Vaginal tablets increase serum estradiol levels for postmenopausal women

Postmenopausal women with moderate to severe genitourinary syndrome experienced small but significant increases in serum estradiol after using vaginal estradiol tablets for 12 weeks, according to a post hoc analysis in JAMA Network Open.

The researchers cautioned that the clinical significance of this increase was likely limited.

“Current guidance from ACOG considers low-dose vaginal estrogen a reasonable treatment choice [for genitourinary symptoms] for women with a history of estrogen-dependent breast cancer,” Caroline M. Mitchell, MD, MPH, director of the vulvovaginal disorders program at Massachusetts General Hospital in Boston, and colleagues wrote.

However, there are no data on the risk for breast cancer with use of vaginal estrogen preparations and little data available on safe estradiol concentration for use by postmenopausal women, according to the study.

Mitchell and colleagues conducted a secondary analysis of the MsFLASH Vaginal Health Trial, which was a randomized, double-blind, placebo-controlled, 12-week clinical trial conducted between April 11, 2016, and April 23, 2017, at Kaiser Permanente Washington Health Research Institute in Seattle and the University of Minnesota, Minneapolis.

The secondary analysis included data from 174 postmenopausal women aged 45 to 70 years who had moderate to severe genitourinary syndrome, 88 of whom were assigned to vaginal estradiol tablet 10 µg plus placebo gel and 86 of whom were assigned to placebo tablet and gel. Participants completed questionnaires on bothersome vaginal symptom severity, sexual activity, quality of life during menopause, depression, anxiety and insomnia and provided blood samples at enrollment and week 12.

Women in the estradiol group had higher estradiol levels at week 12 compared with the placebo group (geometric mean, 4.3 pg/mL vs. 3.5 pg/mL; P = .01). Adjusting for baseline hormone concentrations, age, location and BMI, use of estradiol tablets vs. placebo was associated with significantly higher estradiol levels at 12 weeks (difference, 23.8%; 95% CI, 6.9%-43.3%).

“To better evaluate the potential clinical relevance of this association, we compared characteristics between women with 12-week estradiol concentrations higher than vs. lower than or equal to the value (2.7 pg/mL) previously shown to be associated with an increased risk for breast cancer,” Mitchell and colleagues wrote.

Most women (69.5%) had estradiol levels above 2.7 pg/mL at baseline, with 21 women in the estradiol group and 32 women in the placebo group having concentrations at or below the threshold. Of these, eight (38.1%) women in the estradiol group and 11 (34.4%) in the placebo group had estradiol levels above 2.7 pg/mL at week 12.

Of note, there was no association between assignment to estradiol tablets and levels of estrone and sex hormone-binding globulin.

“Definitively answering the question of whether low-dose vaginal estrogen preparations are safe would require a very large randomized clinical trial,” the researchers wrote.