Legro RS, Barnhart X, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551-566
Summary
Clomiphene citrate (CC) use among women with polycystic ovary syndrome (PCOS) led to significantly higher live birth rates when compared to metformin alone in this 6-month, randomized, placebo-controlled, double-blind clinical trial.
PCOS is the most common endocrine abnormality among reproductive age women and is the most common etiology of ovulatory infertility. It affects about 5% to 8% of women. Diagnosis is made based on the ovulatory defect, hyperandrogenism, and/or polycystic appearing ovaries. Other causes of hyperandrogenism need to be excluded. The exact etiology is unknown but besides genetic causes, metabolic factors, most importantly insulin resistance, are believed to play a role. At least half of the women with PCOS are obese. Obesity itself makes insulin resistance worse and also contributes to the clinical picture.
Lifestyle changes are an important part of any treatment. Weight loss of 5% to 10% may improve the metabolic factors and could result in improved ovulation and pregnancy rates. Besides weight reduction, several other strategies can be chosen. Clomiphene citrate (CC) has been the first-line treatment for a long time. More recently very good results were reported with insulin sensitizing drugs.[1,2] The use of injectable gonadotropins is associated with excellent ovulatory rates, but with frequent side effects (hyperstimulation, multiple gestation) as well. Laparoscopic ovarian drilling is also associated with relatively good ovulation rates, but adhesion formation and lack of long-term benefits limit use.
This multicenter, placebo-controlled, double-blind, randomized study compared the metabolic and reproductive effects of metformin, clomiphene citrate, and combination therapy; 2000 mg extended-release metformin and 50-150 mg CC were administered to 626 women who were randomized and were observed for 6 cycles. Serum progesterone measurement was used to detect ovulation. Live birth was set as the primary outcome. Baseline characteristics were well matched. The mean body mass index (BMI) was well over 30 kg/m2 in all groups.
The live birth rate was significantly higher in the CC alone and CC plus metformin groups when compared with the metformin alone group (22.5% and 26.8% vs 7.2%). Ovulation and pregnancy rates were similarly higher in the CC and combination groups. In cycles where ovulation occurred, conception, singleton pregnancy, and live births were all most likely to occur in the CC and combination groups when compared with metformin alone. The monthly ovulation rate has been rather steady in all 3 groups during the 6 months follow-up period. BMI was significantly reduced among women who took metformin when compared with those treated with CC alone. Additionally, insulin resistance also significantly improved in the metformin-only group when compared to the groups where CC was taken. Total testosterone and the free androgen index were reduced in all groups.
These findings differ from previously reported outcomes with metformin.[2,3] Metformin was reported to be associated with higher ovulation rates and significantly better pregnancy outcome in earlier studies. Differences among patients, in the type of drug (extended-release vs immediately absorbable metformin), length of follow-up, and the endpoint of the study could all explain the observed differences. In many cases metformin will not have an immediate effect, but results will improve with time. Therefore, longer follow-up could have lead to improved reproductive outcome with this drug.
The mean BMI was over 35 in all 3 groups. It is possible that among morbidly obese women metformin is less effective then among leaner women. Other studies that showed a benefit included women with lower BMI. Whether those who fail to ovulate on higher dose of CC could benefit from combination therapy before moving on to gonadotropins was also not answered by this trial.
To date, this is the largest trial studying the reproductive effects of metformin among women with PCOS (mainly obese PCOS women!). Based on the findings it appears that CC should remain the first-line drug. Combination therapy should be offered to those who have inadequate response before more invasive treatment is chosen.
References
- Nestler JE, Jakubowicz DJ, Evans WS et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1999;340:1314-1320.
- Vandermolen DT, Ratts VS, Evans WS. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75:310-315.
- Palomba S, Orios F Jr., Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068-4074. Abstract
Peter Kovacs, MD, Research and Scientific Coordinator, Clinical Reproductive Endocrinologist, Kaali Institute IVF Center, Budapest, Hungary; Visiting Clinical Instructor, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York
Disclosure: Peter Kovacs, MD, has disclosed no relevant financial relationships.
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Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome 
