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Original Investigation
October 2017

Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early PostmenopauseAncillary Study of the Kronos Early Estrogen Prevention Study (KEEPS)

Author Affiliations
  • 1Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
  • 2Yale Center for Analytical Sciences, Yale University School of Public Health, New Haven, Connecticut
  • 3Epidemiology and Biostatistics, University of California at San Francisco
  • 4Utah Foundation for Biomedical Research, Salt Lake City
  • 5Division of Cardiology, Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, California
  • 6Obstetrics and Gynecology, University of California at San Francisco
  • 7Atherosclerosis Research Unit, University of Southern California, Los Angeles
  • 8Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York
  • 9Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 10Veterans Affairs Puget Sound Health Care System, Tacoma, Washington
  • 11Division of Metabolism, Endocrinology and Nutrition, University of Washington, Tacoma
  • 12Department of Surgery, Mayo Clinic, Rochester, Minnesota
  • 13Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
  • 14Obstetrics and Gynecology, New York University School of Medicine, New York
  • 15Division of Reproductive Endocrinology and Infertility, University of Washington Medical School, Seattle
  • 16Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora
  • 17Kronos Longevity Research Institute, Phoenix, Arizona
  • 18Division of Endocrinology, Phoenix Veterans Affairs Medical Center, Phoenix, Arizona
JAMA Intern Med. 2017;177(10):1471-1479. doi:10.1001/jamainternmed.2017.3877
Key Points

Question  What are the effects of transdermal or oral estrogen therapy on sexual function in recently postmenopausal women over time?

Findings  In this ancillary study of a randomized clinical trial that included 670 healthy menopausal women within 3 years of their last menstrual period, transdermal estradiol improved overall sexual function score compared with placebo.

Meaning  Transdermal estradiol therapy may improve sexual function in postmenopausal women with low sexual function.


Importance  Sexual dysfunction, an important determinant of women’s health and quality of life, is commonly associated with declining estrogen levels around the menopausal transition.

Objective  To determine the effects of oral or transdermal estrogen therapy vs placebo on sexual function in postmenopausal women.

Design, Setting, and Participants  Ancillary study of the Kronos Early Estrogen Prevention Study (KEEPS), a 4-year prospective, randomized, double-blinded, placebo-controlled trial of menopausal hormone therapy in healthy, recently menopausal women. Of 727 KEEPS enrollees, 670 agreed to participate in this multicenter ancillary study. Women were 42 to 58 years old, within 36 months from last menstrual period. Data were collected from July 2005 through June 2008 and analyzed from July 2010 through June 2017.

Interventions  Women were randomized to either 0.45 mg/d oral conjugated equine estrogens (o-CEE), 50 µg/d transdermal 17β-estradiol (t-E2), or placebo. Participants also received 200 mg oral micronized progesterone (if randomized to o-CEE or t-E2) or placebo (if randomized to placebo estrogens) for 12 days each month.

Main Outcomes and Measures  Aspects of sexual function and experience (desire, arousal, lubrication, orgasm, satisfaction, and pain) were assessed using the Female Sexual Function Inventory (FSFI; range, 0-36 points; higher scores indicate better sexual function). Low sexual function (LSF) was defined as an FSFI overall score of less than 26.55. Distress related to low FSFI score (required for the diagnosis of sexual dysfunction) was not evaluated.

Results  The 670 participants had a mean (SD) age of 52.7 (2.6) years. The t-E2 treatment was associated with a significant yet moderate improvement in the FSFI overall score across all time points compared with placebo (average efficacy, 2.6; 95% CI, 1.11-4.10; adjusted P = .002). With o-CEE treatment, there was no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, −0.1 to 2.8; adjusted P = .13). There was no difference in FSFI overall score between the t-E2 and o-CEE groups on average across 48 months (adjusted P = .22). In the individual domains of sexual function, t-E2 treatment was associated with a significant increase in mean lubrication (0.61; 95% CI, 0.25-0.97; P = .001) and decreased pain (0.67; 95% CI, 0.25-1.09; P = .002) compared with placebo. Overall, the proportion of women with LSF was significantly lower after t-E2 treatment compared with placebo (67%; 95% CI, 55%-77% vs 76%; 95% CI, 67%-83%; P = .04). For o-CEE there was no significant reduction in the odds of LSF.

Conclusions and Relevance  Treatment with t-E2 modestly improved sexual function in early postmenopausal women, but whether it relieved symptoms of distress is not known.

Trial Registration  clinicaltrials.gov Identifier: NCT00154180