title: Clomiphene citrate and letrozole to reduce follicle-stimulating hormone consumption during ovarian stimulation: systematic review and meta-analysis.
abstract: OBJECTIVE
  To assess the available evidence comparing effectiveness of ovarian stimulation (OS) using clomiphene citrate (CC) and/or letrozole (LTZ) to reduce follicle-stimulating hormone (FSH) consumption compared with standard OS.
  
  
  METHODS
  We performed a systematic review and meta-analysis of randomized controlled trials that compared reproductive outcomes following in-vitro fertilization. We searched 11 electronic databases and hand-searched the reference lists of included studies and related reviews. We stratified the results, separating studies according to the oral agent used (CC or LTZ) and the characteristics of the included women (expected poor ovarian response or other women). When combining the results of the included studies, we assessed the relative risk (RR) for live birth, clinical pregnancy, miscarriage and cycle cancelation, the Peto odds ratio (OR) for ovarian hyperstimulation syndrome (OHSS) and mean difference (MD) for the number of oocytes retrieved and FSH consumption.
  
  
  RESULTS
  A total of 22 studies were included in the review. Considering women with expected poor ovarian response, the available evidence suggested that using CC to reduce FSH consumption during OS provided similar rates of live birth (RR, 0.9 (95% CI, 0.6-1.2), moderate-quality evidence) and clinical pregnancy (RR, 1.0 (95% CI, 0.8-1.4), moderate-quality evidence); the use of LTZ did not cause a relevant change in the number of oocytes retrieved (MD, -0.4 (95% CI, -0.9 to 0.1), high-quality evidence). Considering the studies evaluating other women, the available evidence suggested that using CC to reduce FSH consumption during OS reduced the number of oocytes retrieved (MD, -4.6 (95% CI, -6.1 to -3.0), high-quality evidence) and risk of OHSS (Peto OR, 0.2 (95% CI, 0.1-0.3), moderate-quality evidence), while results were similar for rates of live birth (RR, 0.9 (95% CI, 0.7-1.1), moderate-quality evidence) and clinical pregnancy (RR, 1.0 (95% CI, 0.8-1.1), high-quality evidence). The quality of the evidence was low or very low for other outcomes.
  
  
  CONCLUSIONS
  The use of CC to reduce FSH consumption in women with expected poor ovarian response has the advantage of providing similar reproductive outcomes with reduced costs. For the other women, the use of CC for reducing FSH consumption has the additional advantage of reducing OHSS, but also reduces the total number of oocytes retrieved. More studies are needed to evaluate the effect of LTZ for the same purpose. Future studies should focus on cumulative pregnancy per oocyte retrieval, patient dissatisfaction and agreement to repeat the cycle if not pregnant, which are important outcomes for clinical decisions. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
authors.affiliation: SEMEAR Fertilidade, Reproductive Medicine, Ribeirão Preto, Brazil.|Department of Obstetrics and Gynecology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: T N
authors.initials: TN
authors.lastname: Bechtejew
authors.affiliation: SEMEAR Fertilidade, Reproductive Medicine, Ribeirão Preto, Brazil.|Department of Obstetrics and Gynecology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: M N
authors.initials: MN
authors.lastname: Nadai
authors.affiliation: SEMEAR Fertilidade, Reproductive Medicine, Ribeirão Preto, Brazil.
authors.forename: C O
authors.initials: CO
authors.lastname: Nastri
authors.affiliation: SEMEAR Fertilidade, Reproductive Medicine, Ribeirão Preto, Brazil.|Department of Obstetrics and Gynecology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: W P
authors.identifier: http://orcid.org/0000-0002-7593-5607
authors.initials: WP
authors.lastname: Martins
mesh_terms: D002996:Clomiphene / Q000494:pharmacology*; D004624:Embryo Transfer; D005260:Female; D005307:Fertilization in Vitro; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006801:Humans; D000077289:Letrozole; D009570:Nitriles / Q000494:pharmacology*; D010062:Ovulation Induction / Q000379:methods*; D011247:Pregnancy; D011256:Pregnancy Outcome; D016032:Randomized Controlled Trials as Topic; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D009570:Nitriles; D014230:Triazoles; D002996:Clomiphene; D000077289:Letrozole; D005640:Follicle Stimulating Hormone
keywords: ICSI; IVF; clomiphene; embryo transfer; in-vitro fertilization; infertility; letrozole; ovarian stimulation