MenopausePhase 4NCT05388656
Estrogen Variability and Irritability During the Menopause Transition
A Phase 4 study testing Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release and Progesterone 200 mg in people with Menopause and Irritable Mood, run by University of North Carolina, Chapel Hill at 1 site in United States.
Trial summary
Women in the menopause transition (perimenopause) experience substantial day-to-day variability in estradiol and have a 2-4-fold increase in major depression risk. About 40% of perimenopausal women are susceptible to the emergence of affective symptoms tied to changes in estradiol. Read more about this study
- Who is it for?
- Ages 45 to 59 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Menopause, Irritable Mood
- What is being tested?
- Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release and Progesterone 200 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Jun 2022to 17 Jan 2025
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 45 to 59 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy women 45 - 59 years of age
- In the early menopause transition (defined by variable menstrual cycle length that is 7+ days longer or shorter than usual)
- Increase in irritability since the onset of menstrual cycle changes
- Moderate to severe irritability symptoms, as defined by IDAS ill-temper scale score >10
- Have experienced 1+ very stressful life event (e.g. divorce, death of family member) within the past 6 months
- Negative mammogram within the past two years
- BMI between 18 - 45 kg/m^2
Who cannot join
- Use of psychotropic agents or hormonal preparations, or herbal supplements (other than multivitamins) believed to affect mood or menopausal symptoms
- History of psychosis, bipolar disorder, or substance dependence
- Active psychological symptoms severe enough to require treatment
- Current suicidal intent or recent history of suicide attempts (within past 10 years)
- Personal or family history of cancer indicative of more than average risk for breast, ovarian or endometrial cancers
- Personal history of any cardiovascular disease including coronary artery disease, arteriosclerosis, heart attack, stroke
Show all 15Show fewer
- Personal history of thromboembolic disorders
- History of E2-dependent neoplasia
- History of gallbladder disease
- Recent history of migraine with aura
- Blood pressure classified as higher than stage 2 hypertension (≥160 mmHg systolic or ≥100 mmHg diastolic)
- Liver dysfunction or disease
- Undiagnosed abnormal genital bleeding
- Type I diabetes
- Known sensitivities to the matrix patch system in Climara® or allergy to peanut oil used in Prometrium®
Trial locations and contacts
1 site in 1 country.
United States1 site
Carolina Crossing B, Suite 1
Chapel Hill, North Carolina, 27517
About this study
Official title: Identifying Neurophysiological Mechanisms of Susceptibility to Estradiol Fluctuation and Irritability Symptoms in the Menopause Transition: An Experimental Approach
Women in the menopause transition (perimenopause) experience substantial day-to-day variability in estradiol and have a 2-4-fold increase in major depression risk. About 40% of perimenopausal women are susceptible to the emergence of affective symptoms tied to changes in estradiol. Among the perimenopausal women with affective impairment, most report irritability, not "depression," is their primary source of impairment and distress. The purpose of this research is to determine the neurophysiologic basis of susceptibility to estradiol fluctuations and irritability symptoms in perimenopausal women.
Read the detailed description
Using a within-subjects, cross-over design and transdermal estradiol to stabilize estradiol fluctuations (and increase levels) the investigators will test if neural dynamics (oscillatory activity in the theta and beta frequencies assessed via EEG) associated with key constructs of irritability (attentional bias to threat and frustration to non-reward) represent a biomarker target of irritability symptom response to transdermal estradiol.
- Conditions
- Menopause, Irritable Mood
- Being tested
- Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release, Placebo, Progesterone 200 mg
- Keywords
- Perimenopause, Menopause transition, Estrogen, Stress, Mood, Irritability
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended ReleaseDrug
0.1 mg/day transdermal patch administered for 3 weeks
PlaceboDrug
Estradiol-matched placebo patch administered for 3 weeks
Progesterone 200 mgDrug
Also called Prometrium
200 mg tablet administered by mouth once per day for 10 days after completion of the experimental phase of the study
| Study group | Role | What they receive |
|---|---|---|
| Estradiol, Then Placebo | Experimental | Participants will first receive 0.1 mg/day of transdermal estradiol patch for 3 weeks. After a washout period of 3 weeks, participants will then receive transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks. Upon completion of the second intervention, all participants will receive 200 mg/day of progesterone for 10 days. Receives: Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release; Drug: Placebo; Drug: Progesterone 200 mg |
| Placebo, Then Estradiol | Experimental | Participants will first receive transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks. After a washout period of 3 weeks, participants will then receive 0.1 mg/day of transdermal estradiol patch for 3 weeks. Upon completion of the second intervention, all participants will receive 200 mg/day of progesterone for 10 days. Receives: Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release; Drug: Placebo; Drug: Progesterone 200 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean IDAS Ill Temper Scale Score Over Time
The 5-item ill temper scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be the primary measure of irritability symptom severity. Each symptom item is rated 1 (not at all) to 5 (extremely). The total IDAS ill temper scale score may range from 5-25. Higher scores indicate more severe irritability symptoms. The average daily irritability scores will be evaluated for each 3-week treatment condition (Active Estradiol vs. Placebo).
Measured: 3 weeks during each intervention
Secondary outcomes (2)
Reward Positivity (RewP) in Response to the Affective Posner Paradigm
Dysfunctional reward construct of irritability was indexed by the Reward Positivity (RewP), an event-related potential (ERP), that occurs 250-350 ms after feedback indicating a reward (e.g., a monetary win) compared to non-reward (e.g., too slow). The difference waveform is extracted from the frontal midline electrode (Fz). The average ERP is reported to represent the amplitude in response to stimulus presentation.
Measured: At the end of each three-week treatment period.
Mean LPP Amplitude During Implicit Viewing Task Dysfunctional Threat Processing Was Indexed by Greater Late Positive Potential (LPP) Component for Emotional Face Stimuli, Elicited 400-900 Milliseconds After the Stimulus Presentation.
Implicit Viewing Task: Participants will complete the Implicit Viewing Task while EEG is recorded to examine brain responses (late positive potentials (LPP) to anger stimuli. During the task, participants will be presented with a happy, fear or calm faces and the participant is asked to indicate whether the image shows someone with long or short hair (neutral feature, not emotion related). LPP will be extracted from the midline-parietal electrode (Pz), from 400-900 ms after the stimulus presentation. The average LPP amplitude will be assessed at the end of each 3-week treatment period. Additionally, average LPP amplitude will be evaluated for each condition (Active Estradiol vs. Placebo).
Measured: At the end of each 3-week treatment period
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 May 2022
- Study start15 Jun 2022
- Primary completion17 Dec 2024
- Study completion17 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for MenopauseStudies of the same condition, open and under way.
- 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
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Sponsor
- Investigators
- Susan Girdler, PhD, Principal investigator, University of North Carolina, Chapel HillElizabeth Andersen, PhD, Principal investigator, University of North Carolina, Chapel Hill
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05388656
- Sponsor's protocol ID
- 21-3395
- Other IDs
- R21MH128241
- Status last verified
- Jun 2025
- First submitted
- 18 May 2022
- Last updated
- 26 Nov 2025
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: After the study is completed, the de-identified, archived data will be transmitted to and stored at the National Institute of Mental Health Data Archive (NDA) for use by other researchers including those outside of the study.
Study at a glance
From the registry record, last updated by the sponsor on 26 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identifying Neurophysiological Mechanisms of Susceptibility to Estradiol Fluctuation and Irritability Symptoms in the Menopause Transition: An Experimental Approach
- ClinicalTrials.gov ID
- NCT05388656
- Acronym / sponsor ID
- 21-3395
- Conditions
- Menopause, Irritable Mood
- Keywords
- Perimenopause, Menopause transition, Estrogen, Stress, Mood, Irritability
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 15 Jun 2022 (actual)
- Primary completion
- 17 Dec 2024 (actual)
- Study completion
- 17 Jan 2025 (actual)
- First posted
- 24 May 2022 (actual)
- Results
- Posted 26 Nov 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Women in the menopause transition (perimenopause) experience substantial day-to-day variability in estradiol and have a 2-4-fold increase in major depression risk. About 40% of perimenopausal women are susceptible to the emergence of affective symptoms tied to changes in estradiol. Among the perimenopausal women with affective impairment, most report irritability, not "depression," is their primary source of impairment and distress. The purpose of this research is to determine the neurophysiologic basis of susceptibility to estradiol fluctuations and irritability symptoms in perimenopausal women.
Detailed description
Using a within-subjects, cross-over design and transdermal estradiol to stabilize estradiol fluctuations (and increase levels) the investigators will test if neural dynamics (oscillatory activity in the theta and beta frequencies assessed via EEG) associated with key constructs of irritability (attentional bias to threat and frustration to non-reward) represent a biomarker target of irritability symptom response to transdermal estradiol.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Estradiol, Then Placebo | Experimental | Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release, Drug: Placebo, Drug: Progesterone 200 mgParticipants will first receive 0.1 mg/day of transdermal estradiol patch for 3 weeks. After a washout period of 3 weeks, participants will then receive transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks. Upon completion of the second intervention, all participants will receive 200 mg/day of progesterone for 10 days. |
| Placebo, Then Estradiol | Experimental | Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release, Drug: Placebo, Drug: Progesterone 200 mgParticipants will first receive transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks. After a washout period of 3 weeks, participants will then receive 0.1 mg/day of transdermal estradiol patch for 3 weeks. Upon completion of the second intervention, all participants will receive 200 mg/day of progesterone for 10 days. |
Who may qualify
- Ages
- 45 to 59 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Healthy women 45 - 59 years of age
- In the early menopause transition (defined by variable menstrual cycle length that is 7+ days longer or shorter than usual)
- Increase in irritability since the onset of menstrual cycle changes
- Moderate to severe irritability symptoms, as defined by IDAS ill-temper scale score >10
- Have experienced 1+ very stressful life event (e.g. divorce, death of family member) within the past 6 months
Key exclusion criteria (15 listed)
- Use of psychotropic agents or hormonal preparations, or herbal supplements (other than multivitamins) believed to affect mood or menopausal symptoms
- History of psychosis, bipolar disorder, or substance dependence
- Active psychological symptoms severe enough to require treatment
- Current suicidal intent or recent history of suicide attempts (within past 10 years)
- Personal or family history of cancer indicative of more than average risk for breast, ovarian or endometrial cancers
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 |
|---|---|---|
| Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release0.1 mg/day transdermal patch administered for 3 weeks | Drug | Estradiol, Then Placebo, Placebo, Then Estradiol |
| PlaceboEstradiol-matched placebo patch administered for 3 weeks | Drug | Estradiol, Then Placebo, Placebo, Then Estradiol |
| Progesterone 200 mgAlso: Prometrium200 mg tablet administered by mouth once per day for 10 days after completion of the experimental phase of the study | Drug | Estradiol, Then Placebo, Placebo, Then Estradiol |
Primary outcome
Mean IDAS Ill Temper Scale Score Over Time
Time frame: 3 weeks during each intervention
The 5-item ill temper scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be the primary measure of irritability symptom severity. Each symptom item is rated 1 (not at all) to 5 (extremely). The total IDAS ill temper scale score may range from 5-25. Higher scores indicate more severe irritability symptoms. The average daily irritability scores will be evaluated for each 3-week treatment condition (Active Estradiol vs. Placebo).
2 secondary outcomes
Reward Positivity (RewP) in Response to the Affective Posner Paradigm
Time frame: At the end of each three-week treatment period.
Mean LPP Amplitude During Implicit Viewing Task Dysfunctional Threat Processing Was Indexed by Greater Late Positive Potential (LPP) Component for Emotional Face Stimuli, Elicited 400-900 Milliseconds After the Stimulus Presentation.
Time frame: At the end of each 3-week treatment period
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Nov 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. After the study is completed, the de-identified, archived data will be transmitted to and stored at the National Institute of Mental Health Data Archive (NDA) for use by other researchers including those outside of the study.
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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. This study is not recruiting at the moment.
Susan Girdler, PhD principal investigator
University of North Carolina, Chapel Hill
Elizabeth Andersen, PhD principal investigator
University of North Carolina, Chapel Hill
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 Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release and Progesterone 200 mg in people with Menopause and Irritable Mood, run by University of North Carolina, Chapel Hill 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 7 inclusion and 15 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: finished, as of the sponsor's last update on 26 Nov 2025. 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?
Yes. Results are posted in the registry (first posted 26 Nov 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean IDAS Ill Temper Scale Score Over Time (time frame: 3 weeks during each intervention). 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 26 Nov 2025.