First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis

Reproductive Medicine Network+, International Ovulation Induction IPDMA Collaboration, Rui Wang, Wentao Li, Esmée M. Bordewijk, Richard S. Legro, Heping Zhang, Xiaoke Wu, Jingshu Gao, Laure Morin-Papunen, Roy Homburg, Tamar E. König, Etelka Moll, Sujata Kar, Wei Huang, Neil P. Johnson, Saad A. Amer, Walter Vegetti, Stefano Palomba, Angela FalboÜlkü Özmen, Hakan Nazik, Christopher D. Williams, Grasso Federica, Jonathan Lord, Yilmaz Sahin, Siladitya Bhattacharya, Robert J. Norman, Madelon van Wely, Ben Willem Mol

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

Original languageEnglish
Pages (from-to)717-732
Number of pages16
JournalHuman Reproduction Update
Volume25
Issue number6
DOIs
Publication statusPublished - Nov 5 2019

Fingerprint

Clomiphene
Ovulation Induction
Polycystic Ovary Syndrome
letrozole
Meta-Analysis
Randomized Controlled Trials
Metformin
Live Birth
Time-to-Pregnancy
Confidence Intervals
Infertility
Odds Ratio
Pregnancy Rate
Therapeutics
Birth Rate
Testosterone
Serum
Insulin
Precision Medicine
Tamoxifen

Keywords

  • anovulation
  • clomiphene
  • individual participant data
  • infertility
  • letrozole
  • meta-analysis
  • metformin
  • ovulation induction
  • polycystic ovary syndrome

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynaecology

Cite this

Reproductive Medicine Network+, International Ovulation Induction IPDMA Collaboration, Wang, R., Li, W., Bordewijk, E. M., Legro, R. S., ... Mol, B. W. (2019). First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis. Human Reproduction Update, 25(6), 717-732. https://doi.org/10.1093/humupd/dmz029

First-line ovulation induction for polycystic ovary syndrome : an individual participant data meta-analysis. / Reproductive Medicine Network+; International Ovulation Induction IPDMA Collaboration; Wang, Rui; Li, Wentao; Bordewijk, Esmée M.; Legro, Richard S.; Zhang, Heping; Wu, Xiaoke; Gao, Jingshu; Morin-Papunen, Laure; Homburg, Roy; König, Tamar E.; Moll, Etelka; Kar, Sujata; Huang, Wei; Johnson, Neil P.; Amer, Saad A.; Vegetti, Walter; Palomba, Stefano; Falbo, Angela; Özmen, Ülkü; Nazik, Hakan; Williams, Christopher D.; Federica, Grasso; Lord, Jonathan; Sahin, Yilmaz; Bhattacharya, Siladitya; Norman, Robert J.; van Wely, Madelon; Mol, Ben Willem.

In: Human Reproduction Update, Vol. 25, No. 6, 05.11.2019, p. 717-732.

Research output: Contribution to journalArticle

Reproductive Medicine Network+, International Ovulation Induction IPDMA Collaboration, Wang, R, Li, W, Bordewijk, EM, Legro, RS, Zhang, H, Wu, X, Gao, J, Morin-Papunen, L, Homburg, R, König, TE, Moll, E, Kar, S, Huang, W, Johnson, NP, Amer, SA, Vegetti, W, Palomba, S, Falbo, A, Özmen, Ü, Nazik, H, Williams, CD, Federica, G, Lord, J, Sahin, Y, Bhattacharya, S, Norman, RJ, van Wely, M & Mol, BW 2019, 'First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis', Human Reproduction Update, vol. 25, no. 6, pp. 717-732. https://doi.org/10.1093/humupd/dmz029
Reproductive Medicine Network+, International Ovulation Induction IPDMA Collaboration, Wang R, Li W, Bordewijk EM, Legro RS et al. First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis. Human Reproduction Update. 2019 Nov 5;25(6):717-732. https://doi.org/10.1093/humupd/dmz029
Reproductive Medicine Network+ ; International Ovulation Induction IPDMA Collaboration ; Wang, Rui ; Li, Wentao ; Bordewijk, Esmée M. ; Legro, Richard S. ; Zhang, Heping ; Wu, Xiaoke ; Gao, Jingshu ; Morin-Papunen, Laure ; Homburg, Roy ; König, Tamar E. ; Moll, Etelka ; Kar, Sujata ; Huang, Wei ; Johnson, Neil P. ; Amer, Saad A. ; Vegetti, Walter ; Palomba, Stefano ; Falbo, Angela ; Özmen, Ülkü ; Nazik, Hakan ; Williams, Christopher D. ; Federica, Grasso ; Lord, Jonathan ; Sahin, Yilmaz ; Bhattacharya, Siladitya ; Norman, Robert J. ; van Wely, Madelon ; Mol, Ben Willem. / First-line ovulation induction for polycystic ovary syndrome : an individual participant data meta-analysis. In: Human Reproduction Update. 2019 ; Vol. 25, No. 6. pp. 717-732.
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title = "First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis",
abstract = "BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95{\%} confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95{\%} CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95{\%} CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95{\%} CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95{\%} CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95{\%} CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95{\%} CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95{\%} CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.",
keywords = "anovulation, clomiphene, individual participant data, infertility, letrozole, meta-analysis, metformin, ovulation induction, polycystic ovary syndrome",
author = "{Reproductive Medicine Network+} and {International Ovulation Induction IPDMA Collaboration} and Rui Wang and Wentao Li and Bordewijk, {Esm{\'e}e M.} and Legro, {Richard S.} and Heping Zhang and Xiaoke Wu and Jingshu Gao and Laure Morin-Papunen and Roy Homburg and K{\"o}nig, {Tamar E.} and Etelka Moll and Sujata Kar and Wei Huang and Johnson, {Neil P.} and Amer, {Saad A.} and Walter Vegetti and Stefano Palomba and Angela Falbo and {\"U}lk{\"u} {\"O}zmen and Hakan Nazik and Williams, {Christopher D.} and Grasso Federica and Jonathan Lord and Yilmaz Sahin and Siladitya Bhattacharya and Norman, {Robert J.} and {van Wely}, Madelon and Mol, {Ben Willem}",
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volume = "25",
pages = "717--732",
journal = "Human Reproduction Update",
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TY - JOUR

T1 - First-line ovulation induction for polycystic ovary syndrome

T2 - an individual participant data meta-analysis

AU - Reproductive Medicine Network+

AU - International Ovulation Induction IPDMA Collaboration

AU - Wang, Rui

AU - Li, Wentao

AU - Bordewijk, Esmée M.

AU - Legro, Richard S.

AU - Zhang, Heping

AU - Wu, Xiaoke

AU - Gao, Jingshu

AU - Morin-Papunen, Laure

AU - Homburg, Roy

AU - König, Tamar E.

AU - Moll, Etelka

AU - Kar, Sujata

AU - Huang, Wei

AU - Johnson, Neil P.

AU - Amer, Saad A.

AU - Vegetti, Walter

AU - Palomba, Stefano

AU - Falbo, Angela

AU - Özmen, Ülkü

AU - Nazik, Hakan

AU - Williams, Christopher D.

AU - Federica, Grasso

AU - Lord, Jonathan

AU - Sahin, Yilmaz

AU - Bhattacharya, Siladitya

AU - Norman, Robert J.

AU - van Wely, Madelon

AU - Mol, Ben Willem

PY - 2019/11/5

Y1 - 2019/11/5

N2 - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

KW - anovulation

KW - clomiphene

KW - individual participant data

KW - infertility

KW - letrozole

KW - meta-analysis

KW - metformin

KW - ovulation induction

KW - polycystic ovary syndrome

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JF - Human Reproduction Update

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