5β-Dihydroprogesterone explained

5β-Dihydroprogesterone (5β-DHP, pregnanedione, or 5β-pregnane-3,20-dione) is an endogenous neurosteroid and an intermediate in the biosynthesis of pregnanolone and epipregnanolone from progesterone.^{[1] [2] [3]} It is synthesized from progesterone by the enzyme 5β-reductase.^[4]

5β-DHP has been found to act as a positive allosteric modulator of the GABA_A receptor (albeit with an affinity for this receptor regarded as relatively low in comparison to 3α-hydroxylated progesterone metabolites such as pregnanolone and allopregnanolone)^[5] and also as a negative allosteric modulator of the GABA_A-rho receptor.^[6] In accordance with the former action, it has been found to possess anesthetic, anxiolytic, and antinociceptive effects.^{[7] [8] [9]} 5β-DHP has been found to act as an agonist of the pregnane X receptor (PXR) as well (albeit weakly (EC₅₀ >10,000 μM)),^[10] and has been found to regulate uterine contractility through activation of this receptor.^{[11] [12]} Unlike 5α-dihydroprogesterone, 5β-DHP possesses only very weak affinity for the progesterone receptor (1.2% of that of progesterone in rhesus monkey uterus), and in relation to this, is not a notable progestogen.^{[13] [14]}

A study found that 5β-DHP, but not progesterone, directly bound to and antagonized the oxytocin receptor at nanomolar concentrations, and it was suggested that this may be one of the mechanisms by which progesterone maintains pregnancy.^{[15] [16] [17]} However, a subsequent study was unable to replicate this finding, and there has been no further investigation since. In any case, 5β-DHP has nonetheless been shown to possess tocolytic effects in animals, and this may alternatively be mediated by activation of the PXR.

See also

• 5α-Dihydroprogesterone
• 3α-Dihydroprogesterone
• Isopregnanolone
• 3β-Dihydroprogesterone

Notes and References

1. Book: Neurosteroids and Brain Function. 12 December 2001. Academic Press. 978-0-08-054423-6. 464–.
2. Book: Neurosteroids. Frontiers E-books. 978-2-88919-078-2. 8–.
3. Gilbert Evans. Susan E.. Ross. Lori E.. Sellers. Edward M.. Purdy. Robert H.. Romach. Myroslava K.. 3α-reduced neuroactive steroids and their precursors during pregnancy and the postpartum period. Gynecological Endocrinology. 21. 5. 2005. 268–279. 0951-3590. 10.1080/09513590500361747. 16373246. 71722314.
4. Sheehan PM, Rice GE, Moses EK, Brennecke SP . 5 Beta-dihydroprogesterone and steroid 5 beta-reductase decrease in association with human parturition at term . Mol. Hum. Reprod. . 11 . 7 . 495–501 . 2005 . 16123077 . 10.1093/molehr/gah201 .
5. Ocvirk. Rok. Pearson Murphy. Beverley E.. Franklin. Keith B.J.. Abbott. Frances V.. Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test. Pain. 138. 2. 2008. 402–409. 0304-3959. 10.1016/j.pain.2008.01.019. 18343034. 32370572.
6. Morris KD, Moorefield CN, Amin J . Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids . Mol. Pharmacol. . 56 . 4 . 752–9 . 1999 . 10496958 .
7. Selye. H.. Anesthetic Effect of Steroid Hormones.. Experimental Biology and Medicine. 46. 1. 1941. 116–121. 1535-3702. 10.3181/00379727-46-11907. 87160217.
8. Leb. Colette R.. Hu. Fen-Yun. Pearson Murphy. Beverley E.. Metabolism of Progesterone by Human Lymphocytes: Production of Neuroactive Steroids. The Journal of Clinical Endocrinology & Metabolism. 82. 12. 1997. 4064–4068. 0021-972X. 10.1210/jcem.82.12.4354. 9398714. free.
9. Rodgers. R. Behaviorally Selective Effects of Neuroactive Steroids on Plus-Maze Anxiety in Mice. Pharmacology Biochemistry and Behavior. 59. 1. 1998. 221–232. 0091-3057. 10.1016/S0091-3057(97)00339-0. 9443559. 23583698.
10. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA . The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions . J. Clin. Invest. . 102 . 5 . 1016–23 . 1998 . 9727070 . 508967 . 10.1172/JCI3703 .
11. Hagedorn. K. A.. Cooke. C.-L.. John R. Falck. Falck. J. R.. Mitchell. B. F.. Davidge. S. T.. Sandra Davidge. Regulation of Vascular Tone During Pregnancy: A Novel Role for the Pregnane X Receptor. Hypertension. 49. 2. 2006. 328–333. 0194-911X. 10.1161/01.HYP.0000253478.51950.27. 17159084. free.
12. Mitchell. Bryan F.. Mitchell. Jana M.. Chowdhury. Jeeshan. Tougas. Michelle. Engelen. Sanne M.E.. Senff. Nancy. Heijnen. Iris. Moore. John T.. Goodwin. Bryan. Wong. Susan. Davidge. Sandra T.. Metabolites of progesterone and the pregnane X receptor: A novel pathway regulating uterine contractility in pregnancy?. American Journal of Obstetrics and Gynecology. 192. 4. 2005. 1304–1313. 0002-9378. 10.1016/j.ajog.2005.01.040. 15846226.
13. Lima-Hernández. Francisco J.. Beyer. Carlos. Gómora-Arrati. Porfirio. García-Juárez. Marcos. Encarnación-Sánchez. José L.. Etgen. Anne M.. González-Flores. Oscar. Src kinase signaling mediates estrous behavior induced by 5β-reduced progestins, GnRH, prostaglandin E2 and vaginocervical stimulation in estrogen-primed rats. Hormones and Behavior. 62. 5. 2012. 579–584. 0018-506X. 10.1016/j.yhbeh.2012.09.004. 23010621. 40245594.
14. Illingworth DV, Elsner C, De Groot K, Flickinger GL, Mikhail G . A specific progesterone receptor of myometrial cytosol from the rhesus monkey . J. Steroid Biochem. . 8 . 2 . 157–60 . February 1977 . 405534 . 10.1016/0022-4731(77)90040-1.
15. Book: Alexandros Makriyannis. Alexandros Makriyannis. Diane Biegel. Drug Discovery Strategies and Methods. 4 November 2003. CRC Press. 978-0-8247-5767-0. 190–.
16. Book: Robert K.. Creasy. Robert. Resnik. Jay D.. Iams. Charles J.. Lockwood. Michael F.. Greene. Thomas R.. Moore. Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice. 2013. Elsevier Health Sciences. 978-1-4557-1137-6. 72–.
17. Book: Knobil and Neill's Physiology of Reproduction. 12 December 2005. Academic Press. 978-0-08-053527-2. 2952–.