Changes in serum endogenous estrogen concentrations are mediators of the effect of low-dose oral estradiol on vasomotor symptoms

Objectives The aim of this study was to quantify changes in serum total estradiol (E2) and estrone (E1) concentrations with initiation of low-dose oral estradiol treatment and evaluate whether changes in concentrations mediate the effect of treatment in reducing vasomotor symptom (VMS) frequency. Methods We analyzed baseline and week 8 (W8) data from 171 perimenopausal and postmenopausal women with VMS enrolled in low-dose 17 beta estradiol (n = 72) and placebo (n = 99) groups of a randomized clinical trial. Results From baseline to W8, women in the low-dose estradiol group had a fourfold increase in E2, resulting in a W8 E2 of 23 pg/mL, and a fivefold increase in E1, resulting in a W8 E1 of 110.7 pg/mL. In contrast, E2 and E1 among women in the placebo group were unchanged from baseline to W8. Changes in E2 and E1 from baseline to W8 met criteria for mediating the effect of low-dose estradiol treatment on VMS frequency. With change in estrogen concentration added to treatment assignment in a regression model predicting W8 VMS frequency, the effect of treatment with low-dose estradiol versus placebo was attenuated, with change in E2 representing a 44.1% reduction (P = 0.03) and change in E1 representing a 69.5% reduction (P = 0.02) in total intervention effect. Conclusion Among perimenopausal and postmenopausal women with VMS, treatment with low-dose oral estradiol versus placebo results in four- to fivefold increases in serum E2 and E1. The increases in serum E2 and E1 with low-dose oral estradiol treatment seem to mediate in part the effect of treatment in reducing VMS frequency.

Automated summary

This study found that low-dose oral estradiol treatment can significantly increase serum concentrations of E2 and E1 in perimenopausal and postmenopausal women, and these changes in concentration partially mediate the reduction of vasomotor symptom frequency.