karimzadeh and Javedani (2010)||RCT (n = 343)||62.5% versus 66.6%a||14.1% versus 20%|
|Metformin versus placebo/no treatment|
|Tang et al. (2012)||A Cochrane meta-analysis of RCT||OR 1.81; 95% CI 1.13 to 2.93b||OR 2.31; 95% CI 1.52 to 3.51b||OR: 1.80; 95% CI 0.52 to 6.16|
|Metformin versus clomiphene citrate|
|Palomba et al. (2009a)||Meta-analysis of RCT||OR 1.55; 95% CI 0.40 to 5.99||OR 1.22; 95% CI 0.23 to 6.55||OR 1.17; 95% CI 0.16 to 8.61|
|Siebert et al. (2012)||Meta-analysis of RCT||OR 0.48; 95% CI 0.41 to 0.57b||OR 0.78; 95% CI 0.59 to 1.0||OR 0.48; 95% CI 0.31 to 0.73b|
|Metformin plus clomiphene citrate versus clomiphene citrate|
|Palomba et al. (2009a)||Meta-analysis of RCT||OR 0.84; 95% CI 0.60 to 1.18||OR 0.85; 95% CI 0.62 to 1.15||OR 0.99; 95% CI 0⋅70 to 1⋅40|
|Siebert et al. (2012)||Meta-analysis of RCT||OR 1.6; 95% CI 1.2 to 2.1b||OR 1.3; 95% CI 1.0 to 1.6||OR 1.1; 95% CI 0.78 to 1.5|
a Expressed as resumption of regular menstrual cycles.
b P < 0.05.
CI = confidence interval; n = number of patients; OR = odds ratio; RCT = randomized controlled trial.
Metformin or clomiphene citrate as the first-line pharmacological therapy in women with anovulatory PCOS
The use of metformin as first-line pharmacological treatment option for ovulation induction in PCOS has sparked a heated discussion. A recent Cochrane review reported that metformin was better than placebo or no treatment for ovulation (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.13 to 2.93; 16 RCT; n = 1208) and clinical pregnancy (OR 2.31; 95% CI 1.52 to 3.51; eight RCT; n = 707) rates per patient but not for live birth rate (OR 1.80; 95% CI 0.52 to 6.16; three RCT; n = 115) (Tang et al., 2012) (Table 1). Compared with the gold standard clomiphene citrate, potential advantages of metformin include absence of anti-oestrogenic adverse effects, reduced multiple pregnancies as well as the need for less intensive monitoring (Nestler, 2008). On the basis of these considerations, two systematic review and meta-analyses of RCTs were conducted to evaluate the reproductive efficacy of metformin compared with clomiphene citrate as first-line pharmacological treatment in women with anovulatory PCOS (Palomba et al, 2009a and Siebert et al, 2012) (Table 1).
In a meta-analysis, Palomba et al. (2009a) examined three RCT, and found that metformin was no more effective than clomiphene citrate in stimulating ovulation (OR 1.55; 95% CI 0.40 to 5.99), clinical pregnancy (OR 1.22; 95% CI 0.23 to 6.55), or live birth (OR 1.17; 95% CI 0.16 to 8.61) rates; however, significant heterogeneity (P < 0⋅0001) was detected for all three end-points. Subsequently, in a recent meta-analysis of 14 RCT, Siebert et al. (2012) addressed the same question. Clomiphene citrate alone performed significantly better than metformin alone in ovulation per cycle (OR 0.48; 95% CI 0.41 to 0.57; P < 0.00001; two RCT; number of cycles = 2387) and live birth (OR 0.48; 95% CI 0.31 to 0.73; P = 0.0006; four RCT; n = 612 women) rates but not for clinical pregnancy rate (OR 0.78; 95% CI 0.59 to 1.0; six RCT; n = 1396). Heterogeneity was detected for all three outcomes. On the basis of these two meta-analyses, evidence favouring the use of metformin instead of clomiphene citrate is insufficient, and clomiphene citrate still represents the gold standard first-line pharmacological treamtnet for ovulation induction in anovulatory infertile women with PCOS (Abu Hashim, 2012).
Metformin plus clomiphene citrate versus clomiphene citrate as first-line treatment in women with anovulatory PCOS
In the above mentioned meta-analysis, Palomba et al. (2009a) showed that combination therapy of metformin plus clomiphene citrate did not differ from clomiphene citrate alone in rates of ovulation (OR 0.84; 95% CI 0.60 to 1.18), clinical pregnancy (OR 0.85; 95% CI 0.62 to 1.15), or live birth (OR 0.99; 95% CI 0⋅70 to 1⋅40), with no significant heterogeneity among the three RCT. On the other hand, although Siebert et al. (2012) reported significant benefits of combined therapy over clomiphene citrate alone in terms of ovulation rate (OR 1.6; 95% CI 1.2 to 2.1; P = 0.0009; eight RCT) and a marginal benefit in clinical pregnancy rate (OR 1.3; 95% CI 1.0 to 1.6; P = 0.05; 10 RCT), they did not recommend the combined therapy as a primary method for ovulation induction in women with PCOS owing to no evidence of benefit for the live birth rate (OR 1.1; 95% CI 0.78 to 1.5; four RCT) as well as the side-effect profile of metformin (Table 1). Consequently, clomiphene citrate still represents the first-line pharmacological treatment for ovulation induction in women with newly diagnosed PCOS.
Metformin or clomiphene citrate for non-obese anovulatory infertile women with PCOS
In a recent Cochrane review, subgroup analysis according to BMI revealed that obese women with PCOS (BMI ≥30 kg/m2) under clomiphene citrate had significantly better ovulation per cycle (OR 0.43; 95% CI 0.36 to 0.51; two RCT; number of cycles = 2044; I2 = 0%), clinical pregnancy (OR 0.34; 95% CI 0.21 to 0.55; two RCT; n = 500; I2 = 0%) and live birth (OR 0.30; 95% CI 0.17 to 0.52; I2 = 0%) rates compared with those who received metformin without heterogeneity across the studies. On the other hand, non-obese women (BMI <30 kg/m2 or ≤32 kg/m2) who received metformin had a higher clinical pregnancy (OR 1.94; 95% CI 1.19 to 3.16; three RCTs; n = 349; I2 = 44%), but not ovulation per cycle (OR 0.87; 95% CI 0.60 to 1.26; two RCT, number of cycles = 497; I2 = 0%) rate compared with those who received clomiphene citrate. Pooling of data on live birth rate was not achieved owing to the heterogeneity observed in the non-obese subgroup. The authors pointed out that metformin significantly reduced fasting insulin concentrations in the non-obese group (mean difference −5.65 mIU/l; 95% CI −10.25 to −1.06) but not in obese women with PCOS (mean difference −2.72 mIU/l; 95% CI −6.50 to 1.05), i.e. metformin had limited effect on reducing serum insulin concentrations in the obese compared with the non-obese women with PCOS (Tang et al., 2012).
The Cochrane review by Tang et al. (2012) did not include data on the non-obese subgroup of women of a large RCT (Legro et al., 2007). These important data were considered in a subsequent meta-analysis of four RCT to compare the effectiveness of metformin with clomiphene citrate for improving fertility outcomes in non-obese women with PCOS (BMI <32 kg/m2) (Misso et al., 2013). The authors found no significant difference in ovulation rate per cycle (relative risk [RR] 0.79 95%; CI 0.54 to 1.17; I2 = 78%; two RCT; number of cycles = 909) or clinical pregnancy rate (RR 0.98; 95% CI 0.49 to 1.96; four RCT, I2 = 80%) or live birth rate (RR 0.84; 95% CI 0.22 to 3.26; three RCT; I2 = 90%) per patient for metformin compared with clomiphene citrate given for at least 3 months to non-obese anovulatory infertile women with PCOS. Consequently, the authors concluded that the available evidence is insufficient to recommend metformin as a primary treatment of non-obese women with PCOS. The findings of this meta-analysis are in agreement with another meta-analysis of three RCT addressing this subset (Johnson, 2011).
Metformin plus clomiphene citrate versus clomiphene citrate plus placebo in clomiphene citrate resistant-PCOS
Handling of anovulatory infertile women with clomiphene citrate resistant-PCOS (CCR-PCOS) has witnessed a dramatic revolution in its current ideologies, goals, practice and results. The examination of the potential benefits of combined metformin plus clomiphene citrate had gained the maximum interest of researchers rather than the use of metformin monotherapy in this subset of patients. In a meta-analysis of six RCT, Siebert et al. (2006) reported that metformin plus clomiphene citrate significantly increased the likelihood of ovulation compared with clomiphene citrate with or without placebo in CCR-PCOS patients (OR 6.82; 95% CI 3.59 to 12.96; P < 0.0001). In a subsequent meta-analysis of 12 RCT, Creanga et al. (2008) confirmed these findings (OR 4.39; 95% CI 1.94 to 9.96; number-needed-to-treat 3.7 for ovulation). In addition, they demonstrated the superiority of combined treatment in terms of clinical pregnancy (OR 2.67; 95% CI 1.45 to 4.94, number-needed-to-treat 4.6), but not live birth (OR 1.74; 95% CI 0.79 to 3.86) (Table 2). Different mechanisms underpinning the beneficial effects of adding metformin to clomiphene citrate in treatment of women with clomiphene citrate-resistant PCOS were suggested, including an intrinsic alteration of follicle steroidogenesis through the insulin growth factor-1 pathway in granulosa cells (Kocak et al., 2002), direct inhibition of androgen production in ovarian thecal cells (Attia et al., 2001), reduction of the adrenal steroidogenesis response to adrenocorticotropic hormone (la Marca et al., 1999) and, its central action on the pituitary gland with LH lowering and prolactin effects in women with PCOS (Billa et al., 2009).
|Comparison/references||Study design||Ovulation rate||Clinical pregnancy rate||Live birth rate|
|Metformin plus clomiphene citrate versus clomiphene citrate with or without placebo|
|Siebert et al. (2006)||Meta-analysis of RCT||OR 6.82; 95% CI 3.59 to 12.96a|
|Creanga et al. (2008)||Meta-analysis of RCT||OR 4.39; 95% CI 1.94 to 9.96;a NNT 3.7||OR 2.67; 95% CI 1.45 to 4.94;a NNT 4.6||OR 1.74; 95% CI 0.79 to 3.86|
|Metformin plus clomiphene citrate versus other second-line treatments|
|Abu Hashim et al. (2015)||Meta-analysis of RCT||OR 0.25; 95% CI 0.15 to 0.41a (versus gondotrophins)||OR 0.45; 95% CI 0.27 to 0.75a (versus gondotrophins)||OR 0.33; 95% CI 0.13 to 0.85a (versus gondotrophins)|
|OR 0.88; 95% CI 0.53 to 1.47 (versus LOD)||OR 0.96; 95% CI 0.60 to 1.54 (versus LOD)||OR 0.85; 95% CI 0.28 to 2.58 (versus LOD)|
|OR 0.88; 95% CI 0.58 to 1.34 (versus aromatase inhibitors)||OR 0.85; 95% CI 0.53 to 1.36 (versus aromatase inhibitors)||OR 0.21; 95% CI 0.05 to 0.87a (versus aromatase inhibitors)|
|OR 8.93; 95% CI 4.61 to 17.32a (versus NAC plus clomiphene citrate)||OR 5.28; 95% CI 1.91–14.62a (versus NAC plus clomiphene citrate)|
|OR 0.30; 95% CI 0.03 to 3.41 (versus other insulin sensitizers plus clomiphene citrate)||OR 0.39; 95% CI 0.20 to 0.75a (versus other insulin sensitizers plus clomiphene citrate)||OR 0.62; 95% CI 0.12 to 3.22 (versus other insulin sensitizers plus clomiphene citrate)|
a P< 0.05.
CI = confidence interval; LOD = laparoscopic ovarian diathermy; NAC = N-acetyl-cysteine; NNT = number-needed-to-treat; OR = odds ratio; RCT = randomized controlled trial.
Metformin plus clomiphene citrate versus other second-line treatments in CCR-PCOS
Second-line treatments for infertile women with CCR-PCOS include gonadotrophins, laparoscopic ovarian diathermy (LOD) and other oral agents, such as aromatase inhibitors, N-acetyl-cysteine (NAC), and other insulin sensitizers (Abu Hashim et al, 2013, ESHRE/ASRM, 2008, Franik et al, 2014, Saha et al, 2013, and Tang et al, 2012). Although many RCT have investigated the efficacy of metformin plus different second-line treatment options in CCR-PCOS patients, only two RCT compared metformin monotherapy with LOD with conflicting results. One study (n = 120 overweight primary infertile anovulatory clomiphene citrate-resistant women), demonstrated the superiority of metformin over LOD in clinical pregnancy (21.8% versus 13.4%; P < 0.05) and live birth (86.0% versus 64.5%; P < 0.05), but not ovulation rates (54.8 versus 53.2%) (Palomba et al., 2004). Meanwhile, another RCT of 110 clomiphene citrate-resistant women with PCOS showed that LOD achieved significantly higher rates of ovulation (50.8% versus 33.5%; P < 0.001) and clinical pregnancy (38.2% versus 20.0%; P < 0.03). No data on live birth rate were available (Hamed et al., 2010).
Recently, we conducted a systematic review and meta-analysis to provide pooled estimates of RCT comparing the reproductive outcomes (mainly ovulation and clinical pregnancy rates) of metformin plus clomiphene citrate with different second-line treatments in CCR-PCOS (Table 2). We reported the superiority of gonadotrophins over metformin plus clomiphene citrate in terms of ovulation (OR 0.25; 95% CI 0.15 to 0.41; P < 0.00001; three trials; I2 = 85%; n = 323) and clinical pregnancy (OR 0.45; 95% CI 0.27 to 0.75; P = 0.002, three trials, I2 = 0%, n = 323). Meanwhile, no significant differences were found when metformin plus clomiphene citrate was compared with LOD (OR 0.88; 95% CI 0.53 to 1.47; one trial; n = 282; OR 0.96; 95% CI 0.60 to 1.54; two trials; I2 = 0%; n = 332; for ovulation and clinical pregnancy rates respectively) or with aromatase inhibitors (OR 0.88; 95% CI 0.58 to 1.34; three trials; I2 = 3%; n = 409; OR 0.85; 95% CI 0.53 to 1.36; two trials; n = 309; for ovulation and clinical pregnancy rates, respectively). Additionally, we demonstrated the superiority of metformin plus clomiphene citrate over NAC plus clomiphene citrate in terms of ovulation (OR 8.93; 95% CI 4.61 to 17.32; P < 0.00001; one trial; n = 192) and clinical pregnancy (OR 5.28; 95% CI 1.91 to 14.62; P = 0.001; one trial; n = 192). Meanwhile, meta-analysis of three small trials (n = 155) revealed significantly fewer clinical pregnancies following metformin plus clomiphene citrate compared with other insulin sensitizers plus clomiphene citrate (OR 0.39; 95% CI 0.20 to 0.75; P = 0.005; I2 = 0%), albeit no difference in ovulation rates in a small trial (OR 0.30; 95% CI 0.03 to 3.41; n = 25) (Abu Hashim et al., 2015).
For live birth rate, the outcome of most interest for infertile patients with PCOS, we demonstrated the superiority of gonadotrophins over metformin plus clomiphene citrate (OR 0.33; 95% CI 0.13 to 0.85; P = 0.02; two trials; I2 = 0%; n = 170). No differences were found when metformin plus clomiphene were compared with LOD in one small trial (OR 0.85; 95% CI 0.28 to 2.58; n = 50) or to other insulin sensitizers plus clomiphene in another small trial (OR 0.62; 95% CI 0.12 to 3.22; n = 25). Meanwhile, we observed a significantly lower live birth rate when combined treatment was compared with an aromatase inhibitor in one small trial (OR 0.21; 95% CI 0.05 to 0.87; P = 0.03; n = 59). No data were available on live birth rate when metformin plus clomiphene citrate was compared with NAC plus clomiphene citrate (Table 2) (Abu Hashim et al., 2015).
With this background in mind, we concluded that metformin plus clomiphene citrate could be considered in the management protocol of patients with CCR-PCOS, and that more attempts with metformin plus clomiphene citrate are warranted when access to gonadotrophins is limited (Abu Hashim et al., 2015). It is also important to ensure that, from the available list of choices, the final decision should be tailored to each woman, taking into account her own personal values and circumstances, e.g. economics, side-effects, in addition to what is available in a country or clinic (Figure 3). This is consistent with the fundamental principle of evidence-based medicine as ‘the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients’ (Sackett et al., 2000).
Metformin and gonadotrophins for ovulation induction in CCR-PCOS
Ovulation induction with gonadotrophins in CCR-PCOS requires extensive monitoring, and is also associated with significantly increased risk for ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy unless low-dose step-up protocol is used (ESHRE/ASRM, 2008). In addition, the presence of insulin resistance in those patients was found to be associated with increased dosage and duration of gonadotrophin treatment, increase cancellation rate and a lower conception rate (Dale et al., 1998). The use of metformin in women with PCOS undergoing gonadotrophin ovulation induction was therefore examined in RCT to evaluate possible improvement in treatment outcomes as well as reduction of adverse effects. In a meta-analysis of RCT, Costello et al. (2006) reported no significant improvement in either ovulation (OR 3.27; 95% CI 0.31 to 34.72; one RCT) or clinical pregnancy (OR 3.46; 95% CI 0.98 to 12.2; three RCT) rates with addition of metformin in CCR-PCOS women undergoing gonadotrophin ovulation induction. No data on live birth rate were available. The authors admitted the inability to affirmatively exclude a beneficial clinical treatment effect owing to the limited power of their meta-analysis attributed to the limited number of included trials with very few patients in each.
In a recent meta-analysis of seven RCT, Palomba et al. (2014) demonstrated that adding metformin resulted in significant improvement in rates of clinical pregnancy (OR 2.25; 95% CI 1.50 to 3.38; P < 0.0001; seven RCT; n = 942; I2 = 0%; number needed to treat = 5.7) and live birth (OR 1.94; 95% CI 1.10 to 3.44; P = 0.020; two RCT; n = 661; I2 = 30%; number needed to treat = 14), in addition to a significant reduction of the cancellation rate (OR 0.41; 95% CI 0.24 to 0.72; P = 0.002; I2 = 0%; seven RCT; n = 942). No significant differences were found in multiple pregnancy, spontaneous abortion and OHSS rates. Although significantly lower gonadotrophin doses and duration of stimulation were observed under metformin (MD −306.62 IU; 95% CI −500.02 to −113.22; P = 0.002; and MD −3.28 days; 95% CI −6.23 to −0.32; P = 0.03, respectively) as well as a significant effect on serum oestradiol levels (MD −194.43 pg/ml; 95% CI −313.46 to −75.40; P = 0.001), significant heterogeneity across the studies were highlighted. In conclusion, the authors attributed the two-fold increase in pregnancy and live birth rates with metformin administration to the 60% reduction in cancellation rate in CCR-PCOS patients who had ovulation induction with gonadotrophins. Importantly, they admitted suboptimal quality of the included studies and highlighted the need for further well-designed and adequately powered RCT to confirm their findings.
Metformin as third-line treatment in women with PCOS undergoing assisted reproductive techniques
On the basis of the concept of a reduction of hyperinsulinaemia and hyperandrogenism, the use of metformin, in women with PCOS during IVF or intracytoplasmic sperm injection (ICSI) cycles, has been encouraged to optimize the efficacy of ovarian stimulation with gonadotrophins. A recent meta-analysis of 10 RCT including 845 women with PCOS, showed no evidence that metformin treatment before or during assisted reproductive technique cycles improved clinical pregnancy (OR 1.20; 95% CI 0.90 to 1.61; nine RCT; I2 = 21.4%), or live birth rates (OR 1.69; 95% CI 0.85 to 3.34; seven RCT; I2 = 72.4%), but it reduces significantly the risk of OHSS (OR 0.27; 95% CI 0.16 to 0.46) (Table 3). Additional significant benefits of increased implantation rate (OR 1.42; 95% CI 1.24 to 2.75; six RCT; I2 = 31.3%) and decreased spontaneous abortion rate (OR 0.50; 95% CI 0.30 to 0.83; eight RCT; I2 = 20.3%) were demonstrated and seem to be influenced by higher metformin doses and longer duration of metformin treatment. In conclusion, the authors highlighted that metformin should be regarded as a preventive strategy for OHSS in women with PCOS who receive gonadotrophins during IVF or ICSI cycles, and admitted the need for more RCT to be conducted with specific identification of PCOS phenotypes to evaluate the reproductive effect of metformin (Palomba et al., 2013).
|References||Study design||Clinical pregnancy rate||Live birth rate||OHSS rate|
|Palomba et al. (2013)||Meta-analysis of RCT||OR 1.20; 95% CI 0.90 to 1.61||OR 1.69; 95% CI 0.85 to 3.34||OR 0.27; 95% CI 0.16 to 0.46a|
|Tso et al. (2014)||A Cochrane meta-analysis of RCT||OR 1.52; 95% CI 1.07 to 2.15a||OR 1.39, 95% CI 0.81 to 2.40||OR 0.29; 95% CI 0.18 to 0.49a|
a P < 0.05.
CI = confidence interval; OHSS = ovarian hyperstimulation syndrome; OR = odds ratio; RCT = randomized controlled trial.
A 2014 updated version of a Cochrane review including nine RCT re-evaluated the effects of metformin administration in 816 infertile patients with PCOS who had ovarian stimulation with gonadotrophins for IVF and ICSI cycles (Table 3). Metformin increased the clinical pregnancy rates significantly (OR 1.52; 95% CI 1.07 to 2.15; eight RCT; n = 775; I2 = 18%), but no beneficial effect on the live birth rate was reported (OR 1.39; 95% CI 0.81 to 2.40; five RCT; n = 551; I2 = 52%). The authors demonstrated the significantly reduced risk of OHSS in the metformin group (OR 0.29; 95% CI 0.18 to 0.49; six RCT; n = 798; I2 = 11%) and highlighted that a 27% risk of OHSS without metformin would be expected to be 6–15% if metformin treatment is used. No effect on spontaneous abortion rate was reported (OR 0.76; 95% CI 0.43 to 1.37; six RCT; n = 521; I2 = 0%). The authors admitted imprecision and inconsistency as main limitations in the available evidence, and recommended further large, well-designed RCT to answer definitively the question of whether the use of metformin in women with PCOS undergoing assisted reproduction techniques improves the live birth rate (Tso et al., 2014).
Metformin treatment in different phenotypes of PCOS
In a recent RCT, Hosseini et al. (2013) studied the effectiveness of metformin on ovulation and clinical pregnancy rates among 359 women with PCOS who were divided into four different PCOS phenotypes from A–D. In phenotype A, patients fulfilled all of the three Rotterdam criteria (n = 147). Phenotype B included patients with oligo ovulation and hyperandrogenism without polycystic ovary morphology (n = 26). Phenotype C comprised patients showing hyperandrogenism and polycystic ovaries without oligo ovulation (n = 50) and lastly phenotype D with oligo ovulation and polycystic ovaries on ultrasonography without clinical or biochemical hyperandrogenism (n = 109). In each phenotype, patients were allocated to have 1500 mg of metformin plus 1 mg of folic acid per day or 1 mg of folic acid only for 2 months followed by ovulation induction with letrozole (5 mg/day) for 5 days and intrauterine insemination.
No significant differences in ovulation or clinical pregnancy rates were found in different phenotypes in both metformin and non-metformin groups except for the ovulation rate in patients with phenotype A (62% versus 81.1%; P = 0.04 for metformin versus non-metformin, respectively). No data on live birth rate were available. The authors concluded that metformin treatment does not add beneficial effects to ovulation and clinical pregnancy rates in different phenotypes of PCOS. They recognized, however, the small sample size for B (n = 26) and C (n = 50) phenotypes as well as the lack of blinding as important limitations for their study, and recommended more adequately powered RCT to evaluate their findings (Hosseini et al., 2013).
Metformin and spontaneous abortion risk
A 2009 systematic review and meta-analysis of 17 RCT reported no significant beneficial effect of pregestational metformin administration on the spontaneous abortion risk in women with PCOS who received the drug either alone or combined with other ovulatory drugs (OR 0.89; 95% CI 0.65 to 1.21) (Palomba et al., 2009b). The same findings were reported in the recent Cochrane review when metformin was compared with placebo or no treatment (OR 0.36; 95% CI 0.09 to 1.47; I2 = 0%; three RCT; n = 279) or to clomiphene citrate (OR 1.24; 95% CI 0.60 to 2.58; I2 = 78%; four RCT; n = 173) and when metformin plus clomiphene citrate was compared with clomiphene citrate alone (OR 1.61; 95% CI 1.00 to 2.60; I2 = 0%; seven RCT; n = 937) (Tang et al., 2012). Similarly, no evidence of beneficial effects of metformin administration on spontaneous abortion rate were observed in infertile patients with PCOS who had gonadotrophins for ovulation induction (OR 0.47; 95% CI 0.14 to 1.54; P = 0.210; I2 = 0%; five RCT, n = 292) (Palomba et al., 2014), or in IVF–ICSI cycles (OR 0.76; 95% CI 0.43 to 1.37; six RCT; n = 521; I2 = 0%) (Tso et al., 2014).
Our systematic review and meta-analysis of RCT also demonstrated no significant benefit of metformin plus clomiphene citrate on spontaneous abortion risk in CCR-PCOS patients who received metformin plus clomiphene citrate compared with other second-line treatments such as LOD (OR 0.94; 95% CI 0.39 to 2.27; I2 = 0%; two RCT; n = 332), gonadotrophins (OR 0.70; 95% CI 0.26 to 1.89; I2 = 0%; three RCT; n = 323), armoatase inhibitors (OR 1.41; 95% CI 0.42 to 4.79; two RCT; n = 309), other insulin sensitizers plus clomiphene citrate (OR 0.97; 95% CI 0.19 to 5.04; I2 = 0%; two RCT; n = 125) and NAC plus clomiphene citrate in one trial (OR 1.32; 95% CI 0.29 to 6.06; one RCT; n = 192) (Abu Hashim et al., 2015).
The most commonly encountered side-effects of metformin are gastrointestinal symptoms, including nausea, vomiting, abdominal pain, flatulence, diarrhoea, and indigestion. In the above-mentioned recent Cochrane systematic review and meta-analysis, patients with PCOS who received metformin experienced a higher albeit non-significant incidence of nausea and vomiting compared with the placebo group (OR 3.91; 95% CI 0.98 to 15.64; three RCT; n = 73; I2 = 0%). A significantly higher incidence of other gastrointestinal side-effects occurred in the metformin group (OR 4.27; 95% CI 2.4 to 7.59; P < 0.00001; five RCT; n = 318; I2 = 72%). Additionally, a significantly higher incidence of gastrointestinal side-effects, including nausea and vomiting, were found when metformin plus clomiphene citrate were compared with the clomiphene citrate only group (OR 3.31; 95% CI 2.11 to 5.20; P < 0.00001; two RCT; n = 489; I2 = 0%) (Tang et al., 2012). Furthermore, Tso et al. (2014) reported significantly higher side-effects (mostly gastrointestinal) with metformin treatment before and during IVF–ICSI cycles in women with PCOS compared with placebo (OR 4.49; 95% CI 1.88 to 10.72; P = 0.00074; four RCT; n = 431; I2 = 57%).
In view of the US Food and Drug Administration pregnancy classification, metformin is classified as a category B drug, meaning that ‘animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women’. In view of the current best clinical evidence, metformin safety during the first trimester of pregnancy is reassuring. In a recent meta-analysis of nine controlled studies, Cassina et al. (2014) showed no evidence of increased risk of major birth defects in women with PCOS undergoing metformin treatment during the first trimester (OR 0.86; 95% CI 0.18 to 4.08; I2 = 0%). Six out of the nine studies selected for the meta-analysis, however, were RCT, and no increased risk of congenital malformations in the exposed group was found compared with the control group in each of them. The authors admitted that the studies were designed primarily to evaluate the ovulation, pregnancy and spontaneous abortion rates; however, the live birth rate was reported with continuous follow-up until delivery, when information about the presence of birth defects were available.
In conclusion, examining the potential reproductive benefits of metformin, a drug endowed with the capacity to ameliorate insulin resistance in women with PCOS, has gained a great deal of interest from researchers in the past 2 decades. Importantly, lifestyle modification represents the best first-step treatment for obese anovulatory infertile women with PCOS before resorting to pharmacological ovulation induction. The evidence favouring either the use of metformin alone, or combined with clomiphene citrate instead of clomiphene citrate for ovulation induction in women with newly diagnosed PCOS, is insufficient. Consequently clomiphene citrate still represents the gold standard first-line pharmacological treatment for ovulation induction in anovulatory infertile women with PCOS. It is also important to highlight that the available evidence is insufficient to recommend metformin as a primary treatment in non-obese women with PCOS. On the other hand, metformin plus clomiphene citrate should be considered as an effective option in CCR-PCOS patients. On the basis of the best available clinical evidence, the use of metformin in women with PCOS undergoing gonadotrophin ovulation induction significantly increased the rates of clinical pregnancy and live birth with reduced risk of cancelled cycles. A beneficial effect of metformin co-treatment in increasing the clinical pregnancy rates and reducing the OHSS risk in infertile women with PCOS undergoing assisted reproduction techniques has been shown. A clear evidence-based role for metformin in reducing the spontaneous abortion risk in women with PCOS who received the drug, either alone or combined with other ovulatory drugs, remains unjustifiable. Overall, gastrointestinal symptoms represent the most commonly encountered side-effects of metformin. Finally, it is important to highlight that no evidence of increased risk of major birth defects has been found in women with PCOS undergoing metformin treatment during the first trimester. Future adequately powered RCT are warranted to evaluate the efficacy of metformin treatment in different PCOS phenotypes. Clinical summary and key messages are shown in Table 4.
CCR = clompihene-citrate-resistant; OHSS = ovarian hyperstimulation syndrome; PCOS = polycystic ovary syndrome; RCT = randomized controlled trial.
Appendix. Supplementary material
The following is the supplementary data to this article:
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Dr Hatem Abu Hashim is a Professor of Obstetrics and Gynaecology at Mansoura University, Egypt. He obtained his MD at Mansoura University in 2001, and subsequently obtained his MRCOG in the UK in 2006. His major areas of interest are reproductive endocrinology and infertility, especially polycystic ovary syndrome, the subject of his PhD, which he obtained from the Free University of Brussels (the Vrije Universiteit Brussel, Belgium) in 2013. Professor Abu Hashim is a member of several scientific societies, and peer-reviews for several international scientific journals. He has published several papers in reputed journals.
Department of Obstetrics and Gynaecology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
© 2015 Reproductive Healthcare Ltd., Published by Elsevier B.V.