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INTRODUCTION
Dehydroepiandrosterone (DHEA) is a steroid prohor-
mone. By the age of 70 to 80 years, levels may be as low
as 10% to 20% of those encountered in young individu-
als [1,2]. The mechanism underlying this physiological
decline is unknown. However, this age-related decline
in DHEA levels may correlate with many age-related
phenomena or deterioration in various physiological
functions. Particularly, aging; neurological functions
including decreased well-being, cognition, and memory;
increased depression; aggressiveness; and dementia
have involved changes in body composition, decreased
bone mineral density, obesity, diabetes, increased car-
diovascular morbidity, erectile dysfunction (ED), and
decreased libido [3,4]. Supporting this result, some trials
of DHEA supplementation in healthy, middle-aged, and
elderly subjects have reported improvements in differ-
ent aspects of well-being [5].
Consistently, in our previous study we have dem-
onstrated age-related decline in testosterone level
throughout 4 years of follow-up in patients with ED.
Patients with decreasing testosterone levels were
older than patients with a steady testosterone level [6].
Received: Jan 16, 2018 Revised: Feb 24, 2018 Accepted: Feb 26, 2018 Published online May 11, 2018
Correspondence to: Ahmed I. El-Sakka https://orcid.org/0000-0001-8671-5952
Department of Urology, Faculty of Medicine, Suez Canal University, Round Road, 41111, Ismailia, Egypt.
Tel: +20-122-3456364, Fax: +20-64-3200035, E-mail: aielsakka@yahoo.com
Copyright © 2018 Korean Society for Sexual Medicine and Andrology
Review Article
pISSN: 2287-4208 / eISSN: 2287-4690
World J Mens Health Published online May 11, 2018
https://doi.org/10.5534/wjmh.180005
Dehydroepiandrosterone and Erectile Function:
A Review
Ahmed I. El-Sakka
Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
To review the contemporary knowledge regarding the dehydroepiandrosterone and erectile function. Medline was reviewed
for English-language journal articles spanning the time between January 1990 and December 2017, using the terms ‘erectile
function’, ‘dehydroepiandrosterone’. We used original articles and review articles that found to be relevant to the purpose of
this review. Criteria included all pertinent review articles, randomized controlled trials with tight methodological design, co-
hort studies and retrospective analyses. We also manually revised references from selected articles. Several interesting studies
have addressed the age-related decline in dehydroepiandrosterone levels with many age-related phenomena or deterioration
in various physiological functions. Particularly, aging; neurological functions including decreased well-being, cognition, and
memory; increased depression, decreased bone mineral density, obesity, diabetes, increased cardiovascular morbidity, erec-
tile dysfunction (ED), and decreased libido. Supporting this result, some trials of dehydroepiandrosterone supplementation in
healthy, middle-aged, and elderly subjects have reported improvements in different aspects of well-being. Several studies had
demonstrated that dehydroepiandrosterone level is declined as a part of aging. Large-scale well-designed prospective studies
are warranted to better define indications and therapeutic implications of dehydroepiandrosterone in men with ED.
Keywords: Androgens; Dehydroepiandrosterone; Erectile dysfunction; Testosterone
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
https://doi.org/10.5534/wjmh.180005
2www.wjmh.org
Therefore, this steady decrease in circulating DHEA
concentrations with age might initiate the speculation
that DHEA therapy have potential benefits in several
diseases associated with aging.
Recent analyses for the association between age and
ED revealed positive effects for testosterone, DHEA,
perceived general health, emotional support, intimacy
motivation, and a negative eff ect f or interleukin-6 (IL-6)
(all p<0.05). Higher testosterone and DHEA and lower
IL-6 levels buff ered against an age-related increase
in ED [7]. Furthermore, an interesting study demon-
strated that men who work nonstandard shif ts and
have poor sleep quality are at increased risk f or hypo-
gonadal symptoms and sexual dysfunction however,
no associations between sleep quality and mean serum
testosterone, free testosterone, estrogen, DHEA, follicle
stimulating hormone, and luteinizing hormome levels
were observed [8].
BIOCHEMISTRY OF
DEHYDROEPIANDROSTERONE
DHEA is a steroid prohormone synthesized in the
zona reticularis of the adrenal cortex, the gonads, adi-
pose tissue, brain, and skin. In target tissue, DHEA
transf ormed through intracrine mechanisms to andro-
gens or estrogens. The secretion of DHEA follows a di-
urnal pattern like that of cortisol. While in women ad-
renal prod uction of DHEA and DHEA sulf ate (DHE AS)
contributes substantially to overall androgen produc-
tion, in men the adrenal contribution is very small [1,2].
Together DHEA and DHEAS are the most abundant
steroid in humans. The highest concentrations of these
steroids are observed in men in the second and third
decades of age, and gradually decrease by approxi-
mately 10% per decade [1].
DHEAS exists at approximately 250 times higher
than those of free DHEA in serum. In target tissues
such as the brain, bone, breast, and adipose, DHEAS
is converted to DHEA by the sulfatase enzyme, which
may then be f urther metabolized to androstenediol,
androstenedione, estrone, testosterone, dihydrotestos-
te r o ne, an d 17β-estradiol [9-11]. Meanwhile DHEA is a
prohormone, it is claimed to have several positive ef-
fects on age-related disorders. It would be theoretically
transformed according to local and general hormone
needs.
EFFECT OF
DEHYDROEPIANDROSTERONE
ON ENDOTHELIAL AND SMOOTH
MUSCLES FUNCTION
DHEA is involved in vascular smooth muscle relax-
ation. Furthermore, the general and sexual effects are
not due to the actions of DHEA alone but due to its
function as a precursor of multiple androgens, espe-
cially testosterone and estradiol as well [9,10].
Endothelial dysfunction contributes to the patho-
genesis of atherosclerosis and cardiovascular disease
and leads to the development of insulin resistance.
Since DHEA has its own receptors, primarily on endo-
thelial cells its administration has been shown to im-
prove flow-mediated dilation of the brachial artery, an
endothelium-dependent process; reduced plasminogen
activator inhibitor type 1, a suppressor of fibrinolysis
with a pathogenic role in coronary artery disease; and
improved insulin sensitivity [12]. The improvement of
endothelial function with DHEA was subsequently
confirmed in postmenopausal women [13]. Several in vitr o
experiments have confirmed the anti-atherosclerotic
actions of DHEA [13,14].
These data support the action of DHEA on the endo-
thelium, based on the rapidity of action on endothelial
nitric oxide synthase (eNOS) and failure to block endo-
thelial cell activation with selective estrogen or testos-
terone receptor antagonists [13,14]. The roles of DHEA
in vascular endothelial cell survival [15,16], prolifera-
tion/angiogenesis, and activation, including transcrip-
tional regulation of endothelin-1 were demonstrated
[17]. Although a convincing evidence from in vitro
studies for vasculoprotective effects of DHEA, human
clinical trials of DHEA replacement on metabolic and
vascular function have shown contradictory results.
Epidemiological data in men have demonstrated either
an inverse or no relationship between cardiovascular
mortality and circulating DHEAS levels [18,19].
A specif ic DHEA receptor was identified on bovine
aortic endothelial cells [20]. This receptor is primarily
coupled to Ga12 and Ga13 subtypes of the G protein
family which activates eNOS. Further study had dem-
onstrated the existence of a DHEA-specific receptor in
human vascular smooth muscle cells (VSMC) involving
ERK1 signaling pathways that contributes to remodel-
ing of blood vessels and initiation of atherosclerosis [21].
I n vitro study DHEA also inhibits VSMC proliferation
Ahmed I. El-Sakka: Dehydroepiandrosterone and Erectile Function
3
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through a mechanism independent of its transf orma-
tion into estrogens or androgens and shows minimal
affinity for estrogen and androgen receptors f ound in
VSMC cells, but binds specif ically to putative recep-
tors in the same cells. Although consistent with the
mechanism of action through conversion into testos-
terone and estradiol, these findings will enlighten our
interpretations of the biological actions of DHEA and
the control of sexual f unction, which involves many
vascular mechanisms.
DEHYDROEPIANDROSTERONE AND
NITRIC OXIDE PATHWAY
DHEA is shown to activate potassium channels
via soluble guanylate cyclase activation and enhance
endo thelial function through increased nitric oxide
(NO) synthesis and ultimately dilate arteries, block
hypoxia-induced vasoconstriction [14,22]. Through a
plasma membrane initiated mechanism, DHEA acutely
increase NO release from intact vascular endothelial
cells [23]. The decrease in cytosolic NOS enzyme activ-
ity and penile NOS is not af f ected by adrenalectomy
in castrated rats [24]. Adrenalectomy combined with
castration significantly reduced penile neuronatal NOS
(nNOS) content, in contrast to what was found with
castration or total ablation of androgen binding in the
penis [25], where NOS activity appeared to be inhibited
in the presence of constant NOS levels. The cause of
this reduction in penile nNOS content is unknown. It
may be related to a loss of nerve terminals or a true
NOS downregulation [26]. However, penile eNOS con-
tent remains unaffected af ter 1 week. The rat adrenal
gland contributes to the maintenance of the erectile
mechanism and may affect nNOS content in the rat
pen is [27 ].
In pulmonary artery tissue from DHEA-treated rats,
soluble guanylate cyclase, but not eNOS, levels were
increased [28]. However, in other experiments, DHEA /
DHEAS did not af f ect relaxation induced by acetylcho-
line or sodium nitroprusside, and relaxation responses
were not changed by treatment with methylene blue
[29 ]. N e v e r t h e less, in vitr o studies supporting proper in-
trinsic functions have shown that DHEA may directly
increase NO production from intact endothelial cells,
probably through G protein-dependent activation of
endothelial NO synthetase [23].
DEHYDROEPIANDROSTERONE AND
ERECTILE DYSFUNCTION
DHEA plays an important role in sexual function.
Low levels of DHEA were associated with a higher risk
for ED in men [30,31] and low sexual responsiveness
in women [32]. It has also been speculated that DHEA
plays a role in the process of erection. The Massachu-
setts Male Aging Study investigated 17 hormones, and
DHEAS was the only one inversely correlated to ED
prevalence [31]. This data was later confirmed by an-
other study, which demonstrated that DHEAS levels
were signif icantly lower in men with ED in comparison
to age-matched normal controls [33]. The same group
had demonstrated that DHEA treatment was associ-
ated with higher mean scores for each of the five do-
mains of International Index of Erectile Function (IIEF)
sc o re [34].
In a more recent study, 79 men with sexual dysfunc-
tion and androgen deficiency had received oral testos-
terone undecanoate (80 mg twice daily), DHEA (50 mg
twice daily), or placebo. There were no significant dif-
ferences in sexual performance outcomes between pla-
cebo or intervention, as assessed by IIEF, the Androgen
Deficiency in the Aging Male, Aging Male Symptom
Scale, and Global Assessment Questionnaire [35].
Lacking evidence-based data to show involvement
of DHEA in ED is obvious, however promising data
supporting the possibility of DHEA-specific receptors
availability on vascular endothelial and smooth muscle
cells allows the postulation of its possible involvement
in the vascular mechanisms of erection [21]. DHEA is
only a weak androgen by itself that does not have any
restorative effect on the erectile response in adrenal-
ectomized or castrated animals [36,37]. Furthermore,
DHEA is involved in conditions associated with aging,
immune suppression, and major diseases. In addition,
DHEA enhances the feeling of well-being, but not libi-
do in older men [36,37]. The positive effect of DHEA on
erection supports the notion that adrenal corticoids are
involved in this process. Clinical studies showed that
oral DHEA treatment increased total serum testoster-
one levels, libido, sexual activity, and sexual satisfac-
tion in postmenopausal women [38]. More recent study
reported that higher endogenous levels of testosterone
and DHEA are beneficially related to sexual health in
men and seem to ameliorate the age-related ED [39].
Furthermore, testosterone and DHEA might exert
https://doi.org/10.5534/wjmh.180005
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their positive effects on erectile f unction via their va-
sodilative and molecular properties. Additionally, lower
levels of IL-6 were associated with age-related increase
of ED, which f urther confirms the hypothesis of an as-
sociation between inflammation and ED. The levels of
several proinflammatory cytokines are also elevated in
cardiac dysf unction, and the administration of phos-
phodiesterase type 5 inhibitor such as sildenafil was
reported to cause a sustained reduction of proinflam-
matory cytokines, linking the inf luence of proinflam-
matory cytokines on vasculogenic function and ED [40].
DEHYDROEPIANDROSTERONE
AS A TREATMENT FOR ERECTILE
DYSFUNCTION
Several studies have reported decreased serum
DHEAS levels in patients with ED and denoted that
decreased secretions of DHEA and DHEAS are impor-
tant risk factors f or ED in aging men [41]. DHEA levels
reach their peak in the third decade of age in men. The
serum DHEAS levels were significantly lower in the
younger patients with ED compared with non-ED pa-
tients. Diminished DHEAS levels, especially in young
Table 1. Summary of different clinical trials that assessed DHEA in ED and other conditions
Authors Year Subjects Duration Comments
Feldman
et al [31]
1994 1,265/total 1,709 men in the MMAS
study
8 y follow-up In the MMAS, DHEA sulfate was the only hormone that
showed a negative correlation to the prevalence of
ED among 17 investigated hormones, including T and
estradiol.
Reiter et al [33] 2000 309 patients with ED and 133
healthy volunteers
- Until the age of 60 years, the mean serum level of DHEAS is
lower in patients with ED than in healthy volunteers.
Reiter et al [34] 2001 27 patients with hypertension, 24
patients with diabetes mellitus,
6 patients with neurological
disorders, and 28 patients with no
organic etiology were treated with
50 mg DHEA.
6 mo Oral DHEA-treatment may be of benefit to patients with ED
who have hypertension or to patients with ED without
organic etiology.
Morales
et al [35]
2009 86 men received: oral T (n=29) 80 mg
twice daily, DHEA (n=28) 50 mg
twice daily, or placebo (n=29)
No clinical benefit of T or DHEA supplementation in men
with hypoandrogenism and SD.
Munarriz
et al [38]
2002 Women with sexual dysfunction Androgen replacement therapy with DHEA is a safe and
effective treatment for androgen insufficiency with
female sexual dysfunction.
Nair et al [43] 2006 Placebo-controlled, randomized,
double-blind; 87 men and 57
elderly women
2 y Neither DHEA nor low-dose testosterone replacement in
elderly people has physiologically relevant beneficial
effects on body composition, physical performance,
insulin sensitivity, or quality of life.
Løvås et al [47] 2003 Thirty-nine women 9 mo No evidence of beneficial effects of DHEA on subjective
health status and sexuality in adrenal failure.
Hunt et al [48] 2000 A randomized, double blind study in
which 39 patients with Addison’s
disease
12 wk DHEA then
4-wk washout
period, then
12 wk of placebo
DHEA replacement corrects this steroid deficiency
effectively and improves some aspects of psychological
function.
Yoshida
et al [58]
2010 419 individuals; 208 males and 211
females
- DHEAS is inversely associated with sex dependent diverse
carotid atherosclerosis such as increased maximum and
mean intima-media thickness in males and decreased
common carotid arteries-blood flow volume in females.
Genazzani
et al [63]
2011 48 healthy postmenopausal women
randomized into three groups
received DHEA, daily oral estradiol
plus dihydrogesterone,
or daily oral tibolone
12 mo Daily oral DHEA therapy, hormonal replacement therapy
and tibolone all provided a significant improvement in
sexual function and in frequency of sexual intercourse in
early postmenopausal women
DHEA: dehydroepiandrosterone, ED: erectile dysfunction, MMAS: Massachusetts Male Aging Study, DHEAS: DHEA and DHEA sulfate, T: testoster-
one, SD: sexual dysfunction.
Ahmed I. El-Sakka: Dehydroepiandrosterone and Erectile Function
5
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men with ED, may either be an etiologic factor f or
ED or a negative consequence of it. However, patients
treated with DHEA had a statistically significant in-
crease in all domains of the IIEF in contrast to the
placebo group. Interestingly, the serum DHEAS levels
increased significantly after sildenafil citrate treat-
ment in the ED group (especially in patients younger
than 50 years). Also, patient age was an important f ac-
tor af fecting the sildenaf il citrate response [42].
The f irst clinical effects were reported af ter 8 weeks
of DHEA treatment and a remarkable improvement
in maintaining the erection after 16 weeks. Prostate
volume, postvoid residual, prolactin and PSA were not
significantly changed after DHEA therapy [34]. Despite
the evidence that has questioned the validity of im-
provement in sexual f unction when treatment relied
solely on DHEA administration [43], several previous
studies had demonstrated the usefulness of DHEA in
treating sexual dysfunction associated with testoster-
one or DHEA deficiency [34]. A nice explanation of
that eff ect was demonstrated as both testosterone and
DHEA are considered central neurosteroids and have
been found to modulate endothelial f unction, which ul-
timately influence libido and penile erections [44]. Sev-
eral studies on other organs support the protective role
of DHEA and DHEAS i.e ., reduction of vascular steno-
sis in heterotopic heart transplants [45]. Because there
is also some experimental evidence f or direct effects on
the brain, the possibility of a central effect of DHEA
might be evident. An interesting mechanism that could
better define the role of DHEA in sexual performance
is that administration of DHEA results in biosynthesis
of active androgens by tissue targets without represen-
tation in the peripheral circulation [10].
Although experimental studies had demonstrated
that DHEA has direct genomic and nongenomic ef-
fects on the vascular endothelium, however its clinical
effect as a facilitator of penile erections is not evident
[46]. Most of the literature had not confirmed the role
of DHEA in the field of sexual medicines [43,47]. Addi-
tionally, other studies questioned the concept of DHEA
as a neurosteroid with a central putative effect on libi-
do [48], although this hormone had been found to inf lu-
ence self-esteem and mood in younger individuals [49].
Furthermore, the evidence-based studies supporting an
anti-aging, anti-inflammatory, antiatherosclerotic ac-
tions, and antidepressant effect of DHEA supplemen-
tation are often poor [50,51] (Table 1).
DEHYDROEPIANDROSTERONE
DECLINE AND AGE-RELATED
DISORDERS
Although the underlying mechanism of organic ED
in both middle-age and older men is basically the same,
the middle-aged men’s ED is assumed to have some dif-
ference from older men’s ED [52]. The relation between
biological, psychosocial, and lifestyle factors in terms
of the age-related increase in ED seems to be best
explained by their concomitant inf luence on general
health [53]. This notion is supported by the recent re-
sults, which indicate that perceived general health, as
a proxy of general health, is associated with a buffered
age-related increase in ED [7,54].
Reduction of DHEA with aging is clinically relevant
and has been related to a variety of age-related condi-
tions [54]. A positive relationship between diminution
of DHEA levels and decline in muscle mass, muscle
strength, as well as mobility and a higher risk f or falls,
has been reported with aging [55,56]. The relationship
between DHEA levels and cardiovascular risk factors
such as dyslipidemia and hyperglycemia are inconsis-
tent [54]. Nevertheless, studies have shown that low
DHEA levels are related to a higher risk for athero-
sclerosis, heart failure, cardiovascular complications,
and overall mortality [57-59]. A meta-analysis of endog-
enous DHEA on cardiovascular disease risk indicates
the variations in metabolic effects of DHEA and sug-
gests inconsistency in the positive effects of DHEA on
cardiovascular disease [60].
The relationship between low level of DHEA and
mood disorders and depression symptoms were more
obvious in the literature [61]. Furthermore, DHEA
supplementation has shown positive effects on mood as
well as sexual f unction both f or men and f or women
[62,6 3 ].
Increased DHEA concentrations under hypoglycemic
conditions denotes stimulation of the hypothalamic-
pituitary-adrenal axis on hypoglycemic stress. There-
fore, decline of androgen may have deleterious effects
on glycemic control and ultimately therapeutic effect
in type 2 diabetes mellitus (DM).
In one of our previous studies, we have assessed the
pattern of type-2 DM-associated androgen alteration
in patients with ED. We have shown that there were
signif icant associations between low levels of total tes-
tosterone or DHEAS and poor control of DM [64]. Fur-
https://doi.org/10.5534/wjmh.180005
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thermore, in a consequent study we have demonstrated
that there were significant associations between good
control of DM, decreased fasting blood sugar, and
achievement of normal levels of testosterone at 3- and
6-month follow-up visits. However, no signif icant as-
sociations were detected between controls of DM or de-
creased fasting blood sugar and change in DHEAS and
insulin levels [65]. In addition, administration of testos-
terone to hypogonadal men improves insulin sensitiv-
ity and glucose homeostasis [66]. Earlier study reported
no significant linear correlations between total or free
testosterone with fasting plasma glucose; however,
total testosterone was negatively correlated with glyco-
sylated hemoglobin levels [67]. Among other research-
ers, we expanded the current knowledge regarding, the
percentage of patients with type 2 DM with subnormal
levels of total testosterone or DHEAS is much higher
than that observed with subnormal levels of these
androgen in patients without DM. Further study had
shown that the existence of chronic diseases subtracts
10% to 15% from the values of androgens found in men
without chronic diseases [68]. Other study had shown
also, no positive effects on erectile f unction were f ound
when conditions such as diabetes or neurological disor-
ders were present [34].
The mechanisms of androgen alteration in men with
DM have not been completely discovered. It has been
shown that androgen deficiency in type 2 DM is com-
monly associated with hypogonadotropic hypogonadism
[67]. A more recent study showed that in middle-aged
pre-diabetic men, the more severe lower urinary tract
symptoms were associated with low total testosterone
and DHEAS, while in elderly men were associated with
low free testosterone and DHEAS [69].
FUTURE THERAPEUTIC
SUPPLEMENTATION OF
DEHYDROEPIANDROSTERONE
DHEA has gained a lot of attention and media inter-
est as a dietary supplement and sold over the counter
in some countries as in the USA. In Europe, it is either
forbidden as in France or subjects to medical prescrip-
tion as in Switzerland. Since long time, alleviation of
aging consequences was a dream to obtain durable
and healthy life and to sustain a better quality of life.
DHEA is recently proposed as an antiaging medicine
and is considered as a “fountain of youth” hormone.
As DHEA is claimed to have several positive effects on
age-related disorders. It would be theoretically trans-
formed according to local and general hormone needs.
As a potential f uture therapy, DHEA supplementa-
tion in specific indications such as osteoporosis, mood
and cognitive disorders, sexual well-being and reha-
bilitation protocols, needs to be better studied in more
prospective multicenter and larger studies. We believe
that the route to achieve an ideal antiaging supple-
mentation, which should be readily available, ef f ective
and safe, is still long. Therefore, physicians prescribing
DHEA should consider and inf orm their patients of
the f act that long-term effects not only concerning ef-
ficiency, but also saf ety, remains uncertain [70].
CONCLUSIONS
Several studies had demonstrated that DHEA
level is declined as a part of aging. It is not yet clear
whether this decline should be considered as a physi-
ologic reflection of the aging process or whether active
administration of DHEA might help to prevent and
treat age-related disorders. Furthermore, large-scale
well-designed prospective studies are warranted to bet-
ter define indications and therapeutic implications of
DHEA in men with ED [71,72].
Disclosure
The authors have no potential conflicts of interest to disclose.
Author Contribution
Review conception & design: El-Sakka AI. Data acquisition:
El-Sakka AI. Data interpretation: El-Sakka AI. Draf ting of the
manuscript: El-Sakka AI. Critical revision of the manuscript: El-
Sakka AI. Approval of final manuscript: El-Sakka AI.
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