Rachida Guennoun
Iqbal Sayeed
Donald Stein- 1U1195 Inserm and University Paris-Saclay, Le Kremlin-Bicêtre, France
- 2Department of Emergency Medicine, Emory University, Atlanta, GA, United States
- 3Emeritus College, Emory University, Atlanta, GA, United States
Editorial on the Research Topic
Neuroprotective and therapeutic effects of progesterone, allopregnanolone, and their derivatives
Beyond their classical reproductive roles, steroids exert profound effects on the nervous system (1–3). In particular, progesterone, allopregnanolone, and synthetic progestins have emerged as key players in modulating neuroprotection, synaptic plasticity, mood, stress, cognition and CNS repair (4–7). Extensive preclinical research demonstrated their therapeutic potential, but translating preclinical findings into clinical practice has been elusive.
Allopregnanolone can promote inhibitory neurotransmission and exert rapid antidepressant effects. It is now approved for clinical treatment of postpartum depression (8). Clinical trials of progesterone and allopregnanolone for treating neurodegenerative disease and traumatic brain injury (TBI) had mixed outcomes. Allopregnanolone was evaluated in Phase 1b/2a clinical trials for Alzheimer’s disease (AD), examining its safety and pharmacokinetics. Neuroimaging techniques provided evidence that allopregnanolone may be helpful in promoting regenerative and therapeutic effects for mild AD (9).
Progesterone was evaluated in Phase 2 studies of moderate-to-severe TBI, with early signals of benefit (10, 11); however, two large Phase 3 randomized controlled trials failed to demonstrate its efficacy (12, 13). Subsequent analyses have identified several factors that may have contributed to the failure of these trials, including the high doses of progesterone used; the lack of patient stratification; insufficient consideration of sex- and age-related differences in hormonal status and outcomes; the presence of pre-existing comorbidities; and the use of subjective outcome measures that do not accurately capture deficits or long-term quantitative recovery (5, 14–16). Importantly, while these reviews highlight major translational challenges, they emphasize the pleiotropic potential of progesterone -including anti-inflammatory, anti-apoptotic, neurogenic, and remyelinating effects- in treating complex pathologies such as TBI.
Overall, progesterone and allopregnanolone continue to attract interest as potential therapeutic steroids for neuroprotection and regeneration. Carefully designed future clinical studies, with optimized designs, nuanced patient stratification, and appropriate outcome measures, may help further elucidate their potential role in this evolving field.
The current Research Topic assembles original research articles and a review that highlight mechanistic insights, receptor-specific signaling pathways, and translational opportunities for progesterone and allopregnanolone as neuroprotective agents.
Allopregnanolone: a multifaceted neurosteroid mediator
Wang et al. provide compelling evidence that calcium signaling represents a unifying mechanism for the pleiotropic effects of allopregnanolone in neurons and astrocytes. Using transcriptomic, mitochondrial, and pharmacological analyses, the authors demonstrate that allopregnanolone enhances synaptogenesis, mitochondrial respiration, and oxidative stress resilience through GABAA and L-type Ca2+ channel–dependent pathways. The activation of Ca2+/CREB and NRF1-TFAM signaling cascades supports mitochondrial biogenesis and cellular recovery. This comprehensive analysis provides an integrated view of how allopregnanolone coordinates cellular and metabolic processes that may support brain repair and functional recovery; highlighting its promise as a multifaceted neuroprotective agent.
Progesterone and receptor-specific neuroprotection
Extending this perspective to a disease-specific context, Castelnovo and Thomas explore the neuroprotective role of progesterone in a Parkinson’s disease (PD) cell model. While progesterone has long been studied for its classical genomic effects via nuclear receptors, the authors uncover a critical role of the membrane progesterone receptor α (mPRα/PAQR7) in neuroprotection. Using a human cell-line (SH-SY5Y) as a PD model, they report that progesterone exerts its neuroprotective effects through mPRα/PAQR7 by activating PI3K-AKT and MAPK signaling cascades, which are key pathways for promoting neuronal survival. Nuclear PR and GABAA receptor agonists failed to reproduce this effect, highlighting the specificity of mPRα-mediated signaling. This study underscores the relevance of non-classical progesterone signaling mechanisms in neuroprotection and identifies mPRα as a promising molecular target for developing new therapeutic strategies for PD and related neurodegenerative conditions.
Neurotrophins, glia, and mechanistic diversity of progesterone signaling
Complementing the other papers, Singh et al. provide an integrative review linking progesterone to brain-derived neurotrophic factor (BDNF) and related signaling networks that contribute to neuroprotection. Their synthesis highlights the importance of glial cells and microRNAs in modulating progesterone’s neuroprotective actions. Importantly, they highlight that the type of progestin—whether natural or synthetic—can profoundly influence neuroprotective outcomes, with significant implications for clinical translation and hormone therapy design.
Steroid hormone biomarkers and stroke risk prediction
The translational aspect of this Research Topic is provided by Yang et al., who propose a biomarker-based approach to predict stroke risk using hair-derived hypothalamic-pituitary-gonadal axis hormone levels. Their findings suggest that decreased, pre-stroke testosterone and progesterone concentrations in hair can serve as predictive indicators of stroke vulnerability. These preliminary findings introduce a potential non-invasive biomarker approach offering new possibilities for early cerebrovascular risk assessment; thus, expanding the clinical relevance of neuroendocrine markers in preventive neurology.
Hormonal dysregulation and neurodegenerative vulnerability
Yang et al. explore shared neuroendocrine mechanisms linking premenstrual dysphoric disorder (PMDD) and Alzheimer’s disease (AD). They identify overlapping pathways involving allopregnanolone fluctuations, GABAergic and serotonergic dysregulation and the APOE-ϵ4 allele. This conceptual framework can be taken to suggest that PMDD may be a biological precursor state for AD, emphasizing the role of sex hormones in late-life neurodegenerative risk. Their analysis supports the view that hormonal instability may contribute to long-term neurodegenerative risk in women while emphasizing the need to incorporate sex-specific endocrine dynamics into models of AD pathogenesis and early intervention strategies.
Integrative perspectives and future directions
Collectively, the articles in this Research Topic bring together recent advances in the mechanistic, cellular, and translational dimensions of neurosteroid research. The papers highlight emerging molecular targets such as calcium signaling pathways, mitochondrial dynamics, and membrane progesterone receptors and propose innovative translational and predictive approaches. These contributions highlight the multi-level complexity of neurosteroid action from molecular signaling to systems physiology and development of clinical biomarkers. Taken together, these contributions reinforce several principles:
1. Neurosteroid actions are inherently pleiotropic, involving coordination between neurotransmitter systems, mitochondrial function and signaling pathways.
2. Receptor specificity matters: the differential effects of nuclear versus membrane progesterone receptors underscore the need for precise pharmacological targeting.
3. Sex and age are critical biological variables that shape neurosteroid efficacy, influencing outcomes in preclinical studies as well as for designing clinical trials.
4. Translational biomarkers, such as plasma or hair-based sex steroid hormone measures, may serve as valuable tools for risk stratification and therapeutic monitoring.
Conclusion
Progesterone and allopregnanolone and their derivative continue to emerge as promising therapeutic steroids for neuroprotection and regeneration. Additional clinical investigations, designed with refined methodologies, thoughtful patient stratification, and clinically meaningful outcome measures, would be valuable to further clarify and confirm their clinical potential.
Author contributions
RG: Writing – original draft, Writing – review & editing. IS: Writing – review & editing. DS: Writing – review & editing.
Acknowledgments
The editors thank all authors and reviewers for their valuable contributions to this Research Topic and to Frontiers in Endocrinology for providing a platform to advance research at the intersection of neuroendocrinology and neuroscience.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that RG were an Associate Editor of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Melcangi RC, Garcia-Segura LM, and Mensah-Nyagan AG. Neuroactive steroids: state of the art and new perspectives. Cell Mol Life Sci. (2008) 65:777–97. doi: 10.1007/s00018-007-7403-5
2. Mendell AL and MacLusky NJ. Neurosteroid metabolites of gonadal steroid hormones in neuroprotection: implications for sex differences in neurodegenerative disease. Front Mol Neurosci. (2018) 11:359. doi: 10.3389/fnmol.2018.00359
3. Diotel N, Charlier TD, Lefebvre d’Hellencourt C, Couret D, Trudeau VL, Nicolau JC, et al. Steroid transport, local synthesis, and signaling within the brain: roles in neurogenesis, neuroprotection, and sexual behaviors. Front Neurosci. (2018) 12:84. doi: 10.3389/fnins.2018.00084
4. Schumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, et al. Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors. Prog Neurobiol. (2014) 113:6–39. doi: 10.1016/j.pneurobio.2013.09.004
5. Guennoun R. Progesterone in the brain: hormone, neurosteroid and neuroprotectant. Int J Mol Sci. (2020) 21. doi: 10.3390/ijms21155271
6. Sitruk-Ware R, Sussman H, Brinton R, Schumacher M, Singer P, Kumar N, et al. Nestorone (segesterone acetate) effects on neuroregeneration. Front Neuroendocrinol. (2024) 73:101136. doi: 10.1016/j.yfrne.2024.101136
7. Bencker C, Gschwandtner L, Nayman S, Griksiene R, Nguyen B, Nater UM, et al. Progestagens and progesterone receptor modulation: Effects on the brain, mood, stress, and cognition in females. Front Neuroendocrinol. (2025) 76:101160. doi: 10.1016/j.yfrne.2024.101160
8. Nagpurkar K, Ghive P, Kale M, Nistane N, Taksande B, Umekar M, et al. Neurosteroids as emerging therapeutics for treatment-resistant depression: Mechanisms and clinical potential. Neuroscience. (2025) 577:300–14. doi: 10.1016/j.neuroscience.2025.05.022
9. Raikes AC, Hernandez GD, Matthews DC, Lukic AS, Law M, Shi Y, et al. Exploratory imaging outcomes of a phase 1b/2a clinical trial of allopregnanolone as a regenerative therapeutic for Alzheimer’s disease: Structural effects and functional connectivity outcomes. Alzheimers Dement (N Y). (2022) 8:e12258. doi: 10.1002/trc2.12258
10. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. (2007) 49:391–402, 402.e391-392. doi: 10.1016/j.annemergmed.2006.07.932
11. Xiao G, Wei J, Yan W, Wang W, and Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. (2008) 12:R61. doi: 10.1186/cc6887
12. Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. (2014) 371:2457–66. doi: 10.1056/NEJMoa1404304
13. Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. (2014) 371:2467–76. doi: 10.1056/NEJMoa1411090
14. Stein DG. Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials. Brain Inj. (2015) 29:1259–72. doi: 10.3109/02699052.2015.1065344
15. Schumacher M, Denier C, Oudinet JP, Adams D, and Guennoun R. Progesterone neuroprotection: The background of clinical trial failure. J Steroid Biochem Mol Biol. (2016) 160:53–66. doi: 10.1016/j.jsbmb.2015.11.010
Keywords: allopregnanolone, Alzheimer’s disease, membrane progesterone receptor, mitochondrial respiration, neuroprotection, neurosteroids, Parkinson’s disease, stroke
Citation: Guennoun R, Sayeed I and Stein D (2026) Editorial: Neuroprotective and therapeutic effects of progesterone, allopregnanolone, and their derivatives. Front. Endocrinol. 17:1771389. doi: 10.3389/fendo.2026.1771389
Received: 19 December 2025; Accepted: 02 January 2026;
Published: 15 January 2026.
Edited and reviewed by:
Hubert Vaudry, Université de Rouen, FranceCopyright © 2026 Guennoun, Sayeed and Stein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Rachida Guennoun, cmFjaGlkYS5ndWVubm91bkBpbnNlcm0uZnI=