Trial Outcomes & Findings for Estrogen Variability and Irritability During the Menopause Transition (NCT NCT05388656)

Last Updated: 2025-11-26

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

40 participants

Primary outcome timeframe

3 weeks during each intervention

Results posted on

2025-11-26

Participant Flow

Participants were recruited through medical clinics, UNC Massmail, research listservs (e.g., Research4Me), community flyers, and social media to maximize outreach and participation opportunities.

Forty participants signed informed consent and were enrolled into the study. Of the 40 enrolled participants, 34 met eligibility criteria and proceeded directly to study assignment. Participants who were excluded prior to assignment were those who did not complete initial eligibility confirmation or withdrew consent.

Participant milestones

Participant milestones
Measure	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.	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.
First Intervention (3 Weeks) STARTED	18	16
First Intervention (3 Weeks) COMPLETED	16	15
First Intervention (3 Weeks) NOT COMPLETED	2	1
Washout (3 Weeks) STARTED	16	15
Washout (3 Weeks) COMPLETED	15	15
Washout (3 Weeks) NOT COMPLETED	1	0
Second Intervention (3 Weeks) STARTED	15	15
Second Intervention (3 Weeks) COMPLETED	15	15
Second Intervention (3 Weeks) NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Estrogen Variability and Irritability During the Menopause Transition

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Estradiol, Then Placebo n=18 Participants 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 n=16 Participants 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.	Total n=34 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=492 Participants	0 Participants n=492 Participants	0 Participants n=984 Participants
Age, Categorical Between 18 and 65 years	18 Participants n=492 Participants	16 Participants n=492 Participants	34 Participants n=984 Participants
Age, Categorical >=65 years	0 Participants n=492 Participants	0 Participants n=492 Participants	0 Participants n=984 Participants
Sex: Female, Male Female	18 Participants n=492 Participants	16 Participants n=492 Participants	34 Participants n=984 Participants
Sex: Female, Male Male	0 Participants n=492 Participants	0 Participants n=492 Participants	0 Participants n=984 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=492 Participants	1 Participants n=492 Participants	3 Participants n=984 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	16 Participants n=492 Participants	15 Participants n=492 Participants	31 Participants n=984 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=492 Participants	0 Participants n=492 Participants	0 Participants n=984 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=492 Participants	0 Participants n=492 Participants	0 Participants n=984 Participants
Race (NIH/OMB) Asian	1 Participants n=492 Participants	0 Participants n=492 Participants	1 Participants n=984 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=492 Participants	0 Participants n=492 Participants	0 Participants n=984 Participants
Race (NIH/OMB) Black or African American	5 Participants n=492 Participants	0 Participants n=492 Participants	5 Participants n=984 Participants
Race (NIH/OMB) White	11 Participants n=492 Participants	13 Participants n=492 Participants	24 Participants n=984 Participants
Race (NIH/OMB) More than one race	0 Participants n=492 Participants	1 Participants n=492 Participants	1 Participants n=984 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=492 Participants	2 Participants n=492 Participants	3 Participants n=984 Participants
Region of Enrollment United States	18 Participants n=492 Participants	16 Participants n=492 Participants	34 Participants n=984 Participants
IDAS- 5 question Scale	6.41 scores on a scale STANDARD_DEVIATION 2.44 • n=492 Participants	6.04 scores on a scale STANDARD_DEVIATION 1.97 • n=492 Participants	6.24 scores on a scale STANDARD_DEVIATION 2.23 • n=984 Participants

PRIMARY outcome

Timeframe: 3 weeks during each intervention

Outcome measures

Outcome measures
Measure	Estradiol n=33 Participants Participants received 0.1 mg/day of transdermal estradiol patch for 3 weeks.	Placebo n=31 Participants Participants received transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks.
Mean IDAS Ill Temper Scale Score Over Time	6.19 score on a scale Standard Deviation 1.33	6.02 score on a scale Standard Deviation 1.02

SECONDARY outcome

Timeframe: At the end of each three-week treatment period.

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.

Outcome measures

Outcome measures
Measure	Estradiol n=33 Participants Participants received 0.1 mg/day of transdermal estradiol patch for 3 weeks.	Placebo n=31 Participants Participants received transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks.
Reward Positivity (RewP) in Response to the Affective Posner Paradigm	-2.59 Microvolts Standard Deviation 3.19	-2.13 Microvolts Standard Deviation 3.13

SECONDARY outcome

Timeframe: At the end of each 3-week treatment period

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).

Outcome measures

Outcome measures
Measure	Estradiol n=33 Participants Participants received 0.1 mg/day of transdermal estradiol patch for 3 weeks.	Placebo n=31 Participants Participants received transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks.
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.	2.92 Microvolts Standard Deviation 1.62	2.99 Microvolts Standard Deviation 1.49

Adverse Events

Estradiol

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Progesterone

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Elizabeth Andersen, PhD

University of North Carolina at Chapel Hill

Phone: (970) 420-4944

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Estradiol n=33 participants at risk Participants received 0.1 mg/day of transdermal estradiol patch for 3 weeks. Estradiol Patch, 0.1 mg/24 Hours Weekly Transdermal Film, Extended Release: 0.1 mg/day transdermal patch administered for 3 weeks	Progesterone n=31 participants at risk Participants received progesterone pills (1 pill per day for 10 days) after lab visit 3 (Post-Placebo and Estradiol conditions)	Placebo n=31 participants at risk Participants received transdermal placebo patch (matching transdermal estradiol 0.1 mg/day patch) for 3 weeks. Placebo: Estradiol-matched placebo patch administered for 3 weeks
Vascular disorders Pain in right calf and swelling in legs	3.0% 1/33 • Number of events 2 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	6.5% 2/31 • Number of events 2 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Reproductive system and breast disorders Prolonged bleeding	6.1% 2/33 • Number of events 2 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	9.7% 3/31 • Number of events 3 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Vascular disorders Swelling in left ankle	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Vascular disorders Swelling in legs	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	6.5% 2/31 • Number of events 2 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Reproductive system and breast disorders Increased breast tenderness	6.1% 2/33 • Number of events 2 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Reproductive system and breast disorders Concerning breast lumps	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	6.5% 2/31 • Number of events 2 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Nervous system disorders Migraine headache without aura	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	9.7% 3/31 • Number of events 3 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Eye disorders Changes in vision/trouble with contacts	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Skin and subcutaneous tissue disorders Rash	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Skin and subcutaneous tissue disorders Swollen Lips	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Reproductive system and breast disorders "Bump" on vulva	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Nervous system disorders Non-migrainous headache (no visual symptoms)	15.2% 5/33 • Number of events 24 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	9.7% 3/31 • Number of events 3 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	38.7% 12/31 • Number of events 17 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Cardiac disorders Intermittent chest pain	3.0% 1/33 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Reproductive system and breast disorders Increased nausea and breast tenderness	12.1% 4/33 • Number of events 4 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	6.5% 2/31 • Number of events 2 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Skin and subcutaneous tissue disorders Irritation at patch site	12.1% 4/33 • Number of events 4 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	9.7% 3/31 • Number of events 3 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Vascular disorders Pain in legs	15.2% 5/33 • Number of events 5 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	25.8% 8/31 • Number of events 8 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.
Vascular disorders Numbness in fingertips	0.00% 0/33 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	0.00% 0/31 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.	3.2% 1/31 • Number of events 1 • From the time of the first laboratory visit through final follow up visit, up to approximately 3 months.