Editing Dehydroepiandrosterone (section)

==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>