This is a proof-of-concept phase 2 clinical trial to investigate the safety and effect of the phytoestrogenic supplement PhytoSERM on regional brain metabolism by fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) in peri- and postmenopausal women. The investigators hypothesize that there will be a significant difference between the PhytoSERM group and placebo group in glucose brain metabolism.

This is a double-blinded, randomized, placebo-controlled, parallel designed, proof-of-concept phase 2 clinical trial to determine effect of PhytoSERM in regional brain metabolism, cognition and vasomotor symptoms in menopausal women. PhytoSERM or placebo pills will be administered orally once a week over 24 weeks. Safety and tolerability will also be assessed over the duration of the study.

To determine eligibility, all participants will undergo cognitive assessment, physical and neurological examination, imaging scans, electrocardiogram (ECG), clinical/safety laboratory assessment, and interviews. After a 2-4-week screening period, participants will be randomized to study intervention (PhytoSERM 50mg administered orally, once per day) or matching placebo, in a 1:1 allocation. Brain imaging to evaluate the primary endpoint (standardized uptake value ratio (SUVR) by FDG-PET) will be conducted at screening and 24 weeks (6 months). Study participants will be asked to complete a total of 7 study visits. All participants will be enrolled at a single site, at the Alzheimer's Prevention Program (APP) at Weill Cornell Medical Centre (WCMC, New York).

This study protocol will include an embedded single-dose, 24-hour pharmacokinetic (PK) study in a subset of 12 participants which will begin after the first dose of the study intervention.

Inclusion Criteria:

1. Peri- or postmenopausal women with the latter defined as last menstrual period (LMP) completed ≥ 60 days and ≤ 4 years, per the Stages of Reproductive Aging Workshop (STRAW) criteria.
2. Age 45-60 years.
3. Presence of hot flashes ≥ 7 per day.
4. In good general health as evidenced by medical history.
5. Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the investigator.
6. No medical contraindications to study participation.
7. Stable medications for 4 weeks prior to the baseline visits.
8. Provision of signed and dated informed consent form.
9. Stated willingness to comply with all study procedures and availability for the duration of the study.
10. Ability to take oral medication and be willing to adhere to the PhytoSERM regimen.
11. For females of reproductive potential: Negative pregnancy test and use of highly effective contraception by male partner for at least 1 month prior to screening and agreement to use such a method during study participation.
12. Fluent in English or Spanish.

Exclusion Criteria:

1. Known allergies to isoflavones or soy-based products.
2. Evidence of cognitive impairment on the Mini-Mental State Examination (total score < 27).
3. Pregnancy
4. Use of estrogen or progestin compounds within 8 weeks of baseline.
5. Use of investigational agent within 12 weeks of baseline.
6. Concurrent neurologic, systemic, or psychiatric disease that would influence cognition or ability to provide informed consent and to participate.
7. Known or suspected estrogen-dependent neoplasia, active neoplastic disease, history of breast cancer, or at risk of developing breast cancer, endometrial hyperplasia.
8. History of epilepsy, focal brain lesion, head injury with loss of consciousness or Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse.
9. Thrombophlebitis, thrombosis, thromboembolic disorders, myocardial infarction, ischemic heart disease, cerebrovascular accident, stroke, transient ischemic attack (TIA).
10. Current use of tobacco or a history of alcohol abuse.
11. Use of drugs, herbs, or dietary supplements to treat menopausal or cognitive symptoms less than 8 weeks prior to baseline.
12. Evidence of any significant clinical disorder or laboratory finding.
13. Known allergy to soy-derived products/ proteins or branded over the counter products; hypersensitivity to estrogens or progestins.
14. Visual and auditory acuity inadequate for neuropsychological testing
15. Inability to undergo MRI scans
16. Inability to undergo PET scans