COCHRANE CONCISE
Aromatase inhibitors for subfertile women with polycystic ovary syndrome: summary of a Cochrane review Sebastian Franik, B.Sc.,a Jan A. M. Kremer, Ph.D.,b Willianne L. D. M. Nelen, Ph.D.,b Cynthia Farquhar, M.P.H.,c and Jane Marjoribanks, M.P.H.c a Faculty of Medical School and b Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, the Netherlands; and c Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand
Polycystic ovary syndrome (PCOS) is a common cause of anovulatory subfertility. We evaluated the effectiveness and safety of aromatase inhibitors compared with other methods of ovulation induction in women with anovulatory Use your smartphone PCOS. (Fertil SterilÒ 2014;-:-–-. Ó2014 by American Society for Reproductive Medicine.) to scan this QR code Key Words: Aromatase inhibitors, infertility, polycystic ovary syndrome, ovulation induction, and connect to the letrozole Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/franiks-aromatase-inhibitors-subfertile-pcos-cochrane/
BACKGROUND Polycystic ovary syndrome (PCOS) is the most common cause of infrequent or absent menstrual periods. It affects 4%–8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors are a novel class of drugs that were introduced for ovulation induction in 2001. There has been controversy as to whether the aromatase inhibitor letrozole is at least as effective as the first-line treatment clomiphene citrate. We aimed to evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS.
METHODS We included all randomized controlled trials (RCTs) of aromatase inhibitors
used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Cochrane databases, Medline, Embase, trial registries, and other sources were searched up to September 2014. Our primary outcomes were live birth and ovarian hyperstimulation syndrome (OHSS). Secondary outcomes were pregnancy, miscarriage, and multiple pregnancy. Two review authors independently selected trials, extracted the data, and assessed trial quality. Studies were pooled where appropriate with the use of a fixed effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We used a fixed-effect model, assuming that there was one true effect size underlying all of the studies in the analysis, and
Received August 1, 2014; revised September 24, 2014; accepted October 9, 2014. S.F. has nothing to disclose. J.A.M.K. has nothing to disclose. W.L.D.M.N. has nothing to disclose. C.F. has nothing to disclose. J.M. has nothing to disclose. This is a summary of a systematic review published on the Cochrane Library: Aromatase Inhibitors for Subfertile Women with Polycystic Ovary Syndrome. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD010287. http://dx.doi.org/10.1002/14651858.CD010287.pub2. Correspondence: Jane Marjoribanks, M.P.H., Cochrane Office, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.10.016 VOL. - NO. - / - 2014
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
conducted a sensitivity analysis with the use of a random-effects model to check whether our findings were robust in this assumption. Statistical heterogeneity was assessed with the use of the I2 statistic. The quality of the evidence for each comparison was assessed with the use of GRADE (Grading of Recommendations Assessment Development and Evaluation) methods. Institutional Review Board approval was not required for this work, because it was secondary research.
RESULTS We included 26 RCTs (5,560 women). In all of the studies the aromatase inhibitor was letrozole, with or without adjuncts. Comparators were placebo (one RCT), clomiphene citrate with or without adjuncts followed by either timed intercourse (15 RCTs) or intrauterine insemination (IUI; three RCTs), anastrozole (two RCTs), laparoscopic ovarian drilling with or without metformin (three RCTs) and differing administration regimens for letrozole (two RCTs). Adjuncts used were metformin, hMG, and FSH. 1
COCHRANE CONCISE Live Birth (12 RCTs) When letrozole was compared with placebo in women who were clomiphene resistant, the findings were inconclusive (OR 3.17, 95% CI 0.12–83.17; one RCT; n ¼ 36). When letrozole was compared with clomiphene citrate (with or without adjuncts in one or both arms) followed by timed intercourse, the birth rate was higher in the letrozole group (OR 1.64, 95% CI 1.32–2.04; nine RCTs; n ¼ 1,783; I2 ¼ 3%) (Fig. 1). When letrozole was compared with laparoscopic ovarian drilling, there was no evidence of a difference between groups (OR 1.19, 95% CI 0.76–1.86; two RCTs; n ¼ 407; I2 ¼ 0).
OHSS (16 RCTs) There was no evidence of a difference in the rate of OHSS when letrozole with or without adjuncts was compared with
any of the following: placebo (one RCT; n ¼ 36), clomiphene citrate with or without adjuncts followed by timed intercourse (nine RCTs; n ¼ 2,179), clomiphene citrate followed by IUI (two RCTs; n ¼ 1,494), laparoscopic ovarian drilling (one RCT; n ¼ 260), or anastrozole (one RCT; n ¼ 220). Events were absent or very rare, and no study had more than two cases of OHSS.
Clinical Pregnancy (25 RCTs) When letrozole was compared with placebo in women who were clomiphene resistant, the findings were inconclusive (OR 3.17, 95% CI 0.12–83.17; one RCT; n ¼ 36). When letrozole was compared with clomiphene citrate (with or without adjuncts in one or both arms) followed by timed intercourse, the pregnancy rate was higher in the letrozole group (OR 1.40,
FIGURE 1
Forest plot for live birth: aromatase inhibitor (letrozole) compared with clomiphene citrate (with or without adjuncts in one or both arms) followed by timed intercourse. Franik. Aromatase inhibitors for ovulation induction. Fertil Steril 2014.
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TABLE 1 Summary of findings. Population: Subfertile women with polycystic ovary syndrome. Comparison: Aromatase inhibitor (letrozole) compared with clomiphene citrate, with or without adjuncts in both arms, followed by timed intercourse. Illustrative comparative risksa (95% CI)
Outcomes
Assumed risk, clomiphene citrate with or without adjuncts
Live birth rate
188 per 1,000
Ovarian hyperstimulation syndrome (OHSS) rate
0 per 1,000
Clinical pregnancy rate
202 per 1,000
Corresponding risk, aromatase inhibitor (letrozole) with or without adjuncts
Relative effect (95% CI), fixed-effect model
No. of participants (studies)
275 per 1,000 (234–321) 0 per 1,000
OR 1.64 (1.32–2.04) Risks were calculated from pooled risk differences
1,783 (9 studies)
262 per 1,000 (230–295)
OR 1.40 (1.18–1.65)
2,816 (15 studies)
2,179 (9 studies)
Quality of evidence (GRADE)b 44BB Lowc,d 444B Moderatec
44BB Lowc,e
Comments
OHSS was very rare, with a total of only 2 events in 2,179 women (both in the clomiphene group).
Note: CI ¼ confidence interval; OR ¼ odds ratio. a The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). b GRADE Working Group grades of evidence: High quality: further research is very unlikely to change our confidence in the estimate of effect; Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality: we are very uncertain about the estimate. c Most studies failed to report their methods in adequate detail. d Studies that reported live birth tended to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth, suggesting that results might be less favourable to letrozole if all studies reported live birth. e A funnel plot analysis strongly suggests that there might be more publications without a significant effect which were not published. Franik. Aromatase inhibitors for ovulation induction. Fertil Steril 2014.
95% CI 1.18–1.65; 15 RCTs; n ¼ 2,816; I2 ¼ 26%). When letrozole was compared with clomiphene citrate with or without adjuncts followed by IUI, the pregnancy rate was higher in the letrozole group (OR 1.71, 95% CI 1.30–2.25; three RCTS; n ¼ 1,597). There was no evidence of a difference between groups when letrozole with or without metformin was compared with laparoscopic ovarian drilling (OR 1.14, 95% CI 0.80–1.65; three RCTs; n ¼ 553; I2 ¼ 0) or when differing regimens of letrozole administration were compared. Use of a random-effects model yielded very similar findings.
Evidence Quality The quality of the evidence was rated as low for live birth and pregnancy outcomes. The main limitations in the evidence were poor reporting of study methods and possible publica-
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tion bias. Moreover, there was a tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth, suggesting that results might be somewhat less favorable to letrozole if all studies reported live birth (Table 1).
CONCLUSION Our findings suggest that letrozole is superior to clomiphene citrate for the treatment of subfertility in women with PCOS who have had no previous treatment for ovulation induction or are resistant to clomiphene citrate. There appears to be no difference in effectiveness between letrozole and laparoscopic ovarian drilling, although there were only two relevant studies. OHSS was a very rare event, with no occurrences in most studies. These conclusions should be regarded with some caution because the quality of the evidence was low.
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Aromatase inhibitors for subfertile women with polycystic ovary syndrome: summary of a Cochrane review Sebastian Franik, B.Sc.,a Jan A. M. Kremer, Ph.D.,b Willianne L. D. M. Nelen, Ph.D.,b Cynthia Farquhar, M.P.H.,c and Jane Marjoribanks, M.P.H.c a Faculty of Medical School and b Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, the Netherlands; and c Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand
Polycystic ovary syndrome (PCOS) is a common cause of anovulatory subfertility. We evaluated the effectiveness and safety of aromatase inhibitors compared with other methods of ovulation induction in women with anovulatory Use your smartphone PCOS. (Fertil SterilÒ 2014;-:-–-. Ó2014 by American Society for Reproductive Medicine.) to scan this QR code Key Words: Aromatase inhibitors, infertility, polycystic ovary syndrome, ovulation induction, and connect to the letrozole Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/franiks-aromatase-inhibitors-subfertile-pcos-cochrane/
BACKGROUND Polycystic ovary syndrome (PCOS) is the most common cause of infrequent or absent menstrual periods. It affects 4%–8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors are a novel class of drugs that were introduced for ovulation induction in 2001. There has been controversy as to whether the aromatase inhibitor letrozole is at least as effective as the first-line treatment clomiphene citrate. We aimed to evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS.
METHODS We included all randomized controlled trials (RCTs) of aromatase inhibitors
used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Cochrane databases, Medline, Embase, trial registries, and other sources were searched up to September 2014. Our primary outcomes were live birth and ovarian hyperstimulation syndrome (OHSS). Secondary outcomes were pregnancy, miscarriage, and multiple pregnancy. Two review authors independently selected trials, extracted the data, and assessed trial quality. Studies were pooled where appropriate with the use of a fixed effect model to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We used a fixed-effect model, assuming that there was one true effect size underlying all of the studies in the analysis, and
Received August 1, 2014; revised September 24, 2014; accepted October 9, 2014. S.F. has nothing to disclose. J.A.M.K. has nothing to disclose. W.L.D.M.N. has nothing to disclose. C.F. has nothing to disclose. J.M. has nothing to disclose. This is a summary of a systematic review published on the Cochrane Library: Aromatase Inhibitors for Subfertile Women with Polycystic Ovary Syndrome. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD010287. http://dx.doi.org/10.1002/14651858.CD010287.pub2. Correspondence: Jane Marjoribanks, M.P.H., Cochrane Office, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.10.016 VOL. - NO. - / - 2014
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
conducted a sensitivity analysis with the use of a random-effects model to check whether our findings were robust in this assumption. Statistical heterogeneity was assessed with the use of the I2 statistic. The quality of the evidence for each comparison was assessed with the use of GRADE (Grading of Recommendations Assessment Development and Evaluation) methods. Institutional Review Board approval was not required for this work, because it was secondary research.
RESULTS We included 26 RCTs (5,560 women). In all of the studies the aromatase inhibitor was letrozole, with or without adjuncts. Comparators were placebo (one RCT), clomiphene citrate with or without adjuncts followed by either timed intercourse (15 RCTs) or intrauterine insemination (IUI; three RCTs), anastrozole (two RCTs), laparoscopic ovarian drilling with or without metformin (three RCTs) and differing administration regimens for letrozole (two RCTs). Adjuncts used were metformin, hMG, and FSH. 1
COCHRANE CONCISE Live Birth (12 RCTs) When letrozole was compared with placebo in women who were clomiphene resistant, the findings were inconclusive (OR 3.17, 95% CI 0.12–83.17; one RCT; n ¼ 36). When letrozole was compared with clomiphene citrate (with or without adjuncts in one or both arms) followed by timed intercourse, the birth rate was higher in the letrozole group (OR 1.64, 95% CI 1.32–2.04; nine RCTs; n ¼ 1,783; I2 ¼ 3%) (Fig. 1). When letrozole was compared with laparoscopic ovarian drilling, there was no evidence of a difference between groups (OR 1.19, 95% CI 0.76–1.86; two RCTs; n ¼ 407; I2 ¼ 0).
OHSS (16 RCTs) There was no evidence of a difference in the rate of OHSS when letrozole with or without adjuncts was compared with
any of the following: placebo (one RCT; n ¼ 36), clomiphene citrate with or without adjuncts followed by timed intercourse (nine RCTs; n ¼ 2,179), clomiphene citrate followed by IUI (two RCTs; n ¼ 1,494), laparoscopic ovarian drilling (one RCT; n ¼ 260), or anastrozole (one RCT; n ¼ 220). Events were absent or very rare, and no study had more than two cases of OHSS.
Clinical Pregnancy (25 RCTs) When letrozole was compared with placebo in women who were clomiphene resistant, the findings were inconclusive (OR 3.17, 95% CI 0.12–83.17; one RCT; n ¼ 36). When letrozole was compared with clomiphene citrate (with or without adjuncts in one or both arms) followed by timed intercourse, the pregnancy rate was higher in the letrozole group (OR 1.40,
FIGURE 1
Forest plot for live birth: aromatase inhibitor (letrozole) compared with clomiphene citrate (with or without adjuncts in one or both arms) followed by timed intercourse. Franik. Aromatase inhibitors for ovulation induction. Fertil Steril 2014.
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Fertility and Sterility®
TABLE 1 Summary of findings. Population: Subfertile women with polycystic ovary syndrome. Comparison: Aromatase inhibitor (letrozole) compared with clomiphene citrate, with or without adjuncts in both arms, followed by timed intercourse. Illustrative comparative risksa (95% CI)
Outcomes
Assumed risk, clomiphene citrate with or without adjuncts
Live birth rate
188 per 1,000
Ovarian hyperstimulation syndrome (OHSS) rate
0 per 1,000
Clinical pregnancy rate
202 per 1,000
Corresponding risk, aromatase inhibitor (letrozole) with or without adjuncts
Relative effect (95% CI), fixed-effect model
No. of participants (studies)
275 per 1,000 (234–321) 0 per 1,000
OR 1.64 (1.32–2.04) Risks were calculated from pooled risk differences
1,783 (9 studies)
262 per 1,000 (230–295)
OR 1.40 (1.18–1.65)
2,816 (15 studies)
2,179 (9 studies)
Quality of evidence (GRADE)b 44BB Lowc,d 444B Moderatec
44BB Lowc,e
Comments
OHSS was very rare, with a total of only 2 events in 2,179 women (both in the clomiphene group).
Note: CI ¼ confidence interval; OR ¼ odds ratio. a The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). b GRADE Working Group grades of evidence: High quality: further research is very unlikely to change our confidence in the estimate of effect; Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality: we are very uncertain about the estimate. c Most studies failed to report their methods in adequate detail. d Studies that reported live birth tended to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth, suggesting that results might be less favourable to letrozole if all studies reported live birth. e A funnel plot analysis strongly suggests that there might be more publications without a significant effect which were not published. Franik. Aromatase inhibitors for ovulation induction. Fertil Steril 2014.
95% CI 1.18–1.65; 15 RCTs; n ¼ 2,816; I2 ¼ 26%). When letrozole was compared with clomiphene citrate with or without adjuncts followed by IUI, the pregnancy rate was higher in the letrozole group (OR 1.71, 95% CI 1.30–2.25; three RCTS; n ¼ 1,597). There was no evidence of a difference between groups when letrozole with or without metformin was compared with laparoscopic ovarian drilling (OR 1.14, 95% CI 0.80–1.65; three RCTs; n ¼ 553; I2 ¼ 0) or when differing regimens of letrozole administration were compared. Use of a random-effects model yielded very similar findings.
Evidence Quality The quality of the evidence was rated as low for live birth and pregnancy outcomes. The main limitations in the evidence were poor reporting of study methods and possible publica-
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tion bias. Moreover, there was a tendency for studies that reported live birth to report higher clinical pregnancy rates in the letrozole group than studies that failed to report live birth, suggesting that results might be somewhat less favorable to letrozole if all studies reported live birth (Table 1).
CONCLUSION Our findings suggest that letrozole is superior to clomiphene citrate for the treatment of subfertility in women with PCOS who have had no previous treatment for ovulation induction or are resistant to clomiphene citrate. There appears to be no difference in effectiveness between letrozole and laparoscopic ovarian drilling, although there were only two relevant studies. OHSS was a very rare event, with no occurrences in most studies. These conclusions should be regarded with some caution because the quality of the evidence was low.
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