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

[1]

. Marks and colleagues

[2]

contributedsignificantevidencetothistheorybyfindingthat

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

[2]

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

neoplasms

[3]

. 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

men

[4]

. 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

[5]

. 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