3α-Androstanediol explained

3α-Androstanediol also known as 5α-androstane-3α,17β-diol and sometimes shortened in the literature to 3α-diol, is an endogenous steroid hormone and neurosteroid and a metabolite of androgens like dihydrotestosterone (DHT).[1] [2] [3]

Biological activity

3α-Androstanediol is an inhibitory androstane neurosteroid and weak androgen and estrogen.

As a neurosteroid, it acts as a potent positive allosteric modulator of the GABAA receptor,[4] and has been found to have rewarding,[5] [6] anxiolytic,[7] pro-sexual,[8] and anticonvulsant effects.[9] [10] As androgens such as testosterone and DHT are known to have many of the same effects as 3α-diol and are converted into it in vivo, it is thought that this compound may in part be responsible for said effects.

Relative to its isomer 3β-androstanediol, which is a potent estrogen, 3α-androstanediol has substantially lower, though still significant affinity for the estrogen receptors, with a several-fold preference for ERβ over ERα.[11] [12] It has approximately 0.07% and 0.3% of the affinity of estradiol at the ERα and ERβ, respectively.[13]

Biochemistry

3α-Androstanediol shows high affinity for sex hormone-binding globulin (SHBG), similar to that of testosterone.[14]

Chemistry

See also: List of neurosteroids.

3α-Androstanediol, also known as 5α-androstane-3α,17β-diol, is a naturally occurring androstane steroid and a structural analogue of DHT (5α-androstan-17β-ol-3-one). A notable positional isomer of 3α-androstanediol is 3β-androstanediol.

An orally active synthetic analogue of 3α-androstanediol, 17α-ethynyl-3α-androstanediol (HE-3235, Apoptone), was formerly under investigation for the treatment of prostate cancer and breast cancer.[15]

Notes and References

  1. Book: Reddy DS . Sex Differences in the Human Brain, their Underpinnings and Implications . Neurosteroids . 186 . 113–37 . 2010 . 21094889 . 3139029 . 10.1016/B978-0-444-53630-3.00008-7 . Progress in Brain Research . 9780444536303 .
  2. Jin Y, Penning TM . Steroid 5alpha-reductases and 3alpha-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism . Best Pract. Res. Clin. Endocrinol. Metab. . 15 . 1 . 79–94 . March 2001 . 11469812 . 10.1053/beem.2001.0120 .
  3. Penning TM, Bauman DR, Jin Y, Rizner TL . Identification of the molecular switch that regulates access of 5alpha-DHT to the androgen receptor . Mol. Cell. Endocrinol. . 265-266 . 77–82 . February 2007 . 17223255 . 1857325 . 10.1016/j.mce.2006.12.007 .
  4. Reddy DS, Jian K . The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors . J. Pharmacol. Exp. Ther. . 334 . 3 . 1031–41 . September 2010 . 20551294 . 2939675 . 10.1124/jpet.110.169854 .
  5. Frye CA . Some rewarding effects of androgens may be mediated by actions of its 5alpha-reduced metabolite 3alpha-androstanediol . Pharmacol. Biochem. Behav. . 86 . 2 . 354–67 . February 2007 . 17112575 . 1857333 . 10.1016/j.pbb.2006.10.003 .
  6. Rosellini RA, Svare BB, Rhodes ME, Frye CA . The testosterone metabolite and neurosteroid 3alpha-androstanediol may mediate the effects of testosterone on conditioned place preference . Brain Res. Brain Res. Rev. . 37 . 1–3 . 162–71 . November 2001 . 11744084 . 10.1016/s0165-0173(01)00116-3. 44735355 .
  7. Fernández-Guasti A, Martínez-Mota L . 3150411 . Anxiolytic-like actions of testosterone in the burying behavior test: role of androgen and GABA-benzodiazepine receptors . Psychoneuroendocrinology . 30 . 8 . 762–70 . September 2005 . 15919582 . 10.1016/j.psyneuen.2005.03.006 .
  8. Sánchez Montoya EL, Hernández L, Barreto-Estrada JL, Ortiz JG, Jorge JC . The testosterone metabolite 3α-diol enhances female rat sexual motivation when infused in the nucleus accumbens shell . J Sex Med . 7 . 11 . 3598–609 . November 2010 . 20646182 . 10.1111/j.1743-6109.2010.01937.x . 4360968.
  9. Reddy DS . 29967602 . Anticonvulsant activity of the testosterone-derived neurosteroid 3alpha-androstanediol . NeuroReport . 15 . 3 . 515–8 . March 2004 . 15094514 . 10.1097/00001756-200403010-00026.
  10. Reddy DS . 54391883 . Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3alpha-androstanediol and 17beta-estradiol . Neuroscience . 129 . 1 . 195–207 . 2004 . 15489042 . 10.1016/j.neuroscience.2004.08.002 .
  11. Baker ME . Recent insights into the origins of adrenal and sex steroid receptors . J. Mol. Endocrinol. . 28 . 3 . 149–52 . 2002 . 12063181 . 10.1677/jme.0.0280149. free .
  12. Kuiper. George G. J. M.. Carlsson. Bo. Grandien. Kaj. Enmark. Eva. Häggblad. Johan. Nilsson. Stefan. Gustafsson. Jan-Åke. Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors α and β. Endocrinology. 138. 3. 1997. 863–870. 0013-7227. 10.1210/endo.138.3.4979. 9048584. free.
  13. Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA . Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta . Endocrinology . 138 . 3 . 863–70 . 1997 . 9048584 . 10.1210/endo.138.3.4979 . free .
  14. Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W . Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein . Toxicol. Sci. . 143 . 2 . 333–48 . February 2015 . 25349334 . 10.1093/toxsci/kfu231 . free .
  15. Ahlem C, Kennedy M, Page T, Bell D, Delorme E, Villegas S, Reading C, White S, Stickney D, Frincke J . 24785562 . 17α-alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism . Invest New Drugs . 30 . 1 . 59–78 . 2012 . 20814732 . 10.1007/s10637-010-9517-0 .

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