title: Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis.
abstract: BACKGROUND
  To date, no systematic review or meta-analysis has been published of direct head-to-head studies comparing clomiphene citrate (CC) vs. metformin, or the combination of both drugs as first-line therapy in anovulatory polycystic ovary syndrome (PCOS) patients seeking pregnancy. The aim of the current paper was to define, if possible, the best evidence-based recommendations regarding the use of CC and/or metformin as the initial treatment of PCOS women with anovulatory infertility.
  
  
  METHODS
  Systematic review and meta-analysis of the head-to-head randomized controlled trials (RCTs) available in the literature.
  
  
  METHODS
  A bibliographic search was performed using the following bibliographic databases: Medline, EMBASE, Biological Abstracts, Cochrane Controlled Trials Register and Cochrane Database of Systematic Reviews. Reference lists of included studies, other relevant review articles and textbooks were checked for additional citations of interest.
  
  
  RESULTS
  Four head-to-head RCTs were identified and qualified for inclusion in the analysis. No difference in fertility improvement was observed comparing CC with metformin (OR = 1.22, 95% CI 0.23-6.55, P = 0.815), whereas a significant (P < 0.0001) heterogeneity was observed. Homogeneous data showed no difference in fertility improvement between the combination treatment and CC monotherapy (OR = 0.99, 95% CI 0.70-1.40, P = 0.982), but a significant difference in comparison with metformin monotherapy (OR = 0.23, 95% CI 0.14-0.37, P < 0.0001).
  
  
  CONCLUSIONS
  In PCOS patients with anovulatory infertility and not previously treated, the administration of metformin plus CC is not better than monotherapy (metformin alone or CC alone), whereas to date no specific recommendation can be given regarding the use of CC or metformin as first-step drug.
authors.affiliation: Chair of Gynecology & Obstetrics, University Magna Graecia of Catanzaro, Catanzaro, Italy. stefanopalomba@tin.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Palomba
authors.forename: Renato
authors.initials: R
authors.lastname: Pasquali
authors.forename: Francesco
authors.initials: F
authors.lastname: Orio
authors.forename: John E
authors.initials: JE
authors.lastname: Nestler
mesh_terms: D000858:Anovulation / Q000188:drug therapy / Q000209:etiology; D002996:Clomiphene / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000188:drug therapy* / Q000209:etiology; D008687:Metformin / Q000627:therapeutic use*; D011085:Polycystic Ovary Syndrome / Q000150:complications / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic
chemical_list: D002996:Clomiphene; D008687:Metformin