Polycystic ovary syndrome (PCOS), affecting around 5-10% of all reproductive-aged women, is one of the most common causes of anovulation. The identification of the role of insulin resistance in women with PCOS, who are also commonly resistant to clomiphene citrate (CC), resulted in the use of insulin sensitizers. The use of metformin, an insulin-sensitizing agent, in PCOS patients undergoing IVF or ovulation induction has been extensively researched, but with divergent results. Now, a new study reports that metformin significantly reduces the incidence of ovarian hyperstimulation syndrome (OHSS) and miscarriage, while positively affecting the oocyte and embryo quality in CC-resistant PCOS women undergoing IVF. The results of the randomized controlled study have been published in the Journal of Obstetrics and Gynecology.
Hussein S Qublan, from the Royal Medical Services, IVF Center, Prince Rashed Hospital, Jordan, and coworkers, conducted the prospective study on 66 CC-resistant PCOS patients undergoing IVF, to investigate the efficacy of metformin. The scientists randomly divided the subjects into two groups: 34 women, administered with 850 mg of metformin, and 32 receiving placebo, twice daily, from 1 month prior to the commencement of IVF procedure and continuing till the day of pregnancy test.
The study demonstrated a greater number of good quality embryos, higher implantation rate, and reduced rates of abortion and OHSS in the metformin-treated subjects compared to the placebo group. The metformin group further reported lower cycle cancellation rates, estradiol levels on the day of human chorionic gonadotropin (hCG) administration, and no fetal abnormalities. However, treatment with metformin resulted in substantially fewer number of follicles >14 mm, oocytes retrieved, and mature oocytes as well as shorter human menopausal gonadotropin (HMG) stimulation days and lesser number of HMG ampoules.
Since hyperinsulinemia and hyperandrogenism may be lowered with metformin, few trials have proposed the potential of the drug in improving the rates of pregnancy and live birth in IVF/ICSI cycles. Three such studies (Kocak et al, Fertility and Sterility, 2002; George et al, Human Reproduction, 2003; Siebert et al, Fertility and Sterility, 2006) reported that metformin serves as a safe and effective option in CC-resistant PCOS women as it helps in reducing insulin resistance and hyperandrogenism, and also improves the rates of ovulation, pregnancy, and cervical scores.
On the contrary, a recent review by Tso et al (Cochrane Database of Systemic Review, 2009) concluded that metformin administration prior to and during ART cycles does not increase pregnancy and live birth rates in PCOS women. The systemic analysis of the randomized controlled trials, however, found a reduction in the risk of OHSS with the use of the drug in these patients. The authors recommended further larger trials to evaluate the benefits of metformin in PCOS women opting for ART.
An earlier report of the Practice Committee of American Society for Reproductive Medicine (Fertility and Sterility, 2006) supports the use of combination treatment for ovulation induction with agents like metformin in cases of CC monotherapy failure. Also, for CC-resistant women, alternative treatment such as exogenous gonadotropins, aromatase inhibitors, or ovarian drilling (in rare cases) may be considered.
Generally, the induction of ovulation in PCOS patients opting for infertility treatment is achieved with the use of clomiphene citrate and insulin sensitizers, either as monotherapy or as combination treatment. More recently, in a PCOS Consensus Workshop, sponsored by the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (Fertility and Sterility, 2008), infertility experts arrived at a consensus on the infertility treatment in women with PCOS. The highlights included the following:
• Anti-estrogen clomiphene citrate as the first-line therapeutic strategy for inducing ovulation
• Restrict the use of metformin only in patients with glucose intolerance
• Does not support the use of metformin in routine clinical practice for ovulation induction
References
1. Qublan HS, Al-Khaderei S, Abu-Salem AN, et al. Metformin in the treatment of clomiphene citrate-resistant women with polycystic ovary syndrome undergoing in vitro fertilisation treatment: a randomised controlled trial. J Obstet Gynaecol. 2009 Oct;29(7):651-5.
2. Kocak M, Caliskan E, Simsir C, Haberal A. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril. 2002 Jan;77(1):101-6.
3. George SS, George K, Irwin C, et al. Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized, controlled trial. Hum Reprod. 2003 Feb;18(2):299-304.
4. 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.
5. Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Freitas V. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006105.
6. Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S187-93.
7. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008 Mar;89(3):505-22.
