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The Neurosteroid Tetrahydroprogesterone Attenuates the Endocrine Response to Stress and Exerts Glucocorticoid-like Effects on Vasopressin Gene Transcription in the Rat Hypothalamus
Abstract
The neurosteroid tetrahydroprogesterone (5 alpha-pregnan-3 alpha-ol-20-one, allopregnanolone, THP), has been previously shown to counteract the anxiogenic effects of corticotropin-releasing hormone (CRH) and to interfere with noradrenergic and corticosteroid-mediated regulation of CRH release and gene transcription. Those observations indicated that, besides its sedative and analgesic activity, THP may also affect the neuroendocrine response to stress in a mode resembling that of corticosteroids. To examine this possibility, we compared the ability of THP, its precursor progesterone (P4), and the glucocorticoids dexamethasone (DEX) and corticosterone (CORT) to influence the pituitary-adrenal response to acute emotional stress and the adrenalectomy-induced increase in the gene transcription of the stress-related peptide arginine vasopressin (AVP) and of corticosteroid receptors (MR and GR) in the brain. Pretreatment of rats with a single dose of THP or P4 (50 micrograms/kg) significantly attenuated the elevation of plasma adrenocorticotropin (ACTH) and serum corticosterone after emotional stress; both steroids were, however, less potent than a similar dose of DEX. Administration of 1 mg of THP, CORT, or P4 to adrenalectomized (ADX) rats attenuated the increase in AVP mRNA levels in the ventromedial subdivision of the hypothalamic paraventricular nucleus (PVN), as compared with vehicle-treated ADX rats. However, whereas CORT and P4 influenced the ADX-induced increase in the transcription of both types of corticosteroid receptors in the hippocampus, these were unaffected by THP. In contrast to the glucocorticoids, THP and P4 failed to decrease plasma ACTH levels in rats deprived of endogenous steroids. These results demonstrate that the neurosteroid THP and its precursor P4 resemble glucocorticoids in their suppression of the pituitary-adrenal response to emotional stress; however, THP influences the transcription of glucocorticoid-responsive genes in brain structures involved in the regulation of the hypothalamo-pituitary-adrenal system in a fashion that is quite distinct from that obtained with glucocorticoids.
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“Allopregnanolone has induced the GABAergic inhibition of HPA axis activation in female rats [93,94] and pregnant women [95].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [93]
In the citing paper
“another potent GABAA receptor modulator and deoxycorticosterone-derived steroid, tetrahydrodeoxycorticosterone (TH-DOC), also attenuates the HPA axis function (77, 82, 83).”
From Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis (2020) · cites this paper as [83]
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Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor
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“…[19] activated the HPA axis of Wistar rats with I.C.V. administration of CRF 0.5 µg/rat following subcutaneous administration of 1 mg of 3α,5α-THP; Patchev et al., 1996 [18] injected Wistar rats I.P. with a dose of 50 µg/kg of 3α,5α-THP and 30 min later exposed the animals to airpuff stressor;…”
BackgroundMethodInfluentialCumberland, A. L., Palliser, H. K., Crombie, G. K., Walker, D. W., & Hirst, J. J. (2017) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2017.02.001 · Cited by 13
“In postnatal life, allopregnanolone is increased during acute tress events, to attenuate the release of glucocorticoids and emodel the stress response (Patchev et al., 1996; Purdy et al., 991).”
BackgroundFrye, C. A., & Seliga, A. (2003) · Psychopharmacology · doi:10.1007/s00213-003-1523-x · Cited by 15
“3a,5a-THP is known to have anti-anxiety effects (Bitran et al. 2000; Frye et al. 2000) and may reduce stress-induced activation of the hypothalamic-pituitaryadrenal axis (Purdy et al. 1991; Patchev et al. 1996; Barbaccia et al. 2001).”
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“The elevated circulating progestogens during pregnancy and lactation have anxiolytic effects and reduce hormonal responses to stress (Patchev et al. 1994, 1996).”
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“Of interest in this context is that 3α,5α-THP can modulate the output and feedback of the hypothalamic–pituitary–adrenal/stress axis response (Barbaccia et al., 1996; Patchev et al., 1996).”
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“In the brain, AlloP exerts rapid actions to downregulate CRF gene expression in the hypothalamus [64], reduce circulating glucocorticoid production [65,66], and to restore homeostasis as an endogenous modulator of the HPA axis.”
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“Administration of ALLO reduced anxiety that was induced by CRH (Patchev et al. 1994) in addition to exerting actions within the hypothalamus to dampen the activity of the HPA axis (Patchev et al. 1994, 1996).”
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“1994) and attenuates the stress-induced increase in ACTH and corticosterone (Patchev et al. 1996).”
BackgroundDrinking to Dependence Risk Factors in Nonhuman Primates
Grant, K. A., Ferguson, B. M., Helms, C. M., & McClintick, M. N. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-405941-2.00020-1 · Cited by 7
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Roca, C. A., Schmidt, P. J., & Rubinow, D. R. (1999) · The Neuroscientist · doi:10.1177/107385849900500412 · Cited by 6
“(45) and Patchev and colleagues (44, 46, 47) suggest dramatic (albeit complex) effects of gonadal steroids on the mRNA of GR and mineralocorticoid receptor (MR) (which restrain the axis), as”
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71 – Sex Differences in HPA-Axis Regulation: The Role of Gonadal Hormones
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“…(Paris and Frye, 2008; Brunton et al., 2009), which can be protective to the offspring (Frye and Bayon, 1998; Yawno et al., 2009), and dampen hypothalamic-pituitary-adrenal (HPA) axis reactivity (Patchev et al., 1994, 1996; Patchev and Almeida, 1996; Paris and Frye, 2008; Frye, 2009).”
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Perrot-Sinal, T., Kavaliers, M., & Ossenkopp, K. (1999) · doi:10.1007/978-1-4615-4733-4_44 · Cited by 2
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Gut microbiota shapes how male and female mice react to acute stress
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“It affects anxiety, feeding behavior, and the stress response in mammals (Patchev et al. 1996; Melchior and Ritzmann 1994; Kaur and Kulkarni 2001), in addition to aggression during the non-breeding season and suppression of brain neurogenesis in fish (Soma et al. 2000; Diotel et al. 2013).”
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“Studies which employ exogenous allopregnanolone administration have determined that allopregnanolone attenuates stress-induced HPA axis activity in rats, preventing the increase in plasma ACTH and corticosterone following acute stress (Patchev et al., 1996).”
BackgroundNeonatal stress tempers vulnerability of acute stress response in adult socially isolated rats
Serra, M., & Biggio, G. (2014) · Journal of pediatric and neonatal individualized medicine · doi:10.7363/030264 · Cited by 1
“Allopregnanolone also exerted a potent inhibitory action on HPA axis activity and attenuated the elevation of plasma ACTH and corticosterone elicited by stress [16], an effect similar to that induced by benzodiazepines [17].”
ResultNeurosteroid Derangement in Women Diagnosed with Eating Disorders
Stein, D. J., Maayan, R., Loewenthal, R., & Weizman, A. (2008) · Springer eBooks · doi:10.1007/978-1-4020-6854-6_24 · Cited by 1
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Joyal, K. G., & Maguire, J. L. (2026) · Epilepsy Research · doi:10.1016/j.eplepsyres.2026.107888
Major, G. S., Timpani, C. A., Russell, A. P., Rybalka, E., & Lindsay, A. (2025) · Medical Hypotheses · doi:10.1016/j.mehy.2025.111766
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Guiza-Zayas, R., Flores‐Ramos, M., Bernal-Santamaría, N., Mijares, M. F. D.-P., & Serna-García, M. (2019) · Current Psychopharmacologye · doi:10.2174/2211556008666190724113554
Stress Responsive Neurohormones in Depression and Anxiety
Ströhle, A., & Holsboer, F. (2003) · Pharmacopsychiatry · doi:10.1055/s-2003-45132
Frye, C. A., & Llaneza, D. C. (2011) · Springer eBooks · doi:10.1007/978-94-007-0837-2_17
Biologische Aspekte der posttraumatischen Belastungsstörung
Lahousen, T., Bonelli, R. M., & Hofmann, P. (2004) · Springer eBooks · doi:10.1007/978-3-7091-0615-0_3
Sandman (1999) · doi:10.1002/(sici)1098-2302(199904)34:3
Metadata
- Authors
- Patchev, V
- Affiliations
- Max Planck Institute of Psychiatry (DE)
- Corresponding author
- Patchev, V
- Venue
- Neuropsychopharmacology
- Published
- 1996-12
- Volume
- 15
- Issue
- 6
- Pages
- 533-540
- ISSN
- 0893-133X (ISSN-L)
- OpenAlex
- W2072990514
- Cited by
- 283
- References
- 0
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 10 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 8 · 2019: 11 · 2018: 10 · 2017: 3 · 2016: 10 · 2015: 6 · 2014: 16 · 2013: 12 · 2012: 11
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Max-Planck-Gesellschaft
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- tetrahydroprogesterone, allopregnanolone, neurosteroids, progesterone, pituitary-adrenal response, emotional stress, vasopressin, paraventricular nucleus, corticosteroid receptors, mineralocorticoid receptor, glucocorticoid receptor, ACTH, corticosterone, dexamethasone, adrenalectomy, hypothalamus
- MeSH terms
- Adrenocorticotropic Hormone, Animals, Anti-Inflammatory Agents, Arginine Vasopressin, Corticosterone, Dexamethasone, Glucocorticoids, Hypothalamus, Male, Pregnanolone, Progesterone, Receptors, Steroid, Stress, Psychological, Anti-Anxiety Agents, Transcription, Genetic, Rats, Wistar, Neuroprotective Agents, Rats
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