Dehydroepiandrosterone ( DHEA), also known as androstenolone, is an endogenous steroid hormone precursor.[William F Ganong MD, 'Review of Medical Physiology', 22nd Ed, McGraw Hill, 2005, p. 362.] DHEA is produced in the ,[ The Merck Index, 13th Edition, 7798] the , and the brain.
In the United States, DHEA is sold as an over-the-counter supplement, and medication called prasterone.
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 and
axillary hair growth, adult-type
body odor, increased oiliness of hair and skin, and mild
acne.
DHEA is potentiated locally via conversion into
testosterone and dihydrotestosterone (DHT) in the skin and
.
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.
As an estrogen
DHEA is a weak
estrogen.
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.
As a neurosteroid
As a
neurosteroid and
neurotrophin, DHEA has important effects in the central nervous system.
Biological activity
Hormonal activity
Androgen receptor
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
activity in its own right, acting as a low affinity (K
i = 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
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.
Estrogen receptors
In addition to its affinity for the androgen receptor, DHEA has also been found to bind to (and activate) the ERα and ERβ estrogen receptors with K
i values of 1.1 μM and 0.5 μM, respectively, and EC
50 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 concentrations; indeed, when combined with estradiol with both at levels equivalent to those of their physiological concentrations, overall activation of the ERβ was doubled.
Other nuclear receptors
DHEA does not bind to or activate the progesterone, glucocorticoid, or mineralocorticoid receptors.
Other
nuclear receptor targets of DHEA besides the androgen and estrogen receptors include the PPARα, PXR, and CAR.
However, whereas DHEA is a ligand of the PPARα and PXR in rodents, it is not in humans.
In addition to direct interactions, DHEA is thought to regulate a handful of other
via indirect, genomic mechanisms, including the
CYP2C11 and 11β-HSD1 – the latter of which is essential for the biosynthesis of the
such as
cortisol and has been suggested to be involved in the antiglucocorticoid effects of DHEA – and the
carrier protein IGFBP1.
Neurosteroid activity
Neurotransmitter receptors
DHEA has been found to directly act on several neurotransmitter receptors, including acting as a positive allosteric modulator of the
NMDA receptor, as a negative allosteric modulator of the
GABAA receptor, and as an
agonist of the σ
1 receptor.
Neurotrophin receptors
In 2011, the surprising discovery was made that DHEA, as well as its sulfate ester, DHEA-S, directly bind to and activate
TrkA and p75
NTR, receptors of
like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), with high affinity.
DHEA was subsequently also found to bind to
TrkB and
TrkC with high affinity, though it only activated TrkC not TrkB.
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).
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.
They have since been labeled "steroidal microneurotrophins", due to their
small-molecule and steroidal nature relative to their polypeptide neurotrophin counterparts.
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.
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.
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
d = 27 μM).
However, it is unclear whether DHEA increases binding of MAP2 to
tubulin like pregnenolone.
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.
Other activity
G6PDH inhibitor
DHEA is an uncompetitive inhibitor of (K
i = 17 μM; IC
50 = 18.7 μM), and is able to lower levels and reduce NADPH-dependent
free radical production.
It is thought that this action may possibly be responsible for much of the
antiinflammatory, antihyperplastic,
anticarcinogen, antihyperlipidemic,
antidiabetic, and
antiobesity, as well as certain
immunomodulator activities of DHEA (with some experimental evidence to support this notion available).
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.
Cancer
DHEA supplements have been promoted in supplement form for its claimed cancer prevention properties; there is no scientific evidence to support these claims.
Miscellaneous
DHEA has been found to competitively inhibit TRPV1.
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.
DHEA can help improve bone density as it is related to
Androgen which is important for bone health. DHEA controls the production of
Osteoclast and insulin like growth factor 1 (IGF-1) expression which strengthens bone growth through metabolites. This helps delay the risk of
osteoporosis in early adults.
Biochemistry
, showing DHEA at left among the androgens.
]]
Biosynthesis
DHEA is produced in the
zona reticularis of the
adrenal cortex under the control of adrenocorticotropic hormone (ACTH) and by the
under the control of gonadotropin-releasing hormone (GnRH).
It is also produced in the brain.
DHEA is synthesized from
cholesterol via the
cholesterol side-chain cleavage enzyme (CYP11A1; P450scc) and 17α-hydroxylase/17,20-lyase (CYP17A1), with
pregnenolone and 17α-hydroxypregnenolone as intermediates.
It is derived mostly from the
adrenal cortex, with only about 10% being secreted from the
.
Approximately 50 to 70% of circulating DHEA originates from desulfation of DHEA-S in peripheral tissues.
DHEA-S itself originates almost exclusively from the adrenal cortex, with 95 to 100% being secreted from the adrenal cortex in women.
Increasing endogenous production
Regular exercise is known to increase DHEA production in the body.
Calorie restriction has also been shown to increase DHEA in primates.
[.] 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.
[.]
Distribution
In the circulation, DHEA is mainly bound to albumin, with a small amount bound to sex hormone-binding globulin (SHBG).
The small remainder of DHEA not associated with albumin or SHBG is unbound and free in the circulation.
DHEA easily crosses the blood–brain barrier into the central nervous system.
Metabolism
DHEA is transformed into DHEA-S by
sulfation at the C3β position via the
sulfotransferase SULT2A1 and to a lesser extent SULT1E1.
This occurs naturally in the adrenal cortex and during first-pass metabolism in the
liver and
intestines when
exogenous DHEA is administered orally.
Levels of DHEA-S in circulation are approximately 250 to 300 times those of DHEA.
DHEA-S in turn can be converted back into DHEA in peripheral tissues via steroid sulfatase (STS).
The terminal half-life of DHEA is short at only 15 to 30 minutes.
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.
Pregnancy
During pregnancy, DHEA-S is
metabolism into the sulfates of 16α-hydroxy-DHEA and 15α-hydroxy-DHEA in the
fetus liver as intermediates in the production of the estrogens
estriol and
estetrol, respectively.
Levels
Prior to
puberty in humans, DHEA and DHEA-S levels elevate upon differentiation of the
zona reticularis of the
adrenal cortex.
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.
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.
Conversely, DHEA-S levels are an order of magnitude higher at 1–10 μM.
Levels of DHEA and DHEA-S decline to the lower nanomolar and micromolar ranges in men and women aged 60 to 80 years.
DHEA levels are as follows:
-
Adult men: 180–1250 ng/dL
-
Adult women: 130–980 ng/dL
-
Pregnant women: 135–810 ng/dL
-
Prepubertal children (<1 year): 26–585 ng/dL
-
Prepubertal children (1–5 years): 9–68 ng/dL
-
Prepubertal children (6–12 years): 11–186 ng/dL
-
Adolescent boys (Tanner II–III): 25–300 ng/dL
-
Adolescent girls (Tanner II–III): 69–605 ng/dL
-
Adolescent boys (Tanner IV–V): 100–400 ng/dL
-
Adolescent girls (Tanner IV–V): 165–690 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.
Chemistry
DHEA, also known as androst-5-en-3β-ol-17-one, is a
natural product androstane steroid and a 17-ketosteroid.
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).
DHEA is the 5-
dehydrogenation analogue of
epiandrosterone (5α-androstan-3β-ol-17-one) and is also known as 5-dehydroepiandrosterone or as δ
5-epiandrosterone.
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.
These isomers are also technically "DHEA", since they are dehydroepiandrosterones in which hydrogens are removed from the
epiandrosterone skeleton.
Dehydroandrosterone (DHA) is the 3α-epimer of DHEA and is also an endogenous androgen.
History
DHEA was first isolated from human
urine in 1934 by
Adolf Butenandt and Kurt Tscherning.
See also
Further reading
