Words of Wisdom
Re: Incidence of Prostate Cancer in Hypogonadal Men
Receiving Testosterone Therapy: Observations from
5-Year Median Followup of 3 Registries
Haider A, Zitzmann M, Doros G, Isbarn H, Hammerer P,
Yassin A
J Urol 2015;193:80–6
Experts’ summary:
The recent publication by Haider and colleagues identifies the
incidence of prostate cancer in hypogonadal men receiving
testosterone supplementation therapy (TST). This prospective
study involved three ongoing parallel registries: two cohorts
of patients presenting for erectile dysfunction or hypogonadal
symptoms at private urologic practices (cohorts 1 and 2)
and one cohort of patients presenting for hypogonadism or
Klinefelter syndrome at an academic urology and andrology
clinic (cohort 3). The mean follow-up was approximately 5 yr
for all three cohorts. In total, 1023 men with hypogonadism
received TST and had initial screening for prostate cancer,
which included prostate-specific antigen (PSA) measurement,
digital rectal examination, and transrectal ultrasonography.
The three studies followed patients using these modalities at a
minimum of twice a year.
In all cohorts, baseline PSA was
4 ng/ml, and if PSA
increased abruptly or gradually rose t
4 ng/ml, a prostate
biopsy was performed in accordance with European
Association of Urology guidelines. The prostate cancer
incidence was 2.3% (
= 6/261) in cohort 1 and 1.5%
= 5/340) in cohort 2. There were no cases of prostate
cancer in cohort 3. Of note, there were three cases of
Gleason 5, seven cases of Gleason 6, and one case of Gleason
7 disease. There was no report of Gleason
8. These rates of
prostate cancer incidence are lower than those from the
Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer
screening trial and the European Randomized Study of
Prostate Cancer (ERSPC), which have screened 38 343 and
72 891 patients and reported incidences of 7.35% and 9.6%,
respectively. These findings suggest that men with hypogo-
nadism receiving TST are not at additional risk of developing
prostate cancer when compared to the general population.
Experts’ comments:
Progression of prostate cancer depends to some extent on
testosterone, but controversy surrounds the role of TST in
the development of new lesions. Haider et al present new
evidence that TST does not increase the incidence of new
lesions. Among the strengths of this study are the large
sample size, the inclusion of three entirely separate cohorts,
the relatively long follow-up period, and the ongoing pro-
spective design. However, the study cohorts represent a
younger population than in the PLCO and ERSPC cohorts,
which complicates efforts to compare the data among these
screening trials.
The saturation theory posits that the effect of testos-
terone on the prostate is limited by the capacity and
concentration of prostate androgen receptors (ARs), and
that any testosterone above a certain threshold level will
have no effect on the prostate
. Marks and colleagues
TST increases serum testosterone levels but not intrapro-
static testosterone levels. More importantly, these investi-
gators also found no change in prostate histology, the
expression of testosterone-dependent prostate tissue mar-
kers (PSA, AR, vascular endothelial growth factor), or the
incidence of prostate cancer in response to TST
There is of course evidence that testosterone levels do
correlate with the incidence of prostate cancer. Notably, the
Prostate Cancer Prevention Trial (PCPT) and Reduction by
Dutasteride of Prostate Cancer Events Trial (REDUCE) both
found that use of 5
-reductase inhibitors (which lower
dihydrotestosterone levels), despite correlation with a
lower incidence of all grades of prostate cancer, was
associated with a higher incidence of high-grade prostatic
. It has been hypothesized that the increase in
the incidence of high-grade prostate cancer in patients on
-reductase inhibitors is because of better ability to detect
localized high-grade lesions in a smaller prostate.
We have previously published findings that corroborate
the absence of an increased risk of prostate cancer with TST.
We studied men with hypogonadism who underwent radical
prostatectomy for localized prostate cancer and subsequent-
ly received TST. Patients on TST had a lower rate of cancer
recurrence than an age-matched control group of eugonadal
. In another study we found that hypogonadal
patients with prostate cancer treated with external beam
radiation therapy followed by TST did not have a higher
recurrence rate than eugonadal men
. In a third study, a
small series (
= 13) of hypogonadal men on active surveil-
lance (Gleason 6,
= 12; Gleason 7,
= 1) were treated with
TST and did not have an increase in mean PSA; on follow-up
EUROPEAN UROLOGY 67 (2015) 1186–1192
available at www.sciencedirect.com
journal homepage: www.europeanurology.com