ReviewCurrent state of practice regarding testosterone supplementation therapy in men with prostate cancer
Introduction
Hypogonadism is increasingly becoming a recognized clinical condition in men of all ages. Testosterone levels decrease by ∼1% per year beginning at the age of 30 years [1], and it is estimated that ∼7% of men aged 30–69 years, and 18% of men greater than 70 years old, are currently experiencing symptoms of hypogonadism [2]. Treatment primarily involves supplementation with exogenous testosterone via numerous formulations including topical gels or liquids, injectables and implantable pellets [3], [4]. Indeed, testosterone supplementation therapy (TST) is currently one of the most commonly prescribed pharmaceutical regiments in the world with administration producing improvements in hypogonadal symptoms such as decreased energy, libido, muscle mass, and bone density [5], [6].
Historically, significant concerns have been raised regarding the use of TST in hypogonadal patients who are elderly [7], have cardiovascular disease [8] as well as active or treated (either with radiation or surgery) prostate cancer (PCa) [9], [10]. This concern was founded upon previous clinical observations that PCa was androgen dependent and that androgen deprivation resulted in the regression of PCa with a concurrent decrease in prostate specific antigen (PSA) [11], [12], [13]. As such, traditional teaching declared that a history of PCa was an absolute contraindication for the use of any type of TST. For example, Fowler and Whitmore [14] conducted an early retrospective review focused on the response of 67 patients with metastatic prostatic adenocarcinoma to the administration of exogenous testosterone. The majority of the men exhibited unfavorable responses that regressed following removal of the TST [14].
Recent work is disputing these concepts [9], [10], [15]. A recent manuscript by Feneley and Carruthers [16] highlighted the results of a recent audit examining the incidence of PCa during long-term TST conducted from the UK Androgen Study. A total of 1365 men aged 28–87 years with hypogonadism were followed for up to 20 years with a total of 14 new cases of PCa diagnosed at a rate of one case per 212 years of treatment [16]. All tumors were localized and suitable for curative treatment with the PCa rate during long-term TST equivalent to that of the general population [16]. Given that PCa is the most commonly diagnosed malignancy in men after skin cancer with >200,000 new cases diagnosed yearly [17], and the increasing trend toward active surveillance in PCa, an understanding of the current TST literature is essential (Table 1). This review highlights the basic physiology underlying testosterone action in men and summarizes the current state of practice regarding TST in men with PCa who are currently on active surveillance or have undergone treatment with radiotherapy, brachytherapy or radical prostatectomy.
Section snippets
Physiology of testosterone and the role of androgens in the prostate
In 1941, Huggins and Hodges first demonstrated, in a case series of 3 patients, that PCa regression occurred following orchiectomy [13], [18]. This and the associated series of landmark studies [11], [12], [13], [18] formed the basis of the current standard of care in the treatment of metastatic PCa. By implying a direct correlation between serum testosterone levels and PCa, the premise was simple; a lower testosterone resulted in PCa regression and vice versa. Later in vitro and clinical work
TST in men with PCa on active surveillance
At this time, no prospective, randomized clinical trials have been conducted to determine the risk of developing PCa on TST, or to evaluate the risk of treating men with diagnosed, but as yet untreated, PCa. With respect to the former, the most relevant literature available today is a meta-analysis [39] and a systematic review [40] that suggests no increased risk exists. With regards to the latter, two retrospective case series [15], [41] and a case report [42] comprise the entirety of the
TST in men with PCa post radiotherapy
Similar to the small amount of information that has been published on hypogonadal men with PCa on active surveillance, limited evidence is available regarding men treated with external beam radiation or brachytherapy for PCa on TST. Sarosdy conducted the earliest of these studies in 2007 [45]. In that retrospective chart review, men with PCa treated using brachytherapy from 1996 to 2004 were subsequently diagnosed as hypogonadal (serum testosterone <300 ng/dL and symptomatic) and given TST
TST in men with PCa post radical prostatectomy
Radical prostatectomy (RP) is a common procedure used in the management of PCa wherein the entirety of the prostate is surgically removed. This operative approach is effective in the treatment of PCa [47]. Several studies exist documenting the role of TST in patients who have undergone RP [10], [48], [49], [50].
An early retrospective case series of seven men diagnosed with hypogonadism after RP showed no evidence of local recurrence or distant spread following 1–12 years of TST [49]. Similarly,
Conclusions
Hypogonadism is a common condition that affects older men and has detrimental effects on quality of life. Early studies of TST in patients with PCa suggested that replacement of testosterone had profound implications on the progression and recurrence of PCa due to an androgen-mediated stimulation of prostatic tissue. Recent data however, suggests that the correlation between elevated serum testosterone levels and PCa progression might not be as direct as once perceived. Indeed, a recent study
Conflict of Interest
The authors have no potential conflicts of interest to disclose.
Financial support
This work was supported in part by a Male Reproductive Health Research Career (MHRH) Development Physician-Scientist Award (K12, HD073917-01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program (JRK via DJL), NIH grants P01HD36289 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health (DJL), and 1R01DK078121 from the National Institute of Kidney and Digestive Diseases (DJL).
References (51)
- et al.
Anabolic steroid-induced hypogonadism in young men
J Urol.
(2013) - et al.
Factors influencing patient decisions to initiate and discontinue subcutaneous testosterone pellets (testopel) for treatment of hypogonadism
J Sex Med
(2013) Late-onset hypogonadism
Med Clin North Am
(2011)- et al.
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 mortality
Eur Urol
(2014) - et al.
Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy
J Urol
(2013) - et al.
The response of metastatic adenocarcinoma of the prostate to exogenous testosterone
J Urol
(1981) - et al.
Is testosterone treatment good for the prostate? Study of safety during long-term treatment
J Sex Med
(2012) - et al.
Luteinizing hormone-dependent activity and luteinizing hormone-independent differentiation of rat fetal Leydig cells
Mol Cell Endocrinol
(2001) - et al.
Steroid biosynthesis and prostate cancer
Steroids
(2012) Interrelationships between sex hormone-binding globulin and testosterone, 5 alpha-dihydrotestosterone and oestradiol-17 beta in blood of normal men
Maturitas
(1980)
Androgen receptor (AR) expression in prostate cancer and progression of the tumor: lessons from cell lines, animal models and human specimens
Steroids
Binding properties of androgen receptors. Evidence for identical receptors in rat testis, epididymis, and prostate
J Biol Chem
Testosterone and prostate cancer: revisiting old paradigms
Eur Urol
Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941
J Urol
Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer
J Sex Med
Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia
J Urol
Testosterone replacement therapy after primary treatment for prostate cancer
J Urol
Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men
J Urol
Testosterone replacement therapy following radical prostatectomy
J Sex Med
Andropause: clinical implications of the decline in serum testosterone levels with aging in men
J Gerontol Ser A, Biol Sci Med Sci
Prevalence of symptomatic androgen deficiency in men
J Clin Endocrinol Metab
Testosterone treatment in the aging male: myth or reality?
Swiss Med Wkly
Testosterone replacement therapy in the setting of prostate cancer treated with radiation
Int J Impot Res
Endocrine-induced regression of cancers
Cancer Res.
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