title: Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial.
abstract: OBJECTIVE
  Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date.
  
  
  OBJECTIVE
  To determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS).
  
  
  METHODS
  In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012.
  
  
  METHODS
  Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks.
  
  
  METHODS
  The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments.
  
  
  RESULTS
  Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated.
  
  
  CONCLUSIONS
  Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01418209.
authors.affiliation: Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts2Department of Psychosocial Oncology and Palliative Care, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts3Department of Psychi.
authors.forename: Hadine
authors.initials: H
authors.lastname: Joffe
authors.affiliation: MsFLASH Data Coordinating Center, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Guthrie
authors.affiliation: MsFLASH Data Coordinating Center, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: LaCroix
authors.affiliation: Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Reed
authors.affiliation: Division of Epidemiology and Community Health, Department of Medicine, Veterans Affairs Health System, Minneapolis, Minnesota7Department of Medicine, University of Minnesota, Minneapolis.
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Ensrud
authors.affiliation: Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: JoAnn E
authors.initials: JE
authors.lastname: Manson
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Newton
authors.affiliation: Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia10Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Ellen W
authors.initials: EW
authors.lastname: Freeman
authors.affiliation: MsFLASH Data Coordinating Center, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Garnet L
authors.initials: GL
authors.lastname: Anderson
authors.affiliation: MsFLASH Data Coordinating Center, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Larson
authors.affiliation: MsFLASH Data Coordinating Center, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Julie
authors.initials: J
authors.lastname: Hunt
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Jan
authors.initials: J
authors.lastname: Shifren
authors.affiliation: Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Rexrode
authors.affiliation: Division of Research, Kaiser Permanente of Northern California, Oakland.
authors.forename: Bette
authors.initials: B
authors.lastname: Caan
authors.affiliation: Division of Research, Kaiser Permanente of Northern California, Oakland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sternfeld
authors.affiliation: School of Nursing, Indiana University, Indianapolis.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Carpenter
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Lee
authors.initials: L
authors.lastname: Cohen
mesh_terms: D000328:Adult; D003511:Cyclohexanols / Q000627:therapeutic use*; D004958:Estradiol / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D005260:Female; D019584:Hot Flashes / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D017060:Patient Satisfaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride
chemical_list: D003511:Cyclohexanols; D004958:Estradiol; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride