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Several of the early studies on metformin in PCOS were compiled in a meta-analysis by Lord and colleagues [Lord et al. 2003]. They concluded accordingly that metformin was an effective treatment to induce ovulation in PCOS patients and that it was justifiable to use it as a first-line treatment. However, they emphasized that it should be used in conjunction with a change in lifestyle. They included 7 studies comprising a total of 156 PCOS patients who received metformin of whom 72 (46%) ovulated versus 1154 who received either placebo or no treatment of whom 37 (24%) ovulated. They also reported that the combination of metformin and clomiphene citrate (CC) resulted in more ovulation than CC alone. However, this was based on relatively smaller number of patients included in two and three studies.

In a later meta-analysis by Palomba and colleagues, the authors concluded that the combination of metformin with CC is not superior to CC alone [Palomba et al. 2009] with regards to ovulation, pregnancy, or live birth rates. They also found no difference in the miscarriage rates between the two treatment modalities. With regards to metformin in combination with CC, that was more effective than metformin alone in ovulation and pregnancy rates. They based their conclusion on combinations between four randomised controlled trials (RCTs) that were published after the meta-analysis by Lord and colleagues [Zain et al. 2009; Legro et al.2007; Moll et al. 2006; Palomba et al. 2005]. They also commented on the heterogeneity of body mass index (BMI) among the populations of the four studies and that the patients in the study by Palomba and colleagues were not representative of the PCOS population [Palomba et al. 2005], i.e. they were relatively slimmer. Others used menstrual regularity as evidence of resumption of ovulation and reported in a RCT that included obese PCOS women that weight loss alone through lifestyle modification was more effective in restoring regular menses [Tang et al. 2006].

It is important in analysing the outcome of all such studies and meta-analyses to realize that the duration of treatment also plays a role in the outcome. Metformin is likely to take longer to exert an effect in comparison to CC, therefore CC should be considered the first line of treatment in ovulation induction among PCOS patients and that life-style change leading to a sustainable weight loss is an important adjuvant to all types of medications in such patients.

The use of gonadotrophins for ovulation induction in conjunction with metformin also received attention and was the subject of a meta-analysis [Costello et al. 2006]. However, due to the small number of studies included and small sample size in each study along with the difficulty disentangling potential confounding variables a conclusion could not be reached on the efficacy of metformin as a coadjuvant to gonadotrophins for ovulation induction in PCOS women. It seems, however, that the length of ovarian stimulation was shorter among those receiving a combination of gonadotrophins and metformin [Costello et al. 2006].
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