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SEPTEMBER 2014

VOLUME 11

www.nature.com/nrurol

Introduction

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

density.

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

Hodges,

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

Whitmore

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-

tration.

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

Whitmore,

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,

5,6

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.

inves-

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

OPINION

The safety of testosterone supplementation

therapy in prostate cancer

James M. Dupree, Gavin M. Langille, Mohit Khera and Larry I. Lipshultz

Abstract

| 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;

doi:10.1038/nrurol.2014.163

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.

PERSPECTIVES