MINIREVIEW
Mechanisms of obesity and related pathologies: Androgen
deficiency and endothelial dysfunction may be the link
between obesity and erectile dysfunction
Abdulmaged M. Traish
1
, Robert J. Feeley
1
and Andre Guay
2
1 Department of Biochemistry and Urology, Boston University School of Medicine, MA, USA
2 Department of Endocrinology, Center for Sexual Function, Lahey Clinic, Peabody, MA, USA
Introduction
Erectile function is a neurovascular process that
depends on the health of the central and peripheral
nervous systems, the vascular health of the erectile
tissue, and on the endocrine milieu [1]. Sexual stimula-
tion activates the non-adrenergic, noncholinergic nerve
and activates the neural nitric oxide (NO) syn-
thase ⁄ cGMP pathway. The release of NO facilitates
the relaxation of penile cavernosal arteries and
Keywords
diabetes; dyslipidemia; endothelial
dysfunction; erectile dysfunction;
hypogonadism; inflammatory responses;
metabolic syndrome; testosterone
deficiency; vascular disease; visceral obesity
Correspondence
A. M. Traish, Laboratories for Sexual
Medicine, Institute for Sexual Medicine,
Boston University School of Medicine,

circumference, testosterone levels, body mass index and physical inactivity.
Abbreviations
BAT, bioavailable testosterone; BMI, body mass index; CVD, cardiovascular disease; E
2
, estradiol; ED, erectile dysfunction; FT, free
testosterone; IIEF, International Index of Erectile Function; IL, interleukin; IR, insulin resistance; LH, leutinizing hormone; MCP-1, monocyte
chemoattractant protein-1; M-CSF, macrophage-colony stimulating factor; MetS, metabolic syndrome; NO, nitric oxide; PAI-1, plasminogen
activator inhibitor-1; PVD, peripheral vascular disease; SHBG, sex hormone binding globulin; T2DM, type 2 diabetes mellitus; TNFa, tumor
necrosis factor-a; TT, total testosterone; VD, vascular disease; WC, waist circumference; WHR, waist-to-hip ratio.
FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS 5755
resistance arterioles, which causes vasodilation, and
increases blood flow to the corpus cavernosum. The
increased blood flow stimulates the endothelium lining
the lacunar spaces of the corpus cavernosum to release
endothelial NO from the endothelium NO synthase.
These biochemical and physiological processes result in
trabecular smooth muscle relaxation and expansion of
the sinusoids within the corpora cavernosa, leading to
penile engorgement. This expansion of the corpora
cavernosa against the tunica albuginea results in
veno-occlusion and trapping of blood under pressure.
This process is referred to as the ‘veno-occlusive’
mechanism. Neural and endothelial NO synthases are
regulated by androgens. In addition, the tissue
histo-architecture is dependent on androgens. Thus,
any perturbations or alterations in the neural, vascular
or erectile tissue fibroelastic properties will contribute
to erectile dysfunction (ED), by altering the veno-
occlusion mechanism. In this minireview, we discuss
the relationships between obesity, endothelial dysfunc-

this type of obesity contributes to insulin resistance
(IR) and the increased release of cytokines, as well as
the impairment, clearance and storage of triglycerides
in subcutaneous fat. The World Health Organization
defines obesity based on the BMI; however, BMI val-
ues do not always permit stratification of patients
based on their risk for developing subsequent cardio-
vascular disease (CVD) or type 2 diabetes mellitus
(T2DM). When identifying patients who are at high
risk for developing VD, it is important to consider that
there may be subsets comprising overweight patients,
with virtually identical BMI values, who may or may
not suffer from dyslipidemia and IR [12]. In a recent
study, Barter et al. [12] suggested that dyslipidemic
subjects ( n = 715, mean BMI = 28.7) are at a higher
risk for developing subsequent CVD and diabetes com-
pared to normolipidemic controls (n = 1073, mean
BMI = 28.2) with similar BMI values. One proposed
hypothesis is that the dyslipidemic patients displayed a
marked reduction in circulating androgen levels, and
such a decrease in androgens, rather than BMI alone,
is a stronger predictor for the onset of CVD and dia-
betes in obese patients. Interestingly, Stefan et al. [13]
suggested that ‘metabolically benign obesity; may exist,
in which obese subjects do not exhibit IR or early ath-
erosclerosis and that ectopic fat in the liver, and not
visceral fat, may be responsible for this phenotype.
Androgen measurements in these metabolically benign
obese patients may provide further clues regarding this
pathophysiological state.

flammatory factors contributing to systemic and
peripheral vascular inflammation. These include inter-
leukin (IL)-6, IL-1b, plasminogen activator inhibitor-1
(PAI-1), tumor necrosis factor-a (TNFa), angiotensi-
nogen, angiotensin-converting enzyme, vascular endo-
thelial growth factor, and serum amyloid A [21–28]
(Fig. 1). Adipokines are considered to facilitate mono-
cyte adhesion and migration into the vascular wall and
the conversion of monoctyes to macrophages.
Increased levels of TNFa cause the enhanced expres-
sion of adhesion molecules in both the endothelium
and in vascular smooth muscle cells, and IL-6 stimu-
lates liver production of C-reactive protein, a nonspe-
cific marker of vascular inflammation [29–32]. Yudkin
[33] suggested a mechanism whereby TNFa released
from fat stores surrounding a vessel may contribute to
the dysregulation of insulin modulation of endothelin-1
mediated vasoconstriction and NO-mediated vasodila-
tation favoring vasoconstriction.
A decrease in adiponectin levels observed in obese
patients is also thought to contribute to IR and coro-
nary heart disease (Fig. 1) [10,21,34]. Indeed, Pietilainen
et al. [35,36] suggested that only obese subjects who also
have reduced adiponectin levels exhibited endothelial
dysfunction. Adiponectin may play a larger role than
previously thought in both the amelioration and
pathogenesis of endothelial dysfunction. Sowers [34]
reported that: ‘Adiponectin reduces endothelial cell
apoptosis and may reduce the risk for atherosclerosis by
reducing vascular expression of adhesion molecules and

use of flow-mediated dilation may have been a better
parameter to capture endothelial dysfunction. Employ-
ing the latter approach together with ultrasonography
would have been a better clinical marker and may
have provided more reliable information.
In summary, increased visceral adiposity is associ-
ated with increased proinflammatory factors such as
increased PAI-1, TNFa, leptin, IL-6 and angiotensino-
gen, as well as reduced adiponectin levels. This imbal-
ance in such cytokines and adipokines results in
increased nuclear factor kB. It also results in a
decrease in NO synthase and NO activity, an increase
Fig. 1. Visceral adipose tissue as a potential endocrine organ.
Visceral fat is considered to comprise an active endocrine organ,
which increases the production of inflammatory cytokines (e.g.
IL-6, TNFa) as well as lipoprotein lipase, angiotensinogen, free fatty
acids, resistin, leptin, lactate, PAI-1, insulin and adipsin, and
reduces the levels of adiponectin. When coupled with visceral fat
hypoxia, the tissue also produces other adipokines, resulting in
inflammation, contributing to the onset of hypertension, dyslipide-
mia, diabetes, thrombosis and atherosclerosis. In addition,
increased conversion of cortisone to cortisol and increased aromati-
zation of androgens to estrogens results in reduced testosterone
levels. Thus, visceral fat contributes to PVD, including the vascular
bed of the penis, with adverse effects on endothelial function and
reduced circulating androgen levels. These processes result in
reduced penile tissue compliance and diminished penile hemody-
namics, and hence a physiological response, leading to ED.
Adapted from Lyon et al. [18]. Trayhum et al. [24] and Eckel et al.
[25].

markedly reduced [49]. Visceral obesity may serve as
an endocrine disrupter and influence the endocrine
milieu by reducing the levels of luetinizing hormone
(LH) and testosterone resulting in hypogondoropic-
hypogonadism. The increased aromatase activity of the
visceral and peripheral fat further diminishes the levels
of testosterone and increases the levels of estradiol
(E
2
), which further contributes to preferential deposi-
tion of more visceral fat and exacerbates the vicious
cycle of reduced LH and testosterone with progressive
hypogonadism and increased obesity.
Corona et al. [50–52] reported a higher prevalence
of hypogonadism in MetS patients and these men had
an increased WC and hyperglycemia. The authors sug-
gested that WC and hypogonadism may predict the
condition of MetS. These observations are supported
by studies conducted by Tsao et al. [53] who showed
that WC was correlated with sexual dysfunction in
young males. In addition, Corona et al. [54] reported
that obese patients with ED had reduced SHBG-bound
and unbound testosterone levels even after adjusting
for obesity-related comorbidities. The authors sug-
gested that obesity itself may be the underlying cause
for a hypoandrogenic state.
Kaplan et al. [55] examined testosterone levels in
864 subjects with and without MetS and found that
obese men with MetS had significantly decreased TT
compared to non-obese men with MetS. Kapoor et al.

tin, IL-6, free fatty acids (FFA), adiponectin, angiotensin II and
TNFa. These factors have a downstream effect on the activity of
NO synthase (NOS) and NO synthesis, adhesion molecules, MCP-1
and M-CSF. Adapted from Chudek and Wiecek [37].
Obesity and erectile dysfunction A. M. Traish et al.
5758 FEBS Journal 276 (2009) 5755–5767 ª 2009 The Authors Journal compilation ª 2009 FEBS
This is in accordance with findings obtained by Mohr
et al. [68] who suggested that an over-reliance on TT
levels in the diagnosis of androgen deficiency may
result in substantial misclassification. A plausible
mechanism that may account for a decrease in FT
involves elevated serum leptin levels in individuals with
large fat reserves. In obese individuals, elevated leptin
levels may interfere with LH ⁄ human chorionic gona-
dotropin-stimulated androgen production, suppressing
androgen biosynthesis [18,69]. Another postulated
hypothesis is that high E
2
levels in obese men may be
attributed to an increased peripheral aromatization of
testosterone and the increased E
2
levels may alter LH
levels in obesity, thus modulating the pituitary gonadal
axis [70,71]. Another link between androgen deficiency
and obesity may involve IR, which has been shown to
contribute towards a reduction in circulating androgen
levels [72]. Alternatively, excess cortisol secretion is
considered to be associated with increased BMI, WC
and WHR, potentially suppressing testosterone pro-

men with severe ED (21.7–70%). Corona et al. [54]
also demonstrate that the prevalence of fasting blood
sugar > 110 mgÆdL
)1
, a component of MetS, increases
with the severity of ED. Interestingly, these observa-
tions were not corroborated by Paick et al. [85,86],
who did not find a significant relationship between
ED severity and MetS parameters, except for hyperten-
sion. They hypothesized that the relationship between
MetS and ED severity is not clear-cut and that it may
be selective for specific MetS components.
Wang et al. [87] showed that MetS correlated with
peripheral vascular disease (PVD), suggesting a link
between ED and PVD. The prevalence of ED among
men with MetS increases with the number of MetS com-
ponents [88,89], suggesting that MetS is an independent
risk factor for ED [90] and WC may represent an inde-
pendent predictor of ED [91]. That obesity-related com-
oribidies, such as hypertension, contribute to impaired
penile blood flow is in line with the emerging data sup-
porting a strong link between MetS and ED. Although
there is a tight link between hypogonadism and obesity,
not all hypogonadal patients suffer from ED.
Kupelian et al. [92–94] further suggested that ED
may be a warning sign for the onset of MetS in men
with a BMI < 25 and that early intervention should
be initiated to prevent VD and ED. Although ED
might be considered as a warning sign for MetS, as
noted earlier, the relationship between these two condi-

ratio of 19.37, which outranks the odds ratios of 11.72
and 8.56 for abdominal circumference > 106 cm and
a WHR > 0.91, respectively. However, these results
only applied to subjects aged > 60 years, with men
aged 40–60 years not showing a significant correlation
between ED and these anthropometrical measure-
ments. Andersen et al. [83] investigated the relationship
between obesity and ED in a younger cohort of
Danish men between aged 20–45 years and reported
that obesity (BMI > 30) is associated with ED among
younger men aged 20–45 years, with an odds ratio of
2.74. In a different study, it was found that men with
a BMI > 28.7 carry a 30% higher risk for ED than
those with a normal BMI of 25 [96,97]. Clearly, differ-
ent studies in humans have used different anthropo-
metrical measurements to assess obesity and this, in
addition to the age of the cohort being studied, has
influenced the strength of the correlation between ED
and obesity.
The International Index of Erectile Function (IIEF)
provides an important assessment of ED [98], with a
low score representing increased ED severity. A study
of 110 obese, sedentary men (BMI ‡ 30, < 1 hÆweek
)1
physical activity) in which ED was correlated with BMI
and WHR demonstrated that BMI and WHR had
significant age-adjusted negative correlation coefficients
with ED [81,88]. The authors noted that the lower IIEF
score, the stronger the correlation with a high BMI and
WHR value. Esposito et al. [80,89] examined the effects

vascular risk factors. However, these authors acknowl-
edge that obesity may play a role in the etiology of
ED by citing the results of the Massachusetts Male
Aging Study, which found that men who were obese at
baseline, regardless of their follow-up BMI, as well as
men who led sedentary lifestyles, were at the greatest
risk for suffering from ED. These observations were
corroborated in recent studies [101,102]. This evidence
points towards obesity as having caused irreversible
damage to the vasculature by middle age. However, as
Mulhall et al. [100] point out, the results of the Massa-
chusetts Male Aging Study are limited in that only
two time points were used, a small sample size was
examined, and a short period for follow-up was used,
which could have preceded the onset of ED.
Despite many studies attempting to determine the
role of obesity in ED, the pathophysiological mecha-
nisms are not well understood. Vascular risk factors
commonly associated with obesity may play a key role
in the pathogenesis of ED. Erectile function is a neuro-
vascular process that requires the health of the central
and peripheral nervous system, as well as the vascular
bed of the penis, and depends on a functional veno-
occlusive mechanism [3]. The latter is maintained by
the hormonal milieu. Thus, androgen deficiency and
endothelial dysfunction as manifested in obesity will
contribute to veno-occlusive dysfunction and ED.
Given that obesity-related health risks are evident
among individuals with excessive abdominal obesity,
specifically visceral adipose tissue, which has been

sterone therapy prevents a gain in visceral adipose
tissue in non-obese aging men, and reduces the pro-
duction of proinflammatory cytokines [127–129]. It is
therefore reasonable to suggest that androgens attenu-
ate adipogenesis as well as inflammatory factor pro-
duction. Because androgen deficiency is linked to the
development of IR and T2DM, and the latter contrib-
utes profoundly to endothelium dysfunction and ED
[130,131], the concept of androgen deficiency reinforces
the important role of androgens in vascular health and
erectile function.
Summary and conclusions
Visceral obesity, in particular, is characterized by
increased inflammatory factors, decreased plasma TT
levels and endothelial dysfunction. Obesity is associ-
ated with decreased TT, BAT and FT levels, as well as
elevated E
2
levels. Such a decrease in TT levels is not
associated with increased gonadotropin levels; thus, a
hypogonadotropic hypogonadal cycle emerges and per-
sists. During this vicious hypogonadal state, the depo-
sition of visceral fat ensues, contributing to central
obesity. In this pathological state, aromatase activity is
increased, resulting in the metabolism of testosterone
to E
2
, contributing further to the decrease in testoster-
one concentrations and the preferential accumulation
of abdominal fat, leading to androgen deficiency and a

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Fig. 3. Proposed link between obesity, inflammatory responses,
androgen deficiency, endothelial dysfunction and ED. Based on the
information available in the contemporary literature, we suggest
that visceral obesity contributes to ED via three interdependent
(overlapping) pathophysiological mechanisms: (a) inflammatory cyto-
kines that contribute to endothelial dysfunction and microvascular
disease and reduced androgen levels; (b) the insult on the endothe-
lium resulting in endothelial injury and reduced NO synthase activity
and NO production, leading to reduced tissue relaxation and poor
hemodynamics; and (c) disruption of the endocrine milieu, with a
concomitant decrease in testosterone levels and increased E
2
levels, thus disrupting tissue homeostasis, tissue histo-architecture
and erectile tissue compliance. These pathophysiological states
contribute directly to ED in obesity.
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