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

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

The purpose of this study is to learn more about how estradiol patch treatment affects brain processes, health, and wellbeing.

Study Overview

• Status: Recruiting
• Conditions: Menopause; Healthy Adult; Brain; Postmenopausal
• Intervention / Treatment: Drug: Cyclic Estradiol; Drug: Continuous Estradiol

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Research Services Professional; Phone Number: ‪720-281-9282‬; Email: erin.weinhold@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Anschutz
      • Contact: Research Services Professional; Phone Number: ‪720-281-9282‬; Email: erin.weinhold@cuanschutz.edu
      • Principal Investigator: Neill Epperson, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cyclic Estradiol; Transdermal estradiol 100 mcg/day patch applied for 5 days every 21 days for approximately 12 weeks.	Drug: Cyclic Estradiol; Participants randomized to the cyclic estradiol group apply a transdermal estradiol patch delivering 100 mcg/day for 5 days every 21 days over approximately 12 weeks. The patch is removed on the fifth day of each treatment cycle. The final patch is worn for 7 days.; Other Names: Estradiol Patch; Transdermal Estradiol
Experimental: Continuous Estradiol; Transdermal estradiol 100 mcg/day patch worn continuously and replaced every 6 days for approximately 12 weeks.	Drug: Continuous Estradiol; Participants randomized to the continuous estradiol group apply a transdermal estradiol patch delivering 100 mcg/day continuously for approximately 12 weeks. The patch is replaced every 6 days and worn throughout the treatment period. The final patch is worn for 7 days.; Other Names: Estradiol Patch; Transdermal Estradiol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Dorsolateral Prefrontal Cortex (dlPFC) activation during working memory task in women receiving either cyclic or continuous estradiol administration.	Description: Dorsolateral prefrontal cortex (dlPFC) activation will be measured during performance of the letter N-back task using functional magnetic resonance imaging (fMRI). Change scores will be calculated from baseline to follow-up.	Baseline and approximately 12 weeks after initiation of study treatment
Change from baseline in extracellular vesicle concentration.	Extracellular vesicle (EV) concentration will be measured from plasma samples and reported as particles per milliliter (particles/mL). Changes from baseline will be assessed following cyclic or continuous estradiol administration.	Baseline, Days 1-4, Days 21-24, and approximately 12 weeks after treatment initiation
Change from baseline in extracellular vesicle size.	Extracellular vesicle (EV) size will be measured from plasma samples and reported in nanometers (nm). Changes from baseline will be assessed following cyclic or continuous estradiol administration.	Baseline, Days 1-4, Days 21-24, and approximately 12 weeks after treatment initiation
Change from baseline in extracellular vesicle zeta potential.	Extracellular vesicle (EV) zeta potential will be measured from plasma samples and reported in millivolts (mV). Changes from baseline will be assessed following cyclic or continuous estradiol administration.	Baseline, Days 1-4, Days 21-24, and approximately 12 weeks after treatment initiation
Change in C-reactive protein concentration.	Serum C-reactive protein concentration measured using the Meso Scale Discovery (MSD) V-PLEX Neuroinflammation Panel.	Baseline and approximately 12 weeks after initiation of study treatment
Change in interleukin concentration.	Interleukin concentration measured using the MSD V-Plex Neuroinflammation Panel.	Baseline and approximately 12 weeks after initiation of study treatment
Change in cytokine concentration.	Cytokine concentration measured using the MSD V-Plex Neuroinflammation Panel.	Baseline and approximately 12 weeks after initiation of study treatment
Change in chemokine concentration.	Chemokine concentration measured using the MSD V-Plex Neuroinflammation Panel.	Baseline and approximately 12 weeks after initiation of study treatment
Change in growth factor concentration.	Growth factor concentration measured using the MSD V-Plex Neuroinflammation Panel.	Baseline and approximately 12 weeks after initiation of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in executive function symptoms on the Brown Attention-Deficit Disorder Scale (BADDS).	The BADDS is a validated 40-item self-report measure of executive function difficulties. Total scores range from 0 to 120, with higher scores indicating greater executive dysfunction.	Baseline and approximately 12 weeks after initiation of study treatment
Change in perceived stress on the Perceived Stress Scale (PSS).	The PSS is a 10-item self-report measure of perceived stress. Total scores range from 0 to 40, with higher scores indicating greater perceived stress.	Baseline and approximately 12 weeks after initiation of study treatment
Change in depressive symptoms on the Center for Epidemiologic Studies Depression Scale (CES-D).	The CES-D is a 20-item self-report measure of depressive symptoms. Total scores range from 0 to 60, with higher scores indicating greater severity of depressive symptoms.	Baseline and approximately 12 weeks after initiation of study treatment
Change in anxiety symptoms on the Generalized Anxiety Disorder-7 (GAD-7).	The GAD-7 is a 7-item self-report measure of anxiety symptoms. Total scores range from 0 to 21, with higher scores indicating greater anxiety symptom severity.	Baseline and approximately 12 weeks after initiation of study treatment
Change in hair cortisol concentration.	Hair cortisol concentration is a biomarker of chronic hypothalamic-pituitary-adrenal axis activity. Higher concentrations indicate greater cumulative cortisol exposure over the preceding approximately three months.	Baseline and approximately 12 weeks after initiation of study treatment

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Pedersen Foundation
• Investigators: Principal Investigator: Neill Epperson, MD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2026
• Primary Completion (Estimated): July 15, 2028
• Study Completion (Estimated): July 15, 2028

Study Registration Dates

• First Submitted: August 28, 2026
• First Submitted That Met QC Criteria: September 16, 2026
• First Posted (Actual): September 21, 2026

Study Record Updates

• Last Update Posted (Actual): September 21, 2026
• Last Update Submitted That Met QC Criteria: September 16, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Stress; Cognition; Neuroimaging; Executive Function; Postmenopause; Estradiol; Estrogen; Adverse Childhood Experiences; Extracellular Vesicles; Brain Health; Menopause Hormone Therapy
• Additional Relevant MeSH Terms: Ortho Evra
• Other Study ID Numbers: 25-2688

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No