5 alpha dihydroprogesterone

Summary

Summary: A biologically active 5-alpha-reduced metabolite of plasma PROGESTERONE. It is the immediate precursor of 5-alpha-pregnan-3-alpha-ol-20-one (ALLOPREGNANOLONE), a neuroactive steroid that binds with GABA(A) RECEPTOR.

Top Publications

  1. Frye C, Llaneza D. Corticosteroid and neurosteroid dysregulation in an animal model of autism, BTBR mice. Physiol Behav. 2010;100:264-7 pubmed publisher
    ..Levels of 3alpha,5alpha-THP in the hypothalamus of BTBR mice were significantly higher compared to C57/J and 129S1 mice. These findings suggest that neuroendocrine dysregulation among BTBR mice extends to 3alpha,5alpha-THP. ..
  2. Guerra Araiza C, Gómora Arrati P, García Juárez M, Armengual Villegas A, Miranda Martinez A, Lima Hernández F, et al. Role of progesterone receptor isoforms in female sexual behavior induced by progestins in rats. Neuroendocrinology. 2009;90:73-81 pubmed publisher
    ..These results suggest that the PR-B isoform is essential for the display of the lordosis behavior in rats. ..
  3. Vandyke K, Jackson P, Rowe A, Russell P, Blair J. Androgen decreases osteoprotegerin expression in prostate cancer cells. Prostate Cancer Prostatic Dis. 2007;10:160-6 pubmed
    ..These data suggest that androgen may modulate OPG protein levels in CaP cell lines in vitro using a post-transcriptional mechanism. ..
  4. Lonsdale D, Burnham W. The anticonvulsant effects of progesterone and 5alpha-dihydroprogesterone on amygdala-kindled seizures in rats. Epilepsia. 2003;44:1494-9 pubmed
    ..5alpha-dihydroprogesterone is considerably more potent than progesterone. At low, nonsedative doses, it was effective against both the kindled amygdala focal afterdischarge and the generalized convulsion. ..
  5. Mobley J, Leav I, Zielie P, Wotkowitz C, Evans J, Lam Y, et al. Branched fatty acids in dairy and beef products markedly enhance alpha-methylacyl-CoA racemase expression in prostate cancer cells in vitro. Cancer Epidemiol Biomarkers Prev. 2003;12:775-83 pubmed
    ..Our findings therefore provide a link between the consumption of dietary fatty acids and the enhanced expression of AMACR, an enzyme that may play an important role in genesis and progression of CaP. ..
  6. Wiren K, Toombs A, Zhang X. Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts. J Mol Endocrinol. 2004;32:209-26 pubmed
  7. Robichaud M, Debonnel G. Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids. J Endocrinol. 2004;182:11-21 pubmed
    ..In conclusion, our results offer a cellular basis for potential antidepressant effects of neurosteroids, which may prove important particularly for women with affective disorders. ..
  8. Dubreuil O, Bossus M, Graille M, Bilous M, Savatier A, Jolivet M, et al. Fine tuning of the specificity of an anti-progesterone antibody by first and second sphere residue engineering. J Biol Chem. 2005;280:24880-7 pubmed
    ..The improvements are partly linked to a change in the canonical class of the light chain third hypervariable loop. ..
  9. Ghoumari A, Ibanez C, el Etr M, Leclerc P, Eychenne B, O Malley B, et al. Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem. 2003;86:848-59 pubmed

More Information

Publications52

  1. Labombarda F, Pianos A, Liere P, Eychenne B, Gonzalez S, Cambourg A, et al. Injury elicited increase in spinal cord neurosteroid content analyzed by gas chromatography mass spectrometry. Endocrinology. 2006;147:1847-59 pubmed
    ..Our results strongly suggest an important role for locally biosynthesized neurosteroids in the response of the SC to injury. ..
  2. Lee S, Jung B, Choi S, Kim S, Lee E, Chung B. Influence of ginsenoside Rb1 on brain neurosteroid during acute immobilization stress. Arch Pharm Res. 2006;29:566-9 pubmed
    ..On the other hand, the DHP level was lower in the cerebellum only. This suggests that the metabolism of the brain neurosteroids is linked to psychological stress, and Rb1 attenuates the stress-induced increase in neurosteroids. ..
  3. Rasmusson A, Pinna G, Paliwal P, Weisman D, Gottschalk C, Charney D, et al. Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol Psychiatry. 2006;60:704-13 pubmed
    ..70, p < 0008). Low CSF ALLO levels in premenopausal women with PTSD might contribute to an imbalance in inhibitory versus excitatory neurotransmission, resulting in increased PTSD re-experiencing and depressive symptoms. ..
  4. Frye C, Vongher J. Progesterone and 3alpha,5alpha-THP enhance sexual receptivity in mice. Behav Neurosci. 2001;115:1118-28 pubmed
    ..Thus, P-facilitated receptivity in mice involves P and 3alpha,5alpha-THP and their actions at PRs and GABAA receptors. ..
  5. Hagedorn K, Cooke C, Falck J, Mitchell B, Davidge S. Regulation of vascular tone during pregnancy: a novel role for the pregnane X receptor. Hypertension. 2007;49:328-33 pubmed
  6. Nazarova N, Chikhirzhina G, Tuohimaaa P. [Transcriptional regulation of placental transforming growth factor-beta by calcitriol in prostate cancer cells is androgen-independent]. Mol Biol (Mosk). 2006;40:84-9 pubmed
    ..We do not find an effect of 5alpha-dihydrotestosterone or antiandrogen Casodex on calcitriol-induced PTGF-beta mRNA level and conclude that induction of PTGF-beta transcription by calcitriol is androgen-independent. ..
  7. Sheehan P. A possible role for progesterone metabolites in human parturition. Aust N Z J Obstet Gynaecol. 2006;46:159-63 pubmed
    ..This article provides a brief overview of progesterone in human pregnancy and an outline of progesterone metabolism in the various reproductive tract tissues as well as the evidence for actions of progesterone metabolites in pregnancy. ..
  8. Gilbert Evans S, Ross L, Sellers E, Purdy R, Romach M. 3alpha-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period. Gynecol Endocrinol. 2005;21:268-79 pubmed
    ..These results provide the basis for further study of neuroactive steroids in psychiatric conditions of pregnancy and the postpartum period. ..
  9. He X, Wegiel J, Yang Y, Pullarkat R, Schulz H, Yang S. Type 10 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid modulators of gamma-aminobutyric acid type A receptors. Mol Cell Endocrinol. 2005;229:111-7 pubmed
    ..Immunoreactivity against 17beta-HSD10 was found in a number of neuronal populations. Taken together, evidence suggests that 17beta-HSD10 is the brain enzyme capable of catalyzing the oxidation of steroid modulators of GABA(A) receptors. ..
  10. Muller E, Kerschbaum H. Progesterone and its metabolites 5-dihydroprogesterone and 5-3-tetrahydroprogesterone decrease LPS-induced NO release in the murine microglial cell line, BV-2. Neuro Endocrinol Lett. 2006;27:675-8 pubmed
    ..Because progesterone, DHP, and THP are synthesized in astrocytes and oligodendrocytes, these neurosteroids may locally suppress an immune response. ..
  11. Meyer L, Patte Mensah C, Taleb O, Mensah Nyagan A. Cellular and functional evidence for a protective action of neurosteroids against vincristine chemotherapy-induced painful neuropathy. Cell Mol Life Sci. 2010;67:3017-34 pubmed publisher
    ..Together, these results provide valuable insight into the cellular and functional mechanisms underlying anticancer drug-induced neuropathy and suggest a neurosteroid-based strategy to eradicate painful neuropathy. ..
  12. Canosa L, Pozzi A, Ceballos N. Pregnenolone and progesterone metabolism by the testes of Bufo arenarum. J Comp Physiol B. 1998;168:491-6 pubmed
    ..The 5-ene pathway, including 5-androsten-3 beta, 17 beta diol as intermediate, could be predominant for androgen biosynthesis. Testes bypass not only progesterone but also androstenedione for testosterone biosynthesis...
  13. Pearson Murphy B, Steinberg S, Hu F, Allison C. Neuroactive ring A-reduced metabolites of progesterone in human plasma during pregnancy: elevated levels of 5 alpha-dihydroprogesterone in depressed patients during the latter half of pregnancy. J Clin Endocrinol Metab. 2001;86:5981-7 pubmed
    ..003). These results show that all five of these metabolites rise markedly during pregnancy and suggest that alterations in progesterone metabolites may be involved in the mood changes of pregnancy and the puerperium. ..
  14. Morris K, Amin J. Insight into the mechanism of action of neuroactive steroids. Mol Pharmacol. 2004;66:56-69 pubmed
    ..Based on the above data, a universal model is presented wherein anesthetic compounds like NSs can potentiate or inhibit the activity of ligand-gated ion channels distinct from interaction with alternative binding sites. ..
  15. Nguyen P, Billiards S, Walker D, Hirst J. Changes in 5alpha-pregnane steroids and neurosteroidogenic enzyme expression in fetal sheep with umbilicoplacental embolization. Pediatr Res. 2003;54:840-7 pubmed
    ..These findings suggest that the increased expression of p450scc and 5alphaRII may be a response that maintains AP concentration in the fetal brain after compromised placental function and/or intrauterine stress. ..
  16. Frye C, Petralia S. Lordosis of rats is modified by neurosteroidogenic effects of membrane benzodiazepine receptors in the ventral tegmental area. Neuroendocrinology. 2003;77:71-82 pubmed
    ..These data suggest that neurosteroidogenesis involving MBRs in the VTA mediates lordosis of hormone-primed or behavioral estrous rats. ..
  17. González Flores O, Camacho F, Dominguez Salazar E, Ramírez Orduna J, Beyer C, Paredes R. Progestins and place preference conditioning after paced mating. Horm Behav. 2004;46:151-7 pubmed
    ..The administration of progestins alone did not induce CPP. These results suggest that P and ring A-reduced metabolites facilitate the reward state following pacing. ..
  18. González Flores O, Shu J, Camacho Arroyo I, Etgen A. Regulation of lordosis by cyclic 3',5'-guanosine monophosphate, progesterone, and its 5alpha-reduced metabolites involves mitogen-activated protein kinase. Endocrinology. 2004;145:5560-7 pubmed
    ..These data support the hypothesis that the MAPK pathway is involved in lordosis regulation by P and some of its ring A-reduced metabolites as well as by the second messenger, cGMP. ..
  19. Bidaux G, Roudbaraki M, Merle C, Crepin A, Delcourt P, Slomianny C, et al. Evidence for specific TRPM8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement. Endocr Relat Cancer. 2005;12:367-82 pubmed
    ..Furthermore, as the TRPM8 channel is localized in human prostate cells, it will be interesting to understand its physiological function in the normal prostate and its potential role in prostate cancer development. ..
  20. Sheehan P, Rice G, Moses E, Brennecke S. 5 Beta-dihydroprogesterone and steroid 5 beta-reductase decrease in association with human parturition at term. Mol Hum Reprod. 2005;11:495-501 pubmed
    ..These data are consistent with a possible role for 5betaDHP in the onset of spontaneous human labour. Further studies exploring this hitherto unrecognized endocrinological pathway are indicated. ..
  21. Le Goascogne C, Eychenne B, Tonon M, Lachapelle F, Baumann N, Robel P. Neurosteroid progesterone is up-regulated in the brain of jimpy and shiverer mice. Glia. 2000;29:14-24 pubmed
    ..The role of PROG in myelin repair is discussed...
  22. Trauger J, Jiang A, Stearns B, LoGrasso P. Kinetics of allopregnanolone formation catalyzed by human 3 alpha-hydroxysteroid dehydrogenase type III (AKR1C2). Biochemistry. 2002;41:13451-9 pubmed
    ..These results characterize the role of 3alpha-HSD type III in allopregnanolone formation and suggest that activation of this enzyme by fluoxetine is likely not the mechanism by which fluoxetine increases allopregnanolone concentrations. ..
  23. Hodges J, Heistermann M, Beard A, van Aarde R. Concentrations of progesterone and the 5 alpha-reduced progestins, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one, in luteal tissue and circulating blood and their relationship to luteal function in the African elephant, Loxod. Biol Reprod. 1997;56:640-6 pubmed
    ..They also provide preliminary evidence to suggest that measurements of 5 alpha-reduced metabolites may reflect corpus luteum function more closely than those of P4. ..
  24. Yamada A, Yamada M, Fujita Y, Nishigami T, Nakasho K, Uematsu K. Self-augmentation effect of male-specific products on sexually differentiated progesterone metabolism in adult male rat liver microsomes. J Biol Chem. 2001;276:4604-10 pubmed
  25. Jansen L, Peugh L, Ojemann J. GABA(A) receptor properties in catastrophic infantile epilepsy. Epilepsy Res. 2008;81:188-97 pubmed publisher
    ..These findings may contribute to the mechanisms of intractability in catastrophic infantile epilepsy due to cortical dysplasia, and suggest alternative therapeutic approaches. ..
  26. Osborne D, Frye C. Estrogen increases latencies to seizures and levels of 5alpha-pregnan-3alpha-ol-20-one in hippocampus of wild-type, but not 5alpha-reductase knockout, mice. Epilepsy Behav. 2009;16:411-4 pubmed publisher
    ..Thus, some of the anticonvulsive effects of E(2) may involve formation of 3alpha,5alpha-THP in the hippocampus. ..
  27. Pawlak K, Zhang G, Wiebe J. Membrane 5alpha-pregnane-3,20-dione (5alphaP) receptors in MCF-7 and MCF-10A breast cancer cells are up-regulated by estradiol and 5alphaP and down-regulated by the progesterone metabolites, 3alpha-dihydroprogesterone and 20alpha-dihydroprogesterone,. J Steroid Biochem Mol Biol. 2005;97:278-88 pubmed
  28. González Flores O, Beyer C, Gómora Arrati P, García Juárez M, Lima Hernández F, Soto Sánchez A, et al. A role for Src kinase in progestin facilitation of estrous behavior in estradiol-primed female rats. Horm Behav. 2010;58:223-9 pubmed publisher
    ..This event is one component of the cellular pathways leading to the display of estrous behaviors induced by P and its ring A-reduced metabolites in female rats. ..
  29. Wiebe J, Beausoleil M, Zhang G, Cialacu V. Opposing actions of the progesterone metabolites, 5alpha-dihydroprogesterone (5alphaP) and 3alpha-dihydroprogesterone (3alphaHP) on mitosis, apoptosis, and expression of Bcl-2, Bax and p21 in human breast cell lines. J Steroid Biochem Mol Biol. 2010;118:125-32 pubmed publisher
  30. Byrns M, Duan L, Lee S, Blair I, Penning T. Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer. J Steroid Biochem Mol Biol. 2010;118:177-87 pubmed publisher
  31. Wiebe J, Muzia D. The endogenous progesterone metabolite, 5a-pregnane-3,20-dione, decreases cell-substrate attachment, adhesion plaques, vinculin expression, and polymerized F-actin in MCF-7 breast cancer cells. Endocrine. 2001;16:7-14 pubmed
    ..We conclude that the endogenous progesterone metabolite, 5alphaP, may be involved in promoting breast neoplasia and metastasis by affecting adhesion and cytoskeletal molecules. ..
  32. Jamshidi A, Girard D, Beaudry F, Goff A. Progesterone metabolism in bovine endometrial cells and the effect of metabolites on the responsiveness of the cells to OT-stimulation of PGF2alpha. Steroids. 2007;72:843-50 pubmed
    ..These data suggest that 5-pregnanediones do not play a role in the regulation OT-stimulated PGF(2)alpha secretion during the bovine estrous cycle. ..
  33. Weiler P, Wiebe J. Plasma membrane receptors for the cancer-regulating progesterone metabolites, 5alpha-pregnane-3,20-dione and 3alpha-hydroxy-4-pregnen-20-one in MCF-7 breast cancer cells. Biochem Biophys Res Commun. 2000;272:731-7 pubmed
    ..The results provide further support for the potential importance of progesterone metabolites in breast cancer. ..
  34. Tohda A. [Steroid 5alpha-reductase deficiency]. Nihon Rinsho. 2006;Suppl 2:594-7 pubmed
  35. González Flores O, Etgen A. The nitric oxide pathway participates in estrous behavior induced by progesterone and some of its ring A-reduced metabolites. Horm Behav. 2004;45:50-7 pubmed
    ..These data support the hypothesis that the nitric oxide/cGMP/protein kinase G pathway is involved in the lordosis induced by P and some of its ring A-reduced metabolites. ..
  36. Wittemyer G, Ganswindt A, Hodges K. The impact of ecological variability on the reproductive endocrinology of wild female African elephants. Horm Behav. 2007;51:346-54 pubmed
  37. Kirkman S, Wallace E, van Aarde R, Potgieter H. Steroidogenic correlates of pregnancy in the rock hyrax (Procavia capensis). Life Sci. 2001;68:2061-72 pubmed
    ..This mechanism appears to be analogous to that of the African elephant which is phylogenetically related to the hyrax, except that in the elephant the 5alpha-reduced metabolites are produced by luteal tissue and not the blood...
  38. Tao R, Kawate H, Wu Y, Ohnaka K, Ishizuka M, Inoue A, et al. Testicular zinc finger protein recruits histone deacetylase 2 and suppresses the transactivation function and intranuclear foci formation of agonist-bound androgen receptor competitively with TIF2. Mol Cell Endocrinol. 2006;247:150-65 pubmed
  39. Gupta M, Guryev O, Auchus R. 5alpha-reduced C21 steroids are substrates for human cytochrome P450c17. Arch Biochem Biophys. 2003;418:151-60 pubmed
  40. Pasqualini J, Chetrite G. The anti-aromatase effect of progesterone and of its natural metabolites 20alpha- and 5alpha-dihydroprogesterone in the MCF-7aro breast cancer cell line. Anticancer Res. 2008;28:2129-33 pubmed
    ..The MCF-7aro cell line shows high detectable aromatase activity. The present data indicate that the progesterone metabolite 20alphaDHP, found mainly in normal breast tissue, can act as an anti-aromatase agent. ..
  41. Usami N, Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, et al. Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines. Biol Pharm Bull. 2002;25:441-5 pubmed
    ..Although cloxazolam was a potent and specific inhibitor of AKR1C3, diazepam, estazolam, flunitrazepam, medazepam and nitrazepam, that inhibited AKR1C1 and AKR1C2, may influence the neurosteroid metabolism. ..
  42. Nechmad A, Maayan R, Spivak B, Ramadan E, Poyurovsky M, Weizman A. Brain neurosteroid changes after paroxetine administration in mice. Eur Neuropsychopharmacol. 2003;13:327-32 pubmed
    ..Our results suggest that brain THP may be involved in the antidepressive and anxiolytic activity of paroxetine. ..
  43. Rhodes M, Frye C. Progestins in the hippocampus of female rats have antiseizure effects in a pentylenetetrazole seizure model. Epilepsia. 2004;45:1531-8 pubmed
    ..Together, these data suggest that P can have antiseizure effects, and these effects may be due in part to actions of its metabolite, 3alpha,5alpha-THP, in the hippocampus. ..