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Cited by 199Menstrual Health and DisordersMaternal Mental Health During Pregnancy and PostpartumNeuroscience and Neuropharmacology Research

Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle

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Hantsoo, Liisa, Epperson, C. Neill·2020·Neurobiology of Stress
DOI 10.1016/j.ynstr.2020.100213PMC PMC7231988
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Abstract

Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with core symptoms (affective lability, irritability, depressed mood, anxiety) and increased sensitivity to stress occurring in the luteal phase of the menstrual cycle. PMDD can be conceptualized as a disorder of suboptimal sensitivity to neuroactive steroid hormones (NASs). In this review, we describe the role of the NAS allopregnanolone (ALLO), a positive allosteric modulator of the GABAA receptor (GABAA-R), in PMDD's pathophysiology. We review evidence of impaired interaction between ALLO and GABAA-Rs in terms of affective symptom expression, with evidence from rodent and human studies. We discuss evidence of increased luteal phase stress sensitivity as a result of poor ALLO-GABA control of the HPA axis. Finally, we describe how treatments such as selective serotonin reuptake inhibitors (SSRIs) and new drugs targeting GABAA-Rs provide evidence for impaired ALLO-GABA function in PMDD. In sum, the literature supports the hypothesis that PMDD pathophysiology is rooted in impaired GABAA-R response to dynamic ALLO fluctuations across the menstrual cycle, manifesting in affective symptoms and poor regulation of physiologic stress response.

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  • PMDD is thought to derive from increased sensitivity to stress at the late luteal phase due to poor allopregnanolone-dependent GABA control of the HPA axis.

    “As another example, is PMDD is thought to derive from increased sensitivity to stress at the late luteal phase due to poor allopregnanolone-dependent GABA control of the HPA axis [148].”

    From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [148]

    The HPA-axis section proposes that poor GABA regulation may explain increased stress sensitivity in women with PMDD during the luteal phase. The Conclusion links impaired allopregnanolone function to both PMDD symptoms and elevated stress sensitivity. It does not say that stress sensitivity itself causes PMDD, or confine this proposed mechanism specifically to the late luteal phase. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Hantsoo, L., & Epperson, C. N.
Affiliations
  • Johns Hopkins University (US)
  • University of Colorado Anschutz (US)
Corresponding author
Hantsoo, Liisa
ORCID
Venue
Neurobiology of Stress
Publisher
Elsevier BV
Published
2020-05
Volume
12
Pages
100213
ISSN
2352-2895 (ISSN-L)
DOI
10.1016/j.ynstr.2020.100213
PMC
PMC7231988
OpenAlex
W3004451854
Cited by
199
References
16
Citations by year
2026: 32 · 2025: 35 · 2024: 28 · 2023: 29 · 2022: 26 · 2021: 45 · 2020: 4
FWCI
19.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Stress (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (K23 MH107831)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Menstrual Health and Disorders
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
premenstrual dysphoric disorder, allopregnanolone, GABAA receptor, neurosteroids, menstrual cycle, luteal phase, hypothalamic-pituitary-adrenal axis, stress sensitivity, affective symptoms, positive allosteric modulators, selective serotonin reuptake inhibitors, GABA-A receptor agonists, mood disorders

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