Beyond the HPA Axis: Progesterone-Derived Neuroactive Steroids in Human Stress and Emotion
Open accessAbstract
Stress and social isolation are well-known risk factors for psychopathology. However, more research is needed as to the physiological mechanisms by which social support buffers the impacts of stress. Research in animal models suggests important roles for progesterone (P) and its product, the neuroactive steroid allopregnanolone (ALLO), in stress and psychopathology. These hormones are produced in brain and periphery during stress in rodents, and down-regulate anxiety behavior and hypothalamic-pituitary-adrenal axis activity. Human clinical populations, including depressed patients, have alterations in ALLO levels, but it is unclear whether these basal hormone level differences have clinical import. To begin to address this question, this review examines the role of P and ALLO in stress physiology, and the impact of these hormones on mood, in healthy humans. Evidence largely supports that P and ALLO increase during stress in humans. However, P/ALLO administration appears to cause only mild effects on mood and subjective anxiety, while exerting effects consistent with gamma-aminobutyric acid receptor modulation. Additionally, P is linked to motivation for affiliation/social contact; P (and ALLO) release may be especially responsive to social rejection. These observations lead to the novel hypothesis that stress-related P/ALLO production functions not only to down-regulate stress and anxiety, but also to promote social contact as a long-term coping strategy. Malfunctioning of the P/ALLO system could therefore underlie depression partly by decreasing propensity to affiliate with others.
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Most of progesterone's behavioral effects may result from its conversion to allopregnanolone rather than from classical nuclear progesterone receptor signaling.
“While P4 may exert behavioral effects through the classical nuclear P4 receptor (PR) mechanism64, most of P4’s effect may correspond to P4 conversion to ALLO63.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
In “Neuroactive Steroids and Stress: Background and Research in Laboratory Animals” (page unavailable), the paper says progesterone’s anti-stress and anxiolytic effects are thought to arise from conversion to allopregnanolone rather than intracellular progesterone receptors. It also acknowledges some evidence for receptor-mediated effects. The claim extends that proposed mechanism to most of progesterone’s behavioral effects, a broader conclusion the passage does not establish. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAllopregnanolone and its stereoisomer pregnanolone can be sulphated and thereby modulate glutamatergic neurotransmission through NMDA receptors.
“ALLO and its stereoisomer, pregnanolone, can also be sulphated allowing them to modulate glutamatergic neurotransmission through NMDA receptors63.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
The “Neuroactive Steroids and Stress” section identifies pregnanolone as a stereoisomer of allopregnanolone. It describes both in relation to GABA receptors, but does not say they can be sulphated or that their sulphated forms modulate glutamatergic neurotransmission through NMDA receptors (searched: sulphated, NMDA, glutamatergic). (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe effects of P4 on HPA axis reactivity are thought to be primarily due to conversion of P4 to allopregnanolone rather than through intracellular PR signaling.
“The effects of P4 on HPA axis reactivity are thought to be primarily due to conversion of P4 to ALLO rather than through intracellular PR signaling63.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
In “Neuroactive Steroids and Stress: Background and Research in Laboratory Animals” (page unavailable), the review says P’s anti-stress and anxiolytic effects are thought to act mainly through conversion to ALLO rather than intracellular P receptors. It also reports that ALLO can down-regulate the HPA axis, but does not specifically establish that P’s effects on HPA-axis reactivity follow that mechanism rather than intracellular PR signaling. (LLM, conf=0.83)
Experimental — accuracy not yet measuredStress increases brain and plasma P4 and allopregnanolone concentrations.
“Stress increases brain and plasma P4 and ALLO concentrations”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
The “Neuroactive Steroids and Stress: Background and Research in Laboratory Animals” section (page not provided) states that brain and plasma progesterone (P4) and allopregnanolone (ALLO) rise during stress in rodents. The claim omits that species qualification. In the human-stress section (page not provided), the review describes mixed responses and does not establish increases in both brain and plasma concentrations during stress in humans. (LLM, conf=0.87)
Experimental — accuracy not yet measuredProgesterone and allopregnanolone have been linked to mood and anxiety disorders.
“Neurosteroids, particularly P4 and ALLO, have been associated with mood and anxiety disorders63.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
Allopregnanolone acts as an allosteric modulator at GABAA receptors.
“ALLO interacts with the GABAA receptors as an allosteric modulator63,65”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
At high doses, allopregnanolone acts as a GABAA receptor agonist.
“at high doses, ALLO acts as a GABAA receptor agonist.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
Allopregnanolone enhances GABA-mediated inhibition at GABAA receptors.
“and enhances GABA-mediated inhibition at GABAA receptors”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
Progesterone and allopregnanolone have been implicated in HPA axis modulation and in human psychopathology.
“Progesterone and ALLO have also been implicated in HPA axis modulation and in human psychopathology (for review see 63).”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
Allopregnanolone administration may reduce HPA axis reactivity through reduction of CRH and AVP gene transcription.
“however, ALLO administration may also reduce HPA axis reactivity through reduction of CRH and AVP gene transcription63.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
Increased P4 and allopregnanolone concentrations may allow termination of HPA axis signaling.
“and increased concentrations may allow for termination of HPA axis signaling63.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
Allopregnanolone binds to GABAA receptors to promote inhibition.
“As previously discussed, ALLO binds to GABAA receptors to promote inhibition63”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
Through gonadal steroids, the HPG axis can modulate the HPA axis.
“Through these gonadal steroids, the HPG axis can exert a modulatory effect over the HPA axis (for review see 63,86).”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [63]
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Acevedo‐Rodriguez, A., Kauffman, A. S., Cherrington, B. D., Borges, C. S., Roepke, T. A., & Laconi, M. (2018) · Journal of neuroendocrinology · doi:10.1111/jne.12590 · Cited by 298 · see citing works
Maguire, J. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00083 · Cited by 113 · see citing works
Soni, M., Curran, V. H., & Kamboj, S. K. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.04.003 · Cited by 102 · see citing works
Allopregnanolone-based treatments for postpartum depression: Why/how do they work?
Walton, N., & Maguire, J. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100198 · Cited by 103 · see citing works
Sze, Y., & Brunton, P. J. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14615 · Cited by 85 · see citing works
- Authors
- Wirth, M. M.
- Affiliations
- University of Notre Dame (US)
- Corresponding author
- Wirth, Michelle M.
- ORCID
- Wirth, Michelle M.
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2011
- Volume
- 2
- Pages
- 19-19
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC3355912
- OpenAlex
- W2140161720
- Cited by
- 121
- References
- 131
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 10 · 2023: 5 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 12 · 2018: 10 · 2017: 4 · 2016: 7 · 2015: 9 · 2014: 8 · 2013: 12 · 2012: 3
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health
- National Institute of Mental Health (T32MH018931)
- National Center for Research Resources (UL1RR025011)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- progesterone, allopregnanolone, neurosteroids, stress, social isolation, social support, depression, anxiety, mood, GABA-A receptor modulation, social affiliation, social rejection, hypothalamic-pituitary-adrenal axis, stress coping
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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