Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: A pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy

Yiwei Wang, Gerson Hernandez, Wendy J. Mack, Lon S. Schneider, Fei Yin, Roberta D. Brinton

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Objective:PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation.Methods:In this retrospective analysis involving 46 participants (n=16, placebo; n=18, 50mg/d PhytoSERM; and n=12, 100mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype.Results:Our retrospective responder analysis indicated that participants on 50mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P=0.007). Participants on 50mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P=0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response.Conclusion:Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.

Original languageEnglish (US)
Pages (from-to)57-65
Number of pages9
JournalMenopause
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2020
Externally publishedYes

Keywords

  • APOE
  • Cognitive function
  • Hot flash
  • Mitochondrial haplogroup
  • PhytoSERM

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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