9
ESSM
Today
Key from KOLS:
Testosterone and cardiovascular risk
by Giovanni Corona, Mario Maggi
Cross-sectional epidemiological studies clearly
show a significant relationship between low tes-
tosterone (T) and cardiovascular (CV) diseases
(CVD) (1 – 3). However, longitudinal studies have
failed to document an association between base-
line low T and incident CVD (1 – 3). In addition,
analysis of longitudinal trajectory patterns of
elderly men in the Framingham Heart Study
confirms the lack of association between low T
and incident events (4). In contrast, a significant
increase in risk of incident CV mortality for sub-
jects with low T has been reported in one meta-
analysis (1), while in another a non-significant
trend was observed (2). It has also been sug-
gested that the increased risk associated with low
T could be limited to elderly subjects (3). Mean-
while, conditions associated with high CVD risk,
such as obesity, metabolic syndrome (MetS), type
2 diabetes mellitus (T2DM) and dyslipidaemia,
were all associated with incident hypogonadism,
as demonstrated in the prospective population-
based Study of Health in Pomerania (5 – 6).
Hence, the relationship between hypogonadism
and increased CV risk is at least multi-directional
and, therefore, still a matter of debate. One pos-
sible interpretation of all the aforementioned data
is that low T could be an adaptive condition in
order to be more resilient, by sparing energy in
an adverse state, as is the case for low three
iodothyronine (T3) in the low T3 syndrome.
Hence, the existence of a low T syndrome has
been hypothesized (7). Alternatively, it can be
speculated that CVD-associated hypogonadism
represents a restraint to male fertility, thus limit-
ing fatherhood in unhealthy conditions such as
malnutrition, obesity or chronic illnesses.
Retrospective pharmaco-epidemiological studies
might help in better clarifying this issues. A retro-
spective observational study from Seattle evalu-
ated mortality rate in a series of 1031 T treated,
compared with untreated hypogonadal (total T <
8.7 nmol/liter) male veterans (VA) greater than
40 years old (9). Over a mean follow-up period
of 40.5 years, it was found that men receiving
testosterone supplementation (TS; n=398) have
a 39% decrease in mortality (HR 0.61; 95% CI
0.42 – 0.88), when compared to the untreated
counterpart (9). Similar results have been re-
ported in another retrospective study on type 2
diabetic subjects (10). However, these results
must be interpreted cautiously because residual
confounding may still be a source of bias, in-
cluding the substantial risk of a primary selec-
tion bias due to the nonrandom assignment of
T exposure. In addition, both studies used only
all-cause mortality as the outcome and there-
fore the relevance of CV-related mortality was
not captured. This gap was recently covered by
another pharmaco-epidemiological survey con-
ducted at the University of Texas Medical Branch
at Galveston (US), examining 25,420 Medicare
(the US‘s largest commercial health insurance)
beneficiaries 66 years or older treated with T for
up to eight years (11). The identified cohort was
matched to 19,065 T nonusers at a 1:3 ratio.
The study found that TS was not linked with any
increased risk for heart attack (hazard ratio [HR]
= 0.84; 95% CI = 0.69– 1.02). In contrast, men
at greater risk for heart problems who used T
actually had a lower rate of heart attacks than
similar men who did not receive this treatment.
In apparent contrast with the aforementioned
findings are two other, recently published, phar-
maco-epidemiological studies (12 – 13). The
first retrospectively evaluated a cohort of 8,709
VA, who had undergone coronary angiography
between 2005 and 2011 showing low T levels
(T<10.4 nmol/L). Among men who were receiv-
ing any form of TS, 25.7% had MACE, or died
from any cause, versus 19.9% of those who did
not receive hormonal therapy, with a hazard ratio
of 1.29 (95% CI 1.04 – 1.58; P=0.02), which
was not substantially affected by adjusting for
confounders (12). Although the study presented
many flaws, due to its retrospective design and
to the little information on the VA database, it
has received much attention in the lay media.
One of the main criticisms of the study was
based on an improper exclusion from analysis of
1132 men who had received a T prescription
after experiencing a CV event (myocardial in-
farction or stroke, 14). Quite unexpectedly, the
author’s answer indicated “an incorrect notation”
regarding this value (15). In particular, they as-
serted that the numbers of men excluded for
this reason was 128, not 1132 after the data
revision. This is an 89% error rate, involving
>1000 individuals. In addition, 100 women
were erroneously included in the original group
of 1132 individuals. Considering that the main
results could have been flawed by the gross
study design and execution, a letter recommend-
ing retraction of the article by Vigen et al (12) has
been submitted to the Editor-in-Chief of JAMA
(16). The document was supported by several
professional Societies (including the International
Society for Sexual Medicine and International
Society for the Study of Aging Male), and more
than 100 scientists from 24 countries (16).
Another retrospective study, funded by the
National Institutes of Health, investigated, in a
large health-care database from Truven Health
Analytics, the rate of nonfatal myocardial infarc-
tion in 56,000 middle-aged and older men, who
were prescribed TS (13). The study reported a
doubling in the risk of heart attack among men
aged 65 years and older and a two- to three-fold
increased risk in younger men with a preexisting
history of heart disease, but not in those without
CV events (13).
This contradictory scenario was further compli-
cated in 2010, when the Testosterone in Older
Men with Mobility Limitations (TOM) trial was
dr. giovanni corona
Endocrinology Unit
Maggiore-Bellaria Hospital
Medical Department
Azienda-Usl Bologna
Bologna, Italy
Prof. Mario Maggi
Andrology and Sexual Medicine Unit
Department of Department of
Experimental, Clinical
and Biomedical Sciences
University of Florence
Florence, Italy
