This article is about DHEA as a hormone. For its use as a medication or supplement, seePrasterone. For other uses, seeDHEA (disambiguation). For the precursor hormone of DHEA produced mainly in the adrenal cortex, DHEA sulfate or DHEA-S, seeDehydroepiandrosterone sulfate.
DHEA is a weakestrogen.[4][10][19] In addition, it is transformed into potent estrogens such asestradiol in certain tissues such as thevagina, and thereby produces estrogenic effects in such tissues.[4]
Although it functions as an endogenousprecursor to morepotent androgens such as testosterone and DHT, DHEA has been found to possess some degree ofandrogenic activity in its own right, acting as a lowaffinity (Ki = 1 μM), weakpartial agonist of theandrogen receptor (AR). However, itsintrinsic activity at the receptor is quite weak, and on account of that, due tocompetition forbinding withfull agonists like testosterone, it can actually behave more like an antagonist depending on circulating testosterone anddihydrotestosterone (DHT) levels, and hence, like anantiandrogen. However, its affinity for the receptor is very low, and for that reason, is unlikely to be of much significance under normal circumstances.[19][23]
In addition to its affinity for the androgen receptor, DHEA has also been found to bind to (and activate) theERα andERβestrogen receptors with Ki values of 1.1 μM and 0.5 μM, respectively, andEC50 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 ofestradiol, 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-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.[10][19]
In 2011, the surprising discovery was made that DHEA, as well as its sulfate ester,DHEA-S, directly bind to and activateTrkA andp75NTR, receptors ofneurotrophins likenerve growth factor (NGF) andbrain-derived neurotrophic factor (BDNF), with high affinity.[25][29] DHEA was subsequently also found to bind toTrkB andTrkC with high affinity, though it only activated TrkC not TrkB.[25][30] DHEA and DHEA-S bound to these receptors with affinities in the lownanomolar range (around 5 nM), which were nonetheless approximately two orders of magnitude lower relative to highly potentpolypeptide neurotrophins like NGF (0.01–0.1 nM).[25][29][30] In any case, DHEA and DHEA-S both circulate at requisite concentrations to activate these receptors and were thus identified as important endogenousneurotrophic factors.[25][29] They have since been labeled "steroidal microneurotrophins", due to theirsmall-molecule and steroidal nature relative to their polypeptide neurotrophin counterparts.[31] 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 theevolution of thenervous system.[25][30] The findings that DHEA binds to and potently activatesneurotrophin receptors may explain the positive association between decreased circulating DHEA levels with age and age-relatedneurodegenerative diseases.[25][29]
Some research has shown that DHEA levels are too low in people with ADHD, and treatment with methylphenidate (NDRI stimulant) or bupropion (NDRI antidepressant) normalizes DHEA levels.[32]
DHEA is anuncompetitive inhibitor ofG6PDHTooltip glucose-6-phosphate dehydrogenase (Ki = 17 μM;IC50 = 18.7 μM), and is able to lowerNADPHTooltip nicotinamide adenine dinucleotide phosphate levels and reduce NADPH-dependentfree radical production.[33][34] It is thought that this action may possibly be responsible for much of theantiinflammatory,antihyperplastic,chemopreventative,antihyperlipidemic,antidiabetic, andantiobesic, as well as certainimmunomodulating activities of DHEA (with some experimental evidence to support this notion available).[33][34][35][36] However, it has also been said that inhibition of G6PDH activity by DHEAin vivo has not been observed and that the concentrations required for DHEA to inhibit G6PDHin vitro are very high, thus making the possible contribution of G6PDH inhibition to the effects of DHEA uncertain.[34]
DHEA supplements have been promoted in supplement form for its claimed cancer prevention properties; there is no scientific evidence to support these claims.[37]
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, andlibido.[38] DHEA can help improve bone density as it is related toandrogens which is important for bone health. DHEA controls the production ofosteoblasts and insulin like growth factor 1 (IGF-1) expression which strengthens bone growth through metabolites. This helps delay the risk ofosteoporosis in early adults.[39]
Regular exercise is known to increase DHEA production in the body.[48][49]Calorie restriction has also been shown to increase DHEA in primates.[50] 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.[51]
Theterminal half-life of DHEA is short at only 15 to 30 minutes.[58] In contrast, the terminal half-life of DHEA-S is far longer, at 7 to 10 hours.[58] As DHEA-S can be converted back into DHEA, it serves as a circulating reservoir for DHEA, thereby extending theduration of DHEA.[59][20]
Prior topuberty in humans, DHEA and DHEA-S levels elevate upondifferentiation of thezona reticularis of theadrenal cortex.[25] 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.[25] Plasma levels of DHEA in adult men are 10 to 25 nM, in premenopausal women are 5 to 30 nM, and in postmenopausal women are 2 to 20 nM.[25] Conversely, DHEA-S levels are an order of magnitude higher at 1–10 μM.[25] Levels of DHEA and DHEA-S decline to the lower nanomolar and micromolar ranges in men and women aged 60 to 80 years.[25]
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 ofcongenital adrenal hyperplasia. Women withpolycystic ovary syndrome tend to have elevated levels of DHEA-S.[62]
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 are1-dehydroepiandrosterone (1-androsterone) and4-dehydroepiandrosterone.[38] These isomers are also technically "DHEA", since they are dehydroepiandrosterones in which hydrogens are removed from theepiandrosterone skeleton.[citation needed]
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^Gravanis A, Calogeropoulou T, Panoutsakopoulou V, Thermos K, Neophytou C, Charalampopoulos I (October 2012). "Neurosteroids and microneurotrophins signal through NGF receptors to induce prosurvival signaling in neuronal cells".Science Signaling.5 (246): pt8.doi:10.1126/scisignal.2003387.PMID23074265.S2CID26914550.
^Lee, M. S.; Yang, J. W.; Ko, Y. H.; Han, C.; Kim, S. H.; Lee, M. S.; Joe, S. H.; Jung, I. K. (2008). "Effects of methylphenidate and bupropion on DHEA-S and cortisol plasma levels in attention-deficit hyperactivity disorder".Child Psychiatry and Human Development.39 (2):201–209.doi:10.1007/s10578-007-0081-6.PMID17763937.S2CID11041447.
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^Zbella, E. A.; Ilekis, J.; Scommegna, A.; Benveniste, R. (1986). "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".The Journal of Clinical Endocrinology and Metabolism.63 (3):751–757.doi:10.1210/jcem-63-3-751.ISSN0021-972X.PMID2942557.
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