Estrogen Variability and Irritability During the Menopause Transition

NCT ID: NCT05388656

Last Updated: 2025-11-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-15
• Study Completion Date: 2025-01-17

Brief 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. 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.

Conditions

Menopause; Irritable Mood

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

0.1 mg/day transdermal patch administered for 3 weeks

Placebo

Intervention Type: DRUG

Estradiol-matched placebo patch administered for 3 weeks

Progesterone 200 mg

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

0.1 mg/day transdermal patch administered for 3 weeks

Placebo

Intervention Type: DRUG

Estradiol-matched placebo patch administered for 3 weeks

Progesterone 200 mg

Intervention Type: DRUG

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

Interventions

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

0.1 mg/day transdermal patch administered for 3 weeks

Intervention Type: DRUG

Placebo

Estradiol-matched placebo patch administered for 3 weeks

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Prometrium

Eligibility Criteria

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®

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 59 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Susan Girdler, PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Elizabeth Andersen, PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Locations

Carolina Crossing B, Suite 1

Chapel Hill, North Carolina, United States

Countries

United States

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

R21MH128241

Identifier Type: NIH

Identifier Source: secondary_id

View Link

21-3395

Identifier Type: -

Identifier Source: org_study_id