This article is about DHEA as a hormone. For its use as a medication or supplement, see
Prasterone. For other uses, see
DHEA (disambiguation). For the precursor hormone of DHEA produced mainly in the adrenal cortex, DHEA sulfate or DHEA-S, see
Dehydroepiandrosterone sulfate.
DHEA is a weak
estrogen.[4][10][19] 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.[4]
Although it functions as an endogenous
precursor to more
potent androgens such as testosterone and DHT, DHEA has been found to possess some degree of
androgenic activity in its own right, acting as a low
affinity (Ki = 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
competition for
binding with
full agonists 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.[19][23]
Estrogen receptors
In addition to its affinity for the androgen receptor, DHEA has also been found to bind to (and activate) the
ERα and
ERβestrogen receptors with Ki values of 1.1 μM and 0.5 μM, respectively, and
EC50 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-
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 activate
TrkA and
p75NTR, receptors of
neurotrophins like
nerve growth factor (NGF) and
brain-derived neurotrophic factor (BDNF), with high affinity.[25][29] DHEA was subsequently also found to bind to
TrkB and
TrkC with high affinity, though it only activated TrkC not TrkB.[25][30] DHEA and DHEA-S bound to these receptors with affinities in the low
nanomolar range (around 5 nM), which were nonetheless approximately two orders of magnitude lower relative to highly potent
polypeptide 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 endogenous
neurotrophic factors.[25][29] They have since been labeled "steroidal microneurotrophins", due to their
small-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 the
evolution of the
nervous system.[25][30] The findings that DHEA binds to and potently activates
neurotrophin receptors may explain the positive association between decreased circulating DHEA levels with age and age-related
neurodegenerative diseases.[25][29]
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. [32]
Other activity
G6PDH inhibitor
DHEA is an
uncompetitive inhibitor of
G6PDHTooltip glucose-6-phosphate dehydrogenase (Ki = 17 μM;
IC50 = 18.7 μM), and is able to lower
NADPHTooltip nicotinamide adenine dinucleotide phosphate levels and reduce NADPH-dependent
free radical production.[33][34] It is thought that this action may possibly be responsible for much of the
antiinflammatory,
antihyperplastic,
chemopreventative,
antihyperlipidemic,
antidiabetic, and
antiobesic, as well as certain
immunomodulating 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 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.[34]
Cancer
DHEA supplements have been promoted in supplement form for its claimed cancer prevention properties; there is no scientific evidence to support these claims.[37]
Miscellaneous
DHEA has been found to competitively inhibit
TRPV1.[28]
Regular
exercise is known to increase DHEA production in the body.[46][47]Calorie restriction has also been shown to increase DHEA in primates.[48] 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.[49]
Distribution
In the
circulation, DHEA is mainly bound to
albumin, with a small amount bound to
sex hormone-binding globulin (SHBG).[50][51] The small remainder of DHEA not associated with albumin or SHBG is unbound and free in the circulation.[50]
The
terminal half-life of DHEA is short at only 15 to 30 minutes.[56] In contrast, the terminal half-life of DHEA-S is far longer, at 7 to 10 hours.[56] As DHEA-S can be converted back into DHEA, it serves as a circulating reservoir for DHEA, thereby extending the
duration of DHEA.[57][20]
Prior to
puberty in humans, DHEA and DHEA-S levels elevate upon
differentiation of the
zona reticularis of the
adrenal 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 of
congenital adrenal hyperplasia. Women with
polycystic ovary syndrome tend to have elevated levels of DHEA-S.[60]
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.[62] These isomers are also technically "DHEA", since they are dehydroepiandrosterones in which hydrogens are removed from the
epiandrosterone skeleton.
^Schulman RA, Dean C (2007). Solve It With Supplements. New York City: Rodale, Inc. p. 100.
ISBN978-1-57954-942-8. DHEA (Dehydroepiandrosterone) is a common hormone produced in the adrenal glands, the gonads, and the brain.
^
abMo Q, Lu SF, Simon NG (April 2006). "Dehydroepiandrosterone and its metabolites: differential effects on androgen receptor trafficking and transcriptional activity". The Journal of Steroid Biochemistry and Molecular Biology. 99 (1): 50–8.
doi:
10.1016/j.jsbmb.2005.11.011.
PMID16524719.
S2CID30489004.
^Auci D, Kaler L, Subramanian S, Huang Y, Frincke J, Reading C, Offner H (September 2007). "A new orally bioavailable synthetic androstene inhibits collagen-induced arthritis in the mouse: androstene hormones as regulators of regulatory T cells". Annals of the New York Academy of Sciences. 1110 (1): 630–40.
Bibcode:
2007NYASA1110..630A.
doi:
10.1196/annals.1423.066.
PMID17911478.
S2CID32258529.
^Russell J, Rovere A, eds. (2009). "DHEA". American Cancer Society Complete Guide to Complementary and Alternative Cancer Therapies (2nd ed.). American Cancer Society. pp.
729–733.
ISBN9780944235713.
^Filaire E, Duché P, Lac G (October 1998). "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". European Journal of Applied Physiology and Occupational Physiology. 78 (5): 466–71.
doi:
10.1007/s004210050447.
PMID9809849.
S2CID20583279.
^Roberts E (February 1999). "The importance of being dehydroepiandrosterone sulfate (in the blood of primates): a longer and healthier life?". Biochemical Pharmacology. 57 (4): 329–46.
doi:
10.1016/S0006-2952(98)00246-9.
PMID9933021..
^
abAlesci S, Manoli I, Blackman MR (29 December 2004).
"Dehydroepiandrosterone (DHEA)". In Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD (eds.). Encyclopedia of Dietary Supplements (Print). CRC Press. pp. 169–.
ISBN978-0-8247-5504-1.
^Banaszewska B, Spaczyński RZ, Pelesz M, Pawelczyk L (2003). "Incidence of elevated LH/FSH ratio in polycystic ovary syndrome women with normo- and hyperinsulinemia". Roczniki Akademii Medycznej W Bialymstoku. 48: 131–4.
PMID14737959.
^Schwartz AG, Pashko LL (2001). "Potential therapeutic use of dehydroepiandrosterone and structural analogs". Diabetes Technology & Therapeutics. 3 (2): 221–4.
doi:
10.1089/152091501300209589.
PMID11478328.
Further reading
Labrie F, Martel C, Bélanger A, Pelletier G (April 2017). "Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology". The Journal of Steroid Biochemistry and Molecular Biology. 168: 9–18.
doi:
10.1016/j.jsbmb.2016.12.007.
PMID28153489.
S2CID2620899.