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.

TitleRetrospective 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.
Publication TypeJournal Article
Year of Publication2020
AuthorsWang Y, Hernandez G, Mack WJ, Schneider LS, Yin F, Brinton RD
JournalMenopause
Volume27
Issue1
Pagination57-65
Date Published2020 Jan
ISSN1530-0374
KeywordsApolipoproteins E, Cognition, Cognitive Dysfunction, Double-Blind Method, Equol, Feasibility Studies, Female, Genistein, Haplotypes, Hot Flashes, Humans, Isoflavones, Menopause, Middle Aged, Mitochondria, Phytoestrogens, Pilot Projects, Retrospective Studies, Selective Estrogen Receptor Modulators, Treatment Outcome
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, 50 mg/d PhytoSERM; and n = 12, 100 mg/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 50 mg 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 50 mg 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.

DOI10.1097/GME.0000000000001418
Alternate JournalMenopause
PubMed ID31567873
PubMed Central IDPMC7100617
Grant ListR01 AG033288 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
R37 AG053589 / AG / NIA NIH HHS / United States
R01 MH067159 / MH / NIMH NIH HHS / United States
P01 AG026572 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Fei Yin, Ph.D.