5α-Dihydroprogesterone explained

5α-Dihydroprogesterone (5α-DHP, allopregnanedione,[1] or 5α-pregnane-3,20-dione) is an endogenous progestogen and neurosteroid that is synthesized from progesterone.[2] [3] It is also an intermediate in the synthesis of allopregnanolone and isopregnanolone from progesterone.

5α-DHP is metabolized by the aldo-keto reductases (AKRs) AKR1C1, AKR1C2, and AKR1C4 with high catalytic efficiency.[4] AKR1C1 preferentially forms 20α-hydroxy-5α-pregnane-3-one while AKR1C2 preferentially forms allopregnanolone. Similarly AKR1C1 reduces and consequently inactivates allopregnanolone into 5α-pregnane-3α,20α-diol. In contrast to the other AKRs, AKR1C3 has low catalytic efficiency for reduction of 5α-DHP. These AKRs are highly expressed in the human liver and mammary gland but have relatively modest expression in the human brain and uterus.[5]

5α-DHP is an agonist of the progesterone receptor and a positive allosteric modulator of the GABAA receptor (albeit with an affinity for this receptor that is regarded as relatively low (in comparison to 3α-hydroxylated progesterone metabolites such as allopregnanolone and pregnanolone)).[6] [7] It has also been found to act as a negative allosteric modulator of the GABAA-rho receptor.[8] The steroid has been found to possess 82% of the affinity of progesterone for the progesterone receptor in rhesus monkey uterus.[9] 5α-Dihydroprogesterone has been said to possess about 33% of the relative progestogenic potency of progesterone.[10] In addition, it is a weak agonist of the pregnane X receptor (PXR) (EC50 >10,000 μM), with approximately six-fold lower potency relative to its 5β-isomer, 5β-dihydroprogesterone.[11]

Allopregnanolone is transformed back into 5α-DHP by 3α-hydroxysteroid oxidoreductase, and conversion of allopregnanolone into 5α-DHP is responsible for the progestogenic activity of allopregnanolone.[6] [12] [13] 5α-DHP, via the progesterone receptor, and allopregnanolone, via the GABAA receptor, act together to induce lordosis in animals. A study found that 41% of allopregnanolone that was administered via injection was transformed into 5α-DHP in the rat brain.

Levels of 5α-DHP have been quantified.[14]

Chemistry

See also: List of neurosteroids.

See also

Notes and References

  1. Finn. Deborah A.. Purdy. Robert H.. Neuroactive Steroids in Anxiety and Stress. 2007. 10.1002/9780470101001.hcn026. Handbook of Contemporary Neuropharmacology. 978-0470101001.
  2. Mellon SH . Neurosteroid regulation of central nervous system development . Pharmacol. Ther. . 116 . 1 . 107–24 . October 2007 . 17651807 . 2386997 . 10.1016/j.pharmthera.2007.04.011 .
  3. Guidotti A, Dong E, Matsumoto K, Pinna G, Rasmusson AM, Costa E . The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders . Brain Res. Brain Res. Rev. . 37 . 1–3 . 110–5 . November 2001 . 11744079 . 10.1016/s0165-0173(01)00129-1. 22202599 .
  4. Rižner TL, Penning TM . Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism . Steroids . 79 . 49–63 . January 2014 . 24189185 . 3870468 . 10.1016/j.steroids.2013.10.012 .
  5. Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K . Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones . Biochem. J. . 351 . Pt 1 . 67–77 . October 2000 . 10998348 . 1221336 . 10.1042/bj3510067 .
  6. Rupprecht R, Reul JM, Trapp T . Progesterone receptor-mediated effects of neuroactive steroids . Neuron . 11 . 3 . 523–30 . September 1993 . 8398145 . 10.1016/0896-6273(93)90156-l. 11205767 . etal.
  7. 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.
  8. Johnston GA . Medicinal chemistry and molecular pharmacology of GABA(C) receptors . Curr Top Med Chem . 2 . 8 . 903–13 . 2002 . 12171579 . 10.2174/1568026023393453 . https://web.archive.org/web/20101226170919/http://sydney.edu.au/medicine/pharmacology/adrien-albert/images/pdfs/RefsPDFs/350.pdf . dead . December 26, 2010 .
  9. 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.
  10. Book: Rogerio A. Lobo. Jennifer Kelsey. Robert Marcus. Menopause: Biology and Pathobiology. 22 May 2000. Academic Press. 978-0-08-053620-0. 433–.
  11. 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 .
  12. Beyer C, González-Flores O, Ramírez-Orduña JM, González-Mariscal G . Indomethacin inhibits lordosis induced by ring A-reduced progestins: possible role of 3alpha-oxoreduction in progestin-facilitated lordosis . Horm Behav . 35 . 1 . 1–8 . February 1999 . 10049597 . 10.1006/hbeh.1998.1457 . 11520064 .
  13. Beyer C, Gonzalez-Flores O, Gonzalez-Mariscal G . Ring A reduced progestins potently stimulate estrous behavior in rats: paradoxical effect through the progesterone receptor . Physiol. Behav. . 58 . 5 . 985–93 . November 1995 . 8577898 . 10.1016/0031-9384(95)00141-5 . 25967801 .
  14. Trabert B, Falk RT, Stanczyk FZ, McGlynn KA, Brinton LA, Xu X . Reproducibility of an assay to measure serum progesterone metabolites that may be related to breast cancer risk using liquid chromatography-tandem mass spectrometry . Horm Mol Biol Clin Investig . 23 . 3 . 79–84 . September 2015 . 26353176 . 4966666 . 10.1515/hmbci-2015-0026 .

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