© The Canadian Journal of Urology™; 21(Supplement 2); June 2014
has been supported by studies that have concluded that
treatment with alpha-receptor antagonists, doxazosin,
30
and alfuzosin
31,32
may improve sexual function including
ED. Thismechanismis also attractive because it explains
the link between ED and lower urinary tract symptoms
(LUTS), which was confirmed by the Multinational
Survey of the Aging Male (MSAM7) study.
33
This
study included more than 14,000 men, aged 50-80
years, representative of the population of six European
countries and the United States.
34
A fourth mechanism explaining the link between
the MetS and ED involves increased activation of
the Rho/Rhokinase pathway, acting downstream of
norepinephrine and endothelin1 receptors. Diabetes
and hypertension have been linked to increased
activity in this pathway.
35
Increased activity in Rho/
Rho-kinase pathway results in the inhibition of smooth
muscle and subsequent smooth muscle contraction.
36
Although this mechanism has not been specifically
demonstrated in erectile tissue, it adds to the body of
evidence suggesting that ED is also an expression of
the MetS and could arise via this mechanism.
37
There are several hypotheses concerning the
mechanism linking the MetS andmale hypogonadism.
Obesity, especially visceral obesity, is an established
aspect of the MetS. Activity of aromatase, an adipose
enzyme that is involved in the irreversible conversion
of testosterone into estradiol,
38
is higher inmenwho are
obese and, consequently, they tend to have a decreased
testosterone level and increased estradiol level.
38,39
Thus, the MetS provides an endocrine mechanism
to explain the development of hypogonadotropic
hypogonadism, as it is believed that the effect of
estradiol on gonadotropin suppression is more potent
than that of testosterone.
40
The findings of Zumoff
and colleagues,
41
who treated obese men with oral
testolactone (an aromatase inhibitor), support this
conclusion. After 6weeks, men treatedwith testolactone
had higher levels of testosterone and LHand decreased
levels of estrogen comparedwith their baseline levels.
41
The hypothalamic–pituitary–adrenal (HPA) axis
provides yet another mechanism that could explain
the link between the MetS and hypogonadism. The
HPA axis has been shown to be overactive in subjects
suffering from the MetS,
42
and it is well established
that cortisol inhibits the reproductive axis at several
levels including secretion of GnRH and LH and also
at the level of the testes themselves.
43
This emerging
link between the MetS and male hypogonadism
via increased aromatase activity, hypogonadotropic
hypogonadism and increased activity of the HPAaxis
seems to suggest that male hypogonadism is also a
urological aspect of the MetS.
Primary care cardiometabolic evaluation of
ED
Symptomatic men are presumed to have CVD and
are therefore at high risk for CVD events. A thorough
history, physical exam (including measures of visceral
adiposity), assessment of ED severity and duration,
and evaluation of fasting plasma glucose, resting
electrocardiogram, serum creatinine (estimated
glomerular filtration rate) and albumin: creatinine ratio,
andpresence or absence of themetabolic syndromemay
be used to further characterize CVS risk.
13
Because ED is a well-established, independent
marker for CVD risk
44-48
all men should be questioned
about their sexual history and functioning as part of
the initial assessment of CVD risk. For all men with
ED, particularly those with vasculogenic ED, we
recommend that initial risk stratification be based on
the FR10 or the 2013 ACC/AHARisk Calculator,
11
the
former which estimates the 10 year CVS event risk; the
latter which estimates the 10 year and lifetimeASCVD
risk for both myocardial infarction or stroke.
The Framingham risk score is unique because it is
dominated by chronologic age, systolic blood pressure,
total cholesterol and HDL-C cholesterol, and cigarette
smoking. We also know its limitations: it assesses
the 10 year risk of non-fatal myocardial infarction
or coronary heart disease death rather than a longer
term risk, potentially depriving younger subjects and
women of more intensive therapies. The Framingham
study involved only 5200 patients from Framingham,
Massachusetts. It is unclear whether this population
is generalizable to others, particularly non-Caucasian
populations.
48-50
In addition, the Framinghamrisk score
does not include family history of premature coronary
heart disease, and concepts of exercise and diet, and
other risk factors that may be of great importance for
future CVD risk. It also does not consider some of
the novel biomarkers, such as C-reactive protein. The
authors are therefore concerned that the Framingham
risk score underestimates coronary heart disease
(CHD) risk in the ED patient under the age of 60 years.
The Framingham risk calculator has now been
altered in the form of a new downloadable American
College of Cardiology andAmericanHeartAssociation
risk calculator for 2013.
11
This risk calculator not
only determines 10 year risk of myocardial infarction
(MI) but also risk for other ASCVD events including
cerebrovascular accident (CVA). In addition it
determines both 10 year ASCVD and lifetime ASCVD
for men up to age 59.
11
The following may be used to identify men with
ED whose CVS risk may exceed that determined
28
Miner ET AL.
