Metformin and PCOS
(1). Clinical studies have shown that metformin (500 mg three times per day or 850 mg twice daily with meals) administration to women with PCOS increased the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response to clomiphene citrate (CC) (Clomid®). Benefit has been demonstrated with metformin treatment in PCOS patients both with and without insulin resistance(2). Metformin alone may be less effective in obese PCOS women. Women with PCOS are considered to be at increased risk of miscarriage, as high as 30 50 %. When women were treated with 1000-2000 mg daily of metformin throughout pregnancy, rates of early pregnancy loss were 11.6% in the metformin group compared with 36.3% in the control group (p < 0.0001). Administration of metformin throughout pregnancy to women with PCOS may decrease miscarriage rates(3). Controversy exists when comparing metformin to clomiphene citrate (CC) for treating infertility. A well-designed study showed metformin is better for ovulation induction than CC alone and equivalent for pregnancy achievement. The authors suggest that metformin can be used first for ovulation induction in patients with PCOS regardless of their weight and insulin levels because of its efficacy and known safety profile(4). Alternatively, another study found benefit with metformin if obese (BMI >30 kg/m(2) subjects and women older than 34 years were excluded(5). Another paper pooled the results of 6 studies to examine whether metformin is efficacious when given to patients resistant to CC. They found the addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction(6). Most studies showing benefit were small with fewer than 100 patients. Conversely, two large multicenter trials, one conducted in the US (PPCOS)(7) and one in the Netherlands(8), have shown no benefit from metformin either as a single agent or as adjuvant therapy in combination with clomiphene for the treatment of infertility in women with PCOS. They found metformin increased the occurrence of ovulation but did not increase the chance of becoming pregnant. The PPCOS study is large and well designed, with 626 participants. It differs from other studies by using the extended release form of metformin. One very notable result was the absence of any statistically significant effect of this extended release form of metformin on insulin levels or insulin resistance. There were none of the expected metabolic effects of metformin. Extended-release metformin has not previously been studied in women with PCOS. Thus, it has not been ascertained that its efficacy is comparable to regular metformin in PCOS(9). Additionally, metformin and clomiphene citrate (CC) differ in their therapeutic time frames (the period of time from initiating therapy to achieving maximum effectiveness). CC produces higher rates of ovulation and pregnancy in the early months of treatment than that of metformin and might be preferable to women who wish to become pregnant quickly (5). However, a patient with more time to become pregnant may benefit from metformin's metabolic effects. During the 3 to 6 months that it takes for metformin to become maximally effective, the patient can prepare for pregnancy by losing weight through diet and exercise. Reducing a patient's weight might considerably optimize her pregnancy(9). Metformin induces normal ovulation, and the risk of multiple gestation is no more than that in the general population. Conversely, CC can precipitate the release of multiple eggs in a given menstrual cycle and carries a risk of multiple gestation: in the PPCOS study, multiple gestation was 6% in the clomiphene group and 0% with metformin. Metformin may significantly increase the incidence of multiple pregnancy when used in combination with gonadotropins(10). Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of ovarian hyperstimulation(11). Conclusions:
- PCOS patients should be screened for diabetes before becoming pregnant. Hemoglobin A1c levels should be normal.
- Metformin alone can induce ovulation and may improve the effectiveness of CC. Extended release metformin may not be as effective.
- Metformin may decease miscarriage rates.
- Weight loss may improve the effectiveness of metformin.
- Time to achieve pregnancy may be longer with metformin than CC.
- Metformin may be less effective in older women.
- Metformin does not increase multiple pregnancy rates when used alone.
- Metformin may increase multiple pregnancy rates and decrease ovarian hyperstimulation when used with gonadotropins.
- Long-term benefits of metformin in preventing hypertension and heart disease need further study.
Eldon Schriock, MD References:
- The Practice Committee of the American Society for Reproductive Medicine Committee Opinion. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertility and Sterility
- Nawrocka J, Starczewski A. Effects of metformin treatment in women with polycystic ovary syndrome depends on insulin resistance. Gynecol Endocrinol. 2007 Apr;23(4):231-7.
- Khattab S, Mohsen IA, Foutouh IA, Ramadan A, Moaz M, Al-Inany H. Metformin reduces abortion in pregnant women with polycystic ovary syndrome. Gynecol Endocrinol. 2006 Dec;22(12):680-4.
- Neveu N, Granger L, St-Michel P, Lavoie HB. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. Fertil Steril. 2007 Jan;87(1):113-20.
- Palomba S, Orio 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 anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068-4074.
- Siebert TI, Kruger TF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured literature review. Fertil Steril. 2006 Nov;86(5):1432-7.
- Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551-566.
- Moll E BP, Korevaar JC, Lambalk CB, van der Veen F. Ovulation induction in women with polycystic ovary syndrome: A randomized double blind clinical trial comparing clomiphene citrate plus metformin with clomiphene citrate plus placebo. BMJ. 2006;332:1485.
- Baillargeon JP, Legro RS. Should metformin be used as front-line therapy for fertility in women with PCOS. Sexuality, Reproduction, and Menopause 2007; 5(2):17-19.
- Shibahara H, Kikuchi K, Hirano Y, Suzuki T, Takamizawa S, Suzuki M. Increase of multiple pregnancies caused by ovulation induction with gonadotropin in combination with metformin in infertile women with polycystic ovary syndrome. Fertil Steril. 2007 Jun;87(6):1487-90.
- Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006 Jun; 21(6): 1416-25.