TY - JOUR
T1 - Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline
T2 - A pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy
AU - Wang, Yiwei
AU - Hernandez, Gerson
AU - Mack, Wendy J.
AU - Schneider, Lon S.
AU - Yin, Fei
AU - Brinton, Roberta D.
N1 - Funding Information:
Received April 1, 2019; revised and accepted July 18, 2019. L flashes and night sweats), brain glucose hypometab- Fromthe1School2 ofPharmacy,UniversityofSouthernCalifornia,Los olism, and cognitive decline.1-6 Given the shared metabolic Pharmacology,UniversityofArizona,Tucson,AZ;andAngeles,CA; CenterforInnovationinBrainScienceand3KeckSchoolofDepartmentof and cognitive phenotypes between menopause transition and Medicine, University of Southern California, Los Angeles, CA. late onset Alzheimer’s disease (LOAD),7-12 this natural endo- Funding/support: This work was supported by NIA R01AG033288 and crinological aging transition is also considered a contributor P50AG05142toL.S.S.,andP01AG026572toR.D.B. to the two-fold higher lifetime risk of LOAD in females Supplemental digital content is availablefor this article. Direct URLFinancialdisclosure/conflictsofinterest:Nonereported. compared with males.7,13,14 citationsappearintheprintedtextandareprovidedintheHTMLand Hormone therapy is a proven effective treatment to reduce PDFversionsofthisarticleonthejournal’sWebsite(www.menopause.org). hot flash frequency, improve brain glucose metabolism, Addresscorrespondenceto:RobertaD.Brinton,PhD,CenterforInno- and preserve cognitive function in selected cognitive Tucson,AZ85721.E-mail:rbrinton@email.arizona.eduvationinBrainScience,UniversityofArizona,1230NCherryAve., domains.15-24 However, unopposed estrogen or combined This is an open access article distributed under the terms of the Creative hormone therapy can elevate risks for stroke, heart attack, Commons Attribution-Non Commercial-No Derivatives License 4.0 andbreastcancer,whichhasdeterredestrogentherapyby25-30
Publisher Copyright:
© 2019 by The North American Menopause Society.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - APOE
KW - Cognitive function
KW - Hot flash
KW - Mitochondrial haplogroup
KW - PhytoSERM
UR - http://www.scopus.com/inward/record.url?scp=85072321515&partnerID=8YFLogxK
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U2 - 10.1097/GME.0000000000001418
DO - 10.1097/GME.0000000000001418
M3 - Article
C2 - 31567873
AN - SCOPUS:85072321515
VL - 27
SP - 57
EP - 65
JO - Menopause
JF - Menopause
SN - 1072-3714
IS - 1
ER -