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

Kristine E. Ensrud, Joseph C. Larson, Katherine A. Guthrie, Carolyn J. Crandall, Andrea Z. Lacroix, Susan D. Reed, Shalender Bhasin, Caroline M. Mitchell, Hadine Joffe

Research output: Contribution to journalArticlepeer-review

Abstract

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 17β 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.

Original languageEnglish (US)
Pages (from-to)1014-1020
Number of pages7
JournalMenopause
Volume29
Issue number9
DOIs
StatePublished - Sep 1 2022

Bibliographical note

Funding Information:
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.

Funding Information:
The MsFLASH research network was established under an National Institutes of Health cooperative agreement to conduct studies of the efficacy of treatments for the management of menopausal hot flashes. The studies are sponsored by the National Institute of Aging (NIA), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Research on Women's Health (ORWH).

Funding Information:
Funding/support: MsFLASH 03 was supported by a cooperative agreement issued by the National Institute of Aging (NIA), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Research and Women's Health (ORWH), and NIA grants U01AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, and U01AG032700. A funding renewal was provided by NIA grant 5R01AG048209. At the Indiana University site, the project was funded in part with support from the Indiana Clinical and Translational Sciences Institute, funded in part by grant UL1RR025761 from the National Institutes of Health, National Center for Research Resources, Clinical and Translational Sciences Award. Escitalopram and matching placebo pills were provided by Forest Research Institute. The sponsors had no input into, or control over, the analysis of data, the writing of the manuscript, or the decision to submit the article for publication.

Publisher Copyright:
© Wolters Kluwer Health, Inc. All rights reserved.

Keywords

  • Estradiol treatment
  • Randomized trial
  • Serum estradiol and estrone concentrations
  • Vasomotor symptoms

PubMed: MeSH publication types

  • Journal Article
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

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