Transdermal Estrogen Effective for Low Sexual Function

Ricki Lewis, PhD

August 28, 2017

Estradiol delivered via patch is effective at alleviating vaginal dryness and pain with intercourse in women within 3 years of beginning menopause, according to a report published online August 28 in JAMA Internal Medicine.

Many studies have shown efficacy of exogenous estrogens, given either alone or with progestogens, in ameliorating symptoms of menopause, such as vaginal dryness, pain on intercourse, and lower libido, but delivery route and estrogen composition have been less thoroughly investigated.

Therefore, Hugh S Taylor, MD, from the department of obstetrics, gynecology, and reproductive sciences, Yale School of Medicine, New Haven, Connecticut, and colleagues compared the effects of oral and transdermal estrogen therapy vs placebo on sexual function. They hypothesized that transdermal estradiol (t-E2) might more effectively treat sexual dysfunction in early postmenopausal women than oral estrogens because of an E2-to-estrone ratio more like that of the premenopausal period.

The researchers analyzed data from the Kronos Early Estrogen Prevention Study (KEEPS), which is a randomized, double-blinded, placebo-controlled, multicenter trial that was designed to test whether estrogen-replacement therapy slows progression of atherosclerosis when begun within 36 months of the last menstrual period. The new investigation, which was not a preplanned analysis, compared the efficacy of transdermal 17β-estradiol (t-E2) or oral conjugated equine estrogen (o-CEE) to placebo on menopause symptoms and sexual function over 4 years.

Of the 727 KEEPS participants, 670 took part in the ancillary study on sexual function. The women were 42 to 58 years old (mean, 52.7 years) and within 36 months of the last menstrual period at enrollment, which occurred from July 2005 through June 2008. Data were collected through March 2012.

For 12 days each month, participants received either 0.45-mg/day o-CEE with placebo patch, 50-μg/day t-E2 with placebo pills, or both placebo patches and pills. Those with active pills or patches also received 200-mg micronized progesterone.

The protocol assayed sex hormone–binding globulin (SHBG) level at baseline and 36 and 48 months. Participants took the Female Sexual Function Inventory (FSFI) questionnaire, which assesses desire, arousal, lubrication, orgasm, satisfaction, and pain. Scores below 26.55 indicate female sexual dysfunction, but the researchers consider what they assessed to be "low sexual function," because the Diagnostic and Statistical Manual of Mental Disorders requires clinically significant distress in addition to sexual symptoms for sexual-dysfunction diagnosis, and the new analysis did not assess distress.

At 48 months, the t-E2 treatment was associated with a significant, moderate improvement in FSFI score at all times compared with placebo (average efficacy, 2.6-points higher score; 95% confidence interval [CI], 1.11–4.10; adjusted = .002). In contrast, o-CEE showed no significant difference in FSFI overall score compared with placebo (mean efficacy, 1.4; 95% CI, −0.1 to 2.8; adjusted = .13). However, no difference in score was evidenced between the two treatment groups by 48 months (adjusted = .22).

Transdermal delivery helped in lubrication and pain with intercourse, compared with placebo, but was not associated with improvements in the other components of the score. Desire, arousal, orgasm, and sexual satisfaction improved only modestly at the 18-month mark with t-E2 but declined after that time.

"The hypothesis was that pharmacologically and physiologically, if the transdermal patch didn't upset binding globulins, then you wouldn't reduce the circulating androgens, so you should see more progress in some signs of sexual desire. But this didn't turn out to be true," said Owen Montgomery, MD, professor and chair, obstetrics and gynecology, Drexel University, Philadelphia, Pennsylvania, who was not involved in the trial. SHBG levels remained stable over time in the placebo- and t-E2–treated groups but increased significantly in the o-CEE treatment group.

"The evidence that the positive effect of transdermal E2 on libido and arousal is significantly more evident only at 18 months against oral CEE is intriguing and suggests that the biopsychosocial model has to be taken into account when investigating sexual domains related to mental components. Partner-related issues and other life events may play a role in sexual motivation and satisfaction over time, irrespective of the type of treatment," said Rossella E Nappi, MD, PhD, a professor of obstetrics and gynecology at the University of Pavia, Italy, who also was not involved in the study.

Dr Montgomery also noted that the medications have a greater effect on women who score lower to begin with and that a subset analysis revealed slightly more women in the transdermal group with a lower baseline score. However, "women who use estrogen in any form improve, and there are similarities between oral and transdermal and there may be slight differences," he concluded.

A limitation of the study is that the population was mostly white, highly educated women, and thus it is not clear if the findings can be generalized to other groups.

Dr Taylor reports grant support from Pfizer through Yale University and consultation fees from Pfizer; disclosures for the coauthors are listed in the paper.  Dr Nappi has served as a consultant or advisory board member or speaker for Bayer, Endoceutics, Gedeon Richter, MSD, Novo Nordisk, Pfizer, Shionogi, and Teva. Dr Montgomery has no relevant financial relationships.  

JAMA Intern Med. Published online August 28, 2017. Article

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