title: Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial.
abstract: OBJECTIVE
  To estimate the efficacy of a fixed estrogen step-down and progestin step-up 28-day estradiol (E2) valerate and dienogest oral contraceptive regimen in women with heavy menstrual bleeding, prolonged menstrual bleeding, or heavy and prolonged menstrual bleeding without organic pathology.
  
  
  METHODS
  This double-blind, placebo-controlled study randomized women aged 18 years or older with prolonged, frequent, or heavy menstrual bleeding, objectively confirmed during a 90-day run-in phase, to treatment with E2 valerate and dienogest or placebo (2:1) for 196 days. Data from the last 90 days of treatment and the run-in phase were compared. The primary variable was the "complete response" rate (complete resolution of qualifying abnormal menstrual symptoms, including a 50% or greater reduction in pretreatment menstrual blood loss volume in women with heavy menstrual bleeding). Secondary variables included objective changes in menstrual blood loss volume (alkaline hematin methodology) and iron metabolism parameters. Overall, 180 women were needed to provide 90% power.
  
  
  RESULTS
  There were no marked differences in the characteristics of E2 valerate and dienogest (n=120) and placebo (n=70) recipients. The proportion of "complete responders" in the evaluable group was significantly higher in E2 valerate and dienogest (35/80; 43.8%) compared with placebo (2/48, 4.2%, P<.001) recipients. The mean [standard deviation] reduction in menstrual blood loss with E2 valerate and dienogest from the run-in phase to the efficacy phase was substantial (-353 mL [309 mL]; mean -64.2%; median -70.6%) and significantly greater than that in placebo recipients (-130 mL [338 mL]; mean -7.8%; median -18.7%; P<.001). Significant improvements in hemoglobin, hematocrit, and ferritin were seen with E2 valerate and dienogest, but not with placebo.
  
  
  CONCLUSIONS
  Oral E2 valerate and dienogest was highly effective compared with placebo in the treatment of women with heavy menstrual bleeding, prolonged menstrual bleeding, or heavy and prolonged menstrual bleeding without organic pathology.
  
  
  BACKGROUND
  ClinicalTrials.gov, www.clinicaltrials.gov, NCT00293059.
  
  
  METHODS
  I.
authors.affiliation: From the Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon; the Departments of Clinical Development, Clinical Statistics, and Global Medical Affairs Women's Healthcare, Bayer HealthCare Pharmaceuticals, Berlin, Germany; and the Department of Reproductive Medicine, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Jensen
authors.forename: Susanne
authors.initials: S
authors.lastname: Parke
authors.forename: Uwe
authors.initials: U
authors.lastname: Mellinger
authors.forename: Andrea
authors.initials: A
authors.lastname: Machlitt
authors.forename: Ian S
authors.initials: IS
authors.lastname: Fraser
mesh_terms: D000328:Adult; D016001:Confidence Intervals; D003276:Contraceptives, Oral / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D008595:Menorrhagia / Q000175:diagnosis / Q000188:drug therapy*; D009277:Nandrolone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017060:Patient Satisfaction; D011788:Quality of Life; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D003276:Contraceptives, Oral; C023635:dienogest; D004958:Estradiol; D009277:Nandrolone