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Aromatase inhibitors for infertility in polycystic ovary syndrome. The beginning or the end of a new era?

2008; Elsevier BV; Volume: 89; Issue: 2 Linguagem: Inglês

10.1016/j.fertnstert.2007.10.016

1556-5653

Nikolaos P. Polyzos, Maria Tsappi, Davide Mauri, Vedat Atay, Ivan Cortinovis, Giovanni Casazza,

Ovarian cancer diagnosis and treatment

A meta-analysis of four trials showed significant advantage in pregnancy and delivery rates with aromatase inhibitors compared with CC in women with PCOS. A recent randomized trial demonstrated no clear benefit. A meta-analysis of four trials showed significant advantage in pregnancy and delivery rates with aromatase inhibitors compared with CC in women with PCOS. A recent randomized trial demonstrated no clear benefit. Clomiphene citrate (CC) is the most commonly used oral agent for induction of ovulation in women with polycystic ovary syndrome (PCOS) (1Hammond M.G. Monitoring techniques for improved pregnancy rates during clomiphene ovulation induction.Fertil Steril. 1984; 42: 499-509Abstract Full Text PDF PubMed Google Scholar). Recently, aromatase inhibitors, which were developed to treat advanced breast cancer (2Mauri D. Pavlidis N. Polyzos N.P. Ioannidis J.P. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis.J Natl Cancer Inst. 2006; 98: 1285-1291Crossref PubMed Scopus (226) Google Scholar), have been introduced as a new treatment option for ovulation induction in anovulatory women (3Mitwally M.F. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar). Due to their relatively short 45-hour half-life, compared with the half-life of CC, and the lack of down-regulation of hypothalamic–pituitary estrogen (E) receptors during the late follicular phase (4Casper R.F. Letrozole: ovulation or superovulation?.Fertil Steril. 2003; 80: 1335-1337Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar), aromatase inhibitors may have less adverse effects on peripheral organs such as the endometrium and cervix (5Casper R.F. Mitwally M.F. Review: aromatase inhibitors for ovulation induction.J Clin Endocrinol Metab. 2006; 91: 760-771Crossref PubMed Scopus (208) Google Scholar). We searched the Cochrane Central Trials Registry and PubMed without year and language restriction. The last search was updated on July 2007. We used the searching algorithm: (letrozole OR anastrazole OR aromatase OR aromatase inhibitors) AND (infertility OR ovulation OR anovulation OR polycystic ovary syndrome OR polycystic ovaries OR PCOS). We considered eligible only randomized controlled studies comparing an aromatase inhibitor versus CC in anovulatory women with PCOS for ovulation induction. Trials including women with other causes of infertility other than anovulation due to PCOS were considered ineligible. Trials were considered eligible whether women planned to conceive with sexual intercourse or by intrauterine insemination. If other concomitant treatments were also used (e.g., metformin or gonadotropins), the trial would be eligible if these treatments did not differ systematically between the investigated arms. Trials where the compared arms differed systematically in the use of these additional fertility-related treatments were excluded, because the differences in pregnancy rates (PR) and additional outcomes could not have been attributed necessarily to the contrast of aromatase inhibitors versus standard ovulation induction treatment. Table 1 shows the key characteristics of the included trials. We pooled the data from randomized trials comparing an aromatase inhibitor versus CC. Four randomized controlled trials randomizing 265 women with PCOS to either letrozole or anastrozole versus CC were considered eligible (6Sipe C.S. Davis W.A. Maifeld M. Van Voorhis B.J. A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins.Fertil Steril. 2006; 86: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 7Atay V. Cam C. Muhcu M. Cam M. Karateke A. Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation.J Int Med Res. 2006; 34: 73-76Crossref PubMed Scopus (106) Google Scholar, 8Bayar U. Basaran M. Kiran S. Coskun A. Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial.Fertil Steril. 2006; 86: 1447-1451Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 9Sohrabvand F. Ansari Sh Bagheri M. Efficacy of combined metformin–letrozole in comparison with metformin–clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.Hum Reprod. 2006; 21: 1432-1435Crossref PubMed Scopus (80) Google Scholar). Two-by-two tables were constructed and odds ratio (OR) was calculated for each primary study to estimate the relative risk of pregnancy among aromatase inhibitors group compared to the CC group. The χ2 statistic test was used to test the homogeneity of the estimates of ORs between studies, with a level of significance of .1. In case of homogeneity, pooled OR and 95% confidence interval (CI) were calculated according to the Mantel-Haenszel method (10Egger M. Davey Smith G. Altman D.G. Systematic reviews in health care: meta-analysis in context. 2nd ed. BMJ Books, London2001Crossref Scopus (283) Google Scholar).Table 1Baseline characteristics and main outcome measures of trials.AuthorCountryArms (mg)Patients (eligible)Age meanBMI meanNo. of cyclesInfertility durationPrevious oral agentsDeliveries (No.)Pregnancy (No.)Multiple gestation (No.)Ectopic pregnancy (No.)Atay V (2006)TurkeyLetrozole 2.551 (51)27.126.1512.2 + 0.7 meanNo10110NAClomiphene 10055 (55)26.225.8552.4 + 0.9 meanNo551NABayar U (2006)TurkeyLetrozole 2.540 (38)32.2<25995 (1–10) medianNo8900Clomiphene 10040 (36)31.6<25953 (1–11) medianNo7700Sohrabvand F (2006)IranLetrozole 2.5 + Metformin29 (29)28.2429.98533.78 meanYes/CC resistant10100NAClomiphene 100 + Metformin30 (30)29.5530.21673.81 meanYes/CC resistant350NASipe SC (2006)USAAnastrazole 112 (12)NANA12NAYes3300Clomiphene 1008 (8)NANA8NAYes1201Note: BMI = body mass index; NA = not applicable. Open table in a new tab Note: BMI = body mass index; NA = not applicable. Our analysis revealed a statistical significance in favor of the aromatase inhibitors both for pregnancies and subsequent deliveries. By using the fixed effects model, the OR for pregnancies per patient was 2.0 (95% CI 1.1–3.8, P=.025), and the OR for deliveries per patient was 2.4 (95% CI 1.2–4.6, P=.011), when comparing an aromatase inhibitor to CC. Calculations of ORs for deliveries and live pregnancies per treatment cycle were again in favor of the aromatase inhibitors arm (OR = 2.2, 95% CI 1.2–4.1, P=.015 and OR = 1.8, 95% CI 1.0–3.3, P=.044, respectively). No between-study heterogeneity was observed for all of these outcomes. However, a recently published randomized controlled trial, comparing letrozole to CC in 438 anovulatory women with PCOS found no difference in PRs between medication arms (CC 17.9% vs. letrozole 15.1%; P=.72) (11Badawy A. Abdel Aal I. Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial.Fertil Steril. 2007; (“in press”)https://doi.org/10.1016/j.fertnstert.2007.02.062Abstract Full Text Full Text PDF Scopus (110) Google Scholar). Adverse outcome measures determined by miscarriage was equivalent between groups (4.4% in CC vs. 5.0% in letrozole; P=.43). Contrary to early studies these results lead the investigators to conclude that there was no benefit in terms of PR to justify the use of letrozole over CC in treating anovulatory women with PCOS. In addition, although miscarriage rates were the same in both arms in the trial presented by Badawy et al. (11Badawy A. Abdel Aal I. Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial.Fertil Steril. 2007; (“in press”)https://doi.org/10.1016/j.fertnstert.2007.02.062Abstract Full Text Full Text PDF Scopus (110) Google Scholar), they were usually low (4%) compared to historic averages (15%). Cumulatively, the CC arm miscarriage rate in our pooled analysis of earlier studies was twofold higher than the aromatase inhibitors arm (two miscarriages in the aromatase inhibitors arm vs. four in the CC arm). However, the number of events was too small to make any conclusions. Three twin pregnancies were reported in the CC arm and none in the letrozole arm in the study by Badawy et al. (11Badawy A. Abdel Aal I. Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial.Fertil Steril. 2007; (“in press”)https://doi.org/10.1016/j.fertnstert.2007.02.062Abstract Full Text Full Text PDF Scopus (110) Google Scholar). From the early trials, none except one (7Atay V. Cam C. Muhcu M. Cam M. Karateke A. Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation.J Int Med Res. 2006; 34: 73-76Crossref PubMed Scopus (106) Google Scholar) reported one twin pregnancy and this was in the aromatase inhibitors arm. Furthermore, CC has been linked to negative results on endometrial thickness (12Sereepapong W. Triratanachat S. Sampatanukul P. Pruksananonda K. Boonkasemsanti K. Reinprayoon D. Effects of clomiphene citrate on the endometrium of regularly cycling women.Fertil Steril. 2000; 73: 287-291Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). However, in the Badawy et al. trial they found a significantly thicker endometrial lining in the CC arm (9Sohrabvand F. Ansari Sh Bagheri M. Efficacy of combined metformin–letrozole in comparison with metformin–clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.Hum Reprod. 2006; 21: 1432-1435Crossref PubMed Scopus (80) Google Scholar). Although CC achieves satisfactory rates of ovulation (1Hammond M.G. Monitoring techniques for improved pregnancy rates during clomiphene ovulation induction.Fertil Steril. 1984; 42: 499-509Abstract Full Text PDF PubMed Google Scholar), its persistent antiestrogenic effect on the cervical mucous and endometrial thickness (13Gonen Y. Casper R.F. Sonographic determination of an adverse effect of clomiphene citrate on endometrial growth.Hum Reprod. 1990; 5: 670-674Crossref PubMed Scopus (149) Google Scholar) might be related to a lower implantation rate and therefore diminished PR compared to aromatase inhibitors. An endometrium that is thinner than 5 or 6 mm is usually associated with significant likelihood of failure to conceive (13Gonen Y. Casper R.F. Sonographic determination of an adverse effect of clomiphene citrate on endometrial growth.Hum Reprod. 1990; 5: 670-674Crossref PubMed Scopus (149) Google Scholar). In three of four trials included in our analysis that provide sufficient data (6Sipe C.S. Davis W.A. Maifeld M. Van Voorhis B.J. A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins.Fertil Steril. 2006; 86: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 7Atay V. Cam C. Muhcu M. Cam M. Karateke A. Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation.J Int Med Res. 2006; 34: 73-76Crossref PubMed Scopus (106) Google Scholar, 8Bayar U. Basaran M. Kiran S. Coskun A. Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial.Fertil Steril. 2006; 86: 1447-1451Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar), the endometrial thickness on the day of β-hCG administration was found significantly higher in patients receiving aromatase inhibitors and this might actually reflect higher implantation rates and higher PRs in aromatase inhibitor-treated patients. To highlight these discrepancies between earlier trials included in the meta-analysis (6Sipe C.S. Davis W.A. Maifeld M. Van Voorhis B.J. A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins.Fertil Steril. 2006; 86: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 7Atay V. Cam C. Muhcu M. Cam M. Karateke A. Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation.J Int Med Res. 2006; 34: 73-76Crossref PubMed Scopus (106) Google Scholar, 8Bayar U. Basaran M. Kiran S. Coskun A. Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial.Fertil Steril. 2006; 86: 1447-1451Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 9Sohrabvand F. Ansari Sh Bagheri M. Efficacy of combined metformin–letrozole in comparison with metformin–clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.Hum Reprod. 2006; 21: 1432-1435Crossref PubMed Scopus (80) Google Scholar) and the trial by Badawy et al. (11Badawy A. Abdel Aal I. Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial.Fertil Steril. 2007; (“in press”)https://doi.org/10.1016/j.fertnstert.2007.02.062Abstract Full Text Full Text PDF Scopus (110) Google Scholar) and provide some future directions regarding the design of a trial in this field, we assessed the methodological quality of the trials. We recorded study design items, including whether there was a description of the mode of randomization, allocation concealment, and blinding (14Cochrane Handbook. The Cochrane Handbook for Systematic Reviews of Interventions. Available at http://www.cochrane.org/resources/handbook/handbook.pdf. Last accessed September 25, 2007.Google Scholar). From the early four trials, one was double-blind (8Bayar U. Basaran M. Kiran S. Coskun A. Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial.Fertil Steril. 2006; 86: 1447-1451Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar), two trials were single-blind (6Sipe C.S. Davis W.A. Maifeld M. Van Voorhis B.J. A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins.Fertil Steril. 2006; 86: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 9Sohrabvand F. Ansari Sh Bagheri M. Efficacy of combined metformin–letrozole in comparison with metformin–clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.Hum Reprod. 2006; 21: 1432-1435Crossref PubMed Scopus (80) Google Scholar), three described in detail the mode of randomization (6Sipe C.S. Davis W.A. Maifeld M. Van Voorhis B.J. A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins.Fertil Steril. 2006; 86: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 8Bayar U. Basaran M. Kiran S. Coskun A. Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial.Fertil Steril. 2006; 86: 1447-1451Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 9Sohrabvand F. Ansari Sh Bagheri M. Efficacy of combined metformin–letrozole in comparison with metformin–clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.Hum Reprod. 2006; 21: 1432-1435Crossref PubMed Scopus (80) Google Scholar), and three described some method for ensuring allocation concealment (6Sipe C.S. Davis W.A. Maifeld M. Van Voorhis B.J. A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins.Fertil Steril. 2006; 86: 1676-1681Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 8Bayar U. Basaran M. Kiran S. Coskun A. Gezer S. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial.Fertil Steril. 2006; 86: 1447-1451Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 9Sohrabvand F. Ansari Sh Bagheri M. Efficacy of combined metformin–letrozole in comparison with metformin–clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease.Hum Reprod. 2006; 21: 1432-1435Crossref PubMed Scopus (80) Google Scholar). The last large randomized trial provided an adequate randomization mode, but was not blind, and did not provide a sufficient mode of allocation concealment (11Badawy A. Abdel Aal I. Abulatta M. Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial.Fertil Steril. 2007; (“in press”)https://doi.org/10.1016/j.fertnstert.2007.02.062Abstract Full Text Full Text PDF Scopus (110) Google Scholar). The differences between our pooled analysis of early trials and the one by Badawy et al. could be attributed to potential publication bias. Studies that show a significant effect of treatment are more likely to be published, published in English, be cited by other investigators, and produce multiple publications than other negative studies (15Sterne J.A. Egger M. Smith G.D. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis.BMJ. 2001; 323: 101-105Crossref PubMed Scopus (1442) Google Scholar). Furthermore, our results were based on a smaller number of subjects pooled from four separate studies. However, the results from the early trials were statistically significant without between-study heterogeneity for pregnancy or delivery rates. In conclusion, aromatase inhibitors offer a new mechanism of treatment for anovulatory women with PCOS. The most recent randomized trial suggests that there may be no clear benefit to using aromatase inhibitors over CC, contrary to early trials. Nonetheless, because infertility in women with PCOS is widespread, the public health impact of an increase in fertility rate could be substantial if early data are justified by the results of larger controlled trials. There may be subtleties that can be borne out only through large, properly designed randomized controlled trials, adequately powered to examine PRs, multiple PRs, and miscarriages. At the moment CC remains the first treatment of choice in women with PCOS desiring pregnancy, but aromatase inhibitors may offer another option that might be associated with improved PRs with a lower incidence of multiple pregnancies.