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

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. We analyzed baseline and week 8 (W8) data from 171 perimenopausal and postmenopausal women with VMS enrolled in low-dose 17β estradiol ( n = 72) and placebo ( n = 99) groups of a randomized clinical trial. 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. 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.

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Financial disclosure/conflicts of Interest: S.D.R. reports research funding from Bayer and royalties from UpToDate. S.B. reports his institution has received research grants from MIB, AbbVie, and Transition Therapeutics, on which he is the PI. These grants are unrelated to the work. C.M.M. reports grant support from Merck Inc and consultant and advisory fees from Scynexis and UpToDate. H.J. reports grant support from Merck, Pfizer, NeRRe/KaNDy, and Que Oncology, and consultant and advisory fees from Bayer, Eisai, and Jazz. H.J.'s spouse is an employee of Arsenal Biosciences and has an equity stake in Merck Research Labs and Tango Therapeutics. The other authors declare no conflict of interest.