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OpenTrials
Completed

NCT Number: NCT05388656

Estrogen Variability and Irritability During the Menopause Transition

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.

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Key information

Conditions

Menopause Irritable Mood

Age range

45 year–59 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 4

Primary location

Carolina Crossing B, Suite 1

Chapel Hill, North Carolina, 27517, United States

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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®

Treatment and study plan

Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release

Drug

0.1 mg/day transdermal patch administered for 3 weeks

Placebo

Drug

Estradiol-matched placebo patch administered for 3 weeks

Progesterone 200 mg

Drug

200 mg tablet administered by mouth once per day for 10 days after completion of the experimental phase of the study

Other names: Prometrium

Primary outcomes

  1. 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).

Secondary outcomes

  1. 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.

  2. 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).

Sponsors and collaborators

Lead sponsor

University of North Carolina, Chapel Hill

Other

Collaborators

  • National Institute of Mental Health (NIMH)

Registry information

Official study title

Identifying Neurophysiological Mechanisms of Susceptibility to Estradiol Fluctuation and Irritability Symptoms in the Menopause Transition: An Experimental Approach

Important dates

Study start
2022
Primary completion
2024
Study completion
2025
First posted
May 24, 2022
Registry last updated
Nov 26, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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