Ovulation induction in women with polycystic ovary syndrome

To date, clomiphene citrate (CC) remains the first therapeutical step for inducing ovulation in anovulatory PCOS patients. Metformin alone or combined with CC is a valid second step approach, whereas the laparoscopic ovarian diathermy can be useful only in selected cases. To date, clomiphene citrate (CC) remains the first therapeutical step for inducing ovulation in anovulatory PCOS patients. Metformin alone or combined with CC is a valid second step approach, whereas the laparoscopic ovarian diathermy can be useful only in selected cases. Although several definitions and various criteria have been used to define polycystic ovary syndrome (PCOS), the pivotal feature of this syndrome may still be considered oligo-anovulation due to its social and pharmaco-economic impact. Traditional and well validated treatments used for ovulation induction in women with PCOS are administration of clomiphene citrate (CC) and gonadotropins, and the surgical ovulation induction with the use of laparoscopic ovarian diathermy (LOD). New treatments, which have been gaining a lot of popularity in clinical practice, are the use of insulin sensitizing drugs such as metformin and specific lifestyle programs for obese women with PCOS (1Palomba S. Orio Jr, F. Russo T. Falbo A. Cascella T. Colao A. Lombardi G. Zullo F. Is ovulation induction still a therapeutic problem in patients with polycystic ovary syndrome?.J Endocrinol Invest. 2004; 27: 796-805PubMed Google Scholar). Firstly, it is very important to define whether an infertile PCOS patient is or is not obese. In fact, obesity in a sub-fertile woman is a strong confounding factor because it decreases all reproductive performances by several mechanisms. In these patients, it is crucial to obtain a reduction in body weight by a specific diet and physical activity. Body weight loss improves pregnancy rates and reduces the miscarriage rate in PCOS women who are not following pharmacological treatment and in patients who have undergone any kind of sterility treatment (1Palomba S. Orio Jr, F. Russo T. Falbo A. Cascella T. Colao A. Lombardi G. Zullo F. Is ovulation induction still a therapeutic problem in patients with polycystic ovary syndrome?.J Endocrinol Invest. 2004; 27: 796-805PubMed Google Scholar). In non-obese PCOS women or in obese PCOS women after failure of body weight reduction, CC can still be considered as the first-line medical approach to improve fertility (1Palomba S. Orio Jr, F. Russo T. Falbo A. Cascella T. Colao A. Lombardi G. Zullo F. Is ovulation induction still a therapeutic problem in patients with polycystic ovary syndrome?.J Endocrinol Invest. 2004; 27: 796-805PubMed Google Scholar, 2Beck J.I. Boothroyd C. Proctor M. Farquhar C. Hughes E. Oral anti-oestrogens and medical adjuncts for subfertility associated with anovulation.Cochrane Database Syst Rev. 2005; 1: CD002249PubMed Google Scholar, 3Homburg R. Clomiphene citrate-end of an era? A mini-review.Hum Reprod. 2005; 20: 2043-2051Crossref PubMed Scopus (239) Google Scholar). This treatment is not only effective, but also safe, easy to administer, cheap, and has no need for ongoing monitoring. Clomiphene citrate should be administered at doses of 100–150 mg daily, according to body weight, for no more than 3- or 6-cycles in order to limit their anti-estrogenic effects (2Beck J.I. Boothroyd C. Proctor M. Farquhar C. Hughes E. Oral anti-oestrogens and medical adjuncts for subfertility associated with anovulation.Cochrane Database Syst Rev. 2005; 1: CD002249PubMed Google Scholar, 3Homburg R. Clomiphene citrate-end of an era? A mini-review.Hum Reprod. 2005; 20: 2043-2051Crossref PubMed Scopus (239) Google Scholar). Clomiphene citrate-resistant patients (defined after 3 cycles of ovulation failure) and/or patients who did not achieve pregnancy after 6 ovulatory cycles with CC should be treated with a second-line treatment, which includes the traditional use of gonadotropins and LOD (1Palomba S. Orio Jr, F. Russo T. Falbo A. Cascella T. Colao A. Lombardi G. Zullo F. Is ovulation induction still a therapeutic problem in patients with polycystic ovary syndrome?.J Endocrinol Invest. 2004; 27: 796-805PubMed Google Scholar). Until now, evidence-based clinical data on the more effective and safer dosage, protocol and type of Gns to administer are very few (4Al-Inany H. Aboulghar M.A. Mansour R.T. Proctor M. Recombinant versus urinary gonadotrophins for triggering ovulation in assisted conception.Hum Reprod. 2005; 20: 2061-2073Crossref PubMed Scopus (37) Google Scholar). Moreover, Gns seem to be really effective (4Al-Inany H. Aboulghar M.A. Mansour R.T. Proctor M. Recombinant versus urinary gonadotrophins for triggering ovulation in assisted conception.Hum Reprod. 2005; 20: 2061-2073Crossref PubMed Scopus (37) Google Scholar) and have an efficacy similar to those observed after a 6-12 month follow-up from LOD (1Palomba S. Orio Jr, F. Russo T. Falbo A. Cascella T. Colao A. Lombardi G. Zullo F. Is ovulation induction still a therapeutic problem in patients with polycystic ovary syndrome?.J Endocrinol Invest. 2004; 27: 796-805PubMed Google Scholar). In addition, LOD also exerts long-term beneficial effects at hormonal and metabolic levels. Considering the efficacy, the low costs, the beneficial effects mentioned above and the low rate of multiple pregnancies, several authors (5Kovacs G.T. Clarke S. Burger H.G. Healy D.L. Vollenhoven B. Surgical or medical treatment of polycystic ovary syndrome a cost-benefit analysis.Gynecol Endocrinol. 2002; 16: 53-55PubMed Google Scholar, 6van Wely M. Bayram N. van der Veen F. Bossuyt P.M. 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. 2004; 19: 1741-1745Crossref PubMed Scopus (43) Google Scholar, 7Bayram N. van Wely M. Kaaijk E.M. Bossuyt P.M. van der Veen F. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome randomised controlled trial.BMJ. 2004; 328: 192-198Crossref PubMed Google Scholar) in cost/benefit analyses have concluded that LOD should be considered as the next line of treatment if CC fails to induce ovulation in PCOS women before controlled ovarian stimulation (COS) with gonadotropins. Many reports (8Lord J.M. Flight I.H. Norman R.J. Metformin in polycystic ovary syndrome systematic review and meta-analysis.BMJ. 2003; 327: 951-953Crossref PubMed Google Scholar, 9Palomba S. Orio Jr, F. Falbo A. Manguso F. Russo T. Cascella T. Tolino A. Carmina E. Colao A. Zullo F. 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: 4068-4074Crossref PubMed Scopus (237) Google Scholar, 10Palomba S. Orio Jr, F. Nardo L.G. Falbo A. Russo T. Corea D. Doldo P. Lombardi G. Tolino A. Colao A. Zullo F. 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. 2004; 89: 4801-4809Crossref PubMed Scopus (156) Google Scholar) have shown that metformin is another effective treatment to restore ovulatory menstrual cycles and improve fertility in PCOS women not only after CC failure (administered alone and/or in addition to CC) but also as a first-line treatment (9Palomba S. Orio Jr, F. Falbo A. Manguso F. Russo T. Cascella T. Tolino A. Carmina E. Colao A. Zullo F. 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: 4068-4074Crossref PubMed Scopus (237) Google Scholar). Metformin, similarly to LOD, exerts beneficial effects at hormonal and metabolic levels and has no necessity for intensive monitoring. LOD and metformin were similarly effective for ovulation induction, but metformin was more effective on the other reproductive outcomes, i.e. abortion, pregnancy and live-birth rates, and it is at least twenty-fold less expensive (10Palomba S. Orio Jr, F. Nardo L.G. Falbo A. Russo T. Corea D. Doldo P. Lombardi G. Tolino A. Colao A. Zullo F. 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. 2004; 89: 4801-4809Crossref PubMed Scopus (156) Google Scholar). Figure 1 shows a rational approach on how to treat anovulatory dysfunction in infertile PCOS subjects. In particular, we currently feel that the best initial care for obese infertile women with PCOS should be the lifestyle modification to improve their reproductive function (1Palomba S. Orio Jr, F. Russo T. Falbo A. Cascella T. Colao A. Lombardi G. Zullo F. Is ovulation induction still a therapeutic problem in patients with polycystic ovary syndrome?.J Endocrinol Invest. 2004; 27: 796-805PubMed Google Scholar). On the contrary, non-obese PCOS patients should be initially treated with CC for no more than 3 cycles. When CC therapy fails, the second-step should be metformin treatment alone or in co-administration with CC, and only PCOS patients who did not ovulate, or ovulated but did not achieve a pregnancy within 6 cycles should be treated with COS. On the other hand, LOD still has a role in anovulatory PCOS women during a laparoscopy when organic co-factors of sub-fertility are diagnosed or suspected.