Editing Dehydroepiandrosterone

{{About|DHEA as a hormone|its use as a medication or supplement|Prasterone|other uses|DHEA (disambiguation)|the precursor hormone of DHEA produced mainly in the adrenal cortex, DHEA sulfate or DHEA-S|Dehydroepiandrosterone sulfate}}

{{Chembox
<!-- Images -->
| ImageFile = Dehydroepiandrosteron.svg
| ImageSize = 225px
| ImageAlt =
| ImageClass = skin-invert-image
| ImageFile1 = Dehydroepiandrosterone molecule ball.png
| ImageSize1 = 235px
| ImageAlt1 =
<!-- Names -->
| IUPACName = 3β-Hydroxyandrost-5-en-17-one
| SystematicName = (3a''S'',3b''R'',7''S'',9a''R'',9b''S'',11a''S'')-7-Hydroxy-9a,11a-dimethyl-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1''H''-cyclopenta[''a'']phenanthren-1-one
| OtherNames = Androstenolone; Prasterone; Androst-5-en-3β-ol-17-one; 5,6-Didehydroepiandrosterone;<ref name="Devillers2009">{{cite book| first = James | last = Devillers | name-list-style = vanc |title=Endocrine Disruption Modeling|url=https://books.google.com/books?id=bWHMBQAAQBAJ&pg=PA339|date=27 April 2009|publisher=CRC Press|isbn=978-1-4200-7636-3|pages=339–}}</ref> Dehydroisoepiandrosterone
| Watchedfields = changed
| verifiedrevid = 443682301
<!-- Sections -->
| Section1 = {{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|??}}
| CASNo = 53-43-0
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 28689
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 90593
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5670
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01708
| PubChem = 5881
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H28O2/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/h3,13-16,20H,4-11H2,1-2H3/t13-,14-,15-,16-,18-,19-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FMGSKLZLMKYGDP-USOAJAOKSA-N
| SMILES = O=C3[C@]2(CC[C@@H]1[C@@]4(C(=C/C[C@H]1[C@@H]2CC3)\C[C@@H](O)CC4)C)C
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 459AG36T1B
  }}
| Section2 = {{Chembox Properties
| C=19 | H=28 | O=2
| MolarMass = 288.424 g/mol
| Appearance =
| Density =
| MeltingPt = 148.5
| BoilingPt =
| Solubility =
  }}
| Section3 = {{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
  }}
| Section6 = {{Chembox Pharmacology
| ATCvet = yes
| ATCCode_prefix = A14
| ATCCode_suffix = AA07
| ATC_Supplemental = <br />{{ATC|G03|EA03}} (combination with [[estrogen]])
| AdminRoutes = [[Oral administration|By mouth]], [[vaginal administration|vaginal]] ([[suppository|insert]]), [[intramuscular injection]] (as [[prasterone enanthate]]), [[injection (medicine)|injection]] (as [[prasterone sodium sulfate]])
| Bioavail = 50%<ref name="CuppTracy2002">{{cite book | first1 = Melanie Johns | last1 = Cupp | first2 = Timothy S. | last2 = Tracy | name-list-style = vanc | title=Dietary Supplements: Toxicology and Clinical Pharmacology|url=https://books.google.com/books?id=vuqPBAAAQBAJ&pg=PA135|date=10 December 2002|publisher=Springer Science & Business Media|isbn=978-1-59259-303-3|pages=135–}}</ref>
| Excretion = [[Urine]]
| HalfLife = {{abbr|DHEA|Dehydroepiandrosterone}}: 25&nbsp;minutes<ref name="OddensVermeulen1996">{{cite book | vauthors = Oddens BJ, Vermeulen A | title=Androgens and the Aging Male|url=https://books.google.com/books?id=efEnI1VdmtsC&pg=PA5|date=15 November 1996|publisher=CRC Press|isbn=978-1-85070-763-9|pages=5–}}</ref><br />{{abbr|DHEA-S|Dehydroepiandrosterone sulfate}}: 11&nbsp;hours<ref name="OddensVermeulen1996" />
| Metabolism = [[Liver|Hepatic]]<ref name="CuppTracy2002" />
| ProteinBound =
  }}
}}

'''Dehydroepiandrosterone''' ('''DHEA'''), also known as '''androstenolone''', is an [[endogenous]] [[steroid hormone]] precursor.<ref name="pmid16293766">{{cite journal | vauthors = Labrie F, Luu-The V, Bélanger A, Lin SX, Simard J, Pelletier G, Labrie C | title = Is dehydroepiandrosterone a hormone? | journal = J. Endocrinol. | volume = 187 | issue = 2 | pages = 169–96 | date = November 2005 | pmid = 16293766 | doi = 10.1677/joe.1.06264 | doi-access = free }}</ref> It is one of the most abundant circulating [[steroid]]s in humans.<ref>William F Ganong MD, 'Review of Medical Physiology', 22nd Ed, McGraw Hill, 2005, p. 362.</ref> DHEA is produced in the [[adrenal gland]]s,<ref>''The Merck Index'', 13th Edition, '''7798'''</ref> the [[gonad]]s, and the brain.<ref>{{cite book | last1 = Schulman | first1 = Robert A. | last2 = Dean | first2 = Carolyn | name-list-style = vanc | year = 2007 | title = Solve It With Supplements | publisher = Rodale, Inc. | location = New York City | page = 100 | isbn = 978-1-57954-942-8 | quote = DHEA (Dehydroepiandrosterone) is a common hormone produced in the adrenal glands, the gonads, and the brain.}}</ref> It functions as a [[metabolic intermediate]] in the [[biosynthesis]] of the [[androgen]] and [[estrogen]] [[sex steroid]]s both in the gonads and in various other [[tissue (biology)|tissue]]s.<ref name="pmid16293766" /><ref name="pmid16524719" /><ref name="Scott1996">{{cite book | first = Thomas | last = Scott | name-list-style = vanc | title = Concise Encyclopedia Biology | url = https://archive.org/details/conciseencyclope00scot | url-access = registration | access-date = 25 May 2012 | year = 1996 | publisher = Walter de Gruyter | isbn = 978-3-11-010661-9 | page = [https://archive.org/details/conciseencyclope00scot/page/49 49]}}</ref> However, DHEA also has a variety of potential biological effects in its own right, binding to an array of [[nuclear receptor|nuclear]] and [[cell surface receptor]]s,<ref name="pmid16684650">{{cite journal | vauthors = Webb SJ, Geoghegan TE, Prough RA, Michael Miller KK | title = The biological actions of dehydroepiandrosterone involves multiple receptors | journal = Drug Metabolism Reviews | volume = 38 | issue = 1–2 | pages = 89–116 | year = 2006 | pmid = 16684650 | pmc = 2423429 | doi = 10.1080/03602530600569877 }}</ref> and acting as a [[neurosteroid]] and modulator of [[neurotrophic factor receptor]]s.<ref name="pmid11281367">{{cite journal | vauthors = Friess E, Schiffelholz T, Steckler T, Steiger A | title = Dehydroepiandrosterone--a neurosteroid | journal = European Journal of Clinical Investigation | volume = 30 | pages = 46–50 | date = December 2000 | issue = Suppl 3 | pmid = 11281367 | doi = 10.1046/j.1365-2362.2000.0300s3046.x | s2cid = 30733847 }}</ref>

In the United States, DHEA is sold as an [[over-the-counter]] [[dietary supplement|supplement]], and medication called [[prasterone]].

{{TOC limit|3}}

==Biological function==

===As an androgen===
DHEA and other adrenal androgens such as [[androstenedione]], although relatively weak androgens, are responsible for the androgenic effects of [[adrenarche]], such as early [[pubic hair|pubic]] and [[axillary hair]] growth, adult-type [[body odor]], increased oiliness of hair and skin, and mild [[acne]].<ref name="PescovitzEugster2004">{{cite book| first1 = Ora Hirsch | last1 = Pescovitz | first2  =Erica A. | last2 = Eugster | name-list-style = vanc | title=Pediatric Endocrinology: Mechanisms, Manifestations, and Management|url=https://books.google.com/books?id=9gvBlktAT6YC&pg=PA362|year=2004|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-4059-3|pages=362–}}</ref><ref name="Lifshitz2006">{{cite book|author=Fima Lifshitz|title=Pediatric Endocrinology: Growth, Adrenal, Sexual, Thyroid, Calcium, and Fluid Balance Disorders|url=https://books.google.com/books?id=1CTNBQAAQBAJ&pg=PA289|date=26 December 2006|publisher=CRC Press|isbn=978-1-4200-4272-6|pages=289–}}</ref><ref name="Salhan2011">{{cite book | first = Sudha | last = Salhan | name-list-style = vanc |title=Textbook of Gynecology|url=https://books.google.com/books?id=YUYx1neUEIoC&pg=PA94|date=1 August 2011|publisher=JP Medical Ltd|isbn=978-93-5025-369-4|pages=94–}}</ref> DHEA is potentiated locally via conversion into [[testosterone]] and [[dihydrotestosterone]] (DHT) in the skin and [[hair follicle]]s.<ref name="pmid16293766" /> Women with [[complete androgen insensitivity syndrome]] (CAIS), who have a non-functional [[androgen receptor]] (AR) and are immune to the androgenic effects of DHEA and other androgens, have absent or only sparse/scanty pubic and axillary hair and [[body hair]] in general, demonstrating the role of DHEA and other androgens in body hair development at both adrenarche and [[pubarche]].<ref name="LaverySanfilippo2012">{{cite book | vauthors = Lavery JP, Sanfilippo JS |title=Pediatric and Adolescent Obstetrics and Gynecology|url=https://books.google.com/books?id=l9XTBwAAQBAJ&pg=PA45|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-5064-7|pages=45–}}</ref><ref name="NussbaumMcInnes2015">{{cite book | first1 = Robert L. | last1 = Nussbaum | first2 = Roderick R. | last2 = McInnes  | first3 = Huntington F | last3 = Willard | name-list-style = vanc |title=Thompson & Thompson Genetics in Medicine|url=https://books.google.com/books?id=4yV1CQAAQBAJ&pg=PA102|date=28 April 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-39206-8|pages=102–}}</ref><ref name="SetchellHudson2013">{{cite book | first1 = Marcus E | last1 = Setchell | first2 = C. N. | last2 = Hudson | name-list-style = vanc |title=Shaw's Textbook of Operative Gynaecology|url=https://books.google.com/books?id=XHcWNRVHWsEC&pg=PA129|date=4 April 2013|publisher=Elsevier Health Sciences|isbn=978-81-312-3481-5|pages=129–}}</ref><ref name="BissonnetteDalens2006">{{cite book | first1 = Bruno | last1 = Bissonnette | first2 = Bernard | last2 = Dalens | name-list-style = vanc | title=Syndromes: Rapid Recognition and Perioperative Implications|url=https://books.google.com/books?id=uRR1MYa-w5wC|date=20 July 2006|publisher=McGraw Hill Professional|isbn=978-0-07-135455-4|page=184}}</ref>

===As an estrogen===
DHEA is a weak [[estrogen]].<ref name="pmid16293766" /><ref name="pmid16684650" /><ref name="pmid15994348" /> In addition, it is transformed into potent estrogens such as [[estradiol]] in certain tissues such as the [[vagina]], and thereby produces estrogenic effects in such tissues.<ref name="pmid16293766" />

===As a neurosteroid===
As a [[neurosteroid]] and [[neurotrophin]], DHEA has important effects in the [[central nervous system]].<ref name="Weizman2008" /><ref name="GravanisMellon2011">{{cite book | first1 = Achille G. | last1 = Gravanis | first2  =Synthia H. | last2 = Mellon | name-list-style = vanc |title=Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis|url=https://books.google.com/books?id=YmQAhOeaFtUC&pg=PT349|date=24 June 2011|publisher=John Wiley & Sons|isbn=978-3-527-63397-5|pages=349–}}</ref><ref>{{cite book|title=Sex difference in the human brain, their underpinnings and implications|url=https://books.google.com/books?id=JFpq6hYQRhQC&pg=PA127|date=3 December 2010|publisher=Elsevier|isbn=978-0-444-53631-0|pages=127–}}</ref>

==Biological activity==

===Hormonal activity===

====Androgen receptor====
Although it functions as an endogenous [[precursor (biochemistry)|precursor]] to more [[potency (pharmacology)|potent]] androgens such as testosterone and DHT, DHEA has been found to possess some degree of [[androgen]]ic activity in its own right, acting as a low [[affinity (pharmacology)|affinity]] (K<sub>i</sub> = 1 μM), weak [[partial agonist]] of the [[androgen receptor]] (AR). However, its [[intrinsic activity]] at the receptor is quite weak, and on account of that, due to [[competitive inhibition|competition]] for [[molecular binding|binding]] with [[full agonist]]s like testosterone, it can actually behave more like an antagonist depending on circulating testosterone and [[dihydrotestosterone]] (DHT) levels, and hence, like an [[antiandrogen]]. However, its affinity for the receptor is very low, and for that reason, is unlikely to be of much significance under normal circumstances.<ref name="pmid15994348">{{cite journal | vauthors = Chen F, Knecht K, Birzin E, Fisher J, Wilkinson H, Mojena M, Moreno CT, Schmidt A, Harada S, Freedman LP, Reszka AA | title = Direct agonist/antagonist functions of dehydroepiandrosterone | journal = Endocrinology | volume = 146 | issue = 11 | pages = 4568–76 | date = November 2005 | pmid = 15994348 | doi = 10.1210/en.2005-0368 | doi-access = free }}</ref><ref name="pmid16159155">{{cite journal | vauthors = Gao W, Bohl CE, Dalton JT | title = Chemistry and structural biology of androgen receptor | journal = Chemical Reviews | volume = 105 | issue = 9 | pages = 3352–70 | date = September 2005 | pmid = 16159155 | pmc = 2096617 | doi = 10.1021/cr020456u }}</ref>

====Estrogen receptors====
In addition to its affinity for the androgen receptor, DHEA has also been found to bind to (and activate) the [[Estrogen receptor alpha|ERα]] and [[Estrogen receptor beta|ERβ]] [[estrogen receptor]]s with K<sub>i</sub> values of 1.1 μM and 0.5 μM, respectively, and [[EC50|EC<sub>50</sub>]] values of >1 μM and 200 nM, respectively. Though it was found to be a partial agonist of the ERα with a maximal efficacy of 30–70%, the concentrations required for this degree of activation make it unlikely that the activity of DHEA at this receptor is physiologically meaningful. Remarkably however, DHEA acts as a full agonist of the ERβ with a maximal response similar to or actually slightly greater than that of [[estradiol]], and its levels in circulation and local tissues in the human body are high enough to activate the receptor to the same degree as that seen with circulating estradiol levels at somewhat higher than their maximal, non-[[ovulation|ovulatory]] concentrations; indeed, when combined with estradiol with both at levels equivalent to those of their physiological concentrations, overall activation of the ERβ was doubled.<ref name="pmid16684650" /><ref name="pmid15994348" />

====Other nuclear receptors====
DHEA does not bind to or activate the [[progesterone receptor|progesterone]], [[glucocorticoid receptor|glucocorticoid]], or [[mineralocorticoid receptor]]s.<ref name="pmid15994348" /><ref name="pmid21747041">{{cite journal | vauthors = Lindschau C, Kirsch T, Klinge U, Kolkhof P, Peters I, Fiebeler A | title = Dehydroepiandrosterone-induced phosphorylation and translocation of FoxO1 depend on the mineralocorticoid receptor | journal = Hypertension | volume = 58 | issue = 3 | pages = 471–8 | date = September 2011 | pmid = 21747041 | doi = 10.1161/HYPERTENSIONAHA.111.171280 | url = http://hyper.ahajournals.org/cgi/pmidlookup?view=long&pmid=21747041 | doi-access = free }}</ref> Other [[nuclear receptor]] targets of DHEA besides the androgen and estrogen receptors include the [[peroxisome proliferator-activated receptor|PPARα]], [[pregnane X receptor|PXR]], and [[constitutive androstane receptor|CAR]].<ref name="pmid26908835" /> However, whereas DHEA is a [[ligand (biochemistry)|ligand]] of the PPARα and PXR in rodents, it is not in humans.<ref name="Watson2011">{{cite book| first = Ronald Ross | last = Watson | name-list-style = vanc |title=DHEA in Human Health and Aging|url=https://books.google.com/books?id=pKXMBQAAQBAJ&pg=PA208|date=22 July 2011|publisher=CRC Press|isbn=978-1-4398-3884-6|pages=208–}}</ref> In addition to direct interactions, DHEA is thought to regulate a handful of other [[protein]]s via indirect, genomic mechanisms, including the [[enzyme]]s [[CYP2C11]] and [[11β-hydroxysteroid dehydrogenase type 1|11β-HSD1]] – the latter of which is essential for the biosynthesis of the [[glucocorticoid]]s such as [[cortisol]] and has been suggested to be involved in the [[antiglucocorticoid]] effects of DHEA – and the [[carrier protein]] [[Insulin-like growth factor-binding protein 1|IGFBP1]].<ref name="pmid15994348" /><ref name="pmid8035785">{{cite journal | vauthors = Kalimi M, Shafagoj Y, Loria R, Padgett D, Regelson W | title = Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA) | journal = Molecular and Cellular Biochemistry | volume = 131 | issue = 2 | pages = 99–104 | date = February 1994 | pmid = 8035785 | doi = 10.1007/BF00925945 | s2cid = 26893297 }}</ref>

===Neurosteroid activity===

====Neurotransmitter receptors====
DHEA has been found to directly act on several [[neurotransmitter receptor]]s, including acting as a [[positive allosteric modulator]] of the [[NMDA receptor]], as a [[negative allosteric modulator]] of the [[GABAA receptor|GABA<sub>A</sub> receptor]], and as an [[agonist]] of the [[sigma-1 receptor|σ<sub>1</sub> receptor]].<ref name="King2012" /><ref name="pmid26908835" />

====Neurotrophin receptors====
{{main|Neurotrophic factor receptor}}

In 2011, the surprising discovery was made that DHEA, as well as its sulfate ester, [[dehydroepiandrosterone sulfate|DHEA-S]], directly bind to and activate [[TrkA]] and [[p75NTR|p75<sup>NTR</sup>]], receptors of [[neurotrophin]]s like [[nerve growth factor]] (NGF) and [[brain-derived neurotrophic factor]] (BDNF), with high affinity.<ref name="pmid26908835">{{cite journal | vauthors = Prough RA, Clark BJ, Klinge CM | title = Novel mechanisms for DHEA action | journal = Journal of Molecular Endocrinology | volume = 56 | issue = 3 | pages = R139–55 | date = April 2016 | pmid = 26908835 | doi = 10.1530/JME-16-0013 | doi-access = free }}</ref><ref name="pmid21541365">{{cite journal | vauthors = Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, Calogeropoulou T, Castanas E, Gravanis A | title = Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis | journal = PLOS Biology | volume = 9 | issue = 4 | pages = e1001051 | date = April 2011 | pmid = 21541365 | pmc = 3082517 | doi = 10.1371/journal.pbio.1001051 | doi-access = free }}</ref> DHEA was subsequently also found to bind to [[TrkB]] and [[TrkC]] with high affinity, though it only activated TrkC not TrkB.<ref name="pmid26908835" /><ref name="pmid25330101">{{cite journal | vauthors = Pediaditakis I, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris AN, Charalampopoulos I, Gravanis A | title = Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors | journal = Endocrinology | volume = 156 | issue = 1 | pages = 16–23 | date = January 2015 | pmid = 25330101 | doi = 10.1210/en.2014-1596 | url = https://zenodo.org/record/894291 | doi-access = free }}</ref> DHEA and DHEA-S bound to these receptors with affinities in the low [[nanomolar]] range (around 5&nbsp;nM), which were nonetheless approximately two orders of magnitude lower relative to highly potent [[polypeptide]] neurotrophins like NGF (0.01–0.1&nbsp;nM).<ref name="pmid26908835" /><ref name="pmid21541365" /><ref name="pmid25330101" /> In any case, DHEA and DHEA-S both circulate at requisite concentrations to activate these receptors and were thus identified as important endogenous [[neurotrophic factor]]s.<ref name="pmid26908835" /><ref name="pmid21541365" /> They have since been labeled "steroidal microneurotrophins", due to their [[small-molecule]] and steroidal nature relative to their polypeptide neurotrophin counterparts.<ref name="pmid23074265">{{cite journal | vauthors = Gravanis A, Calogeropoulou T, Panoutsakopoulou V, Thermos K, Neophytou C, Charalampopoulos I | title = Neurosteroids and microneurotrophins signal through NGF receptors to induce prosurvival signaling in neuronal cells | journal = Science Signaling | volume = 5 | issue = 246 | pages = pt8 | date = October 2012 | pmid = 23074265 | doi = 10.1126/scisignal.2003387 | s2cid = 26914550 }}</ref> Subsequent research has suggested that DHEA and/or DHEA-S may in fact be phylogenetically ancient "ancestral" ligands of the neurotrophin receptors from early on in the [[evolution]] of the [[nervous system]].<ref name="pmid26908835" /><ref name="pmid25330101" /> The findings that DHEA binds to and potently activates [[neurotrophin receptor]]s may explain the positive association between decreased circulating DHEA levels with age and age-related [[neurodegenerative disease]]s.<ref name="pmid26908835" /><ref name="pmid21541365" />

====Microtubule-associated protein 2====
Similarly to [[pregnenolone]], its synthetic derivative [[3β-methoxypregnenolone]] (MAP-4343), and [[progesterone]], DHEA has been found to bind to [[microtubule-associated protein 2]] (MAP2), specifically the MAP2C subtype (K<sub>d</sub> = 27&nbsp;μM).<ref name="pmid26908835"/> However, it is unclear whether DHEA increases binding of MAP2 to [[tubulin]] like pregnenolone.<ref name="pmid26908835" />

====ADHD====
Some research has shown that DHEA levels are too low in people with ADHD, and treatment with methylphenidate or bupropion (stimulant type of medications) normalizes DHEA levels. <ref>{{cite journal | url=https://pubmed.ncbi.nlm.nih.gov/17763937/ | pmid=17763937 | year=2008 | last1=Lee | first1=M. S. | last2=Yang | first2=J. W. | last3=Ko | first3=Y. H. | last4=Han | first4=C. | last5=Kim | first5=S. H. | last6=Lee | first6=M. S. | last7=Joe | first7=S. H. | last8=Jung | first8=I. K. | title=Effects of methylphenidate and bupropion on DHEA-S and cortisol plasma levels in attention-deficit hyperactivity disorder | journal=Child Psychiatry and Human Development | volume=39 | issue=2 | pages=201–209 | doi=10.1007/s10578-007-0081-6 | s2cid=11041447 }}</ref>

===Other activity===

====G6PDH inhibitor====
DHEA is an [[uncompetitive inhibitor]] of {{abbrlink|G6PDH|glucose-6-phosphate dehydrogenase}} (K<sub>i</sub> = 17&nbsp;μM; [[IC50|IC<sub>50</sub>]] = 18.7&nbsp;μM), and is able to lower {{abbrlink|NADPH|nicotinamide adenine dinucleotide phosphate}} levels and reduce NADPH-dependent [[free radical]] production.<ref name="pmid15177053">{{cite journal | vauthors = Schwartz AG, Pashko LL | title = Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity | journal = Ageing Research Reviews | volume = 3 | issue = 2 | pages = 171–87 | date = April 2004 | pmid = 15177053 | doi = 10.1016/j.arr.2003.05.001 | s2cid = 11871872 }}</ref><ref name="pmid12097275">{{cite journal | vauthors = Ciolino HP, MacDonald CJ, Yeh GC | title = Inhibition of carcinogen-activating enzymes by 16alpha-fluoro-5-androsten-17-one | journal = Cancer Research | volume = 62 | issue = 13 | pages = 3685–90 | date = July 2002 | pmid = 12097275 }}</ref> It is thought that this action may possibly be responsible for much of the [[antiinflammatory]], [[growth inhibition|antihyperplastic]], [[anticarcinogen|chemopreventative]], [[lipid-lowering agent|antihyperlipidemic]], [[antidiabetic]], and [[antiobesity|antiobesic]], as well as certain [[immunomodulator|immunomodulating]] activities of DHEA (with some experimental evidence to support this notion available).<ref name="pmid15177053" /><ref name="pmid12097275"/><ref name="pmid16952912">{{cite journal | vauthors = McCormick DL, Johnson WD, Kozub NM, Rao KV, Lubet RA, Steele VE, Bosland MC | title = Chemoprevention of rat prostate carcinogenesis by dietary 16alpha-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone | journal = Carcinogenesis | volume = 28 | issue = 2 | pages = 398–403 | date = February 2007 | pmid = 16952912 | doi = 10.1093/carcin/bgl141 | doi-access = free }}</ref><ref name="pmid17911478">{{cite journal | vauthors = Auci D, Kaler L, Subramanian S, Huang Y, Frincke J, Reading C, Offner H | title = A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: androstene hormones as regulators of regulatory T cells | journal = Annals of the New York Academy of Sciences | volume = 1110 | pages = 630–40 | date = September 2007 | issue = 1 | pmid = 17911478 | doi = 10.1196/annals.1423.066 | bibcode = 2007NYASA1110..630A | s2cid = 32258529 }}</ref> However, it has also been said that inhibition of G6PDH activity by DHEA ''[[in vivo]]'' has not been observed and that the concentrations required for DHEA to inhibit G6PDH ''[[in vitro]]'' are very high, thus making the possible contribution of G6PDH inhibition to the effects of DHEA uncertain.<ref name="pmid12097275" />

====Cancer====
DHEA supplements have been promoted in supplement form for its claimed cancer prevention properties; there is no scientific evidence to support these claims.<ref>{{cite book |publisher=American Cancer Society |title=American Cancer Society Complete Guide to Complementary and Alternative Cancer Therapies |chapter-url=https://archive.org/details/americancancerso0000unse |chapter-url-access=registration |edition=2nd |year=2009 |isbn=9780944235713 |veditors=Russell J, Rovere A |pages=[https://archive.org/details/americancancerso0000unse/page/729 729–733] |chapter=DHEA}}</ref>

====Miscellaneous====
DHEA has been found to competitively inhibit [[TRPV1]].<ref name="King2012">{{cite book | first = Steven R. | last = King | name-list-style = vanc | title = Neurosteroids and the Nervous System|url=https://books.google.com/books?id=D1fOTC6CP3kC&pg=PA1|date=9 November 2012|publisher=Springer Science & Business Media|isbn=978-1-4614-5559-2|pages=15–16}}</ref>

== DHEA in regards to aging ==
DHEA levels peak in early adulthood and gradually decline with age. By supplementing with DHEA, some individuals aim to restore hormone levels, potentially improving energy levels, mood, and [[libido]]. <ref name="JosephyRadt2013" /> DHEA can help improve bone density as it is related to [[Androgen|androgens]] which is important for bone health. DHEA controls the production of [[Osteoclast|osteoblasts]] and insulin like growth factor 1 [[IGF-1|(IGF-1)]] expression which strengthens bone growth through metabolites. This helps delay the risk of [[osteoporosis]] in early adults. <ref name="pmid11478328" />

==Biochemistry==
[[File:Steroidogenesis.svg|thumb|450px|right|Comprehensive overview of [[steroidogenesis]], showing DHEA at left among the androgens.<ref name="HäggströmRichfield2014">{{cite journal|last1=Häggström|first1=Mikael|last2=Richfield|first2=David|title=Diagram of the pathways of human steroidogenesis|journal=WikiJournal of Medicine|volume=1|issue=1|year=2014|issn=2002-4436|doi=10.15347/wjm/2014.005|doi-access=free}}</ref>
]]

===Biosynthesis===
DHEA is produced in the [[zona reticularis]] of the [[adrenal cortex]] under the control of [[adrenocorticotropic hormone]] (ACTH) and by the [[gonad]]s under the control of [[gonadotropin-releasing hormone]] (GnRH).<ref name="Erkkola2006">{{cite book | first = Risto | last = Erkkola | name-list-style = vanc |title=The Menopause|url=https://books.google.com/books?id=1AU_NI__fpUC&pg=PA5|year=2006|publisher=Elsevier|isbn=978-0-444-51830-9|pages=5–}}</ref><ref name="KleineRossmanith2016">{{cite book| first1 = Bernhard | last1 = Kleine | first2 = Winfried G. | last2 = Rossmanith | name-list-style = vanc | title=Hormones and the Endocrine System: Textbook of Endocrinology|url=https://books.google.com/books?id=boqRCwAAQBAJ&pg=PA264|date=11 February 2016|publisher=Springer|isbn=978-3-319-15060-4|pages=264–265}}</ref> It is also produced in the brain.<ref name="Pizzorno2013">{{cite book | first = Joseph E. | last = Pizzorno | name-list-style = vanc |title=Textbook of Natural Medicine|url=https://books.google.com/books?id=6cjgo1IixvEC&pg=PA711|year=2013|publisher=Elsevier Health Sciences|isbn=978-1-4377-2333-5|pages=711–}}</ref> DHEA is synthesized from [[cholesterol]] via the [[enzyme]]s [[cholesterol side-chain cleavage enzyme]] (CYP11A1; P450scc) and [[17α-hydroxylase/17,20-lyase]] (CYP17A1), with [[pregnenolone]] and [[17α-hydroxypregnenolone]] as [[metabolic intermediate|intermediate]]s.<ref name="pmid17945481">{{cite journal | vauthors = Rainey WE, Nakamura Y | title = Regulation of the adrenal androgen biosynthesis | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 108 | issue = 3–5 | pages = 281–6 | date = February 2008 | pmid = 17945481 | pmc = 2699571 | doi = 10.1016/j.jsbmb.2007.09.015 }}</ref> It is derived mostly from the [[adrenal cortex]], with only about 10% being secreted from the [[gonad]]s.<ref name="Adler2009">{{cite book | first = Robert A. | last = Adler | name-list-style = vanc |title=Osteoporosis: Pathophysiology and Clinical Management|url=https://books.google.com/books?id=eShjlIWB7gEC&pg=PA387|date=14 December 2009|publisher=Springer Science & Business Media|isbn=978-1-934115-19-0|pages=387–}}</ref><ref name="SchillComhaire2006">{{cite book | first1=  Wolf-Bernhard | last1 = Schill | first2 = Frank H. | last2 = Comhaire | first3 = Timothy B. | last3 = Hargreave | name-list-style = vanc |title=Andrology for the Clinician|url=https://books.google.com/books?id=5Ts_AAAAQBAJ&pg=PA243|date=26 August 2006|publisher=Springer Science & Business Media|isbn=978-3-540-33713-3|pages=243–}}</ref><ref name="LinosHeerden2005">{{cite book | first1 = Dimitrios A. | last1 = Linos | first2 = Jon A. | last2 = van Heerden | name-list-style = vanc |title=Adrenal Glands: Diagnostic Aspects and Surgical Therapy|url=https://books.google.com/books?id=r8OLj1LLw3IC&pg=PA161|date=5 December 2005|publisher=Springer Science & Business Media|isbn=978-3-540-26861-1|pages=161–}}</ref> Approximately 50 to 70% of circulating DHEA originates from desulfation of DHEA-S in peripheral tissues.<ref name="Adler2009" /> DHEA-S itself originates almost exclusively from the adrenal cortex, with 95 to 100% being secreted from the adrenal cortex in women.<ref name="Erkkola2006"/><ref name="LinosHeerden2005" />

====Increasing endogenous production====
Regular exercise is known to increase DHEA production in the body.<ref>{{cite journal | vauthors = Filaire E, Duché P, Lac G | title = Effects of amount of training on the saliva concentrations of cortisol, dehydroepiandrosterone and on the dehydroepiandrosterone: cortisol concentration ratio in women over 16 weeks of training | journal = European Journal of Applied Physiology and Occupational Physiology | volume = 78 | issue = 5 | pages = 466–71 | date = October 1998 | pmid = 9809849 | doi = 10.1007/s004210050447 | s2cid = 20583279 }}</ref><ref>{{cite journal | vauthors = Copeland JL, Consitt LA, Tremblay MS | title = Hormonal responses to endurance and resistance exercise in females aged 19-69 years | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 57 | issue = 4 | pages = B158–65 | date = April 2002 | pmid = 11909881 | doi = 10.1093/gerona/57.4.B158 | doi-access = free }}</ref> [[Calorie restriction]] has also been shown to increase DHEA in primates.<ref>{{cite journal | vauthors = Mattison JA, Lane MA, Roth GS, Ingram DK | title = Calorie restriction in rhesus monkeys | journal = Experimental Gerontology | volume = 38 | issue = 1–2 | pages = 35–46 | year = 2003 | pmid = 12543259 | doi = 10.1016/S0531-5565(02)00146-8 | s2cid = 41481691 | url = https://zenodo.org/record/1260075 }}.</ref> Some theorize that the increase in endogenous DHEA brought about by calorie restriction is partially responsible for the longer life expectancy known to be associated with calorie restriction.<ref>{{cite journal | vauthors = Roberts E | title = The importance of being dehydroepiandrosterone sulfate (in the blood of primates): a longer and healthier life? | journal = Biochemical Pharmacology | volume = 57 | issue = 4 | pages = 329–46 | date = February 1999 | pmid = 9933021 | doi = 10.1016/S0006-2952(98)00246-9 }}.</ref>

===Distribution===
In the [[circulatory system|circulation]], DHEA is mainly bound to [[human serum albumin|albumin]], with a small amount bound to [[sex hormone-binding globulin]] (SHBG).<ref name="CoatesPaul2004">{{cite book | first1 = Salvatore | last1 = Alesci | first2 = Irini | last2 = Manoli | first3 = Marc R. | last3 = Blackman | editor-first1 = Paul M. | editor-last1 = Coates | editor-first2 = Marc R. | editor-last2 = Blackman | editor-first3 =  Gordon M. | editor-last3 = Cragg | editor-first4 = Mark | editor-last4 = Levine | editor-first5 = Joel | editor-last5 = Moss | editor-first6 = Jeffry D. | editor-last6 = White | name-list-style = vanc |title= Encyclopedia of Dietary Supplements (Print) | chapter = Dehydroepiandrosterone (DHEA) |chapter-url= https://books.google.com/books?id=Sfmc-fRCj10C&pg=PA169|date=29 December 2004|publisher=CRC Press|isbn=978-0-8247-5504-1|pages=169–}}</ref><ref name="Becker2001">{{cite book | first = Kenneth L. | last = Becker | name-list-style = vanc |title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA712|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=712–}}</ref> The small remainder of DHEA not associated with albumin or SHBG is unbound and free in the circulation.<ref name="CoatesPaul2004" />

DHEA easily crosses the [[blood–brain barrier]] into the [[central nervous system]].<ref name="Pizzorno2013" />

===Metabolism===
DHEA is transformed into DHEA-S by [[sulfation]] at the C3β position via the [[sulfotransferase]] [[enzyme]]s [[SULT2A1]] and to a lesser extent [[SULT1E1]].<ref name="pmid17945481" /><ref name="pmid26213785">{{cite journal | vauthors = Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA | title = The Regulation of Steroid Action by Sulfation and Desulfation | journal = Endocr Rev | volume = 36 | issue = 5 | pages = 526–63 | date = October 2015 | pmid = 26213785 | pmc = 4591525 | doi = 10.1210/er.2015-1036 }}</ref><ref name="Lash2005">{{cite book | first = Lawrence H | last = Lash | name-list-style = vanc |title=Drug Metabolism and Transport: Molecular Methods and Mechanisms|url=https://books.google.com/books?id=-sK8NM_9UVsC&pg=PA353|year=2005|publisher=Springer Science & Business Media|isbn=978-1-59259-832-8|pages=353–}}</ref> This occurs naturally in the adrenal cortex and during [[first-pass metabolism]] in the [[liver]] and [[intestines]] when [[exogenous]] DHEA is administered orally.<ref name="pmid26213785" /> Levels of DHEA-S in circulation are approximately 250 to 300 times those of DHEA.<ref name="Weizman2008">{{cite book | first = Abraham | last = Weizman | name-list-style = vanc |title=Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment|url=https://books.google.com/books?id=uABKkFdPjhkC&pg=PA229|date=1 February 2008|publisher=Springer Science & Business Media|isbn=978-1-4020-6854-6|pages=229–}}</ref> DHEA-S in turn can be converted back into DHEA in peripheral tissues via [[steroid sulfatase]] (STS).<ref name="Morfin2003">{{cite book | first = Robert | last = Morfin | name-list-style = vanc |title=DHEA and the Brain|url=https://books.google.com/books?id=uZp62ctguF0C&pg=PA28|date=2 September 2003|publisher=CRC Press|isbn=978-0-203-30121-0|pages=28–}}</ref><ref name="Karasek2006">{{cite book | first = Michał | last = Karasek | name-list-style = vanc |title=Aging and Age-related Diseases: The Basics|url=https://books.google.com/books?id=A_PN9oxKpP0C&pg=PA66|year=2006|publisher=Nova Publishers|isbn=978-1-59454-426-2|pages=66–}}</ref>

The [[terminal half-life]] of DHEA is short at only 15 to 30&nbsp;minutes.<ref name="WhitePorterfield2013">{{cite book | first1 = Bruce Alan | last1 = White | first2 =Susan P. | last2 = Porterfield | name-list-style = vanc | title=Endocrine and Reproductive Physiology, Mosby Physiology Monograph Series (with Student Consult Online Access),4: Endocrine and Reproductive Physiology|url=https://books.google.com/books?id=zMb4uoiXzzcC&pg=PA164|year=2013|publisher=Elsevier Health Sciences|isbn=978-0-323-08704-9|pages=164–}}</ref> In contrast, the terminal half-life of DHEA-S is far longer, at 7 to 10&nbsp;hours.<ref name="WhitePorterfield2013" /> As DHEA-S can be converted back into DHEA, it serves as a circulating reservoir for DHEA, thereby extending the [[duration of action|duration]] of DHEA.<ref name="KalimiRegelson2000">{{cite book | first1 = Mohammed Y. | last1 = Kalimi | first2 = William | last2 = Regelson | name-list-style = vanc | title = Dehydroepiandrosterone (DHEA): Biochemical, Physiological and Clinical Aspects|url=https://books.google.com/books?id=Cn0tcGjTD8YC&pg=PA41|year=2000|publisher=Walter de Gruyter|isbn=978-3-11-016111-3|pages=41–}}</ref><ref name="Weizman2008" />

[[Metabolite]]s of DHEA include DHEA-S, [[7α-hydroxy-DHEA]], [[7β-hydroxy-DHEA]], [[7-keto-DHEA]], [[7α-hydroxyepiandrosterone]], and [[7β-hydroxyepiandrosterone]], as well as [[androstenediol]] and [[androstenedione]].<ref name="pmid16524719">{{cite journal | vauthors = Mo Q, Lu SF, Simon NG | title = Dehydroepiandrosterone and its metabolites: differential effects on androgen receptor trafficking and transcriptional activity | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 99 | issue = 1 | pages = 50–8 | date = April 2006 | pmid = 16524719 | doi = 10.1016/j.jsbmb.2005.11.011 | s2cid = 30489004 }}</ref>

====Pregnancy====
During pregnancy, DHEA-S is [[metabolism|metabolized]] into the sulfates of [[16α-hydroxy-DHEA]] and [[15α-hydroxy-DHEA]] in the [[fetus|fetal]] [[liver]] as [[metabolic intermediate|intermediate]]s in the production of the estrogens [[estriol]] and [[estetrol]], respectively.<ref>{{Cite journal |last1=Zbella |first1=E. A. |last2=Ilekis |first2=J. |last3=Scommegna |first3=A. |last4=Benveniste |first4=R. |title=Competitive studies with dehydroepiandrosterone sulfate and 16 alpha-hydroxydehydroepiandrosterone sulfate in cultured human choriocarcinoma JEG-3 cells: effect on estrone, 17 beta-estradiol, and estriol secretion |url=https://pubmed.ncbi.nlm.nih.gov/2942557/ |journal=The Journal of Clinical Endocrinology and Metabolism |year=1986 |volume=63 |issue=3 |pages=751–757 |doi=10.1210/jcem-63-3-751 |issn=0021-972X |pmid=2942557}}</ref>

===Levels===
Prior to [[puberty]] in humans, DHEA and DHEA-S levels elevate upon [[cellular differentiation|differentiation]] of the [[zona reticularis]] of the [[adrenal cortex]].<ref name="pmid26908835" /> Peak levels of DHEA and DHEA-S are observed around age 20, which is followed by an age-dependent decline throughout life eventually back to prepubertal concentrations.<ref name="pmid26908835" /> Plasma levels of DHEA in adult men are 10 to 25&nbsp;nM, in premenopausal women are 5 to 30&nbsp;nM, and in postmenopausal women are 2 to 20&nbsp;nM.<ref name="pmid26908835" /> Conversely, DHEA-S levels are an order of magnitude higher at 1–10&nbsp;μM.<ref name="pmid26908835" /> Levels of DHEA and DHEA-S decline to the lower nanomolar and micromolar ranges in men and women aged 60 to 80&nbsp;years.<ref name="pmid26908835" />

DHEA levels are as follows:<ref name="QuestDiagnostics">{{Cite web |title=DHEA (Dehydroepiandrosterone) |url=https://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/DHEA.pdf |archive-url=https://web.archive.org/web/20200927033608/https://www.questdiagnostics.com/hcp/intguide/EndoMetab/EndoManual_AtoZ_PDFs/DHEA.pdf |archive-date=Sep 27, 2020 |website=[[Quest Diagnostics]]}}</ref>
* Adult men: 180–1250&nbsp;ng/dL
* Adult women: 130–980&nbsp;ng/dL
* Pregnant women: 135–810&nbsp;ng/dL
* Prepubertal children (<1 year): 26–585&nbsp;ng/dL
* Prepubertal children (1–5 years): 9–68&nbsp;ng/dL
* Prepubertal children (6–12 years): 11–186&nbsp;ng/dL
* Adolescent boys (Tanner II–III): 25–300&nbsp;ng/dL
* Adolescent girls (Tanner II–III): 69–605&nbsp;ng/dL
* Adolescent boys (Tanner IV–V): 100–400&nbsp;ng/dL
* Adolescent girls (Tanner IV–V): 165–690&nbsp;ng/dL

===Measurement===
As almost all DHEA is derived from the adrenal glands, blood measurements of DHEA-S/DHEA are useful to detect excess adrenal activity as seen in adrenal cancer or hyperplasia, including certain forms of [[congenital adrenal hyperplasia]]. Women with [[polycystic ovary syndrome]] tend to have elevated levels of DHEA-S.<ref name="pmid14737959">{{cite journal |last=Khorram |first=O. |last2=Vu, L., & Yen, S. S |year=1997 |title=Activation of immune function by dehydroepiandrosterone (DHEA) in age-advanced men |url=https://doi.org/10.1093/gerona/52a.1.m1 |journal=The Journals of Gerontology Series A: Biological Sciences and Medical Sciences |volume= |pages= |pmid=}}</ref>

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

DHEA, also known as androst-5-en-3β-ol-17-one, is a [[natural product|naturally occurring]] [[androstane]] [[steroid]] and a [[17-ketosteroid]].<ref name="Elks2014">{{cite book |last=de Menezes |first=K. J. |url=https://doi.org/10.2174/1745017901612010024 |title=Dehydroepiandrosterone, its sulfate and cognitive functions. |last2=Peixoto, C., Nardi, A. E., Carta, M. G., Machado, S., & Veras, A. B. |date=2016 |publisher=Clinical Practice &amp; Epidemiology in Mental Health |isbn= |pages=}}</ref> It is closely related structurally to [[androstenediol]] (androst-5-ene-3β,17β-diol), [[androstenedione]] (androst-4-ene-3,17-dione), and [[testosterone]] (androst-4-en-17β-ol-3-one).<ref name="Elks2014" /> DHEA is the 5-[[dehydrogenation|dehydro]] [[structural analog|analogue]] of [[epiandrosterone]] (5α-androstan-3β-ol-17-one) and is also known as 5-dehydroepiandrosterone or as δ<sup>5</sup>-epiandrosterone.<ref name="Elks2014" />

===Isomers===
The term "dehydroepiandrosterone" is ambiguous chemically because it does not include the specific positions within epiandrosterone at which hydrogen atoms are missing. DHEA itself is 5,6-didehydroepiandrosterone or 5-dehydroepiandrosterone. A number of naturally occurring isomers also exist and may have similar activities. Some isomers of DHEA are [[1-dehydroepiandrosterone]] (1-androsterone) and [[4-dehydroepiandrosterone]].<ref name="JosephyRadt2013">{{cite book |author1=Traish |first=A. M. |url=https://doi.org/10.1111/j.1743-6109.2011.02523.x |title=Dehydroepiandrosterone (dhea)—a precursor steroid or an active hormone in human physiology (CME). |author2=Kang, H. P., Saad, F., & Guay, A. T. |date=2011 |publisher=The Journal of Sexual Medicine |isbn= |pages=2608–}}</ref> These isomers are also technically "DHEA", since they are dehydroepiandrosterones in which hydrogens are removed from the [[epiandrosterone]] skeleton.{{citation needed|date=November 2024}}

[[Dehydroandrosterone]] (DHA) is the 3α-[[epimer]] of DHEA and is also an endogenous androgen.

==History==
{{See also|Prasterone#History}}

DHEA was first isolated from human [[urine]] in 1934 by [[Adolf Butenandt]] and Kurt Tscherning.<ref name="pmid11478328">{{cite journal |last=Kirby |first=D. J. |last2=Buchalter, D. B., Anil, U., & Leucht, P. |year=2020 |title=DHEA in bone: The role in osteoporosis and Fracture Healing. |url=https://doi.org/10.1007/s11657-020-00755-y |journal=Archives of Osteoporosis |volume= |issue= |pages= |doi= |pmid=}}</ref>

==See also==
* [[Epigenetic clock]]

==References==
{{Reflist|32em}}

==Further reading==
{{Refbegin}}
* {{cite journal | vauthors = Labrie F, Martel C, Bélanger A, Pelletier G | title = Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 168 | pages = 9–18 | date = April 2017 | pmid = 28153489 | doi = 10.1016/j.jsbmb.2016.12.007 | s2cid = 2620899 }}
{{Refend}}

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