MenopausePhase 4CEREBRANCT07831499
Cyclic vs. Constant Estradiol: Regimens' Effects on Brain Health
A Phase 4 study testing Cyclic Estradiol and Continuous Estradiol in people with Menopause and Healthy Adult, run by University of Colorado, Denver at 1 site in United States.
Trial summary
The purpose of this study is to learn more about how estradiol patch treatment affects brain processes, health, and wellbeing. Read more about this study
- Who is it for?
- Ages 38 to 60 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Menopause, Healthy Adult, Brain
- What is being tested?
- Cyclic Estradiol and Continuous Estradiol
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Jul 2026to 15 Jul 2028
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 38 to 60 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Ages 38 to 60.
- Ability to give written informed consent.
- 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.
- 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.
- 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).
- Report final menstrual period (FMP) occurred between 12 months and 48 months at the time of screening.
- Right-handed.
- 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.
Who cannot join
- Current psychiatric diagnosis as assessed by the Mini International Neuropsychiatric Interview (MINI, Sheehan et al., 1998).
- Active psychiatric illness within the previous 12 months or lifetime diagnosis of a psychotic disorder.
- 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.
- 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.
- Chronic use of steroid medication and other medications that could impact immune function and alter glucocorticoid levels.
- Inability to forgo use of non-steroidal anti-inflammatory medications for 4 days prior to the Baseline Visit, Van Visits, and Follow Up Visit.
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- 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.
- 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.
- History of suicidal behavior within the past 2 years
- Undiagnosed abnormal genital bleeding.
- Known, suspected, or history of breast cancer.
- Active deep vein thrombosis, pulmonary embolism, or history of these conditions.
- History of cardiovascular disease
- Known liver dysfunction or disease.
- Needle phobia or history of vasovagal response to phlebotomy.
- History of clinically relevant claustrophobia or inability to tolerate a scanning environment in the past.
- 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.).
- Current treatment with Central nervous system (CNS) depressants (e.g., opioids, benzodiazepines).
- Treatment with corticosteroids within the past 30 days.
- Known allergy to progesterone or peanut allergy.
- 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).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Colorado Anschutz
Aurora, Colorado, 80045
Research Services Professional, 720-281-9282, erin.weinhold@cuanschutz.edu
Neill Epperson, MD
About this study
Official title: 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.
- Conditions
- Menopause, Healthy Adult, Brain, Postmenopausal
- Being tested
- Cyclic Estradiol, Continuous Estradiol
- Keywords
- Estradiol, Estrogen, Menopause Hormone Therapy, Postmenopause, Brain Health, Neuroimaging, Stress, Extracellular Vesicles, Adverse Childhood Experiences, Cognition, Executive Function
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cyclic EstradiolDrug
Also called Estradiol Patch, Transdermal 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.
Continuous EstradiolDrug
Also called Estradiol Patch, Transdermal 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.
| Study group | Role | What they receive |
|---|---|---|
| Cyclic Estradiol | Experimental | Transdermal estradiol 100 mcg/day patch applied for 5 days every 21 days for approximately 12 weeks. Receives: Drug: Cyclic Estradiol |
| Continuous Estradiol | Experimental | Transdermal estradiol 100 mcg/day patch worn continuously and replaced every 6 days for approximately 12 weeks. Receives: Drug: Continuous Estradiol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and approximately 12 weeks after initiation of study treatment
Change in interleukin concentration.
Interleukin concentration measured using the MSD V-Plex Neuroinflammation Panel.
Measured: Baseline and approximately 12 weeks after initiation of study treatment
Change in cytokine concentration.
Cytokine concentration measured using the MSD V-Plex Neuroinflammation Panel.
Measured: Baseline and approximately 12 weeks after initiation of study treatment
Change in chemokine concentration.
Chemokine concentration measured using the MSD V-Plex Neuroinflammation Panel.
Measured: 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.
Measured: Baseline and approximately 12 weeks after initiation of study treatment
Secondary outcomes (5)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and approximately 12 weeks after initiation of study treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2026
- Study start15 Jul 2026
- Primary completion15 Jul 2028 (estimated)
- Study completion15 Jul 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MenopauseStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- Pedersen Foundation
- Responsible party
- Sponsor
- Investigators
- Neill Epperson, MD, Principal investigator, University of Colorado, Denver
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07831499
- Sponsor's protocol ID
- 25-2688
- Acronym
- CEREBRA
- Status last verified
- Sep 2026
- First submitted
- 28 Aug 2026
- Last updated
- 21 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cyclic vs. Constant Estradiol: Regimens' Effects on Brain Health (CEREBRA Study)
- ClinicalTrials.gov ID
- NCT07831499
- Acronym / sponsor ID
- CEREBRA / 25-2688
- Conditions
- Menopause, Healthy Adult, Brain, Postmenopausal
- Keywords
- Estradiol, Estrogen, Menopause Hormone Therapy, Postmenopause, Brain Health, Neuroimaging, Stress, Extracellular Vesicles
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- University of Colorado, DenverUniversity, hospital or other
- Collaborators
- Pedersen Foundation
- Study start
- 15 Jul 2026 (actual)
- Primary completion
- 15 Jul 2028 (estimated)
- Study completion
- 15 Jul 2028 (estimated)
- First posted
- 21 Sep 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to learn more about how estradiol patch treatment affects brain processes, health, and wellbeing.
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cyclic Estradiol | Experimental | Drug: Cyclic EstradiolTransdermal estradiol 100 mcg/day patch applied for 5 days every 21 days for approximately 12 weeks. |
| Continuous Estradiol | Experimental | Drug: Continuous EstradiolTransdermal estradiol 100 mcg/day patch worn continuously and replaced every 6 days for approximately 12 weeks. |
Who may qualify
- Ages
- 38 to 60 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Ages 38 to 60.
- Ability to give written informed consent.
- 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.
- 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.
- 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).
Key exclusion criteria (21 listed)
- Current psychiatric diagnosis as assessed by the Mini International Neuropsychiatric Interview (MINI, Sheehan et al., 1998).
- Active psychiatric illness within the previous 12 months or lifetime diagnosis of a psychotic disorder.
- 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.
- 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.
- Chronic use of steroid medication and other medications that could impact immune function and alter glucocorticoid levels.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cyclic EstradiolAlso: Estradiol Patch, Transdermal EstradiolParticipants 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. | Drug | Cyclic Estradiol |
| Continuous EstradiolAlso: Estradiol Patch, Transdermal EstradiolParticipants 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. | Drug | Continuous Estradiol |
Primary outcome
Change in Dorsolateral Prefrontal Cortex (dlPFC) activation during working memory task in women receiving either cyclic or continuous estradiol administration.
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
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.
Change from baseline in extracellular vesicle concentration.
Time frame: Baseline, Days 1-4, Days 21-24, and approximately 12 weeks after treatment initiation
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.
Change from baseline in extracellular vesicle size.
Time frame: Baseline, Days 1-4, Days 21-24, and approximately 12 weeks after treatment initiation
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.
Change from baseline in extracellular vesicle zeta potential.
Time frame: Baseline, Days 1-4, Days 21-24, and approximately 12 weeks after treatment initiation
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.
Change in C-reactive protein concentration.
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Serum C-reactive protein concentration measured using the Meso Scale Discovery (MSD) V-PLEX Neuroinflammation Panel.
Change in interleukin concentration.
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Interleukin concentration measured using the MSD V-Plex Neuroinflammation Panel.
Change in cytokine concentration.
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Cytokine concentration measured using the MSD V-Plex Neuroinflammation Panel.
Change in chemokine concentration.
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Chemokine concentration measured using the MSD V-Plex Neuroinflammation Panel.
Change in growth factor concentration.
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Growth factor concentration measured using the MSD V-Plex Neuroinflammation Panel.
5 secondary outcomes
Change in executive function symptoms on the Brown Attention-Deficit Disorder Scale (BADDS).
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Change in perceived stress on the Perceived Stress Scale (PSS).
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Change in depressive symptoms on the Center for Epidemiologic Studies Depression Scale (CES-D).
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Change in anxiety symptoms on the Generalized Anxiety Disorder-7 (GAD-7).
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Change in hair cortisol concentration.
Time frame: Baseline and approximately 12 weeks after initiation of study treatment
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Neill Epperson, MD principal investigator
University of Colorado, Denver
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Cyclic Estradiol and Continuous Estradiol in people with Menopause and Healthy Adult, run by University of Colorado, Denver at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Research Services Professional (720-281-9282, erin.weinhold@cuanschutz.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Dorsolateral Prefrontal Cortex (dlPFC) activation during working memory task in women receiving either cyclic or continuous estradiol administration. (time frame: Baseline and approximately 12 weeks after initiation of study treatment). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2026.