Estrogen Variability and Irritability During the Menopause Transition

Phase 4

Recruiting

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

• Registration Number: NCT05388656
• Lead Sponsor: University of North Carolina, Chapel Hill

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.

Study Timeline

• Study First Submitted: 2022-05-18
• Study First Submitted QC: 2022-05-18
• Study First Posted: 2022-05-24
• Study Start: 2022-06-15
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-02
• Last Update Posted: 2023-10-04
• Primary Completion: 2024-12
• Study Completion: 2024-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 50

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

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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®

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Estradiol, Then Placebo	Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release	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.
Placebo, Then Estradiol	Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release	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.
Placebo, Then Estradiol	Progesterone 200 mg	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.
Estradiol, Then Placebo	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.
Placebo, Then Estradiol	Placebo	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.
Estradiol, Then Placebo	Progesterone 200 mg	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.

Primary Outcome Measures

Name	Time	Method
Mean IDAS Ill Temper Scale Score Over Time	up to Week 13	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 (IDAS) score over 1 week (7 days) will be assessed at baseline (Week 4), the last week of Condition 1 (Week 7), and the last week of Condition 2 (Week 13).

Secondary Outcome Measures

Name	Time	Method
Theta Oscillatory Activity (4-8 Hz) In Response To Dot Probe Task (Indexing Threat) Over Time	up to Week 13	Participants will complete the Dot Probe Task while EEG is recorded to examine brain responses (theta oscillations) to threat. During the task, participants will be presented with a pair of faces on each side of the screen. In anger trials, one face is angry and the other is neutral. The pair of faces is followed by an asterisk, half of the time presented on the same side as the angry face and half of the time presented on the side of the neutral face. Trials will be angry-neutral, happy-neutral, and neutral-neutral. Theta recorded at the frontal midline electrode during the different task conditions will be assessed at baseline (Week 4), Condition 1 (Week 7), and Condition 2 (Week 13).
Beta Oscillatory Activity (13-30 Hz) In Response To Affective Posner Paradigm (probing Frustration) Over Time	up to Week 13	Participants will complete the Affective Posner Paradigm while EEG is recorded to examine brain activity (beta oscillations) during frustrating task events. The Affective Posner Paradigm is a reward task designed to measure frustration to non-reward, consisting of three runs with varying degrees of reward as the participant performs the task. Beta oscillatory activity during the three task conditions will be assessed at baseline (Week 4), Condition 1 (Week 7), and Condition 2 (Week 13).

Trial Locations

Locations (1)

Carolina Crossing B, Suite 1; 🇺🇸 Chapel Hill, North Carolina, United States