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Ranjith Ramasamy, Larry I. Lipshultz*
Department of Urology, Baylor College of Medicine, Houston, TX, USA
*Corresponding author. 6624 Fannin Street, #1700, Houston,
TX 77030, USA.
Re: In Older Men an Optimal Plasma Testosterone Is
Associated With Reduced All-cause Mortality and Higher
Dihydrotestosterone with Reduced Ischemic Heart
Disease Mortality, While Estradiol Levels Do Not Predict
Yeap BB, Alfonso H, Chubb SA, et al.
J Clin Endocrinol Metab. In press.
The recent paper by Yeap et al. addresses an important and
emerging issue: the association between testosterone and
cardiovascular mortality in elderly men. Designed as a cohort
study, the population was derived from community-dwelling
elderly men in Perth, Western Australia. The men were given
an initial work-up between the years 1996 and 1999, followed
by another assessment in the years 2001–2004.
In total, 3690 men were followed for a mean of 6.7 yr.
During this time, there were 947 deaths, with 325 directly
attributable to ischemic heart disease (IHD). Overall, men
who died had lower mean baseline levels of serum
testosterone (12.8 vs 13.2 nmol/l;
= 0.013), dihydrotes-
tosterone (DHT) (1.4 vs 1.5 nmol/l;
0.002), and estradiol
(71.6 vs 74.0 pmol/l;
0.022). Following adjustment for
several risk factors, both testosterone and DHT were found
to be associated with all-cause mortality. Furthermore, men
with baseline serum testosterone levels in the middle two
quartiles (between 283 ng/dl and 453 ng/dl) had lower rates
of mortality from IHD compared to men in the lowest or
The findings of Yeap et al. illustrate an interesting U-shaped
association between serum testosterone levels and cardiovas-
cular mortality in which
levels appear to be protec-
tive. Furthermore, these findings appear consistent with
recent studies in which elderly men with cardiovascular dis-
ease were examined
, as well as data from the Testosterone
in Older Men (TOM) trial
In the first of these studies, Vigen et al.
an association existed between testosterone supplementa-
tion therapy (TST) and cardiovascular morbidity in men
60 yr of age. However, on more detailed analysis, the men
on TST were found to have mean serum testosterone levels
of only approximately 320 ng/dl, with the majority of men
. Thus, if data from the Vigen et al. study
are transposed to the quartiles identified in the current
study by Yeap et al., a significant proportion of men on TST
actually corresponded to the lowest quartile (
These men can thus be considered at increased risk for
cardiovascular mortality based on their serum testosterone
levels alone, regardless of whether they had TST or not.
Furthermore, the findings of Yeap et al., that cumulative
mortality was highest in those men with total testosterone
levels in the lowest quartile, correspond to the Vigen et al.
, as well as to large studies on male veterans that
show hypogonadism is an important risk factor for
increased mortality [3,4]. Taken together, it can be
concluded that hypogonadism alone, independent of TST,
remains an independent risk factor for cardiovascular
morbidity and mortality in elderly men.
In the TOM trial
, a population of older men with
limitations in mobility and several comorbidities was
assessed. Application of testosterone gel (100 mg/d) was
associated with an increased risk for adverse cardiovascular
events. In this trial, the mean testosterone level in men on
TST was 574 ng/dl
. If the post-treatment testosterone
500 ng/dl, the dose was increased to 15 g/d.
Comparingthesevalues tothose obtainedbyYeapetal.,itcan
be inferred that these men were in the highest testosterone
quartile—a group of men who experienced the second
highest rate of mortality. As such, had serum testosterone
levels in elderly men been
, or within the middle
quartiles, one can only speculate whether mortality would
have actually been different.
The question now becomes (while acknowledging the
inherent variability in serum testosterone assays), how does
one apply these findings to clinical practice? Should
clinicians aim for certain serum testosterone values in
elderly men on TST? For example, while injectable TST
(ie, testosterone cypionate) is a less expensive modality, it
yields higher and more variable levels of serum testoster-
one, often reaching supraphysiologic levels. Would lower,
more physiologically stable levels obtained from subcuta-
neous implantable pellets or gels be more desirable for
lower long-term cardiovascular protection? While it is
known that testosterone has a dose-dependent stimulatory
effect on erythropoiesis that is more pronounced in older
, it is thus theoretically possible that increased blood
viscosity could aggravate vascular disease in coronary,
cerebrovascular, or peripheral vascular circulation in this
. Given the preponderance of the
current evidence, an association between cardiovascular
disease, TST, and serum testosterone levels in elderly men
EUROPEAN UROLOGY 65 (2014) 843–848