Estrogen Variability and Irritability During the Menopause Transition

Sponsor

University of North Carolina, Chapel Hill (Other)

Overall Status

Recruiting

CT.gov ID

NCT05388656

Collaborator

National Institute of Mental Health (NIMH) (NIH)

Enrollment

Location

Arms

29.6

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Menopause Irritable Mood	Drug: Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release Drug: Placebo Drug: Progesterone 200 mg	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

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.

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Jun 15, 2022

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

45 Years to 55 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy women 45 - 55 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 year
BMI between 18 - 35 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 stage 2 hypertension or higher (≥140 mmHg systolic or ≥90 mmHg diastolic)
Liver dysfunction or disease
Undiagnosed abnormal genital bleeding
Type I or Type II diabetes
Known sensitivities to the matrix patch system in Climara® or allergy to peanut oil used in Prometrium®

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Carolina Crossing B, Suite 1	Chapel Hill	North Carolina	United States	27517

Sponsors and Collaborators

University of North Carolina, Chapel Hill
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