The benefits of testosterone supplementa-
tion therapy (TST) for hypogonadal men
are well described in the literature. These
benefits include increased libido, improved
erectile function, increased muscle mass,
decreased adipose tissue, improved physi-
cal strength, and improved bone mineral
Nevertheless, the use of TST in
men with prostate cancer remains a contro-
versial subject. Prostate cancer begins as
an androgen-dependent neoplasm and
androgen- deprivation therapy (ADT) is
widely used to slow tumour growth in
men with metastatic disease; conversely,
supplementation of testosterone has his-
torically been thought to promote prostate
cancer growth and, therefore, apprehension
regarding TST in men with this disease has
persisted despite a recent accumulation
of evidence to the contrary. The concerns
that TST might cause prostate- cancer
progression originated in the seminal
work published in 1941 by Huggins and
part of Huggins’ research on
hormone- responsive cancer for which he
was eventually awarded the Nobel Prize.
These investigators found that reducing
serum testosterone to castrate levels in
patients with prostate cancer resulted in
tumour regression.
In addition, the authors
reported that, conversely, the adminis-
tration of testosterone to three patients,
at least one of whom had been castrated,
was associated with increases in prostate-
cancer markers.
Later, in 1981, Fowler and
reported that 45 of 52 men with
metastatic prostate cancer had an ‘unfavour-
able’ outcome after receiving exogenous tes-
tosterone. However, 48 of the men included
in this study had been androgen-deprived
at the time of testosterone administration;
notably, in three of the four eugonadal men
assessed, the disease followed relatively
benign courses after testosterone adminis-
Thus, this report suggests that men
on ADT respond differently to testosterone
administration compared with moderately
hypogonadal men.
A plethora of studies on this topic have
been published over the past 10 years,
with the findings of most of these investi-
gations supporting the safety of care-
fully administered and closely monitored
TST in hypogonadal patients with pros-
tate cancer. In fact, in the modern era of
PSA testing, no peer-reviewed publica-
tions have demonstrated that TST causes
prostate-cancer progression.
In this Perspectives article, we write in
support of the safety of TST in men with
prostate cancer or a history of prostate
cancer. Herein, we challenge the persis-
tent historical urological paradigm that
TST results in the progression of prostate
cancer by highlighting the lack of evidence
supporting this claim. Furthermore, we
present contrary data indicating that low
testosterone levels—not high testoster-
one levels—might be associated with an
increased risk of prostate cancer, and that
TST can be safely administered to hypo-
gonadal men with treated prostate cancer,
or with caution in those with untreated
prostate cancer.
Profoundly hypogonadal
men, such as those studied by Fowler and
are beyond the scope of this
article, and we focus instead on the more
common situation of hypogonadal men
with serum testosterone levels in excess of
150–200 ng/dl and who have not received
ADT. Importantly however, consistent with
Endocrine Society Guidelines and AUA
position statements,
TST should only be
considered in men who have laboratory
evidence of low testosterone levels and
symptoms consistent with hypogonadism,
regardless of their prostate cancer status.
TST—effects on the prostate
The ‘prostate-saturation theory’ forms the
foundation for the contemporary under-
standing of the safety of TST in men with
prostate cancer.
In 2006, Marks
et al.
tigated the effects of testosterone therapy
on normal prostate tissue. These authors
studied TST in 44 men aged 44–78 years with
symptomatic hypogonadism (serum testos-
terone <300 ng/dl), 40 of whom completed
the study.
The patients were randomized
The safety of testosterone supplementation
therapy in prostate cancer
James M. Dupree, Gavin M. Langille, Mohit Khera and Larry I. Lipshultz
| Patients with prostate cancer can present with hypogonadism and experience
health and quality-of-life declines related to low testosterone levels. Despite generations
of urological dogma suggesting that testosterone supplementation therapy (TST) for
hypogonadism causes prostate-cancer progression, a review of the contemporary
literature provides evidence to the contrary. The prostate saturation model suggests that
the androgen receptor (AR) is saturated at serum testosterone levels of 150–200 ng/dl,
and that additional serum testosterone above this level has limited, if any, effects within
the prostate. Indeed, studies in the modern era of PSA assessments indicate that TST
does not affect prostate size, intraprostatic testosterone levels, or prostate-cancer
progression, provided the baseline serum testosterone level is greater than this AR
saturation point. However, the body of data on this subject comes from a small number
of cases, and TST should only be administered to patients with prostate cancer after
thorough discussions of the risks and benefits, with subsequent careful monitoring.
Dupree, J. M.
et al.
Nat. Rev. Urol
, 526–530 (2014); published online 29 July 2014;
This article forms part of a Point/Counterpoint discussion of the use of testosterone supplementation
in prostate cancer.
Competing interests
M.K. declares that he has acted as a consultant
for Auxillium, Merck, Meda, and Lilly. L.I.L.
declares that he is a member of the speakers’
bureau and/or has received honouraria from,
and has acted as a consultant for, Auxillium,
Endo, Respro Therapeutics, and Lilly. J.M.D.
and G.M.L. declare no competing interests.
© 2014 Macmillan Publishers Limited. All rights reserved