Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 273280

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Journal of Steroid Biochemistry and Molecular Biology

journal homepage: www.elsevier.com/locate/jsbmb

Neurobiology of DHEA and effects on sexuality, mood and cognition

N. Pluchino a, , P. Drakopoulos a , F. Bianchi-Demicheli a , J.M. Wenger a , P. Petignat a ,
A.R. Genazzani b
a
Division of Gynecology and Obstetrics, University Hospital of Geneva, Geneva, Switzerland
b
Division of Gynecology and Obstetrics, University of Pisa, Pisa, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the most abundant steroid hormones
Received 27 February 2014 in the humans. However, their physiological signicance, their mechanisms of action and their possible
Received in revised form 14 April 2014 roles as treatment are not fully claried.
Accepted 20 April 2014
Biological actions of DHEA(S) in the brain involve neuroprotection, neurite growth, neurogenesis
Available online 2 June 2014
and neuronal survival, apoptosis, catecholamine synthesis and secretion, as well as anti-oxidant, anti-
inammatory and antiglucocorticoid effects. In addition, DHEA affects neurosteroidogenis and endorphin
Keywords:
synthesis/release. We also demonstrated in a model of ovariectomized rats that DHEA therapy increases
DHEA
DHEAS
proceptive behaviors, already after 1 week of treatment, affecting central function of sexual drive. In
Brain women, the analyses of clinical outcomes are far from being conclusive and many issues should still be
DHEA treatment addressed. Although DHEA preparations have been available in the market since the 1990s, there are
Sexual function very few denitive reports on the biological functions of this steroid. We demonstrate that 1 year DHEA
administration at the dose of 10 mg provided a signicant improvement in comparison with vitamin D in
sexual function and in frequency of sexual intercourse in early postmenopausal women. Among symp-
tomatic women, the spectrum of symptoms responding to DHEA requires further investigation, to dene
the type of sexual symptoms (e.g. decreased sexual function or hypoactive sexual desire disorder) and
the degree of mood/cognitive symptoms that could be responsive to hormonal treatment. In this regard,
our ndings are promising, although they need further exploration with a larger and more representative
sample size.
This article is part of a Special Issue entitled: Essential role of DHEA.
2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
2. DHEA(S) synthesis and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
2.1. DHEA as neurosteroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
3. Mechanisms of DHEA action in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
3.1. Action of DHEA on neurotransmitter release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
3.2. DHEA allopregnanolone and beta-endorphin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
4. Effect of DHEA on sexual function using an in vivo model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
5. DHEA level and measures of depression and anxiety disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
5.1. Anxiety spectrum disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
5.2. Effect of DHEA administration on depressive symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
6. Effect of DHEA on sexual fuction in women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
6.1. Effect of 1 year, low dose DHEA therapy on climacteric symptoms and female sexuality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
7. DHEA(S) and cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
8. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

Corresponding author at: Ob/Gyn Division, Boulevard de la Cluse 30, 1205 Geneva, Switzerland. Tel.: +41 795532341.
E-mail address: nicola.pluchino@hcuge.ch (N. Pluchino).

http://dx.doi.org/10.1016/j.jsbmb.2014.04.012
0960-0760/ 2014 Elsevier Ltd. All rights reserved.
274 N. Pluchino et al. / Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 273280
1. Introduction
The growth, differentiation, normal physiology and aging of
the central nervous system (CNS) are all now recognized to be
inuenced by gonadal steroid hormones. Dehydroepiandrosterone
(DHEA) and its sulfate ester, DHEAS, represent the most abundant
steroid hormones in the human body. However, their physiolog-
ical signicance, their mechanisms of action and their possible
roles in disease remains to be dened in different tissues. DHEA
and DHEAS concentrations in humans typically decrease steadily
with age, approaching a nadir at about the time many diseases
of aging become more prevalent. Observations such as these,
coupled with basic and preclinical demonstrations of DHEAs bio-
logical effects, fostered hope that restoring DHEA to youthful
levels might, conservatively, increase well-being and, optimisti-
cally, extend life, protect the brain, ameliorate sex function and
retard the ravages of aging, as recently reported by Maninger et al.
[1].
Though a large attention has been given to the study of post-
menopause and to the options in hormone replacement therapy
(HRT), relative attention and awareness has been focused on the
activity of endogenous or exogenous androgens in women. In fact
the middle age of women life is characterized by the coexistence
of menopause and adrenopause that sometimes both participate to
create an androgen-deciency syndrome. In these terms, the eld
of inquiry into the neurobiological actions of DHEA and DHEAS is
rapidly growing.
The aims of present article are (1) to review briey basic and pre-
clinical studies of DHEA(S) biological actions in the brain and their
supposed mechanisms of action, (2) to evaluate DHEA(S) specic
effects on brain function including sexual function in vivo, and (3)
the therapeutic potential of DHEA(S) in postmenopausal women
using measures of mood, sexuality and cognition.
2. DHEA(S) synthesis and metabolism
A detailed description of synthesis and secretion of DHEA and
DHEAS is beyond the scope of the present article and reviews have
recently been published [1]. However specic aspects of DHEA/S
synthesis, metabolism and action in the brain are described in the
present review.
Pregnenolone is converted into DHEA by the enzyme
cytochrome P450c17; this single enzyme catalyzes both the
17-hydroxylation reaction converting pregnenolone to 17-OH
pregnenolone and the 17,20-lyase reaction converting 17-OH preg-
nenolone to DHEA [2]. The sulfation of DHEA into its more stable
sulfate ester DHEAS is catalyzed by the enzyme hydroxysteroid
sulfotransferase (HST, SULT2A1), commonly known as DHEA sul-
fotransferase. DHEAS can be converted back into DHEA by steroid
sulfatase (STS). P450c17 is encoded by a single gene (cyp17) and
mutations can cause either 17-hydroxylase or 17,20-lyase de-
ciency or both [3]. In addition to its expression in human adrenals
and gonads, P450c17 is also expressed in the brain [4], where it
may synthesize DHEA from pregnenolone.
Adrenal secretion of DHEA and DHEAS increases during adrenar-
che in children at the age of 68 years. Maximal values of circulating
DHEAS are reached between the ages of 20 and 30 years. There-
after, serum DHEA and DHEA-S levels decrease markedly [5,6]. The
marked reduction in the formation of DHEAS by the adrenals during
aging results in a fall in the formation of androgens and estro-
gens in peripheral target tissues. Despite most animal models used
in the laboratory, where the secretion of sex steroids takes place
exclusively in the gonads with no signicant amount excreted by
adrenals [6], humans peripheral target tissues have the capacity to
transformate the adrenal precursor steroids DHEAS and DHEA into
androgens and/or estrogens [7].
Higher concentrations of DHEA are found in brain in compar-
ison with plasma values with a brain-to-plasma ratio of 6.5 [8].
In a study of 10 postmortem human brains, DHEA concentrations
were 29.4 nmol/kg in prefrontal lobe, 16.3 nmol/kg in parietal lobe,
13.1 nmol/kg in temporal cortex, 16.9 nmol/kg in cerebellum, and
18.7 nmol/kg in corpus callosum [9]. These data were derived from
nine women and one man (7693 years old), and it is worth not-
ing that large individual differences in DHEA brain concentrations
were observed.
Analyses of sulfated steroids also conrmed high concentrations
of DHEAS and pregnenolone sulfate in rodent and human brains
[10,11].
Humans and rodents differ in the pathways through which sex
steroids are synthesized. Whereas DHEAS is the most abundant cir-
culating steroid hormone in the human body [12], rats and mice
have low circulating concentrations of DHEA(S) in the periphery
[1316]. Brain DHEA in rat is derived from local synthesis and not
from peripheral synthesis. In humans, brain DHEA concentration is
the result of from both local synthesis and peripheral synthesis.
2.1. DHEA as neurosteroid
Although adrenal cortex is considered to be the primary source
of DHEAS in the brain, it was reported that DHEAS did not dis-
appear or decrease in the brain 15 days neither after orchiectomy,
adrenalectomy, or both, nor after the inhibition of adrenal secretion
by dexamethasone. DHEA and DHEAS were among the rst neuros-
teroids identied in rat brains. Cytochrome P450c17 was found in a
subset of neurons of embryonic rodent brains [17]. While P450c17
protein was readily detected in the brain, the abundance of P450c17
mRNA transcripts in the embryonic mouse brain [18] or hippocam-
pus of adult male rats was low, and was approximated to be 1/200th
of the expression in testis.
In addition DHEA can be synthesized in vivo in rat brains. Rat
brains were capable of converting pregnenolone into DHEA and
this may be activity-dependent [19]. Basal P450c17 steroidogenic
enzyme activity was low, but could be enhanced by expos-
ing neurons to N-methyl-d-aspartate (NMDA) [19]. In addition
immunohistochemical studies localized P450c17 in both neu-
ros and glial cells in the spinal rat cord, showing evidence that
the spinal cord tissue is another region of CNS that express
P450c17. Frog brains also were found to synthesize DHEA from
pregnenolone, and this enzymatic activity was reduced in a
concentration-dependent manner by ketoconazole, an inhibitor of
P450c17 [20].
DHEAS may be synthesized in the brain from DHEA [21]. Sulfa-
tion of DHEA has been observed in the brains of rhesus monkeys
in vivo and in human fetal brain slices in vitro [21]. DHEA sulfo-
transferase (HST or SULT2A1) is an enzyme that sulfonates DHEA (in
addition to pregnenolone) [22,23]. Western blotting and immuno-
histochemistry showed protein expression of an HST in adult
Wistar rat brain [3]. In addition SULT2A1 mRNA expression has
been shown in rat brains.
DHEAS is predominately transported out of the brain across the
bloodbrain barrier and DHEAS found in the brain is most likely
due to local synthesis [1,24,25].
3. Mechanisms of DHEA action in the brain
The mechanisms by which DHEA(S) operate his action are not
fully understood [25]. DHEA(S) may mediate some of its actions
through conversion into more potent sex steroids and activa-
tion of androgen or estrogen receptors in tissue (i.e. skin, bone,
 N. Pluchino et al. / Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 273280
fat, liver, brain) [26]. In addition DHEA(S) may also have effects
through its more immediate metabolites, such as 7-hydroxy-
DHEA [27]. Additional actions of actions of DHEA(S) in the human
brain can be further classied to presynaptic and postsynaptic.
Indeed, DHEA(S) modulates actions of the -aminobutyric acid type
A (GABAA) receptor, the NMDA receptor, and the sigma subtype 1
(1) receptor [2833] among others [3436]. The GABAA recep-
tor is the principal inhibitory neurotransmitter receptor in the
brain. This ligand-gated ion channel is a hetero-oligomeric pro-
tein that can be activated by agonists, increasing Cl inux into
the cell. DHEA(S) act by diminishing the amplitudes of inhibitory
postsynaptic currents and shortening their decay time constants
in a concentration-dependent manner [37]. DHEA and DHEAS gen-
erally act as noncompetitive antagonists at the GABAA receptor,
with DHEAS having more potent antagonistic effects than DHEA
[38,39]. However, Melchior and Ritzmann [40] also reported that
DHEAS might have agonistic effect on the GABAA receptor under
certain circumstances. Based on this possible effect it was demon-
strated that DHEAS may be neuroprotective in a reversible ischemia
model of male New Zealand White rabbits if administered early
during the ischemic event, suggesting that DHEAS might modu-
late the function of a neurotransmitter [41]. DHEA(S) generally acts
as a positive allosteric modulator of the NMDA receptor, although
the binding of DHEA(S) with an interaction site on the NMDA
receptor is not well documented [28,31]. Chen et al. [42] pro-
vided evidence that chronically administered DHEAS might play
a priming role in frequency-dependent long-term potentiation
(LTP) induction in the rat hippocampal CA1 region. They identi-
ed that the putative potentiation of NMDA receptor by DHEAS
may depend on Src activation because PP2, a selective Src inhibitor,
abolished the potentiated NMDA-induced [Ca2+] increase. In
addition evidence suggests that DHEA(S) can potentiate NMDA
receptor function and the NMDA evoked release of (3H) nore-
pinephrine through its action as 1 receptor agonist [30,43]. Sigma
1 receptor is widely expressed in both neurons and oligoden-
drocytes in the CNS and is enriched in the prefrontal cortex,
hippocampus and striatum, where it functions to regulate ion
channel activity and neurotransmitter release [44]. In particu-
lar, 1 receptor stimulation induces increases in extracellular
acetylcholine levels, promotes calcium transport through NDMA
receptor and enhances glutamase presynaptic release in the hip-
pocampus and prelimbic cortex [45]. DHEA(S), as 1 receptor
agonist, promotes these actions which are responsible for changes
in synaptic plasticity of the molecular mechanism underlying cog-
nitive/behavioral functions and different neurological diseases.
Apart from the interaction with the 1 receptor, the interaction of
DHEA(S) with the GABAA and NMDA receptors has also been pos-
tulated as an underlying mechanism for the cognitive-enhancing
effects of DHEA(S) [46]. Additional intracellular sites where DHEA
may act have also been described. DHEA may interact directly with
certain cytoskeleton components or novel membrane receptors
[47]. Intriguing leads are emerging for possible DHEA receptor sites
in the periphery that may also exist in the central nervous system
[4850,25].
3.1. Action of DHEA on neurotransmitter release
Neurobiological action of DHEA on neurotransmitters involve
directly DHEAS, DHEA and its more immediate metabolites (e.g.
7-hydroxy-DHEA) in the brain but they are also due to conversion
of DHEA(S) into sex steroids estradiol (E2), testosterone, dihy-
drotestosterone (DHT), 3-diol, 3-diol. Neurobiological actions
of E2 and testosterone are well established [5154], but less
characterized are the function attributable directly to DHEA and
DHEAS. DHEAS has been showed to modulate a variety of synap-
tic transmission, including cholinergic, GABAergic, dopaminergic
275
and glutamatergic transmission. The effect of DHEAS on presynap-
tic glutamate release has received a great deal of attention because
glutamate is the most important excitatory neurotransmitter in the
brain and plays a vital role in mediating a variety of brain functions
and brain diseases. In addition, the effects of DHEAS on hippocam-
pal ACh release were investigated in rats using in vivo microdialysis
[7]. The results showed that peripheral administration of DHEAS
enhanced hippocampal ACh release in vivo, and that this enhance-
ment occurred in a dose-dependent manner. Similarly, DHEAS also
inuenced dopamnine (DA) release. DHEAS produced a 10-fold and
16-fold increase in DA release in the hypothalamic cells, respec-
tively. DHEAS could also signicantly increase DA release of PC-12
cells via a fast nongenomic mechanism, docking initially at the
plasma membrane [55]. Major neurobiological actions of DHEA(S)
involve neuroprotection, neurite growth, neurogenesis and neu-
ronal survival, apoptosis, as well as anti-oxidant, anti-inammatory
and anti-glucocorticoid effects. In addition, DHEA affects neuros-
teroidogenis and endorphin synthesis/release.
3.2. DHEA allopregnanolone and beta-endorphin
Allopregnanolone is a 3-, 5- reduced metabolite of proges-
terone [56], and its major sources are the gonads and adrenal cortex,
and, to a lesser extent, the CNS [56]. Allopregnanolone acts as an
agonist of GABAA receptor, modulating stress, mood, and behav-
ior. Gonadal steroids may modulate allopregnanolone levels, as
suggested by several experimental studies on animal models. In
fact, overiectomized (ovx) female rats present increased adrenal
allopregnanolone content and reduction in allopregnanolone lev-
els in brain and serum; this may be due to an estrogen-mediated
enzymatic induction in the synthesis of allopregnanolone [5658].
Beta-endorphin (-EP) is the most important and biologically
active endogenous opioid peptide; it has behavioral, analgesic,
thermoregulatory, and neuroendocrine properties. A decrease in
central and peripheral -EP levels in ovx rats and in circulating
-EP levels in postmenopausal women has been shown [59].
DHEA administration induces an increase in -EP content in
anterior and neurointermediate pituitary and hippocampus in a
dose-dependent manner. High-dose DHEA administration induces
an increase in -EP circulating levels to those observed in fer-
tile animals and an even greater increase in the hypothalamus.
In addition, DHEA administration induces an increase in allopreg-
nanolone content in the hypothalamus, anterior pituitary, serum,
and hippocampus, where DHEA administration restores allopreg-
nanolone levels to those observed in fertile rats. Brain infusion of
allopregnanolone showed positive effect on all aspects of socio-
sexual activities, enhancing exploratory, anti-anxiety and social
function [60]. The mechanisms of action of DHEA on neurosteroige-
nesis are not clear. Present data seem to indicate that the effect
of DHEA administration may not be entirely ascribed to the con-
version in estrogenic metabolites. In fact, the E2 levels reached in
DHEA-treated ovx animals were not signicantly different from
those observed in untreated ovx animals and were signicantly
lower than those obtained in ovx animals in response to E2 valerate
administration [60].
4. Effect of DHEA on sexual function using an in vivo model
The eld of behavioral pharmacology is showing an increasing
interest in female rat sexual behavior as a model for evaluating
drug actions and steroid interference. Endogenous sex steroids
modify female sexual behavior in rats. They inuence the neu-
robiology of sexual function, acting directly on their receptors at
nuclear and membrane level or indirectly throughout their effects
on neuropeptides (oxytocin, beta-endorphin), neurotransmitters
276 N. Pluchino et al. / Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 273280
(dopamine, serotonin) and neurosteroid metabolism (mainly allo-
pregnanolone) [61,62].
Sexual behavior in the female rat is characterized by both recep-
tive and proceptive behaviors [63]. Receptive behavior consists in
a reexive posture, called lordosis, which represents the female
readiness to allow copulation [63]. Proceptive behaviors, including
hops, darts and ear-wigglings, are exhibited by a sexually receptive
female to arouse male sexual interest [64].
We evaluated the inuence of DHEA administration on recep-
tive and proceptive components of female rat sexual behavior and
whether the co-administration of estrogens might enhance sexual
response in a model of ovx rats, using different behavioral tests [65].
In addition, we evaluated the effects of DHEA and co-administration
of DHEA with estradiol benzoate (EB) on allopregnanolone, -EP
and circulating hormonal levels. Results of this study conrmed
that chronic treatment (6 weeks) of ovx rats with DHEA only at
the dose of 5 mg/kg increases allopregnanolone and -EP content
in different brain areas and in plasma when compared with avail-
able reference values of ovx rats [8]. Similarly, circulating hormonal
changes after treatment with DHEA resulted in physiological dose-
related increase of plasma E2, within the available range values of
fertile animals [8]. In addition co-administration of EB and DHEA
showed a synergic effect on brain neurosteroidogenesis and opi-
oid content compared to single treatments. Beta-endorphin infused
into the medial pre-optic area affects mounting and intromission
of female rats in dose-dependent way [66]. In animals receiving the
conditioning treatment with EB, DHEA therapy amplied measures
of sexual motivation. On the contrary, the increase of circulation
testosterone levels in rats receiving only DHEA did not induce any
signicant changes in sexual behavior.
In conclusion, it can be assumed that chronic treatment
with DHEA might enhance or balance the biological response
of certain brain circuits to the acute administration of EB, with
neurochemical, hormonal and behavioral consequences, especially
for sexual function. DHEA treatment seems to affect mainly sexual
motivation during behavioral tests.
5. DHEA level and measures of depression and anxiety
disorders
According to existing assumption of the biology of depression,
DHEA(S) ability to modulate many neurobiological actions could
underlie relationships between endogenous and/or exogenously-
supplemented DHEA(S) concentrations and depression. There is
evidence that DHEAS concentrations are negatively correlated with
ratings of depressed mood [67]. However, the remaining literature
examining plasma and serum DHEA(S) concentrations in depres-
sion is still inconsistent and other plasma indexes were studied
in order to more accurately discriminate depressed from nonde-
pressed individuals. Hypothalamicpituitaryadrenal axis (HPA)
hyperactivity has been demonstrated in chronic diseases affecting
nervous system disorders like depression [68]. The end products
of HPA axis, glucocorticoids (GCs), regulate many physiological
functions and play an important role in affective regulation and
dysregulation. Despite DHEAS levels which markedly decrease
throughout adulthood, an increase in circulating cortisol with
advanced age has been observed in human and nonhuman primates
[69].
In addition, unlike DHEA(S) concentrations that decline under
conditions of chronic stress and medical illness, cortisol concen-
trations generally either rise or do not change, and subsequently
result in a decrease in DHEA(S)-to-cortisol ratios [7073]. There-
fore, it may be important to consider the ratio of both steroids in
addition to their absolute concentrations. The resulting decrease in
the DHEA: cortisol ratio may have drastic implications for many
physiological processes, including learning and memory, a view
that is supported by the nding that lower DHEA: cortisol ratios are
associated with greater cognitive impairment [74]. Several stud-
ies have found that morning DHEAS-to-cortisol ratio in serum
and saliva is lower in depressed patients and that patients who
remained depressed several months after the initial assessment
had lower salivary DHEA-to-cortisol ratios at baseline [8]. However,
the relationship between DHEA(S) concentrations and depression
is complex. It has been recently reported that repeated DHEA treat-
ments ameliorate cognitive decits and depressive like behaviors
in bulbectomized mice by enhancing neurogenesis via activation of
1 receptor in the hippocampus [75,76].
5.1. Anxiety spectrum disorders
The anxiety disorder that has received the greatest attention
with regard to plasma, serum, and salivary DHEA(S) concentrations
is post-traumatic stress disorder (PTSD). Studies have uniformly
identied elevated DHEA and/or DHEAS concentrations in PTSD, as
well as increases in the DHEA(S)-to-cortisol ratio. Despite the uni-
formity of studies showing elevations in DHEA or DHEAS in PTSD
and under conditions of stress, researchers have suggested that
the increase in DHEA(S) is rather than pathophysiologic and that
DHEA(S) may play a role in resilience and in successful adaptation to
stress [7779]. In fact, the peak change in plasma DHEA (in response
to ACTH stimulation) is negatively correlated with PTSD symptoms,
suggesting that increased capacity of adrenal DHEA release may
mitigate the severity of PTSD symptoms.
Many, but not all, studies have reported lowered serum con-
centrations of DHEA(S) in patients with poor life satisfaction,
psychosocial stress and functional limitations [80].
Higher plasma and serum concentrations of DHEAS have also
been associated with greater amount, frequency, and enjoyment
of leisure activities and healthier psychological proles. However
most of these studies examined concentrations of DHEAS rather
than DHEA, and many assessed female rather than male popu-
lations, so the generalizability of these ndings is uncertain. A
recent small randomized control trial examined salivary cortisol
and DHEA concentrations in adolescents suffering from anorexia
nervosa [81]. Adolescents with anorexia nervosa had greater con-
centrations of these hormones than the healthy group, conrming
the hypothesis that hyperactivity of HPA axis is associated with this
serious and complex condition.
5.2. Effect of DHEA administration on depressive symptoms
Although clinical trials of DHEA treatment for depression are
few in number, they consistently suggest benecial effects. Two
small randomized control trials showed that DHEA used alone or
as an antidepressant adjunct in refractory depressed patients, has
signicant antidepressant effects (as shown by improvements in
Hamilton Depression Ratings and Symptom Checklist-90 ratings)
in some of them [82,83]. Although baseline serum DHEA concentra-
tions did not predict antidepressant response, responders to DHEA
in both studies achieved higher serum DHEA concentrations follow-
ing treatment and antidepressant effects were directly correlated
with changes in serum DHEA concentrations. In addition the psy-
chological symptoms of depression improved in both studies to a
greater extent than the neurovegetative symptoms (e.g. sleep and
appetite disturbances). These results concerning the DHEA as effec-
tive antidepressant were conrmed later by Schimdt et al. [84].
Bulbectomized mice which serve as animal model of depressive
like behaviors, exhibit down-regulation of the cholinergic system
marked by decreased choline acetyltransferase levels in cortex,
hippocampus and amygdala and decreased acetylcholinesterase
levels in the hippocampus [85]. Depressive like behaviors are
 N. Pluchino et al. / Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 273280
also associated with impaired neurogenesis in the subgranular
zone of the hippocampal dentate gyrus. The implication of the
1 receptor in depressive behaviors was recently revealed, as 1
receptor knockout mice reportedly display depressive-like behav-
iors when subjected to a forced swim test [86]. In addition several
antipsychotic drugs, as well as antidepressant drugs, such as u-
voxamine, have high afnity for the 1 receptor. As mentioned
above, DHEA acts as 1 receptor agonist and promotes cholinergic
neuronal activity and neuronal proliferation in the CNS. Chronic
DHEA treatment at 30 or 60 mg/kg per os for 14 days was found
to ameliorate depressive like behaviors, by enhancing hippocam-
pal neurogenesis in these mice [76]. Although these data are
encouraging, more large-scale studies will be required to estab-
lish the place, if any, of DHEA in the management of patients with
depression. Moreover, more trials are needed comparing DHEA
to standard antidepressants. The risks and benets of long-term
DHEA administration, as also the appropriate dose remain to be
further claried. More evidence is expected after administration
of 7-keto DHEA alone or in combination with other psychiatric
drugs.
6. Effect of DHEA on sexual fuction in women
Aging and menopausal transition may in themselves impair the
integrity of multiple biological systems involved in the normal sex-
ual response. Relationships between androgens and sexual function
were investigated in a cross-sectional study of 1423 nonhealth
care-seeking women, aged 1875 years old [87]. Androstenedione
and total and free testosterone were not related to sexual function
scores. However, women aged 45 years or more with low sexual
responsiveness had a greater likelihood of having a serum DHEAS
value below the 10th centile for their age (odds ratio (OR), 3.9;
95% condence interval (CI), 1.549.81; P 0.004). For women aged
1844 years, having low sexual desire, sexual arousal, or sexual
responsiveness was also associated with having a DHEAS value
below the 10th percentile for their age. Nevertheless, a cut-off level
below which women can be said to be more likely to have low sex-
ual function cannot be identied, as the normal range for serum
DHEAS among young women is relatively large and a signicant
proportion of women with low DHEAS do not have low sexual
function.
It has then been proposed that treatment of postmenopausal
women with DHEA will result in androgenic effects and hence
improve libido and well-being via its conversion to testosterone
and estrogenic effects resulting in improvements in menopausal
vasomotor symptoms. DHEA has been administered orally and
parenterally, either by the transdermal or vaginal route. When
administered to postmenopausal women, DHEA is mainly trans-
formed to androgens rather than estrogens. Oral administration of
DHEA for 12 months resulted in 4- to 5-fold increase in serum 3-
diol,3G, 3-diol,17G and ADT-G, where total T levels increased by
about 100% and serum DHT rested relatively unchanged [88]. How-
ever transdermal DHEA resulted in signicant lower increase of
androgen levels, since the mode of administration of DHEA inu-
ence its metabolism [89].
Although the prevalence, incidence, and antecedents of female
sexual dysfunction remain under-researched, the most commonly
reported sexual problems in women is related to sexual desire
and interest, pleasure, and global satisfaction. To date, there are
eight published randomized trials of oral and vaginal DHEA treat-
ment for low sexual function in healthy, postmenopausal women
[8897]. Some of the studies demonstrated a positive effect of DHEA
treatment on sexual function whereas others did not show any
benets. Labrie et al. [93] used intravaginal DHEA and a clear posi-
tive effect was shown. However, early studies in which DHEA was
277
ineffective were also limited by small sample size, short treatment
duration, use of nonvalidated instruments, or supraphysiological
doses. Overall, the evidence from published RCT does not support
efcacy of systemic DHEA therapy for the treatment of female sex-
ual dysfunction. However, vaginal application of DHEA may benet
postmenopausal women with vaginal atrophy experiencing dys-
pareunia.
6.1. Effect of 1 year, low dose DHEA therapy on climacteric
symptoms and female sexuality
As cited above, the effects of DHEA therapy on sexual function
in postmenopausal women are controversial and there is still no
conclusive evidence for its clinical use. On this basis, we aimed to
evaluate the effects exerted by 1-year, low-dose oral DHEA ther-
apy (10 mg/day) in symptomatic healthy postmenopausal women
on measures of sexual function and on hormonal changes in com-
parison with other three active treatments: daily oral continuous
combined treatment with 1 mg micronized E2 plus 5 mg dydroges-
terone (HRT) or oral tibolone (2.5 mg/day) or vitamin D/calcium
carbonate [98]. Validated tools (self-administered questionnaires)
were used to properly diagnose sexual symptoms affecting desire,
arousal, orgasm, sexual pain and to gain information on any sexual
relationship. Our study showed evidence that symptomatic, early
postmenopausal women receiving 1-year oral DHEA therapy at a
daily dose of 10 mg improved their climacteric symptoms. The mag-
nitude of this effect seems to be similar to the effect in women
receiving 1-year therapy with tibolone or HRT. In addition, all hor-
mone treatments used (DHEA, HRT and tibolone) improved quality
of sexual life in postmenopausal women. DHEA supplementation
for 1 year enhanced plasma levels of estradiol and progesterone,
it modied adrenal synthesis of cortisol (reduction) and allo-
pregnanolone (increase) and it increased plasma concentration of
-endorphin. The different impact of DHEA, in comparison with
tibolone and HRT, on the androgenic circulating prole is also con-
rmed in the present study in which DHEA increased plasma 5
and 4 androgens levels, whereas HRT or tibolone did not induce
any changes. The benecial effects of DHEA on sexual function
might be, at least in part, the direct consequence of this concomitant
increase of estrogens, androgens and progesterone in symptomatic
postmenopausal women. Indeed, sex steroids (estrogens, andro-
gens and progesterone) positively affect critical aspects of sexual
function in the central nervous system and, peripherally, in the
genital tract.
7. DHEA(S) and cognition
The response of HPA axis to stress with age becomes less
resilient and less sensitive to the negative feedback signals of GCs.
As consequence, the altered HPA axis as part of multiple hor-
monal dysregulation occurring with age, may exert an important
role of the development of cognitive impairment in the elderly.
If age seems to be the most relevant pathogenic factor for the
altered HPA sensitivity toward steroid inhibition, the occurrence of
neurodegenerative cognitive impairment could play an additional
role leading to a vicious cycle HPA axis hyperactivation-cognitive
impairment. DHEA and DHEAS production dramatically decrease
with aging, and during the eighth decade is only 1020% of the max-
imal value usually recorded at 30 years. The imbalance between
glucocorticoid and androgen secretions may be caused by the
age-related selective impairment of the zona reticularis of the
adrenal cortex, the sole source of DHEA and DHEAS. It has been
proposed that approximately 20% of circulating DHEA in post-
menopausal women is of ovarian origin and 80% from the adrenals
[99].
278 N. Pluchino et al. / Journal of Steroid Biochemistry & Molecular Biology 145 (2015) 273280
Low DHEA and DHEAS levels in older adults may make these
subjects more vulnerable to the damaging effects of cortisol. This
evidence, coupled with DHEA effects on cholinergic neurotransmis-
sion and post-synaptic receptors, have stimulated clinical research
in healthy individuals as well as in patients with dementia [100].
Recent studies evidenced that higher endogenous DHEAS levels are
associated with better cognitive ability in women. Susan R. Davis
by using a cross-sectional design showed that women with higher
circulating levels of DHEAS exhibit better performance in terms
of executive function, concentration, and working memory [101].
In another study based on the InCHIANTI Study, Valenti showed
a signicant and positive association between DHEAS and cogni-
tive function, assessed by MMSE test, independently of age and
other potential confounders. Moreover, low DHEAS levels predict
accelerated decline in MMSE score during the 3-year follow-up
period [102]. More recently lower DHEAS levels were associated
with incident frailty in older men and with fatal and nonfatal frailty-
related adverse outcomes in older women [103]. However, results
from interventional studies are far to be conclusive and most of
the clinical studies with DHEA supplementation failed to provide
convincing evidence supporting clear neuroactive effect of DHEA.
However, to date, there are only eight studies available investi-
gating the role of DHEA on measure of cognition and memory.
Unfortunately they differ in the age of patients enrolled, dose and
duration of treatment and cognitive measures analyzed [104].
8. Conclusions and perspectives
Over the past 10 years, hormone preparations of dehy-
droepiandrosterone (DHEA) have been available over the counter
and have been sold as the fountain of youth. This has raised con-
cerns about the real clinical efcacy and the possible effects of such
uncontrolled and widespread hormonal self-administration and
the lack of quality control in this increasingly nancially reward-
ing business. Upcoming experimental and clinical studies renew
the attention and the debate on one of the most attractive and
controversial issues in the physiology of the aging process that is
still far from being clearly dened by the scientic community. The
most relevant aspect meriting attention is certainly the controver-
sial nding among the studies that investigate the correlation of
the endogenous DHEA sulfate (DHEAS) level, the aging process or
organ illness with the results coming from studies focusing on the
effects of exogenous DHEAS administration on brain function, sex-
uality, cardiovascular health and metabolic syndrome. Indeed, the
marked age-related decline in serum DHEA and DHEAS has sug-
gested that a deciency of these steroids may be causally related
to the development of a series of diseases that are generally associ-
ated with aging. The postulated consequences of low DHEA levels
include insulin resistance, obesity, cardiovascular disease, cancer,
reduction of the immune defense system as well as psychosocial
problems such as depression and a general deterioration in the sen-
sation of well-being and cognitive function, DHEA replacement may
seem an attractive treatment opportunity. Nevertheless, the anal-
yses of clinical outcomes are far from being conclusive and many
issues should still be addressed. Although DHEA preparations have
been available in the market since the 1990s, there are very few
denitive reports on the biological functions of this steroid, and it
is still the case that its regulation is unclear and its mechanisms of
action remains to be dened in different tissues.
Although there is still debate on DHEA receptors, these ndings
corroborate the evidence that DHEA is not just a pre-hormone of
the adrenals, but rather a hormone in its own right, and that it mod-
ulates a series of biological processes, with a remarkable tropism
for the central nervous system. Clinically, the spectrum of women
that would benet from DHEA therapy is not clearly dened and
nor is the dosage of hormone treatment. Whether DHEA therapy
could be prescribed as a general anti-aging therapy or could be
an alternative treatment for women suffering from androgen de-
ciency syndrome remains uncertain across studies. In particular,
among symptomatic women, the spectrum of symptoms respond-
ing to DHEA requires further investigation, to dene the type of
sexual symptoms (e.g. decreased sexual function or hypoactive sex-
ual desire disorder) and the degree of mood/cognitive symptoms
that could be responsive to hormonal treatment. Similarly, the def-
inition of criteria for the choice of the starting dosage of DHEA to be
prescribed in postmenopausal women needs further investigation:
the extent of the symptoms, baseline DHEA(S) plasma levels, con-
comitant estrogen therapy or the combination of all the previous
should be considered.
Plasma DHEA(S) levels at baseline and during treatment merit
attention given that a cut-off value for DHEA(S) deciency is not
yet dened and the plasma level might not represent the rate of
tissue conversion into estrogens or delta-4 androgens. This fact is
also coupled with the route of administration of DHEA, given that
oral, vaginal and parenteral administrations seem to induce dif-
ferent steroid concentrations in the plasma, with different clinical
consequences and applications. All these ndings may have far-
reaching implications in the debate about the role of DHEA(S) in the
female aging process and might reconcile discordant ndings from
basic science and clinical studies. The lack of denitive evidence for
biological mechanisms and the presence of only a few studies that
address these emerging issues of DHEA therapy in postmenopausal
women might encourage a new critical analysis of the available lit-
erature, evidencing current limits and incongruities. Concurrently,
new clinical trials, specically planned to relate to the biology
of symptomatic postmenopausal women and designed for the
translation of basic science into clinical practice, are now a required
step to move forward the scientic debate on DHEA.
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