How Effective is Metformin Plus Clomiphene in Women With PCOS?

Combined Metformin-Clomiphene in Clomiphene-Resistant Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abu Hashim H, Foda O, Ghayaty E
Acta Obstet Gynecol Scand. 2015;94:921-930


metforminPolycystic ovary syndrome (PCOS) is the most common endocrine abnormality affecting reproductive-age women and the most likely cause of anovulation.[1] PCOS is diagnosed based on irregular cycles (oligo- or anovulation), clinical or laboratory evidence of excess androgens, and the classical polycystic ovaries. In order to establish the right diagnosis, other endocrinopathies that could partially explain the findings (adrenal hyperplasia, thyroid dysfunction, hyperprolactinemia, etc.) need to be ruled out.[2]

PCOS is a complex medical problem; the most widely accepted pathomechanism involves malfunctioning glucose metabolism leading to insulin resistance.[3] The excess insulin secreted affects ovarian function in a way that promotes androgen synthesis, which will arrest folliculogenesis and explain many of the clinical findings. Women with PCOS are not just affected by gynecologic or cosmetic problems but are at risk for diabetes, cardiovascular disease, and metabolic syndrome. Therefore, the correct identification and proper treatment of such patients is important for both short-term and long-term results.

Many of these women will turn first to their gynecologist, either for the cycle irregularity or for infertility. Ovulation is rare or is missing in these cases. While each case has to be approached individually, there are some standard parts of treatment. Endocrine, metabolic, and cardiovascular screening has to be offered as part of the initial evaluation. Because many of these women are overweight or obese, proper nutritional counseling and the introduction of daily cardiovascular exercise has to be part of their care.[4]Helping them to ovulate and achieve a pregnancy can only be a secondary goal once the medical problems have been properly addressed. Clomiphene, an antiestrogen, is the first-line drug to restore ovulation. Some women, however, will not respond to even higher doses of it. For these women, the use of insulin sensitizers, gonadotropins, aromatase inhibitors, or their combination as well as laparoscopic ovarian drilling (LOD) can be offered.[5] This systematic review compared the gynecologic effect of these secondary treatment options in women resistant to clomiphene.


Randomized controlled trials that compared clomiphene plus metformin to gonadotropins, aromatase inhibitors, LOD, N-acetyl cysteine, or other insulin sensitizers were considered for the review, and 12 such trials were identified. These studies evaluated ovulation rate, pregnancy rate, live-birth rate, miscarriage rate, and ovarian hyperstimulation syndrome (OHSS) as their main outcome parameters.

When compared with gonadotropins, clomiphene plus metformin resulted in significantly fewer ovulations (odds ratio [OR]: 0.25; 95% confidence interval [CI], 0.15-0.41). Ovulation rates were observed with similar frequency when clomiphene plus metformin and aromatase inhibitors, other insulin sensitizers, or LOD were compared.

Significantly fewer pregnancies were conceived with clomiphene plus metformin when compared with gonadotropins (OR: 0.45; 95% CI, 0.27-0.75). Pregnancy rates were comparable when clomiphene plus metformin was compared with LOD and aromatase inhibitors. The meta-analysis of the results of three small trials found lower pregnancy rates with clomiphene plus metformin when compared with other insulin sensitizers.

There was no difference in multiple pregnancy or miscarriage rates when clomiphene plus metformin was compared with gonadotropins or other insulin sensitizers. OHSS was only seen in the gonadotropin-treated women and overall had a low incidence.

The authors concluded that in clomiphene-resistant PCOS patients, gonadotropins were superior to clomiphene plus metformin to induce ovulation and to help the patient become pregnant.


This systematic review found gonadotropins to be superior to clomiphene plus metformin for most outcomes studied in clomiphene-resistant patients. Gonadotropin use is invasive, expensive, and requires careful monitoring. The person supervising the cycle has to be aware of signs of hyperstimulation, has to be prepared to cancel the cycle in case of multiple follicle growth, and has to be prepared to convert the treatment to an IVF cycle to avoid complications. Furthermore, knowledge of the care of women with OHSS is important as well. The more complicated cases should be referred to a reproductive endocrinologist who is able to provide properly monitored care.


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