PhytoSERM for Menopause-related Cognitive Impairment

Recruiting in Palo Alto (17 mi)

Overseen by Roberta D Brinton, PhD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Arizona

Must not be taking: Estrogen, Progestin

Disqualifiers: Cognitive impairment, Breast cancer, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests PhytoSERM, a plant-based supplement that mimics estrogen, in peri- and postmenopausal women. The goal is to see if it helps the brain use glucose better, potentially improving brain function and reducing menopausal symptoms. Participants will take the supplement for several months, with brain scans before and after to measure effects. PhytoSERM is a formulation of genistein, daidzein, and S-equol that may enhance neuron function and estrogenic mechanisms in the brain.

Will I have to stop taking my current medications?

The trial requires that your medications have been stable for at least 4 weeks before starting. If you are using estrogen or progestin compounds, or drugs, herbs, or supplements for menopausal or cognitive symptoms, you must stop them at least 8 weeks before starting the trial.

What data supports the effectiveness of the treatment PhytoSERM for menopause-related cognitive impairment?

Research suggests that phytoestrogens like genistein, daidzein, and S-equol, which are components of PhytoSERM, may improve cognitive function in postmenopausal women and offer neuroprotective benefits similar to estrogen, without the associated risks. Studies have shown that these compounds can enhance memory and reduce symptoms related to menopause, potentially lowering the risk of Alzheimer's disease. ^{1 2 3 4 5}

Is PhytoSERM safe for humans?

Studies show that PhytoSERM, a mix of genistein, daidzein, and S-equol, is generally safe for humans, particularly in perimenopausal and postmenopausal women, without causing unwanted estrogen-like effects in other parts of the body. ^{2 3 5 6 7}

How is the PhytoSERM treatment different from other treatments for menopause-related cognitive impairment?

PhytoSERM is unique because it selectively targets estrogen receptor-β (ERβ) in the brain, potentially enhancing brain function without affecting other tissues, unlike traditional hormone therapies that can have broader effects. It contains natural compounds like genistein, daidzein, and S-equol, which are phytoestrogens (plant-derived compounds with estrogen-like activity) that may offer neuroprotective benefits without the feminizing side effects of conventional estrogen treatments. ^{2 5 6 7 8}

Research Team

Gerson D Hernandez, MD, MPH

Principal Investigator

University of Arizona

Roberta D Brinton, PhD

Principal Investigator

University of Arizona

Eligibility Criteria

This trial is for peri- or postmenopausal women aged 45-60, experiencing hot flashes at least 7 times a day. Participants must be in good health, fluent in English/Spanish, and willing to follow the study procedures. They can't join if they've had recent cardiovascular issues, are pregnant, have used hormone treatments recently, or have certain cognitive impairments.

Inclusion Criteria

Your lab test results need to be normal, or if they're not, the doctor will decide if it's not a big problem.

I am not pregnant and will use effective birth control during the study.

No medical contraindications to study participation

Exclusion Criteria

I have never had epilepsy, severe head injuries, or major psychiatric disorders.

Use of investigational agent within 12 weeks of baseline

I do not have any significant health issues or abnormal lab results.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive PhytoSERM or placebo orally every day for 24 weeks

24 weeks

7 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PhytoSERM (Phytoestrogenic Supplement)
• Placebo (Other)

Trial Overview The trial tests PhytoSERM's safety and its effect on brain metabolism compared to a placebo in menopausal women. It measures changes using an imaging technique called 18F-FDG-PET that tracks glucose metabolism in the brain.

Participant Groups

Group I: PhytoSERM group Experimental Treatment 1 Intervention

PhytoSERM 50mg tablet composed of the phytoestrogens daidzein, genistein and S-equol, administered orally every day for 24 weeks.

Group II: Placebo group Placebo Group 1 Intervention

Placebo product with identical shape, size and color with absence of daidzein, genistein, and S-equol. Administered orally every day for 24 weeks.

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

Dr. Richard Carmona

University of Arizona

Chief Medical Officer since 2021

MD, University of Arizona

Dr. Evan Unger

University of Arizona

Chief Executive Officer since 2021

PhD in Medical Imaging, University of Arizona

Roberta Brinton

Lead Sponsor

Trials

2

Recruited

110+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Dr. Richard J. Hodes

National Institute on Aging (NIA)

Chief Executive Officer since 1993

MD from Harvard Medical School

Dr. Marie Bernard

National Institute on Aging (NIA)

Chief Medical Officer

MD from Harvard Medical School

Cornell University

Collaborator

Trials

179

Recruited

14,090,000+

Matthew DeLisa

Cornell University

Chief Executive Officer since 2019

PhD in Chemical Engineering from Cornell University

Tami Magnus

Cornell University

Chief Medical Officer since 2015

MBA from Binghamton University

ADM Diagnostics

Collaborator

Trials

2

Recruited

300+

Findings from Research

Estrogen-containing hormone therapy (HT) can provide health benefits for women within 10 years of menopause, but long-term use poses risks like breast cancer and stroke, highlighting the need for safer alternatives.

Research on soy-based isoflavones shows mixed results in improving cognitive function in postmenopausal women, suggesting that a standardized formulation and careful population selection could enhance therapeutic efficacy and provide benefits for both genders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WHI and WHIMS follow-up and human studies of soy isoflavones on cognition. Zhao, L., Brinton, RD.[2007]

The use of 17 β-estradiol in menopausal women has been shown to reduce vasomotor symptoms and improve cognitive function, particularly in those with Alzheimer's disease.

Genistein, a flavonoid, may also help alleviate vasomotor symptoms and has potential neuroprotective effects, although more research is needed to fully understand its impact on cognition during menopause.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of the use of 17 β-estradiol and genistein in Alzheimer's disease in women with menopause]. Chávez-Pérez, C., Ceballos-Ramírez, A., Suárez-Castro, A.[2021]

The novel phyto-β-SERM formulation shows a strong preference for binding to the estrogen receptor subtype β (ERβ), which is linked to neuroprotective effects and alleviation of menopause-related symptoms, without causing feminizing effects in other body areas.

In a study with a female mouse model of Alzheimer's disease, a 9-month dietary supplementation with the phyto-β-SERM formulation improved physical health, memory, and reduced amyloid-β plaque formation, suggesting its potential as a preventive treatment for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early intervention with an estrogen receptor β-selective phytoestrogenic formulation prolongs survival, improves spatial recognition memory, and slows progression of amyloid pathology in a female mouse model of Alzheimer's disease. Zhao, L., Mao, Z., Chen, S., et al.[2021]

A combination of phytoestrogens (genistein, daidzein, and equol) significantly enhances neural protective responses, showing a 30% increase in selectivity for the estrogen receptor beta (ERbeta) compared to individual phytoestrogens.

This combination not only improves neuronal survival and promotes defense mechanisms against neurodegeneration but also does not affect uterine growth, suggesting a safer alternative to conventional estrogen therapy for cognitive health in menopausal women.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A select combination of clinically relevant phytoestrogens enhances estrogen receptor beta-binding selectivity and neuroprotective activities in vitro and in vivo. Zhao, L., Mao, Z., Brinton, RD.[2009]

In a phase Ib/IIa trial involving 46 participants, PhytoSERM (50 mg daily) significantly reduced hot flash frequency compared to baseline and placebo, indicating its potential as a safe and effective treatment for menopause-related symptoms.

The study also suggested that genetic factors, such as mitochondrial haplogroup and APOE genotype, may influence the response to PhytoSERM, supporting a precision medicine approach for its further development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Wang, Y., Hernandez, G., Mack, WJ., et al.[2021]

The phytoestrogen formulation (phytoSERM) containing genistein, daidzein, and S-equol was well-tolerated in a study of 18 perimenopausal and postmenopausal women, with no reported adverse events after a single dose.

Pharmacokinetic analysis showed that the phytoSERM was rapidly absorbed, with plasma concentrations of the active compounds peaking at different times depending on the dose, indicating a clear dose-dependent response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor β-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women. Hernandez, G., Zhao, L., Franke, AA., et al.[2019]

The phytoSERM formulation, which targets estrogen receptor-β, was well tolerated in a 12-week trial with 71 perimenopausal women, showing that both 50 mg and 100 mg daily doses were safe, with mild adverse events reported.

Despite some adverse effects, including mild vaginal bleeding, the 50 mg dose was preferred for further efficacy trials due to better safety outcomes and potential benefits on cognitive and vasomotor symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and feasibility of estrogen receptor-β targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial. Schneider, LS., Hernandez, G., Zhao, L., et al.[2023]

The phytoestrogenic combination containing S-equol was found to be more effective than the R/S-equol combination in enhancing mitochondrial function and energy production in neuronal cultures and a mouse model of menopause.

Both phytoSERM combinations improved key bioenergetic pathways and did not induce any feminizing effects, suggesting their potential as safe nutraceuticals for alleviating menopause-related symptoms and promoting brain health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potentiation of brain mitochondrial function by S-equol and R/S-equol estrogen receptor β-selective phytoSERM treatments. Yao, J., Zhao, L., Mao, Z., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

WHI and WHIMS follow-up and human studies of soy isoflavones on cognition. [2007]

2. Spain pubmed.ncbi.nlm.nih.gov

[Effects of the use of 17 β-estradiol and genistein in Alzheimer's disease in women with menopause]. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Early intervention with an estrogen receptor β-selective phytoestrogenic formulation prolongs survival, improves spatial recognition memory, and slows progression of amyloid pathology in a female mouse model of Alzheimer's disease. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

A select combination of clinically relevant phytoestrogens enhances estrogen receptor beta-binding selectivity and neuroprotective activities in vitro and in vivo. [2009]

5. United States pubmed.ncbi.nlm.nih.gov

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. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor β-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Safety and feasibility of estrogen receptor-β targeted phytoSERM formulation for menopausal symptoms: phase 1b/2a randomized clinical trial. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Potentiation of brain mitochondrial function by S-equol and R/S-equol estrogen receptor β-selective phytoSERM treatments. [2021]