Estrogen Variability and Irritability During the Menopause Transition

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: Completed
• Conditions: Menopause; Irritable Mood
• Intervention / Treatment: Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release; Drug: Placebo; Drug: Progesterone 200 mg

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: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	At the end of each 3-week treatment period

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: 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

Study Major Dates

• Study Start (Actual): June 15, 2022
• Primary Completion (Actual): December 17, 2024
• Study Completion (Actual): January 17, 2025

Study Registration Dates

• First Submitted: May 18, 2022
• First Submitted That Met QC Criteria: May 18, 2022
• First Posted (Actual): May 24, 2022

Study Record Updates

• Last Update Posted (Actual): November 26, 2025
• Last Update Submitted That Met QC Criteria: November 18, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Stress; Mood; Irritability; Estrogen; Perimenopause; Menopause transition
• Additional Relevant MeSH Terms: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Gonadal Steroid Hormones; Gonadal Hormones; Pregnenediones; Pregnenes; Corpus Luteum Hormones; Progesterone Congeners; Progesterone
• Other Study ID 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