Comparison of Clomiphene Citrate (CC), Metformin or the Combination for First Line Ovulation Induction and Achievement of Pregnancy in 154 Women With Polycystic Ovary Syndrome (PCOS)

Abstract

PCOS is one of the most common causes of infertility. Response to lifestyle and medical treatment is often challenging. There is no clear evidence as to which first line treatment intervention is more effective for restoring fertility. CC has been the standard medication for ovulation induction in these patients for many years. But as insulin resistance has been shown to be overwhelmingly important in this syndrome, metformin has gained more popularity and is being used before CC in many patients. But there is no head to head trial comparing metformin to CC for ovulation induction and pregnancy achievement. As well, all the published series so far comprise of a few patients or are meta-analyses . Follow up exceeding 6 months is also lacking. The objectives of this study are first, to determine which medication is more effective first line in PCOS patients for ovulation and pregnancy achievement. Second, to verify if any patient characteristic is associated with a better response to therapy, to guide initial medication selection. This is a retrospective study of 154 consecutive women referred to our fertility clinic for PCOS and infertility. They were assigned to 3 groups according to which treatment they were initially prescribed for induction of ovulation. Group 1 (56 patients) received CC 50 mg from day 5 to 9 of the cycle. Group 2 (57 patients) received 500 mg tid of metformin. Group 3 (41 patients) received both medications. Doses were adjusted to tolerance and to successful ovulation induction. All women fit the 1990 NIH consensus criteria and had a thorough medical evaluation including a metabolic and hormonal profile, a hysterosalpingogram and a spouse sperm analysis. Statistical analysis was done by ANOVA, 2 × 2 comparison by Tuckey test and Chi square tests. Regression analysis was used to correct for time. Mean overall follow up was : 9.4 months (range : 2 to 78). Among the baseline characteristics, BMI was higher in groups 2 and 3 compared to 1 (34.3 ± 1 and 32.1 ± 1.2 vs 27.4 ± 1.3 kg/m2; mean ± SEM, Group 2,3,1; p<0.001). Despite this, patients receiving metformin alone had an increased ovulation rate compared to the ones receiving CC (75.4% vs 50%, p=0.005). There was no benefit to the combination for ovulation induction. When excluding patients with morbid obesity (BMI>40), the difference in BMI for the 3 groups was no longer significant (p=0.111). The ovulation rate between groups 1 and 2 remained statistically different (p=0.029). Pregnancy rates were equivalent in the 3 groups (35.7%, 45.6% and 31.7%, Group 1,2,3; p=0.332). Interestingly, patients taking 0.5 g to 1 g / day of metformin ovulated just as well as patients taking 1.5 to 2g / day. Finally, non smoking is associated with better ovulatory response overall (p=0.013), as well as lower systolic blood pressure and fasting glucose for CC and lower total testosterone and androstenedione for metformin. Our study shows that metformin is better for ovulation induction than clomiphene citrate and equivalent for pregnancy achievement. We propose that metformin should be offered first line in all women with PCOS considering its efficacy and better safety profile than CC (no increased multiple births, ovarian cysts or miscarriage rate) and its known beneficial effect on the overall metabolic profile. Finally, non smoking and a lower systolic blood pressure, fasting glucose, total testosterone and androstenedione are associated with a better ovulatory response.