{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T15:41:21Z","timestamp":1787845281914,"version":"build-2784847793"},"reference-count":85,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,10,24]],"date-time":"2019-10-24T00:00:00Z","timestamp":1571875200000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Australian government research training programme scholarship"},{"name":"Australian National Health and Medical Research Council-funded Centre for Research Excellence in Polycystic Ovary Syndrome","award":["APP1078444"],"award-info":[{"award-number":["APP1078444"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>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\u2013covariate interaction analyses and therefore offers an opportunity for personalised medicine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>OBJECTIVE AND RATIONALE<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SEARCH METHODS<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>OUTCOMES<\/jats:title>\n                    <jats:p>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\u20131.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23\u20131.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38\u20132.15, 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\u20131.65). 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\u20131.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00\u20131.57, 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\u20131.35, 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\u20131.06).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humupd\/dmz029","type":"journal-article","created":{"date-parts":[[2019,8,7]],"date-time":"2019-08-07T07:16:04Z","timestamp":1565162164000},"page":"717-732","source":"Crossref","is-referenced-by-count":117,"title":["First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis"],"prefix":"10.1093","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6622-8134","authenticated-orcid":false,"given":"Rui","family":"Wang","sequence":"first","affiliation":[{"name":"Robinson Research Institute and Adelaide Medical School, University of Adelaide, North Adelaide, SA, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esm\u00e9e M","family":"Bordewijk","sequence":"additional","affiliation":[{"name":"Centre for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S","family":"Legro","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Yale University School of Public Health, New Haven, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1767-7344","authenticated-orcid":false,"given":"Xiaoke","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingshu","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Morin-Papunen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical Research Center, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Homburg","sequence":"additional","affiliation":[{"name":"Homerton Fertility Centre, Homerton University Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar E","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etelka","family":"Moll","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis (OLVG) West, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujata","family":"Kar","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Kar Clinic and Hospital, Bhubaneswar, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil P","family":"Johnson","sequence":"additional","affiliation":[{"name":"Robinson Research Institute and Adelaide Medical School, University of Adelaide, North Adelaide, SA, Australia"},{"name":"Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8321-1302","authenticated-orcid":false,"given":"Saad A","family":"Amer","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Nottingham, Royal Derby Hospital, Derby, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Vegetti","sequence":"additional","affiliation":[{"name":"Infertility Unit, Fondazione I.R.C.C.S. Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Palomba","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Grande Ospedale Metropolitano of Reggio Calabria, Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Falbo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Azienda USL-IRCCS di Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00dclk\u00fc","family":"\u00d6zmen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, School of Medicine, Zonguldak Bulent Ecevit University, Kozlu, Zonguldak, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakan","family":"Nazik","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Adana City Training and Research Hospital, Adana, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D","family":"Williams","sequence":"additional","affiliation":[{"name":"Reproductive Medicine and Surgery Center of Virginia, Charlottesville, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grasso","family":"Federica","sequence":"additional","affiliation":[{"name":"Department of Surgery Obstetrics and Gynecology, University of Catania, Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Lord","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Royal Cornwall Hospital, University of Exeter Medical School, Truro, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilmaz","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Erciyes University, Kayseri, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siladitya","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Aberdeen Centre for Women\u2019s Health Research, University of Aberdeen, Aberdeen, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J","family":"Norman","sequence":"additional","affiliation":[{"name":"Robinson Research Institute and Adelaide Medical School, University of Adelaide, North Adelaide, SA, Australia"},{"name":"Fertility SA, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelon","family":"van Wely","sequence":"additional","affiliation":[{"name":"Centre for Reproductive Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben Willem","family":"Mol","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"},{"name":"Robinson Research Institute and Adelaide Medical School, University of Adelaide, North Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Reproductive Medicine Network+","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the International Ovulation Induction IPDMA Collaboration","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,10,23]]},"reference":[{"key":"2019111117210095400_ref1","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.mefs.2013.05.002","article-title":"Clomiphene citrate alone, in combination with metformin or in combination with pioglitazone as first line therapy in induction of ovulation in infertile women with polycystic ovary syndrome, a randomized controlled trial","volume":"18","author":"Abuelghar","year":"2013","journal-title":"Middle East Fertil Soc J"},{"key":"2019111117210095400_ref2","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1093\/humrep\/dex227","article-title":"Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome","volume":"32","author":"Amer","year":"2017","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1177\/147323000603400109","article-title":"Comparison of letrozole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation","volume":"34","author":"Atay","year":"2006","journal-title":"J Int Med Res"},{"key":"2019111117210095400_ref4","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4103\/0974-1208.112372","article-title":"Metformin-clomiphene citrate vs. clomiphene citrate alone: polycystic ovarian syndrome","volume":"6","author":"Ayaz","year":"2013","journal-title":"J Hum Reprod Sci"},{"key":"2019111117210095400_ref5","first-page":"195","article-title":"The use of letrozole for ovulation induction in infertile women with polycystic ovarian syndrome [in Turkish]","volume":"29","author":"Aygen","year":"2007","journal-title":"Erciyes Tip Dergisi"},{"key":"2019111117210095400_ref6","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.fertnstert.2007.02.062","article-title":"Clomiphene citrate or letrozole for ovulation induction in women with polycystic ovarian syndrome: a prospective randomized trial","volume":"92","author":"Badawy","year":"2009","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref7","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.ejogrb.2011.07.015","article-title":"Clomiphene citrate versus tamoxifen for ovulation induction in women with PCOS: a prospective randomized trial","volume":"159","author":"Badawy","year":"2011","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2019111117210095400_ref8","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s00404-011-2091-7","article-title":"Comparison of efficacy of letrozole and clomiphene citrate in ovulation induction in Indian women with polycystic ovarian syndrome","volume":"285","author":"Banerjee Ray","year":"2012","journal-title":"Arch Gynecol Obstet"},{"key":"2019111117210095400_ref9","first-page":"31","article-title":"Enhanced ovarian folliclular development by metformin does not correlate with pregnancy rate: a randomized trial","volume":"6","author":"Basirat","year":"2012","journal-title":"Int J Fertil Steril"},{"key":"2019111117210095400_ref10","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/j.fertnstert.2006.04.026","article-title":"Use of an aromatase inhibitor in patients with polycystic ovary syndrome: a prospective randomized trial","volume":"86","author":"Bayar","year":"2006","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref11","first-page":"i129","article-title":"Randomized trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in polycystic ovary syndrome","volume":"21","author":"Beigi","year":"2006","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref12","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/S0015-0282(01)01749-6","article-title":"A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction","volume":"75","author":"Boostanfar","year":"2001","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref13","first-page":"335","article-title":"Indication of metformin in the management of hormonal dysfunction secondary to polycystic ovarian syndrome: prospective comparative study of 63 cases [in French]","volume":"88","author":"Boudhraa","year":"2010","journal-title":"Tunis Med"},{"key":"2019111117210095400_ref14","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/humupd\/dmq043","article-title":"Individual patient data meta-analysis: a promising approach for evidence synthesis in reproductive medicine","volume":"16","author":"Broeze","year":"2010","journal-title":"Hum Reprod Update"},{"key":"2019111117210095400_ref15","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1093\/humrep\/dew243","article-title":"Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies","volume":"31","author":"Cassar","year":"2016","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref16","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.12669\/pjms.326.11391","article-title":"Effects of letrozole in combination with low-dose intramuscular injection of human menopausal gonadotropin on ovulation and pregnancy of 156 patients with polycystic ovary syndrome","volume":"32","author":"Chen","year":"2016","journal-title":"Pak J Med Sci"},{"key":"2019111117210095400_ref17","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/S0015-0282(16)35947-7","article-title":"Induction of ovulation with clomiphene citrate. A double-blind study","volume":"17","author":"Cudmore","year":"1966","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref18","doi-asserted-by":"crossref","first-page":"18","DOI":"10.4103\/0974-1208.51337","article-title":"The efficacy of metformin and clomiphene citrate combination compared with clomiphene citrate alone for ovulation induction in infertile patients with PCOS","volume":"2","author":"Dasari","year":"2009","journal-title":"J Hum Reprod Sci"},{"key":"2019111117210095400_ref19","first-page":"23","article-title":"Comparison of the effects of letrozole and clomiphene citrate on ovulation and pregnancy rate in patients with polycystic ovary syndrome","volume":"34","author":"Dehbashi","year":"2009","journal-title":"Iran J Med Sci"},{"key":"2019111117210095400_ref20","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1093\/humupd\/dmw027","article-title":"Interactions between androgens, FSH, anti-Mullerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary","volume":"22","author":"Dewailly","year":"2016","journal-title":"Hum Reprod Update"},{"key":"2019111117210095400_ref21","first-page":"hoy007","article-title":"A protocol developing, disseminating and implementing a core outcome set for infertility","author":"Duffy","year":"2018","journal-title":"Hum Reprod Open 2018"},{"key":"2019111117210095400_ref22","first-page":"43","article-title":"The use of metformin to augment the induction of ovulation in obese infertile patients with polycystic ovary syndrome","volume":"6","author":"El-Biely","year":"2001","journal-title":"Mid East Fertil Soc J"},{"key":"2019111117210095400_ref23","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1093\/humupd\/dmr042","article-title":"Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society","volume":"18","author":"Escobar-Morreale","year":"2012","journal-title":"Hum Reprod Update"},{"key":"2019111117210095400_ref24","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1093\/humrep\/dey056","article-title":"Protect us from poor-quality medical research","volume":"33","author":"Eshre Capri Workshop Group","year":"2018","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref25","first-page":"285","article-title":"Comparison of efficacy of clomiphene citrate alone and with metformin for treatment of infertility in polycystic ovarian syndrome","volume":"43","author":"Fatima","year":"2018","journal-title":"Rawal Med J"},{"key":"2019111117210095400_ref26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1177\/1536867X1501500203","article-title":"Two-stage individual participant data meta-analysis and generalized forest plots","volume":"15","author":"Fisher","year":"2015","journal-title":"Stata J"},{"key":"2019111117210095400_ref27","doi-asserted-by":"crossref","first-page":"j573","DOI":"10.1136\/bmj.j573","article-title":"Meta-analytical methods to identify who benefits most from treatments: daft, deluded, or deft approach?","volume":"356","author":"Fisher","year":"2017","journal-title":"BMJ"},{"key":"2019111117210095400_ref28","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1210\/jcem.87.2.8261","article-title":"Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial","volume":"87","author":"Fleming","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2019111117210095400_ref29","first-page":"CD010287","article-title":"Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome","volume":"5","author":"Franik","year":"2018","journal-title":"Cochrane Database Syst Rev"},{"key":"2019111117210095400_ref30","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/S0015-0282(16)48915-6","article-title":"Behavioral and emotional factors and treatment responses in a study of anovulatory infertile women","volume":"44","author":"Garcia","year":"1985","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref31","author":"Higgins","year":"2011"},{"key":"2019111117210095400_ref32","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1093\/humrep\/der401","article-title":"Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study","volume":"27","author":"Homburg","year":"2012","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref33","first-page":"42","article-title":"Recombinant FSH compared to clomiphene citrate as the first-line in ovulation induction in polycystic ovary syndrome using newly designed pens: a randomized controlled trial","volume":"10","author":"Hossein-Rashidi","year":"2016","journal-title":"J Family Reprod Health"},{"key":"2019111117210095400_ref34","first-page":"E503","article-title":"Comparative study of efficacy among metformin, clomiphene citrate and aromatase inhibitor (letrozole) as the first-line medication for ovulation induction, achievement of pregnancy and live birth in Asian women with polycystic ovarian syndrome: a prospective trial","volume":"131","author":"Jahan","year":"2015","journal-title":"Int J Gynecol Obstet"},{"key":"2019111117210095400_ref35","doi-asserted-by":"crossref","first-page":"253","DOI":"10.7326\/0003-4819-154-4-201102150-00006","article-title":"Measuring the performance of markers for guiding treatment decisions","volume":"154","author":"Janes","year":"2011","journal-title":"Ann Intern Med"},{"key":"2019111117210095400_ref36","first-page":"265","article-title":"The efficacy of clomiphene citrate for induction of ovulation. A controlled study","volume":"11","author":"Johnson","year":"1966","journal-title":"Int J Fertil"},{"key":"2019111117210095400_ref37","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1093\/humrep\/deq100","article-title":"PCOSMIC: a multi-centre randomized trial in women with polycystic ovary syndrome evaluating metformin for infertility with clomiphene","volume":"25","author":"Johnson","year":"2010","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref38","doi-asserted-by":"crossref","first-page":"262","DOI":"10.4103\/0974-1208.106338","article-title":"Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: a prospective randomized trial","volume":"5","author":"Kar","year":"2012","journal-title":"J Hum Reprod Sci"},{"key":"2019111117210095400_ref39","doi-asserted-by":"crossref","first-page":"197","DOI":"10.4103\/0974-1208.170373","article-title":"Clomiphene citrate, metformin or a combination of both as the first line ovulation induction drug for Asian Indian women with polycystic ovarian syndrome: a randomized controlled trial","volume":"8","author":"Kar","year":"2015","journal-title":"J Hum Reprod Sci"},{"key":"2019111117210095400_ref40","first-page":"174","article-title":"The effect of administration of metformin on lipid profile changes and insulin resistance in patients with polycystic ovary syndrome","volume":"12","author":"Karimzadeh","year":"2007","journal-title":"Middle East Fertil Soc J"},{"key":"2019111117210095400_ref41","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.fertnstert.2009.02.078","article-title":"An assessment of lifestyle modification versus medical treatment with clomiphene citrate, metformin, and clomiphene citrate-metformin in patients with polycystic ovary syndrome","volume":"94","author":"Karimzadeh","year":"2010","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref42","first-page":"46","article-title":"Induction ovulation in polycystic ovary patient with clomiphene citrate and letrozole","volume":"9","author":"Keikha","year":"2011","journal-title":"Iran J Reprod Med"},{"key":"2019111117210095400_ref43","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.fertnstert.2005.10.042","article-title":"Two weeks of metformin improves clomiphene citrate-induced ovulation and metabolic profiles in women with polycystic ovary syndrome","volume":"85","author":"Khorram","year":"2006","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref44","first-page":"299","article-title":"Ovulation induction with clomiphene citrate and metformin in women with polycystic ovary syndrome","volume":"66","author":"Leanza","year":"2014","journal-title":"Minerva Ginecol"},{"key":"2019111117210095400_ref45","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1056\/NEJMoa063971","article-title":"Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome","volume":"356","author":"Legro","year":"2007","journal-title":"N Engl J Med"},{"key":"2019111117210095400_ref46","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1056\/NEJMoa1313517","article-title":"Letrozole versus clomiphene for infertility in the polycystic ovary syndrome","volume":"371","author":"Legro","year":"2014","journal-title":"N Engl J Med"},{"key":"2019111117210095400_ref47","first-page":"1","article-title":"Comparison of clomiphene citrate and letrozole for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial","author":"Liu","year":"2017","journal-title":"Gynecol Endocrinol"},{"key":"2019111117210095400_ref48","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.fertnstert.2016.05.003","article-title":"Criteria, prevalence, and phenotypes of polycystic ovary syndrome","volume":"106","author":"Lizneva","year":"2016","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref49","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/S1472-6483(10)61273-4","article-title":"Ovulation induction in women with polycystic ovary syndrome: randomized trial of clomiphene citrate versus low-dose recombinant FSH as first line therapy","volume":"9","author":"Lopez","year":"2004","journal-title":"Reprod Biomed Online"},{"key":"2019111117210095400_ref50","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1111\/j.1471-0528.2006.00966.x","article-title":"The effect of metformin on fat distribution and the metabolic syndrome in women with polycystic ovary syndrome--a randomised, double-blind, placebo-controlled trial","volume":"113","author":"Lord","year":"2006","journal-title":"BJOG"},{"key":"2019111117210095400_ref51","article-title":"Comparison of effects letrozole and clomiphene citrate for ovulation induction in women with polycystic ovary syndrome [in Persian]","volume":"14","author":"Lorzadeh","year":"2011","journal-title":"Iran J Obstet Gynecol Infertil"},{"key":"2019111117210095400_ref52","doi-asserted-by":"crossref","DOI":"10.3109\/09513590.2015.1037269","article-title":"The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with polycystic ovary syndrome","author":"Maged","year":"2015","journal-title":"Gynecol Endocrinol"},{"key":"2019111117210095400_ref53","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0015-0282(00)01705-2","article-title":"Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate","volume":"75","author":"Mitwally","year":"2001","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref54","first-page":"905","article-title":"Comparison of the efficacy of letrozole and clomiphene citrate for ovulation induction in infertile women with polycystic ovary syndrome","volume":"8","author":"Mobusher","year":"2014","journal-title":"Pak J Med Health Sci"},{"key":"2019111117210095400_ref55","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1136\/bmj.38867.631551.55","article-title":"Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial","volume":"332","author":"Moll","year":"2006","journal-title":"BMJ"},{"key":"2019111117210095400_ref56","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1210\/jc.2011-3061","article-title":"Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial","volume":"97","author":"Morin-Papunen","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2019111117210095400_ref57","first-page":"CD003053","article-title":"Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility","volume":"11","author":"Morley","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"2019111117210095400_ref58","doi-asserted-by":"crossref","first-page":"88","DOI":"10.5530\/ami.2016.2.19","article-title":"The effect of clomiphene citrate versus tamoxifen versus letrozol on endometrial thickness and blood flow in ovulation induction in women with polycystic ovaries","volume":"3","author":"Moussa","year":"2016","journal-title":"Acta Medica Int"},{"key":"2019111117210095400_ref59","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1093\/humupd\/dmv025","article-title":"Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis","volume":"21","author":"Naderpoor","year":"2015","journal-title":"Hum Reprod Update"},{"key":"2019111117210095400_ref60","first-page":"879","article-title":"Comparison of efficacy of letrozole and clomiphene citrate in ovulation induction for women with polycystic ovarian syndrome","volume":"6","author":"Nazik","year":"2012","journal-title":"HealthMED"},{"key":"2019111117210095400_ref61","doi-asserted-by":"crossref","first-page":"4068","DOI":"10.1210\/jc.2005-0110","article-title":"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","volume":"90","author":"Palomba","year":"2005","journal-title":"J Clinical Endocrinol Metab"},{"key":"2019111117210095400_ref62","doi-asserted-by":"crossref","first-page":"j3932","DOI":"10.1136\/bmj.j3932","article-title":"Multivariate and network meta-analysis of multiple outcomes and multiple treatments: rationale, concepts, and examples","volume":"358","author":"Riley","year":"2017","journal-title":"BMJ"},{"key":"2019111117210095400_ref63","doi-asserted-by":"crossref","first-page":"c221","DOI":"10.1136\/bmj.c221","article-title":"Meta-analysis of individual participant data: rationale, conduct, and reporting","volume":"340","author":"Riley","year":"2010","journal-title":"BMJ"},{"key":"2019111117210095400_ref64","doi-asserted-by":"crossref","first-page":"S273","DOI":"10.1016\/S0015-0282(03)01695-9","article-title":"Metformin added to clomiphene citrate does not improve pregnancy rates in hyperandrogenic, chronic anovulatory women: a randomized trial","volume":"80","author":"Robinson","year":"2003","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref65","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/humrep\/deh098","article-title":"Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)","volume":"19","author":"Rotterdam ESHRE\/ASRM-Sponsored PCOS Consensus Workshop Group","year":"2004","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref66","doi-asserted-by":"crossref","first-page":"20","DOI":"10.4103\/0974-1208.97789","article-title":"A prospective randomized trial comparing the efficacy of letrozole and clomiphene citrate in induction of ovulation in polycystic ovarian syndrome","volume":"5","author":"Roy","year":"2012","journal-title":"J Hum Reprod Sci"},{"key":"2019111117210095400_ref67","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.ejogrb.2003.09.036","article-title":"The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome","volume":"113","author":"Sahin","year":"2004","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2019111117210095400_ref68","first-page":"455","article-title":"Comparison between clomiphene citrate and metformin for induction of ovulatory cycles in infertile nonobese women with polycystic ovary syndrome [in Italian]","volume":"31","author":"Santonocito","year":"2009","journal-title":"Giornale Italiano di Ostetricia e Ginecologia"},{"key":"2019111117210095400_ref69","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1089\/gyn.2012.0033","article-title":"Letrozole and clomiphene citrate effect on endometrial and subendometrial vascularity in treating infertility in women with polycystic ovary syndrome","volume":"28","author":"Selim","year":"2012","journal-title":"J Gynecol Surg"},{"key":"2019111117210095400_ref70","first-page":"531","article-title":"Comparison of the effectiveness of clomiphene citrate, tamoxifen and letrozole in ovulation induction in infertility due to isolated unovulation","volume":"10","author":"Seyedoshohadaei","year":"2012","journal-title":"Iran J Reprod Med"},{"key":"2019111117210095400_ref71","first-page":"1149","article-title":"Comparison of letrazole and clomiphene citrate in women with polycystic ovaries undergoing ovarian stimulation","volume":"65","author":"Sharief","year":"2015","journal-title":"J Pak Med Assoc"},{"key":"2019111117210095400_ref72","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.mefs.2010.11.004","article-title":"Predictors and characteristics of letrozole induced ovulation in comparison with clomiphene induced ovulation in anovulatory PCOS women","volume":"16","author":"Sheikh-El-Arab Elsedeek","year":"2011","journal-title":"Middle East Fertil Soc J"},{"key":"2019111117210095400_ref73","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1001\/jama.2015.3656","article-title":"Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD statement","volume":"313","author":"Stewart","year":"2015","journal-title":"JAMA"},{"key":"2019111117210095400_ref74","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1093\/humrep\/dei311","article-title":"Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study","volume":"21","author":"Tang","year":"2006","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref75","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1093\/humrep\/dey256","article-title":"Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome","volume":"33","author":"Teede","year":"2018","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref76","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1016\/j.jclinepi.2015.05.024","article-title":"How individual participant data meta-analyses have influenced trial design, conduct, and analysis","volume":"68","author":"Tierney","year":"2015","journal-title":"J Clin Epidemiol"},{"key":"2019111117210095400_ref77","first-page":"507","article-title":"Tamoxifen versus clomiphene citrate for ovulation induction in women with polycystic ovary syndrome: a prospective randomized trial","volume":"62","author":"Top\u00e7u","year":"2017","journal-title":"J Reprod Med"},{"key":"2019111117210095400_ref78","first-page":"S234","author":"Vegetti","year":"1999"},{"key":"2019111117210095400_ref79","doi-asserted-by":"crossref","first-page":"j138","DOI":"10.1136\/bmj.j138","article-title":"Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis","volume":"356","author":"Wang","year":"2017","journal-title":"BMJ"},{"key":"2019111117210095400_ref80","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/humrep\/dew287","article-title":"The Rotterdam criteria for polycystic ovary syndrome: evidence-based criteria?","volume":"32","author":"Wang","year":"2017","journal-title":"Hum Reprod"},{"key":"2019111117210095400_ref81","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1177\/1536867X1501500403","article-title":"Network meta-analysis","volume":"15","author":"White","year":"2015","journal-title":"Stata Journal"},{"key":"2019111117210095400_ref82","doi-asserted-by":"crossref","first-page":"S105","DOI":"10.1016\/j.fertnstert.2009.07.1076","article-title":"A randomized, placebo-controlled study of the influence of instant-release metformin on response to clomiphene citrate and time to conception in polycystic ovary syndrome","volume":"92","author":"Williams","year":"2009","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref83","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1001\/jama.2017.7217","article-title":"Effect of acupuncture and clomiphene in Chinese women with polycystic ovary syndrome: a randomized clinical trial","volume":"317","author":"Wu","year":"2017","journal-title":"JAMA"},{"key":"2019111117210095400_ref84","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.fertnstert.2007.12.002","article-title":"Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial","volume":"91","author":"Zain","year":"2009","journal-title":"Fertil Steril"},{"key":"2019111117210095400_ref85","first-page":"36","article-title":"Efficacy of letrozole in ovulation induction compared to that of clomiphene citrate in patients with polycystic ovarian syndrome","volume":"55","author":"Zeinalzadeh","year":"2010","journal-title":"J Reprod Med"}],"container-title":["Human Reproduction Update"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/humupd\/article-pdf\/25\/6\/717\/30648114\/dmz029.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/humupd\/article-pdf\/25\/6\/717\/30648114\/dmz029.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,11,11]],"date-time":"2019-11-11T17:28:10Z","timestamp":1573493290000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humupd\/article\/25\/6\/717\/5603051"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,23]]},"references-count":85,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,10,23]]},"published-print":{"date-parts":[[2019,11,5]]}},"URL":"https:\/\/doi.org\/10.1093\/humupd\/dmz029","relation":{},"ISSN":["1355-4786","1460-2369"],"issn-type":[{"value":"1355-4786","type":"print"},{"value":"1460-2369","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,11]]},"published":{"date-parts":[[2019,10,23]]}}}