title: Combined metformin-clomiphene in clomiphene-resistant polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.
abstract: OBJECTIVE
  Our objective was to compare the effectiveness of metformin plus clomiphene citrate vs. gonadotrophins, laparoscopic ovarian diathermy, aromatase inhibitors, N-acetyl-cysteine and other insulin sensitizers+clomiphene for improving fertility outcomes in women with clomiphene-resistant polycystic ovary syndrome.
  
  
  METHODS
  PubMed, SCOPUS and CENTRAL databases were searched until April 2014 with the key words: PCOS, polycystic ovary syndrome, metformin, clomiphene citrate, ovulation induction and pregnancy. The search was limited to articles conducted with humans and published in English.
  
  
  METHODS
  The PRISMA statement was followed. Twelve randomized controlled trials (n = 1411 women) were included.
  
  
  METHODS
  Ovulation and clinical pregnancy rates per woman randomized.
  
  
  RESULTS
  Compared with gonadotrophins, the metformin+clomiphene combination resulted in significantly fewer ovulations (odds ratio 0.25; 95% confidence interval 0.15-0.41; p < 0.00001, 3 trials, I(2) = 85%, n = 323) and pregnancies (odds ratio 0.45; 95% confidence interval 0.27-0.75; p = 0.002, 3 trials, I(2) = 0%, n = 323). No significant differences were found when metformin+clomiphene was compared with laparoscopic ovarian diathermy (odds ratio 0.88; 95% confidence interval 0.53-1.47; p = 0.62, 1 trial, n = 282; odds ratio 0.96; 95% confidence interval 0.60-1.54; p = 0.88, 2 trials, I(2) = 0%, n = 332, for ovulation and pregnancy rates, respectively). Likewise, no differences were observed in comparison with aromatase inhibitors (odds ratio 0.88; 95% confidence interval 0.58-1.34; p = 0.55, 3 trials, I(2) = 3%, n = 409; odds ratio 0.85; 95% confidence interval 0.53-1.36; p = 0.50, 2 trials, n = 309, for ovulation and pregnancy rates, respectively).
  
  
  CONCLUSIONS
  There is evidence for the superiority of gonadotrophins, but the metformin+clomiphene combination is mainly relevant for clomiphene-resistant polycystic ovary syndrome patients and, if not effective, a next step could be gonadotrophins. More attempts with metformin+clomiphene are only relevant if there is limited access to gonadotrophins.
authors.affiliation: Department of Obstetrics & Gynecology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Hatem
authors.initials: H
authors.lastname: Abu Hashim
authors.affiliation: Department of Internal Medicine, Endocrinology Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Osama
authors.initials: O
authors.lastname: Foda
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Essam
authors.initials: E
authors.lastname: Ghayaty
mesh_terms: D002996:Clomiphene / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005300:Fertility Agents, Female / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D011085:Polycystic Ovary Syndrome / Q000628:therapy*; D011247:Pregnancy; D018873:Pregnancy Rate
chemical_list: D005300:Fertility Agents, Female; D007004:Hypoglycemic Agents; D002996:Clomiphene; D008687:Metformin
keywords: Polycystic ovary syndrome; clomiphene citrate; metformin; ovulation induction; pregnancy