Estrogen Variability and Irritability During the Menopause Transition

NCT05388656 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: 21-3395R21MH128241
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Menopause; Irritable Mood

Keywords

Perimenopause; Menopause transition; Estrogen; Stress; Mood; Irritability

Outcome Measures

Primary Outcomes (1)

• 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).

  3 weeks during each intervention

Secondary Outcomes (2)

• Reward Positivity (RewP) in Response to the Affective Posner Paradigm

  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.

  At the end of each 3-week treatment period

Study Arms (2)

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.

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.

Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release; Drug: Placebo; Drug: Progesterone 200 mg

Interventions

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

0.1 mg/day transdermal patch administered for 3 weeks

Estradiol, Then Placebo; Placebo, Then Estradiol

Placebo DRUG

Estradiol-matched placebo patch administered for 3 weeks

Estradiol, Then Placebo; Placebo, Then Estradiol

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

Also known as: Prometrium

Estradiol, Then Placebo; Placebo, Then Estradiol

Eligibility Criteria

• Age: 45 Years - 59 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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®

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

Carolina Crossing B, Suite 1

Chapel Hill, North Carolina, 27517, United States

Location

MeSH Terms

Interventions

Progesterone

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones

Results Point of Contact

• Title: Elizabeth Andersen, PhD
• Organization: University of North Carolina at Chapel Hill

elizabeth_andersen@med.unc.edu

(970) 420-4944

Study Officials

• Susan Girdler, PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

• Elizabeth Andersen, PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: There will be one unblinded Research Assistant administering interventions to preserve masking of research personnel and participants involved. Care provider may be unmasked for specific participants if there are adverse events requiring referral.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2022
• First Posted: May 24, 2022
• Study Start: June 15, 2022
• Primary Completion: December 17, 2024
• Study Completion: January 17, 2025
• Last Updated: November 26, 2025
• Results First Posted: November 26, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Raw experimental data will not be released or shared until publication or after the project end date, whichever comes first.
• Access Criteria: Refer to National Institute of Mental Health Data Archive (NDA) for details.

Locations

US (1)