# Allopregnanolone and Gamma-Aminobutyric Acid Receptor (GABA-A-R) Plasticity in Women with Premenstrual Mood Symptoms

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $258,969

## Abstract

PROJECT SUMMARY
Roughly 20% of women experience clinically significant anxiety, irritability, or depressive symptoms in the
premenstrual (luteal) phase of the menstrual cycle. This includes premenstrual dysphoric disorder (PMDD), a
severe affective disorder impacting millions of women worldwide. Despite this morbidity, research on PMDD’s
pathophysiology lags behind that of other brain disorders. A potential contributor to PMDD’s pathophysiology is
allopregnanolone (ALLO), a progesterone metabolite and powerful GABA-A receptor (GABA-A-R) modulator
that fluctuates across the luteal phase. Importantly, rodent models of PMDD indicate impaired GABA-A-R
plasticity in response to ALLO fluctuations. Building on this preclinical literature and clinical findings from the
PI’s K23 (NIMH K23MH107831), the proposed research will test the hypothesis that rapid ALLO changes
across the luteal phase, in interaction with suboptimal GABA-A-R receptor subunit reconfiguration,
contribute to premenstrual mood symptoms. We will assess 67 women with regular menstrual cycles (33
controls, 34 with premenstrual dysphoric disorder (PMDD)) based on the gold standard Daily Record of
Severity of Problems. We will capture two outcome measures: 1) We will measure plasma ALLO changes
within subjects at multiple timepoints across the luteal phase using precise gas chromatography/mass
spectrometry (GC/MS) methods. 2) We will use a novel biomarker, GABA-A-R subunit expression in peripheral
blood mononuclear cell (PBMCs) measured via real-time polymerase chain reaction (RT-qPCR), to examine
GABA-A-R subunit expression across the luteal phase. We hypothesize that controls and women with PMDD
will differ in luteal phase decline in ALLO levels (e.g. controls will have a more gradual decline), and will differ
in GABA-A-R subunit expression as ALLO levels decline. Combining these powerful methodologies will enable
us to examine a mechanistic hypothesis about ALLO dynamics and GABA-A-R plasticity in women with
premenstrual mood symptoms, in a prospective within-subject manner. The investigators bring complementary
expertise; Dr. Hantsoo in prospectively studying women with PMDD, and Dr. Pinna in applying state-of-the-art
methods to study the impact of ALLO on GABA-A-R function. This study represents a critical step in elucidating
ALLO - GABA-A-R dynamics in this population, and will lead to an R01 that examines ALLO - GABA-A-R
dynamics in women with PMDD when treated with selective serotonin reuptake inhibitors (SSRIs).
Understanding PMDD’s pathophysiology may inform treatment development; only 60% of women with PMDD
respond to the first-line treatment (SSRIs), and new GABA-modulating drugs are being developed (e.g.
brexanolone and sepranolone, GABA-A modulating steroid antagonists). Before meaningful work is done in
treatment development and personalized medicine in PMDD, mechanisms such as ALLO - GABA-A-R
dynamics must be clarified.

## Key facts

- **NIH application ID:** 10363837
- **Project number:** 1R21MH125936-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Liisa Victoria Hantsoo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $258,969
- **Award type:** 1
- **Project period:** 2022-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363837

## Citation

> US National Institutes of Health, RePORTER application 10363837, Allopregnanolone and Gamma-Aminobutyric Acid Receptor (GABA-A-R) Plasticity in Women with Premenstrual Mood Symptoms (1R21MH125936-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10363837. Licensed CC0.

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