Androsterone

{{Infobox drug

| verifiedrevid = 457130388

| IUPAC_name = (3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-one

| image = androsteron.svg

| image_class = skin-invert-image

| alt = Skeletal formula of androsterone

| width = 210

| image2 = Androsterone-3D-balls.png

| alt2 = Ball-and-stick model of the androsterone molecule

| width2 = 220

| pregnancy_category =

| legal_status =

| routes_of_administration =

| bioavailability =

| metabolism =

| excretion =

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 53-41-8

| ATC_prefix = none

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 87285

| PubChem = 5879

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 5668

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = C24W7J5D5R

| synonyms = 3α-hydroxy-5α-androstan-17-one, 5α-androstan-3α-ol-17-one

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 16032

| C=19 | H=30

| O=2

| smiles = O=C2[C@]1(CC[C@H]3[C@H]([C@@H]1CC2)CC[C@H]4C[C@H](O)CC[C@]34C)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C19H30O2/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/h12-16,20H,3-11H2,1-2H3/t12-,13+,14-,15-,16-,18-,19-/m0/s1

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = QGXBDMJGAMFCBF-HLUDHZFRSA-N

}}

Androsterone, or 3α-hydroxy-5α-androstan-17-one, is an endogenous steroid hormone, neurosteroid, and putative pheromone.{{cite journal | vauthors = Motofei IG | title = A dual physiological character for cerebral mechanisms of sexuality and cognition: common somatic peripheral afferents | journal = BJU International | volume = 108 | issue = 10 | pages = 1634–1639 | date = November 2011 | pmid = 21489118 | doi = 10.1111/j.1464-410X.2011.10116.x | s2cid = 25941894 }} It is a weak androgen with a potency that is approximately 1/7 that of testosterone.{{cite book | vauthors = Scott T | title = Concise Encyclopedia Biology | url = https://books.google.com/books?id=LorrYj5pkKYC&pg=PA49 | access-date = May 25, 2012 | year = 1996 | publisher = Walter de Gruyter | isbn = 978-3-11-010661-9 | page = 49 | archive-date = March 8, 2024 | archive-url = https://web.archive.org/web/20240308025011/https://books.google.com/books?id=LorrYj5pkKYC&pg=PA49 | url-status = live }} Androsterone is a metabolite of testosterone and dihydrotestosterone (DHT). In addition, it can be converted back into DHT via 3α-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase, bypassing conventional intermediates such as androstanedione and testosterone, and as such, can be considered to be a metabolic intermediate in its own right.{{cite book | vauthors = Stanczyk FZ, Bretsky | chapter = Biosynthesis, Transport, and Metabolism of Steroid HormonesHenderson BE, Ponder BA, Ross RK | title = Hormones, Genes, and Cancer | chapter-url = https://books.google.com/books?id=VzIWd4faVVQC&pg=PA23 | access-date = May 25, 2012 | date = March 13, 2003 | publisher = Oxford University Press | isbn = 978-0-19-513576-3 | page = 23 }}{{cite journal | vauthors = Kamrath C, Hochberg Z, Hartmann MF, Remer T, Wudy SA | title = Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 3 | pages = E367–E375 | date = March 2012 | pmid = 22170725 | doi = 10.1210/jc.2011-1997 | doi-access = free }}

Androsterone is also known to be an inhibitory androstane neurosteroid,{{cite book | vauthors = Reddy DS, Rogawski MA | chapter = Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy | veditors = Noebels JL, Avoli M, Rogawski MA | title = Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US) | date = 2012 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK98218/ | display-editors = etal | publisher = National Center for Biotechnology Information (US) | pmid = 22787590 | access-date = August 29, 2017 | archive-date = September 25, 2019 | archive-url = https://web.archive.org/web/20190925133626/https://www.ncbi.nlm.nih.gov/books/NBK98218/ | url-status = live }}{{cite book | vauthors = Reddy DS | chapter = Neurosteroids | title = Sex Differences in the Human Brain, their Underpinnings and Implications | volume = 186 | pages = 113–137 | year = 2010 | pmid = 21094889 | pmc = 3139029 | doi = 10.1016/B978-0-444-53630-3.00008-7 | isbn = 9780444536303 | series = Progress in Brain Research }} acting as a positive allosteric modulator of the GABA_A receptor,{{cite journal | vauthors = Li P, Bracamontes J, Katona BW, Covey DF, Steinbach JH, Akk G | title = Natural and enantiomeric etiocholanolone interact with distinct sites on the rat alpha1beta2gamma2L GABAA receptor | journal = Molecular Pharmacology | volume = 71 | issue = 6 | pages = 1582–1590 | date = June 2007 | pmid = 17341652 | pmc = 3788649 | doi = 10.1124/mol.106.033407 | s2cid = 44286086 }} and possesses anticonvulsant effects.{{cite journal | vauthors = Kaminski RM, Marini H, Kim WJ, Rogawski MA | title = Anticonvulsant activity of androsterone and etiocholanolone | journal = Epilepsia | volume = 46 | issue = 6 | pages = 819–827 | date = June 2005 | pmid = 15946323 | pmc = 1181535 | doi = 10.1111/j.1528-1167.2005.00705.x }} The unnatural enantiomer of androsterone is more potent as a positive allosteric modulator of GABA_A receptors and as an anticonvulsant than the natural form.{{cite journal | vauthors = Zolkowska D, Dhir A, Krishnan K, Covey DF, Rogawski MA | title = Anticonvulsant potencies of the enantiomers of the neurosteroids androsterone and etiocholanolone exceed those of the natural forms | journal = Psychopharmacology | volume = 231 | issue = 17 | pages = 3325–3332 | date = September 2014 | pmid = 24705905 | pmc = 4134984 | doi = 10.1007/s00213-014-3546-x }} Androsterone's 3β-isomer is epiandrosterone, and its 5β-epimer is etiocholanolone. The 3β,5β-isomer is epietiocholanolone.

Biological function

Androsterone has generally been considered to be an inactive metabolite of testosterone, which when conjugated by glucuronidation and sulfation allows testosterone to be removed from the body, but it is a weak neurosteroid that can cross into the brain and could have effects on brain function.

The view of androsterone as generally being of low significance however, seems to need review in the light of 21st century research, which suggests that androsterone significantly affects masculinization in mammalian fetuses. Masculinization of the external genitalia in humans is subject to dihydrotestosterone (DHT) derived via the recognised androgenic pathway and also via a backdoor pathway.{{cite journal|doi=10.15347/WJM/2023.003 |doi-access=free |title=Alternative androgen pathways |year=2023 | vauthors = Masiutin M, Yadav M |journal=WikiJournal of Medicine |volume=10 |pages=X |s2cid=257943362}} Therefore, androstanediol can be used a marker of the backdoor pathway of DHT synthesis.{{cite journal | vauthors = Rohayem J, Zitzmann M, Laurentino S, Kliesch S, Nieschlag E, Holterhus PM, Kulle A | title = The role of gonadotropins in testicular and adrenal androgen biosynthesis pathways-Insights from males with congenital hypogonadotropic hypogonadism on hCG/rFSH and on testosterone replacement | journal = Clinical Endocrinology | volume = 94 | issue = 1 | pages = 90–101 | date = January 2021 | pmid = 32871622 | doi = 10.1111/cen.14324 | doi-access = free }} Spectrometric studies identify androsterone as the main backdoor androgen in the human male fetus. Circulating levels are sex dependent, DHT being essentially absent in the female, in which titres of backdoor intermediates also are very low.

In males, backdoor intermediates occur mainly in the liver and adrenal of the fetus, and in the placenta — hardly at all in the testis. Instead, progesterone in the placenta is the main backdoor substrate for androgen synthesis. This also is consistent with the observation that placental insufficiency has been associated with disruptions of development of fetal genitalia.{{cite journal | vauthors = O'Shaughnessy PJ, Antignac JP, Le Bizec B, Morvan ML, Svechnikov K, Söder O, Savchuk I, Monteiro A, Soffientini U, Johnston ZC, Bellingham M, Hough D, Walker N, Filis P, Fowler PA | display-authors = 6 | title = Alternative (backdoor) androgen production and masculinization in the human fetus | journal = PLOS Biology | volume = 17 | issue = 2 | pages = e3000002 | date = February 2019 | pmid = 30763313 | pmc = 6375548 | doi = 10.1371/journal.pbio.3000002 | doi-access = free }}

=Pheromone=

Androsterone is found in the human axilla and skin as well as in the urine.{{cite book| vauthors = Maiworm RE, Langthaler WU |chapter=Influence of Androstenol and Androsterone on the Evalulation of Men of Varying Attractiveness Levels |title=Chemical Signals in Vertebrates 6 |year=1992|pages=575–579|doi=10.1007/978-1-4757-9655-1_88|isbn=978-1-4757-9657-5}} It may also be secreted by human sebaceous glands. It is described as having a musky odor similar to that of androstenol. Androsterone has been found to affect human behavior when smelled.

Biochemistry

=Biosynthesis=

Androsterone and its 5β-isomer, etiocholanolone, are produced in the body as metabolites of testosterone. Testosterone is converted to 5α-dihydrotestosterone and 5β-dihydrotestosterone by 5α-reductase and 5β-reductase, respectively. The enzyme 3α-hydroxysteroid dehydrogenase converts the reduced forms to 3α-androstanediol and 3β-androstanediol, which are subsequently converted by 17β-hydroxysteroid dehydrogenase to androsterone and etiocholanolone, respectively. Androsterone and etiocholanolone can also be formed from androstenedione via the action of 5α-reductase and 5β-reductase forming 5α-androstanedione and 5β-androstanedione which are then converted to androsterone and etiocholanolone by 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase, respectively.

=Metabolism=

Androsterone is sulfated into androsterone sulfate and glucuronidated into androsterone glucuronide and these conjugates are excreted in urine.

Chemistry

=Sources=

Androsterone has been shown to naturally occur in pine pollen, celery, truffles and is well known in many animal species.{{cite journal | vauthors = Janeczko A, Skoczowski A | title = Mammalian sex hormones in plants | journal = Folia Histochemica et Cytobiologica | volume = 43 | issue = 2 | pages = 71–79 | date = 2005 | pmid = 16044944 }}{{cite journal | vauthors = Wysocki CJ, Dorries KM, Beauchamp GK | title = Ability to perceive androstenone can be acquired by ostensibly anosmic people | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 20 | pages = 7976–7978 | date = October 1989 | pmid = 2813372 | pmc = 298195 | doi = 10.1073/pnas.86.20.7976 | doi-access = free | bibcode = 1989PNAS...86.7976W }}

History

Androsterone was first isolated in 1931, by Adolf Friedrich Johann Butenandt and Kurt Tscherning. They distilled over {{convert|17000|liter}} of male urine, from which they got {{convert|50|mg}} of crystalline androsterone, which was sufficient to find that the chemical formula was very similar to estrone.