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3β-Androstanediol

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3β-Androstanediol
Names
IUPAC name
5α-Androstane-3β,17β-diol
Systematic IUPAC name
(1S,3aS,3bR,5aS,7S,9aS,9bS,11aS)-9a,11a-Dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-1,7-diol
Other names
3β-Androstanediol; 3β-Diol; Maxterone
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.008.487 Edit this at Wikidata
UNII
  • InChI=1S/C19H32O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h12-17,20-21H,3-11H2,1-2H3/t12-,13-,14-,15-,16-,17-,18-,19-/m0/s1
    Key: CBMYJHIOYJEBSB-YSZCXEEOSA-N
  • InChI=1/C19H32O2/c1-18-9-7-13(20)11-12(18)3-4-14-15-5-6-17(21)19(15,2)10-8-16(14)18/h12-17,20-21H,3-11H2,1-2H3/t12-,13-,14-,15-,16-,17-,18-,19-/m0/s1
    Key: CBMYJHIOYJEBSB-YSZCXEEOBK
  • O[C@H]4CC[C@]3([C@@H](CC[C@H]2[C@@H]1CC[C@H](O)[C@@]1(C)CC[C@@H]23)C4)C
Properties
C19H32O2
Molar mass 292.463 g·mol−1
Melting point 168–170 °C (334–338 °F; 441–443 K)[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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

Biological activity

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3β-Androstanediol is a selective, high-affinity agonist of the ERβ, and hence, an estrogen.[2] In contrast to ERβ, 3β-androstanediol does not bind to the androgen receptor (AR).[3] 3β-Androstanediol has been reported to also bind to ERα with low nanomolar affinity, with several-fold lower affinity relative to ERβ.[4][5] It has approximately 3% and 7% of the affinity of estradiol at the ERα and ERβ, respectively.[6] Unlike 3α-androstanediol, 3β-androstanediol does not bind to the GABAA receptor.[7]

3β-Androstanediol may be the primary endogenous ligand of ERβ in the prostate gland, and as a result of activation of the ERβ, 3β-androstanediol has antiproliferative effects against prostate cancer cells.[8] Through the ERβ, 3β-androstanediol positively regulates oxytocin neurons and signaling in the paraventricular nucleus of hypothalamus,[9][10] and has been found to have antidepressant,[11] anxiolytic,[12] cognitive-enhancing,[12] and stress-relieving effects via this action.[13][14] Androgens, including testosterone and DHT, are known to downregulate the hypothalamic-pituitary-adrenal axis, and this has been found to be due in part or full to their conversion into 3β-androstanediol rather than to activation of the AR.[13][14][15]

Biochemistry

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Testosterone metabolism in humans
Testosterone structures
The image above contains clickable links
This diagram illustrates the metabolic pathways involved in the metabolism of DHT in humans. In addition to the transformations shown in the diagram, conjugation (e.g., sulfation and glucuronidation) occurs with DHT and metabolites that have one or more available hydroxyl (–OH) groups.

3β-Androstanediol is a 5α-reduced and 17β-hydroxylated metabolite of dehydroepiandrosterone (DHEA) as well as a 3β-hydroxylated metabolite of DHT (and by extension of testosterone).

A determination of the circulating levels of 3β-androstanediol in humans found concentrations of 239 ± 76 pg/ml and 82 ± 45 pg/ml of the compound in normal male and female serum, respectively.[16]

3β-Androstanediol shows high affinity for sex hormone-binding globulin (SHBG), similar to that of DHT.[17]

Chemistry

[edit]

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

17α-Ethynyl-3β-androstanediol is a 17α-substituted derivative of 3β-androstanediol and is an estrogen similarly.[18][19]

References

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  1. ^ Wang, Xingbin; Liu, Hui; Yan, Peiyun; Liu, Jinliang; Li, Yan; Sun, Qian; Wang, Cunde (1 May 2011). "Simultaneously rapid deprotection of 3-acyloxy groups and reduction of D-ring ketones (nitrile) of steroids using DIBAL-H/NiCl2". Journal of Chemical Research. 35 (5): 291–293. doi:10.3184/174751911X13050949941793. S2CID 197144530.
  2. ^ C.Y. Cheng (24 October 2009). Molecular Mechanisms in Spermatogenesis. Springer Science & Business Media. pp. 259–. ISBN 978-0-387-09597-4.
  3. ^ Oliveira AG, Coelho PH, Guedes FD, Mahecha GA, Hess RA, Oliveira CA (December 2007). "5alpha-Androstane-3beta,17beta-diol (3beta-diol), an estrogenic metabolite of 5alpha-dihydrotestosterone, is a potent modulator of estrogen receptor ERbeta expression in the ventral prostrate of adult rats". Steroids. 72 (14): 914–22. doi:10.1016/j.steroids.2007.08.001. PMID 17854852. S2CID 54258086.
  4. ^ Baker ME (2002). "Recent insights into the origins of adrenal and sex steroid receptors" (PDF). J. Mol. Endocrinol. 28 (3): 149–52. doi:10.1677/jme.0.0280149. PMID 12063181.
  5. ^ Kuiper, George G. J. M.; Carlsson, Bo; Grandien, Kaj; Enmark, Eva; Häggblad, Johan; Nilsson, Stefan; Gustafsson, Jan-Åke (1997). "Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors α and β". Endocrinology. 138 (3): 863–870. doi:10.1210/endo.138.3.4979. ISSN 0013-7227. PMID 9048584.
  6. ^ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. doi:10.1210/endo.138.3.4979. PMID 9048584.
  7. ^ Reddy, D. S.; Jian, K. (2010). "The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors". Journal of Pharmacology and Experimental Therapeutics. 334 (3): 1031–1041. doi:10.1124/jpet.110.169854. ISSN 0022-3565. PMC 2939675. PMID 20551294.
  8. ^ Weihua Z, Lathe R, Warner M, Gustafsson JA (October 2002). "An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth". Proceedings of the National Academy of Sciences of the United States of America. 99 (21): 13589–94. Bibcode:2002PNAS...9913589W. doi:10.1073/pnas.162477299. PMC 129718. PMID 12370428.
  9. ^ Sharma, Dharmendra; Handa, Robert J.; Uht, Rosalie M. (2012). "The ERβ Ligand 5α-androstane, 3β,17β-diol (3β-diol) Regulates Hypothalamic Oxytocin (Oxt) Gene Expression". Endocrinology. 153 (5): 2353–2361. doi:10.1210/en.2011-1002. ISSN 0013-7227. PMC 3339641. PMID 22434086.
  10. ^ Hiroi, Ryoko; Lacagnina, Anthony F.; Hinds, Laura R.; Carbone, David G.; Uht, Rosalie M.; Handa, Robert J. (2013). "The Androgen Metabolite, 5α-Androstane-3β,17β-Diol (3β-Diol), Activates the Oxytocin Promoter Through an Estrogen Receptor-β Pathway". Endocrinology. 154 (5): 1802–1812. doi:10.1210/en.2012-2253. ISSN 0013-7227. PMC 3628024. PMID 23515287.
  11. ^ Huang, Q; Zhu, H; Fischer, D; Zhou, J (2008). "An estrogenic effect of 5α-androstane-3β, 17β-diol on the behavioral response to stress and on CRH regulation". Neuropharmacology. 54 (8): 1233–1238. doi:10.1016/j.neuropharm.2008.03.016. ISSN 0028-3908. PMID 18457850. S2CID 9052079.
  12. ^ a b Frye, C; Koonce, C; Edinger, K; Osborne, D; Walf, A (2008). "Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice". Hormones and Behavior. 54 (5): 726–734. doi:10.1016/j.yhbeh.2008.07.013. ISSN 0018-506X. PMC 3623974. PMID 18775724.
  13. ^ a b Handa, R. J.; Weiser, M. J.; Zuloaga, D. G. (2009). "A Role for the Androgen Metabolite, 5α-Androstane-3β,17β-Diol, in Modulating Oestrogen Receptor β-Mediated Regulation of Hormonal Stress Reactivity". Journal of Neuroendocrinology. 21 (4): 351–358. doi:10.1111/j.1365-2826.2009.01840.x. ISSN 0953-8194. PMC 2727750. PMID 19207807.
  14. ^ a b Handa, Robert J.; Sharma, Dharmendra; Uht, Rosalie (2011). "A Role for the Androgen Metabolite, 5alpha Androstane 3beta, 17beta Diol (3?-Diol) in the Regulation of the Hypothalamo-Pituitary?Adrenal Axis". Frontiers in Endocrinology. 2: 65. doi:10.3389/fendo.2011.00065. ISSN 1664-2392. PMC 3355903. PMID 22649380.
  15. ^ Handa, Robert J.; Pak, Toni R.; Kudwa, Andrea E.; Lund, Trent D.; Hinds, Laura (2008). "An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol". Hormones and Behavior. 53 (5): 741–752. doi:10.1016/j.yhbeh.2007.09.012. ISSN 0018-506X. PMC 2430080. PMID 18067894.
  16. ^ Laband P, Tresguerres JA, Lisboa BP, Volkwein U, Tamm J (August 1978). "The determination of 5alpha-androstane-3alpha, 17beta-diol in human plasma by radioimmunoassay". Acta Endocrinologica. 88 (4): 778–86. doi:10.1530/acta.0.0880778. PMID 581118.
  17. ^ Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W (February 2015). "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. doi:10.1093/toxsci/kfu231. PMID 25349334.
  18. ^ Beyler AL, Clinton RO (June 1956). "Uterine growth stimulating and testicular growth suppressing activities of 17alpha-ethinylandrostane-3beta, 17beta-diol, its delta 5-analog and derivatives". Proc. Soc. Exp. Biol. Med. 92 (2): 404–8. doi:10.3181/00379727-92-22493. PMID 13350363. S2CID 87469965.
  19. ^ Ahlem C, Kennedy M, Page T, Bell D, Delorme E, Villegas S, Reading C, White S, Stickney D, Frincke J (February 2012). "17α-alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism". Invest New Drugs. 30 (1): 59–78. doi:10.1007/s10637-010-9517-0. PMID 20814732. S2CID 24785562.


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