Reply to: Are laparoscopic ovarian diathermy and gonadotropin administration the only therapeutic second-steps in clomiphene-citrate resistant women with polycystic ovary syndrome?
1 Center for Reproductive Medicine, Department of Obstetrics and Gynaecology and 2 Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
3 To whom correspondence should be addressed. Email: m.vanwely{at}amc.uva.nl
Sir,
We would like to thank Dr Palomba and colleagues for their interest in our paper (van Wely et al., 2004
). In Western Europe, recombinant FSH is most commonly used for ovulation induction in women with polycystic ovary syndrome (PCOS) that does not respond to clomiphene citrate (CC). Urinary FSH is practically not used anymore in The Netherlands. The only alternative gonadotrophin to rFSH that is available on the market is human menopausal gonadotrophin (hMG). We agree with Dr Palomba and colleagues that there is no evidence of a difference in effectiveness and safety between rFSH and hMG for this indication (van Wely et al., 2003; Bayram et al., 2004). However, we chose to compare a laparoscopic electrocautery strategy with rFSH, as ovulation induction with rFSH best represents current practice in the Netherlands.
In their response, Dr Palomba and colleagues also emphasize the role of metformin. At the time of designing our study, both laparoscopic electrocautery strategy and rFSH were established therapies, while metformin was not yet being used in PCOS. During the last few years it has become common practice to use metformin, generally as co-treatment, for ovulation induction in women with polycystic ovary syndome. In a recently published Cochrane review, metformin and CC were shown to result in a higher ovulation rate than clomiphene citrate combined with a placebo in women with CC-resistant PCOS (risk rate using a random effect model: 2.31, 95% CI 1.08–4.96; Lord et al., 2004). This result was based on five trials, with a total number of only 71 versus 70 clomiphene citrate resistant women.
Following these results, it can be concluded that metformin may be of value for ovulation induction in women with polycystic ovary syndrome. Given the small numbers, we feel there is not enough ground for drawing definitive conclusions in favour of metformin. Although metformin seems to be a relatively safe medication, it should not be forgotten that metformin is associated with a high incidence of nausea, vomiting and other gastrointestinal disturbance (Lord et al. 2004).
Furthermore, although there are indications that metformin can improve ongoing pregnancy rates, data regarding metformin safety during pregnancy are very limited (Glueck et al., 2001; Jakubowicz et al., 2002; Heard et al., 2002). Therefore, we should not prescribe metformin during pregnancy before large randomized controlled trials have been performed in which the safety and benefit is proven.
We look forward to the publication of the randomized trial by Palomba et al. (2004) in which metformin is compared with laparoscopic electrocautery in CC-resistant women with PCOS.
References
Bayram N, van Wely M and van der Veen F (2004) Recombinant FSH versus urinary gonadotrophins or recombinant FSH for ovulation induction in subfertility associated with polycystic ovary syndrome (Cochrane review). The Cochrane Library, Issue 2. John Wiley & Sons, Chichester, UK.
Glueck CJ, Phillips H, Cameron D, Sieve-Smith L and Wang P (2001) Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 75, 46–52.[CrossRef][Web of Science][Medline]
Heard MJ, Pierce A, Carson SA and Buster JE (2002) Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Fertil Steril 77, 669–673.[CrossRef][Web of Science][Medline]
Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA and Nestler JE (2002) Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 87, 524–529.
Lord JM, Flight IH and Norman RJ (2004) Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome (Cochrane Review). Cochrane Library, issue 2. John Wiley & Sons, Chichester, UK.
Palomba S, Orio F Jr, Nardo LG, Falbo A, Russo T, Corea D, Doldo P, Lombardi G, Colao A and Zullo F (2004) Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebo-controlled trial. J Clin Endocrinol Metab (in press).
van Wely M, Bayram N and van der Veen F (2003) Recombinant FSH in alternative doses or versus urinary gonadotrophins for ovulation induction in subfertility associated with polycystic ovary syndrome: a systematic review based on a Cochrane review. Hum Reprod 18, 1143–1149.
van Wely M, Bayram N, Van Der Veen F and Bossuyt PM (2004) An economic comparison of a laparoscopic electrocautery strategy and ovulation induction with recombinant FSH in women with clomiphene citrate-resistant polycystic ovary syndrome. Hum Reprod, 19, 1741-1745.
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