Estrogen Variability and Irritability During the Menopause Transition

November 18, 2025 updated by: University of North Carolina, Chapel Hill

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • United States
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27517
        • Carolina Crossing B, Suite 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

41 years to 55 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • 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®

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Estradiol, Then Placebo
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.
Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release
0.1 mg/day transdermal patch administered for 3 weeks
Drug: Placebo
Estradiol-matched placebo patch administered for 3 weeks
Drug: Progesterone 200 mg
200 mg tablet administered by mouth once per day for 10 days after completion of the experimental phase of the study
Other Names:
  • Prometrium
Experimental: Placebo, Then Estradiol
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.
Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release
0.1 mg/day transdermal patch administered for 3 weeks
Drug: Placebo
Estradiol-matched placebo patch administered for 3 weeks
Drug: Progesterone 200 mg
200 mg tablet administered by mouth once per day for 10 days after completion of the experimental phase of the study
Other Names:
  • Prometrium

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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).
3 weeks during each intervention

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Reward Positivity (RewP) in Response to the Affective Posner Paradigm
Time Frame: At the end of each three-week treatment period.
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.
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
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).
At the end of each 3-week treatment period

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of North Carolina, Chapel Hill

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Mental Health (NIMH)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Susan Girdler, PhD, University of North Carolina, Chapel Hill
  • Principal Investigator: Elizabeth Andersen, PhD, University of North Carolina, Chapel Hill

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 15, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 17, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 17, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 18, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 18, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 24, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 26, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 18, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 21-3395
  • R21MH128241 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing Time Frame

Raw experimental data will not be released or shared until publication or after the project end date, whichever comes first.

IPD Sharing Access Criteria

Refer to National Institute of Mental Health Data Archive (NDA) for details.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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