View source for Androstenedione

{{short description|Endogenous weak androgen}}
{{cs1 config|name-list-style=vanc}}
{{About|androstenedione the hormone|other uses|Androstenedione (disambiguation)}}
{{Distinguish|androstanedione|androstanediol|androstenediol|androstadienol}}
{{Drugbox
| verifiedrevid      = 443662098
| IUPAC_name         = (8''R'',9''S'',10''R'',13''S'',14''S'')-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1''H''-cyclopenta[''a'']phenanthrene-3,17-dione
| image              = Androstendion.svg
| image_class=skin-invert-image
| width              = 225px
| image2             = Androstediona3D.png
| image_class2       = bg-transparent
| width2             = 225px

<!--Clinical data-->| pregnancy_category = 
| legal_US           = Schedule III
| routes_of_administration = [[Oral administration|By mouth]]
| class              = [[Androgen]]; [[Anabolic steroid]]

<!--Pharmacokinetic data-->| bioavailability    = 
| protein_bound      = 
| metabolism         = [[Liver]]
| elimination_half-life = 
| excretion          = <!--Identifiers-->
| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 63-05-8
| ATC_prefix         = None
| PubChem            = 6128
| IUPHAR_ligand      = 2860
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB01536
| KEGG               = D00051
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 5898
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 409J2J96VR
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 16422
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 274826
| synonyms           = A4; Δ<sup>4</sup>-dione; Androstenedione; Androst-4-ene-3,17-dione; 4-Androstene-3,17-dione; 17-Ketotestosterone; 17-Oxotestosterone; 3,17-Dioxoandrost-4-ene; Fecundin

<!--Chemical data-->| C                  = 19
| H                  = 26
| O                  = 2
| SMILES             = O=C4/C=C3/CC[C@@H]2[C@H](CC[C@@]1(C(=O)CC[C@H]12)C)[C@@]3(C)CC4
| density_notes      = (predicted) at 20°C and 760 Torr. Calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (© 1994-2023 ACD/Labs).
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/C19H26O2/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/h11,14-16H,3-10H2,1-2H3/t14-,15-,16-,18-,19-/m0/s1
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| density            = 1.11±0.1 <ref>{{cite web | url = https://scifinder-n.cas.org/searchDetail/substance/655266ab41fa5e0a55e5b971/substanceDetails=Top | title = Androstenedione | work = SciFinder | publisher = American Chemical Society }}</ref>
| StdInChIKey        = AEMFNILZOJDQLW-QAGGRKNESA-N

<!--Physical data-->| melting_point      = 173-174<ref>{{cite web | url = https://pubchem.ncbi.nlm.nih.gov/compound/androstenedione#section=Top | title = Androstenedione Compound Summary | work = PubChem | publisher = National Center for Biotechnology Information. U.S. National Library of Medicine }}</ref>
}}

'''Androstenedione''', or '''4-androstenedione''' (abbreviated as '''A4''' or '''Δ<sup>4</sup>-dione'''), also known as '''androst-4-ene-3,17-dione''', is an [[endogenous]] weak [[androgen]] [[steroid hormone]] and [[chemical intermediate|intermediate]] in the [[biosynthesis]] of [[estrone]] and of [[testosterone]] from [[dehydroepiandrosterone]] (DHEA). It is closely related to [[androstenediol]] (androst-5-ene-3β,17β-diol).

== Function ==
Androstenedione is a precursor of testosterone and other androgens, as well as of estrogens like estrone, in the body. In addition to functioning as an endogenous [[prohormone]], androstenedione also has weak androgenic activity in its own right.

Androstenedione has been found to possess some [[estrogen]]ic activity, similarly to other DHEA metabolites.<ref name="pmid23123738">{{cite journal | vauthors = Miller KK, Al-Rayyan N, Ivanova MM, Mattingly KA, Ripp SL, Klinge CM, Prough RA | title = DHEA metabolites activate estrogen receptors alpha and beta | journal = Steroids | volume = 78 | issue = 1 | pages = 15–25 | date = January 2013 | pmid = 23123738 | pmc = 3529809 | doi = 10.1016/j.steroids.2012.10.002 }}</ref> However, in contrast to [[androstenediol]], its [[affinity (pharmacology)|affinity]] for the [[estrogen receptor]]s is very low, with less than 0.01% of the affinity of [[estradiol]] for both the [[ERα]] and [[ERβ]].<ref name="pmid9048584">{{cite journal | vauthors = Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA | title = Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta | journal = Endocrinology | volume = 138 | issue = 3 | pages = 863–70 | date = March 1997 | pmid = 9048584 | doi = 10.1210/endo.138.3.4979 | doi-access = free }}</ref>

===Adrenarche===
In children aged 6 to 8 years old, there is a rise in androstenedione secretion along with DHEA during [[adrenarche]]. This rise in androstenedione and DHEA is hypothesized to play a crucial role for learning social, cultural and ecological skills, such as the development and understanding of sexual attraction. Furthermore, it is thought that androstenedione plays a role in levels of aggression and competition in boys, as a positive correlation between the two were observed, while testosterone levels were below detection.<ref name="pmid27449532">{{cite journal | vauthors = Gray PB, McHale TS, Carré JM | title = A review of human male field studies of hormones and behavioral reproductive effort | journal = Hormones and Behavior | volume = 91 | pages = 52–67 | date = May 2017 | pmid = 27449532 | doi = 10.1016/j.yhbeh.2016.07.004 | s2cid = 4243812 }}</ref>

==Biochemistry==

===Biosynthesis===
[[File:Steroidogenesis.svg|thumb|left|400px|class=skin-invert-image|[[Steroidogenesis]]. Androstenedione is at center.<ref name="HäggströmRichfield2014">{{cite journal| vauthors = Häggström M, Richfield D |year=2014 |title=Diagram of the pathways of human steroidogenesis |journal=WikiJournal of Medicine |volume=1 |issue=1 |doi=10.15347/wjm/2014.005 |issn=2002-4436 |doi-access=free}}</ref>]]

Androstenedione is the common [[precursor (biochemistry)|precursor]] of the androgen and estrogen [[sex hormones]].<ref>{{cite book| vauthors = Devlin TM | title = Textbook of Biochemistry: with Clinical Correlations | year = 2010 | publisher = John Wiley & Sons | location = Hoboken, NJ | isbn = 978-0-470-28173-4 | page  =432 | edition = 7th }}</ref>

Androstenedione can be biosynthesized in one of two ways. The primary pathway involves conversion of [[17α-hydroxypregnenolone]] to DHEA by way of [[CYP17A1|17,20-lyase]], with subsequent conversion of DHEA to androstenedione via the enzyme [[3β-hydroxysteroid dehydrogenase]]. The secondary pathway involves conversion of [[17α-hydroxyprogesterone]], most often a precursor to [[cortisol]], to androstenedione directly by way of [[CYP17A1|17,20-lyase]]. Thus, 17,20-lyase is required for the synthesis of androstenedione, whether immediately or one step removed.

Androstenedione is produced in the [[adrenal gland]]s and the [[gonad]]s. The production of adrenal androstenedione is governed by [[adrenocorticotrophic hormone]] (ACTH), whereas production of gonadal androstenedione is under control by the [[gonadotropin]]s. In [[premenopausal]] women, the adrenal glands and [[ovary|ovaries]] each produce about half of the total androstenedione (about 3&nbsp;mg/day). After [[menopause]], androstenedione production is about halved, due primarily to the reduction of the steroid secreted by the ovary. Nevertheless, androstenedione is the principal steroid produced by the [[postmenopausal]] ovary.

Some androstenedione is also secreted into the [[blood plasma|plasma]], and may be converted in peripheral tissues to testosterone and estrogens.

{{Production rates, secretion rates, clearance rates, and blood levels of major sex hormones}}

===Metabolism===
Androstenedione is converted to either [[testosterone]] or [[estrone]]. Conversion of androstenedione to testosterone requires the enzyme [[17β-hydroxysteroid dehydrogenase]]. Androstenedione is released into the blood by [[Theca of follicle|theca cells]]. Conversion of androstenedione to estrone requires the enzyme [[aromatase]]. Androstenedione is a substrate for [[estrogen]] production in [[granulosa cells]] which produce aromatase. Thus, theca cells and granulosa cells work together to form estrogens.<ref>{{cite book | vauthors = Boulpaep EL, Boron WF | title = Medical Physiology: A Cellular and Molecular Approach | date = 2005 | publisher = Elsevier Saunders | location = Philadelphia, Pa. | isbn = 978-1-4160-2328-9 | page = 1155 | edition = Updated }}</ref>

[[Androstanedione]] is a [[5α-reductase|5α-reduced]] [[metabolite]] of 4-androstenedione which serves as an intermediate in the biosynthesis of the androgen and [[neurosteroid]] [[androsterone]].<ref name="pmid21361868">{{cite journal | vauthors = Paba S, Frau R, Godar SC, Devoto P, Marrosu F, Bortolato M | title = Steroid 5α-reductase as a novel therapeutic target for schizophrenia and other neuropsychiatric disorders | journal = Current Pharmaceutical Design | volume = 17 | issue = 2 | pages = 151–67 | year = 2025 | pmid = 21361868 | doi = 10.2174/138161211795049589 | doi-broken-date = 11 July 2025 |url=s://www.ingentaconnect.com/content/ben/cpd/2011/00000017/00000002/art00008 | hdl = 11380/1331413 | hdl-access = free }}</ref>

Androstenedione also has a variety of metabolites in different species. In cattle, androstenedione is converted into oestradiol-17 and epitestosterone.<ref>{{cite journal | vauthors = Möstl E, Choi HS, Bamberg E |year=1980 |title=Rapid conversion of androstenedione into epitestosterone in bovine blood invitro |journal=[[IRCS Medical Science: Biochemistry]] |volume=8 |pages=440}}</ref> In sheep, the molecule is transformed into the 17-epimer.<ref>{{cite journal | vauthors = Tsan CP | title = Metabolism of (4-14C)estrone by sheep erythrocytes around the time of parturition | journal = Canadian Journal of Biochemistry | volume = 54 | issue = 7 | pages = 666–669 | date = July 1976 | pmid = 8195 | doi = 10.1139/o76-096 }}</ref> Androstenedione is converted into different metabolites in invertebrates. As is the case for ''Marisa cornuarietis,'' freshwater ramshorn snail, where androstenedione is converted into 5α-dihydrotestosterone (DHT) and testosterone (T) in male and into 5α-dihydroandrostenedione (DHA) in females.<ref>{{cite journal | vauthors = Janer G, LeBlanc GA, Porte C | title = A comparative study on androgen metabolism in three invertebrate species | journal = General and Comparative Endocrinology | volume = 143 | issue = 3 | pages = 211–221 | date = September 2005 | pmid = 15922341 | doi = 10.1016/j.ygcen.2005.03.016 }}</ref>

===Levels===
Levels are normally 30–200&nbsp;ng/dL (1.0–7.0&nbsp;nmol/L) in females and 40–150&nbsp;ng/dL (1.4–5.2&nbsp;nmol/L) in males. 

In premature infants, serum androstenedione levels hover between 80 and 446 ng/dL. In full-term newborns, levels range from 20 to 290 ng/dL, and between 1 month and 1 year old, serum levels typically stay at less than 69 ng/dL.

Serum levels of androstenedione greater than or equal to 500 ng/dL may indicate the presence of an adrenal or gonadal tumor.<ref>{{cite web | url = http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9709 | title = Androstenedione, Serum | publisher = [[Mayo Clinic]] | access-date = 1 March 2014 | work = Test Catalog }}</ref>

==Pharmacology==
Androstenedione has been shown to increase serum testosterone levels over an eight-hour period in men when taken as a single oral dose of 300&nbsp;mg per day, but a dose of 100&nbsp;mg had no significant effect on serum testosterone.<ref name="pmid10683057">{{cite journal | vauthors = Leder BZ, Longcope C, Catlin DH, Ahrens B, Schoenfeld DA, Finkelstein JS | title = Oral androstenedione administration and serum testosterone concentrations in young men | journal = JAMA | volume = 283 | issue = 6 | pages = 779–82 | date = February 2000 | pmid = 10683057 | doi =  10.1001/jama.283.6.779| doi-access = free }}</ref> However, serum levels of estradiol increased following both the 100&nbsp;mg and 300&nbsp;mg doses.<ref name="pmid10683057" /> The study also reported that the serum level of estrogens and testosterone produced varied widely between individuals.<ref name="pmid10683057" />

A 2006 6-7 6-7 review paper summarized several studies that examined the effect of androstenedione on [[strength training]].<ref name="pmid16888459">{{cite journal | vauthors = Brown GA, Vukovich M, King DS | title = Testosterone prohormone supplements | journal = Medicine and Science in Sports and Exercise | volume = 38 | issue = 8 | pages = 1451–61 | date = August 2006 | pmid = 16888459 | doi = 10.1249/01.mss.0000228928.69512.2e | doi-access = free }}</ref> At dosages of 50&nbsp;mg or 100&nbsp;mg per day, androstenedione had no effect on muscle strength or size, or on body fat levels.<ref name="pmid16888459" /> One study used a daily dosage of 300&nbsp;mg of androstenedione combined with several other supplements, and also found no increase in strength when compared to a control group that did not take the supplements.<ref name="pmid16888459" />

The review authors speculate that sufficiently high doses may indeed lead to increased muscle size and strength.<ref name="pmid16888459" /> However, due to the federal ban on androstenedione supplements, it is difficult to carry out new research on its effects.<ref name="pmid16888459" /> The review authors conclude that individuals should not use androstenedione supplements due to the lack of evidence of beneficial effects, the wide variation in individual responses to the supplement, and the risk of unknown side effects.<ref name="pmid16888459" />  Side effects for women may include the development of male characteristics, [[clitoromegaly]], voice deepening, hirsutism, abnormal menstrual cycles and abnormal bleeding, blood clots, and metabolic disruption based on a study following 10 healthy females administering 100 mg androstenedione.<ref name=":0">{{cite journal | vauthors = Badawy MT, Sobeh M, Xiao J, Farag MA | title = Androstenedione (a Natural Steroid and a Drug Supplement): A Comprehensive Review of Its Consumption, Metabolism, Health Effects, and Toxicity with Sex Differences | journal = Molecules | volume = 26 | issue = 20 | pages = 6210 | date = October 2021 | pmid = 34684800 | pmc = 8539210 | doi = 10.3390/molecules26206210 | doi-access = free }}</ref>

==Medical use==
Under the brand name Metharmon-F and in combination with [[sex steroid]]s ([[pregnenolone]], [[testosterone (medication)|testosterone]], [[estrone]], [[androstenediol]]) and [[thyroid hormone]] ([[desiccated thyroid]]), androstenedione is or has been marketed for medical use in [[Thailand]].<ref name="Martindale">{{cite book | veditors = Sweetman SC |title=Martindale: the complete drug reference |date=2009 |publisher=Pharmaceutical Press |location=London |isbn=978-0-85369-840-1 |edition=36th}}</ref>

==Chemistry==
{{See also|List of androgens/anabolic steroids}}

Androstenedione, also known as androst-4-ene-3,17-dione, is a [[natural product|naturally occurring]] [[androstane]] [[steroid]] and a [[17-ketosteroid]]. It is closely related structurally to [[androstenediol]] (A5; androst-5-ene-3β,17β-diol), [[dehydroepiandrosterone]] (DHEA; androst-5-en-3β-ol-17-one), and [[testosterone]] (androst-4-en-17β-ol-3-one), as well as to [[5α-androstanedione]] (5α-androstane-3,17-dione) and [[estrone]] (estra-1,3,5(10)-triene-3-ol-17-one or 19-norandrost-1,3,5(10)-triene-3-ol-17-one).

==History==

===Use as a supplement===
Androstenedione was manufactured as a [[dietary supplement]], often called ''andro'' or ''andros'' for short. ''[[Sports Illustrated]]'' credits [[Patrick Arnold]] with introducing androstenedione to the North American market.<ref name=si>{{cite news | vauthors = Dohrmann G | url = https://vault.si.com/vault/2006/10/09/is-this-dr-evil/ | work = CNN | title = Is This Dr. Evil? | date = 9 October 2006 | archive-url = https://archive.today/20121208225833/http://sportsillustrated.cnn.com/vault/article/magazine/MAG1104278/2/index.htm|archive-date = 8 December 2012 | url-status = live }}</ref> Androstenedione supplements are credited with increasing testosterone levels, enhancing athletic performance, building body muscles, reducing fats, increasing energy, maintaining healthy RBCs, and increasing sexual performance.<ref name=":0" /> Although, all of these effects have not been proven through scientific study. Androstenedione was legal and able to be purchased [[over the counter]], and, as a consequence, it was in common use in [[Major League Baseball]] throughout the 1990s by record-breaking sluggers like [[Mark McGwire]].<ref>{{cite web | vauthors = Rovell D |url=https://www.cnbc.com/2010/01/12/mcgwires-andro-cover-was-very-profitable.html|title = McGwire's Andro Cover Was Very Profitable|website = [[CNBC]]|date = 12 January 2010}}</ref>

[[Barry R. McCaffrey]], in his capacity as director of the [[White House]] [[Office of National Drug Control Policy]] from 1996 to 2001, determined that androstenedione could not be classified as an anabolic steroid because there is no proof that it promotes muscle growth.<ref name="ReferenceA"/>

==Society and culture==
===Regulation===
Androstenedione is banned by the [[World Anti-Doping Agency]], and from the [[Olympic Games]]. The International Olympic Committee in 1997 banned androstenedione and placed it under the category of androgenic-anabolic steroids.<ref name="ReferenceA">{{cite book | vauthors = Reents S | title = Sport and Exercise Pharmacology | date = 2000 | publisher = Human Kinetics | location =Champaign, Ill. | isbn = 978-0-87322-937-1 }}</ref> Androstenedione is banned by MLB, the NFL, USOC, NCAA, and by the NBA.<ref name="ReferenceA"/>

On March 12, 2004, the Anabolic Steroid Control Act of 2004 was introduced into the United States Senate. It amended the [[Controlled Substances Act]] to place both [[anabolic steroid]]s and [[prohormone]]s on a list of [[controlled substance]]s, making possession of the banned substances a federal crime. The law took effect on January 20, 2005. However, androstenedione was legally defined as an anabolic steroid, even though there is scant evidence that androstenedione itself is anabolic in nature. On April 11, 2004, the United States [[Food and Drug Administration]] banned the sale of androstenedione, citing that the drug poses significant health risks commonly associated with steroids. Androstenedione is currently banned by the [[Military of the United States|U.S. military]].<ref>{{cite web | vauthors = Lopez CT | url =  http://airforcemedicine.afms.mil/sg_newswire/jan_05/Andro.htm | title = 'Andro' supplement off limits in new year | work = U.S. Air Force Medical Service | archive-url = https://web.archive.org/web/20120210060741/http://airforcemedicine.afms.mil/sg_newswire/jan_05/Andro.htm | url-status = dead | archive-date = 10 February 2012 | date = January 2005 }}</ref>

==References==
* [https://www.madeformedical.com/androstenedione/ Androstenedione]

; Citations
{{Reflist}}

{{Endogenous steroids}}
{{Navboxes
| title = [[Biological activity]]
| titlestyle = background:#ccccff
| list1 = 
{{Androgen receptor modulators}}
{{Estrogen receptor modulators}}
{{Xenobiotic-sensing receptor modulators}}
}}

[[Category:Androgens]]
[[Category:Androstanes]]
[[Category:Diketones]]
[[Category:Estrogens]]
[[Category:Pregnane X receptor agonists]]