# Identifying neurophysiological mechanisms of susceptibility to estradiol fluctuation and irritability symptoms in the menopause transition: An experimental approach

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $233,250

## Abstract

PROJECT SUMMARY
The emergence of irritability, not depressed mood, is the primary source of distress and impairment for
perimenopausal women. Irritability, the predisposition to exhibit anger, is a dimensional construct seen across
psychiatric disorders, including depression, anxiety, and psychosis. Dysregulation of limbic neural networks is
central to the neuropathology of aberrant responses to threat and frustration to non-reward, two interconnected
constructs of irritability. Cortico-limbic engagement during threat reactivity and frustration to non-reward can be
reliably studied using electroencephalography (EEG). The functional coupling of frontal and limbic neural
networks relies on synchronous neural oscillations in theta (4-8Hz) and beta (13-30Hz) frequencies, and their
ratio (theta/beta) is an index of frontal top-down control of limbic-mediated affective processing.
The menopause transition is characterized by substantial variability in estradiol (E2), a potent modulator of
limbic networks involved in affective and reward processing. Vulnerability to normal changes in E2 is
etiologically relevant to reproductive mood disorders, with 40% of perimenopausal women showing
susceptibility to affective symptoms triggered by changes in E2. Although predictors of this susceptibility to E2
change are identified (early menopause transition stage and recent stressful life events), the neurophysiologic
mechanisms of this susceptibility are unknown. The primary objective of this research is to determine the
neurophysiological basis of susceptibility to E2 fluctuations and irritability symptoms in the perimenopause.
We will study 30 perimenopausal women, 45 – 55 years of age, who have high probability for affective
susceptibility to changes in E2 by recruiting women who: 1) report the emergence of significant irritability
concurrent with entering the menopause transition; 2) are in the early menopause transition stage; and 3) have
had 1+ recent severe stressful life event. At baseline (one week) we will use daily urinary E1G (highly correlated
metabolite of E2) to index E2 variability and determine relationships between: E1G variability and irritability
symptom severity; E1G variability and theta/beta ratios during task-induced threat reactivity (Dot Probe task) and
frustration to non-reward (Point Subtraction Aggression Paradigm); and task-induced theta/beta ratios and
irritability symptoms. Following baseline, we will experimentally manipulate the E2 environment to determine the
role of E2 in task-induced behavioral and neurophysiological responses, and in irritability symptoms. Using a
within-subjects, randomized, placebo-controlled, cross-over design, each participant will be studied under two
conditions: 3 weeks on transdermal E2 (0.1 mg/day) to stabilize E2 variability and 3 weeks on placebo. E1G
variability, irritability symptoms, and EEG measures will be assessed in each condition. Stabilizing E2 variability
with transdermal E2 is expected to i...

## Key facts

- **NIH application ID:** 10348341
- **Project number:** 1R21MH128241-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Elizabeth Helen Andersen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2021-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348341

## Citation

> US National Institutes of Health, RePORTER application 10348341, Identifying neurophysiological mechanisms of susceptibility to estradiol fluctuation and irritability symptoms in the menopause transition: An experimental approach (1R21MH128241-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10348341. Licensed CC0.

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