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 induces GABAergic inhibition of HPA axis activation in female rats and pregnant women.
“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]
Tetrahydrodeoxycorticosterone (TH-DOC) attenuates HPA axis function.
“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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“Allopregnanolone is a major metabolite of progesterone, yet it is also itself released from the adrenals and synthesized by brain glial cells in response to stress (Patchev et al. 1996).”
Morrow, A., Porcu, P., Boyd, K. N., & Grant, K. (2006) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2006.8.4/amorrow · Cited by 94 · see citing works
Windle, R. J., Gamble, L. E., Kershaw, Y. M., Wood, S. A., Lightman, S. L., & Ingram, C. D. (2006) · Endocrinology · doi:10.1210/en.2005-1079 · Cited by 90 · see citing works
“an emotional stress (2-min intermittent air puff stress) (64),”
BackgroundNeurogenic Pain and Steroid Synthesis in the Spinal Cord
Patte‐Mensah, C., Kibaly, C., Boudard, D. L., Schaeffer, V., Béglé, A., Saredi, S., Meyer, L., & Mensah‐Nyagan, A. G. (2006) · Journal of Molecular Neuroscience · doi:10.1385/jmn:28:1:17 · Cited by 90 · see citing works
Walf, A. A., Sumida, K., & Frye, C. A. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0100-x · Cited by 77 · see citing works
“Notably, 3α,5α-THP dampens the HPA response (Patchev et al. 1996).”
Alcohol intoxication increases allopregnanolone levels in male adolescent humans
Torres, J. M., & Ortega, E. (2004) · Psychopharmacology · doi:10.1007/s00213-003-1662-0 · Cited by 89 · see citing works
“It is possible that alcohol, through ACTH, CRF, and other substances, may influence the synthesis or release of allopregnanolone.”
InfluentialNeurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions
Frye, C. A. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.07.005 · Cited by 88 · see citing works
“We now know that hormone levels can change in response to extreme environmental and/or behavioral situations and, thereby, influence the likelihood of subsequent hormone-mediated processes (Barbaccia et al., 1996; Drugan et al., 1995; Patchev et al., 1994, 1996).”
BackgroundRelationship between salivary cortisol and progesterone levels in humans
Wirth, M. M., Meier, E. A., Fredrickson, B. L., & Schultheiss, O. C. (2006) · Biological Psychology · doi:10.1016/j.biopsycho.2006.06.007 · Cited by 86 · see citing works
“In rodents, PROG and allopregnanolone down-regulate HPA axis responses to stress (Guo et al., 1995; Patchev et al., 1994, 1996).”
Toufexis, D. J., Davis, C., Hammond, A., & Davis, M. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.1386-04.2004 · Cited by 86 · see citing works
“THP also reduced stress-induced transcription of vasopressin in the ventromedial paraventricular nucleus of adrenalectomized, castrated rats (Patchev et al., 1996).”
BackgroundSix-month oral dehydroepiandrosterone supplementation in early and late postmenopause
Stomati, M., Monteleone, P., Casarosa, E., Quirici, B., Puccetti, S., Bernardi, F., Genazzani, A. D., Rovati, L., Luisi, M., & Genazzani, A. R. (2000) · Gynecological Endocrinology · doi:10.3109/09513590009167703 · Cited by 86 · see citing works
Sze, Y., & Brunton, P. J. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14615 · Cited by 85 · see citing works
“The mechanisms involved are not clear, but GABAA receptors are likely targets for allopregnanolone and THDOC actions, given their affinity for these receptors and their potent stress-suppressing and anxiolytic actions through potentiating GABA signalling (Patchev et al., 1996, 1994).”
BackgroundHippocampal 3α,5α-THP may alter depressive behavior of pregnant and lactating rats
Frye, C. A., & Walf, A. A. (2004) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2004.03.024 · Cited by 82 · see citing works
Khisti, R. T., & Chopde, C. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02373-8 · Cited by 83 · see citing works
Programming the Brain and Behaviour by Early‐Life Stress: A Focus on Neuroactive Steroids
Brunton, P. J. (2015) · Journal of Neuroendocrinology · doi:10.1111/jne.12265 · Cited by 85 · see citing works
“Administration of allopregnanolone has been shown to attenuate stress-induced HPA axis activity in male (115) and female rats (116), to attenuate”
BackgroundKonakchieva, R., Mitev, Y., Almeida, O., & Patchev, V. (1998) · Neuroendocrinology · doi:10.1159/000054312 · Cited by 82 · see citing works
Self-citationMultifunctional aspects of allopregnanolone in stress and related disorders
Bali, A., & Jaggi, A. S. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.09.005 · Cited by 87 · see citing works
“Allopregnanolone downregulates the gene transcription of the HPA axis hormones including corticosterone release hormone and adrenocorticotropic hormone to produce anti-stress and anxiolytic effects (Childs et al., 2010; Patchev et al., 1994, 1996).”
BackgroundMensah‐Nyagan, A. G., Kibaly, C., Schaeffer, V., Venard, C., Meyer, L., & Patte‐Mensah, C. (2008) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2008.03.002 · Cited by 75 · see citing works
Kalil, B., Leite, C., Carvalho-Lima, M., & Anselmo-Franci, J. (2013) · Stress · doi:10.3109/10253890.2013.777832 · Cited by 78 · see citing works
“Additionally, the administration of progesterone and 3a,5a-THP has been shown to attenuate ACTH and corticosterone responses (Patchev et al., 1996).”
BackgroundSkilbeck, K. J., Johnston, G. A. R., & Hinton, T. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06539.x · Cited by 85 · see citing works
Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers
Sofuoglu, M., Mouratidis, M., & Mooney, M. E. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2010.07.005 · Cited by 76 · see citing works
“…its active metabolites modulate several CNS functions, including reward, stress response, cognition and neuroprotection (Del Rio et al., 1998; Frye, 2007; Patchev et al., 1996) and likely contribute to sex and menstrual cycle influences on these CNS functions (Becker, 1999; Becker and Hu, 2008).”
Fluoxetine-treated male wrasses exhibit low AVT expression
Semsar, K., Perreault, H. A. N., & Godwin, J. (2004) · Brain Research · doi:10.1016/j.brainres.2004.09.030 · Cited by 73 · see citing works
Mitev, Y., Darwish, M., Wolf, S., Holsboer, F., Almeida, O. F. X., & Patchev, V. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00287-2 · Cited by 76 · see citing works
Self-citationCozzoli, D. K., Tanchuck-Nipper, M. A., Kaufman, M. N., Horowitz, C. B., & Finn, D. A. (2014) · Alcohol · doi:10.1016/j.alcohol.2014.07.015 · Cited by 75 · see citing works
“Additionally, the neurosteroid allopregnanolone (ALLO), a potent positive allosteric modulator of GABAA receptors, inhibits HPA axis activity and the stress-induced increase in plasma CORT (Patchev et al., 1996).”
BackgroundHistories of depression, allopregnanolone responses to stress, and premenstrual symptoms in women
Klatzkin, R. R., Morrow, A. L., Light, K. C., Pedersen, C. A., & Girdler, S. S. (2005) · Biological Psychology · doi:10.1016/j.biopsycho.2005.02.007 · Cited by 63 · see citing works
“In animal models, ALLO prevents CRF release and gene expression in the hypothalamus as well as CRF-induced anxiety (Patchev et al., 1994), and also significantly attenuates the elevation of plasma ACTH and corticosterone following stress (Guo et al., 1995; Patchev et al., 1996).”
BackgroundA history of depression in women is associated with an altered GABAergic neuroactive steroid profile
Girdler, S. S., Lindgren, M., Porcu, P., Rubinow, D. R., Johnson, J. L., & Morrow, A. L. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.08.004 · Cited by 66 · see citing works
“, 1991), restoring both normal GABAergic and HPA-axis function following acute stress (Barbaccia et al., 1997; Guo et al., 1995; Patchev et al., 1996; Strous et al., 2006).”
BackgroundNey, L. J., Matthews, A. J., Bruno, R., & Felmingham, K. L. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.07.006 · Cited by 66 · see citing works
“Similarly, both progesterone and ALLO given to rodents reduced corticosterone responses to acute stress (Patchev et al., 1996), and reduced PTSD behaviours and improved extinction retention (Pinna and Rasmusson, 2014).”
BackgroundBiggio, F., Pisu, M. G., Garau, A., Boero, G., Locci, V., Mostallino, M. C., Olla, P., Utzeri, C., & Serra, M. (2014) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2014.03.009 · Cited by 63 · see citing works
He, X., Węgiel, J., & Yang, S. (2005) · Brain Research · doi:10.1016/j.brainres.2005.01.022 · Cited by 65 · see citing works
Brunton, P. J., & Russell, J. A. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.146233 · Cited by 58 · see citing works
“Furthermore, allopregnanolone attenuates stressinduced HPA axis activity in male rats (Patchev et al. 1996).”
BackgroundCrowley, S. K., O’Buckley, T. K., Schiller, C. E., Stuebe, A. M., Morrow, A. L., & Girdler, S. S. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4217-x · Cited by 64 · see citing works
“…are associated with diminished capacity to negatively modulate the HPA axis and facilitate its recovery following stress exposure (Guo et al. 1995; Patchev et al. 1996), then the blunted ALLO + pregnanolone stress response that was observed in our study sample may be one mechanism that may…”
BackgroundEthanol and neurosteroid interactions in the brain
Morrow, A. L., VanDoren, M. J., Fleming, R. L., & Penland, S. (2001) · International review of neurobiology · doi:10.1016/s0074-7742(01)46068-5 · Cited by 54 · see citing works
Sex-specific effects of prenatal stress on glucose homoeostasis and peripheral metabolism in rats.
Brunton, P., Sullivan, K., Kerrigan, D., Russell, J., Seckl, J., & Drake, A. (2013) · Journal of Endocrinology · doi:10.1530/joe-12-0540 · Cited by 59 · see citing works
“…10.1530/JOE-12-0540 Printed in Great Britain as allopregnanolone (3a-hydroxy-5a-pregnan-20-one) and androstanediol (5a-androstane-3b,17b-diol), which have anxiolytic and stress-reducing actions (Bitran et al. 1995, Patchev et al. 1996, Edinger & Frye 2004, Brunton et al. 2009, Handa et al. 2009).”
BackgroundInfluential
- 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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