# The Menopause Transition: Estrogen Variability, HPA axis and Affective Symptoms

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $551,252

## Abstract

PROJECT SUMMARY
Vulnerability to the deleterious mood effects of normal changes in reproductive hormones is a likely
underpinning to reproductive mood disorders. The menopause transition (MT) is associated with pronounced
hormonal variability (within the context of relative E2 deprivation) and substantially increased risk for clinically
impairing anxiety and anhedonia. Anxiety is characterized by cognitive bias to interpret ambiguous stimuli in a
threat-related manner. Anhedonia can be defined by decreased motivation to approach rewards. The
neurobiologically-based constructs of ‘threat reactivity’ and ‘approach motivation’ provide a framework for
studying the pathophysiology of the clinical impairment experienced by 25% of women in the MT. Although the
causes of affective symptoms in the MT remain unknown, severe life stress proximate to the MT is a strong
predictor. Framed within a diathesis-stress model, the primary objective of this research is to determine the
pathophysiological mechanisms of estradiol (E2) in the clinical anxiety and anhedonia seen in the MT.
Specifically whether E2 variability or E2 levels predict exaggerated hypothalamic-pituitary-adrenal (HPA) axis
reactivity and impaired recovery to stress and, in turn, deficits in behavioral indices of threat responsivity and
approach motivation and symptoms of anxiety and anhedonia. The secondary objective of the research is to
use a hormonal manipulation as a mechanistic probe to stabilize E2 variability in premenopausal ranges and
determine if: a) HPA axis reactivity/recovery represents a biomarker of behavioral and symptom responses to
E2 stabilization; b) whether recent severe life stress predicts the HPA axis response to hormone stabilization.
A total of 170 women in the early or late MT who are eligible for the hormonal probe will be recruited to reflect
the full continuum of anxiety and anhedonia symptoms based on self-report to the State-Trait Anxiety Inventory
and the Snaith-Hamilton Pleasure Scale, respectively. However, we will over-represent the clinically impairing
end of the anxious and anhedonic phenotype (75% of the sample). Over an 8-week baseline, anxiety and
anhedonia symptoms and serum E2 measured by liquid chromatography-tandem mass spectrometry (LC-
MS/MS) will be assessed on a weekly basis. At baseline week 8, HPA axis (plasma cortisol and ACTH)
response to the Trier Social Stress Test and behavioral measures of threat responsivity (via Dot-Probe task)
and approach motivation (Effort Expenditure for Rewards Task ‘EEfRT’) will be determined. Using transdermal
E2 as a pharmacological probe to stabilize variability of E2 in premenopausal ranges, women will then be
randomized to transdermal E2 (0.10 mg) or placebo for 16 weeks. This is not a clinical efficacy trial. We will
use an RCT design with a hormonal manipulation in order to investigate the pathophysiologic role of E2
variability (or E2 levels) in HPA axis dysregulation and, in turn, threat responsivity and a...

## Key facts

- **NIH application ID:** 9959466
- **Project number:** 5R01MH108690-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** SUSAN S. GIRDLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $551,252
- **Award type:** 5
- **Project period:** 2016-09-08 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959466

## Citation

> US National Institutes of Health, RePORTER application 9959466, The Menopause Transition: Estrogen Variability, HPA axis and Affective Symptoms (5R01MH108690-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9959466. Licensed CC0.

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