Cyclic vs. Constant Estradiol: Regimens' Effects on Brain Health (CEREBRA)

Inclusion Criteria:

1. Ages 38 to 60.
2. Ability to give written informed consent.
3. Fluent in written and verbal English, though may use Spanish to speak with study staff if preferred. This criterion is based on methodological necessity and feasibility, to ensure participants can accurately understand task instructions and questionnaire items which are available only in English for this pilot study.
4. Participants must be up to date on age-appropriate cancer screening. Specifically, participants must have had a pap smear within the previous 3 years and a mammogram within the previous 2 years (American College of Obstetricians and Gynecologists, 2026; Health Resources and Services Administration, n.d.). Documentation may be requested to verify screening history.
5. Have estradiol level below 40 pg/ml and follicle stimulating hormone (FSH) level above 25 at Van Visit Day 1. Individuals with high estradiol or low FSH levels may be retested, and eligibility determination will be at the discretion of the Principal Investigator (PI).
6. Report final menstrual period (FMP) occurred between 12 months and 48 months at the time of screening.
7. Right-handed.
8. Participants are required to have at least some college education. Setting a minimum education level reduces variability due to educational disparities and supports the validity and interpretability of cognitive performance data. These tasks involve higher-order verbal learning, memory, and executive processes that can be strongly influenced by educational attainment. The investigators will re-evaluate this criterion in future larger-scale studies as resources allow.

Exclusion Criteria:

1. Current psychiatric diagnosis as assessed by the Mini International Neuropsychiatric Interview (MINI, Sheehan et al., 1998).
2. Active psychiatric illness within the previous 12 months or lifetime diagnosis of a psychotic disorder.
3. Current use of antipsychotic medications or mood stabilizers. Participants may have sporadic use of benzodiazepines during the course of the study as long as they can forgo use at least 4 days prior to study procedures.
4. Current or history of substance use disorder within previous 12 months. However, individuals with mild disorders, disorders solely limited to cannabis or alcohol, and/or those who have achieved close to one year of remission may be eligible at the discretion of the PI.
5. Chronic use of steroid medication and other medications that could impact immune function and alter glucocorticoid levels.
6. Inability to forgo use of non-steroidal anti-inflammatory medications for 4 days prior to the Baseline Visit, Van Visits, and Follow Up Visit.
7. Any current or recent medical, psychiatric or social condition which, in the investigator's opinion, is likely to interfere with the conduct of the study, confound the interpretation of study results, or endanger the subject's well-being.
8. Use of systemic hormone therapy (including but not limited to estradiol, progesterone, testosterone, combined hormonal contraceptives, and other systemic hormonal preparations) within 3 months prior to study enrollment. Use of local vaginal estrogen therapy (e.g., vaginal cream or Estring) is permitted. For participants with a history of systemic hormone use, the study investigator may review treatment history to determine whether postmenopausal status can be confirmed.
9. History of suicidal behavior within the past 2 years
10. Undiagnosed abnormal genital bleeding.
11. Known, suspected, or history of breast cancer.
12. Active deep vein thrombosis, pulmonary embolism, or history of these conditions.
13. History of cardiovascular disease
14. Known liver dysfunction or disease.
15. Needle phobia or history of vasovagal response to phlebotomy.
16. History of clinically relevant claustrophobia or inability to tolerate a scanning environment in the past.
17. Metal in body unsafe for magnetic resonance imaging (MRI) or other conditions that would make MRI unsafe for participants (i.e., aneurysm clip, cardiac pacemaker, etc.).
18. Current treatment with Central nervous system (CNS) depressants (e.g., opioids, benzodiazepines).
19. Treatment with corticosteroids within the past 30 days.
20. Known allergy to progesterone or peanut allergy.
21. Any history of chemotherapy as negative effects on cognitive performance have been reported for years post cessation of treatment (Guida et al., 2021; Koppelmans et al., 2012).