Best Practice & Research Clinical Endocrinology & Metabolism
7Safety of androgen therapy in men with prostate cancer
Introduction
Male hypogonadism is characterised by the presence of signs and symptoms related to androgen deficiency in conjunction with consistently low testosterone levels, measured on at least two occasions [1]. Testosterone regulates spermatogenesis, secondary sexual functions, erythropoiesis, and bone health [2] and thus hypogonadism is associated with infertility, anaemia, and metabolic disorders [[3], [4], [5], [6]]. Longitudinal studies have shown that testosterone progressively decreases with age [[7], [8], [9]]. The development of low testosterone with age has been described as ‘late-onset hypogonadism’ (LOH) or ‘functional hypogonadism’. LOH has been associated with a higher risk of metabolic conditions such as obesity, cardiovascular disease, and insulin resistance [10]. The European Male Ageing Study (EMAS) was a large, multi-centre cross-sectional study which investigated the prevalence of LOH in a study cohort of 3219 men [11]. The authors observed that the estimated prevalence of LOH was 2.1% in the study cohort, which increased up to 5.9% in patients aged between 70 to 79 years [11]. Although age is a contributing factor to low testosterone levels, the EMAS reported that obesity (body mass index ≥30 kg/m2) was the biggest contributing factor to reduced total testosterone levels compared to the non-obese reference group (mean total testosterone −5.09 nmol/L, p < 0.001) [12].
Testosterone replacement therapy (TRT) is the primary therapy for male hypogonadism, and repletion of androgen levels has been shown to be effective in ameliorating the symptoms of LOH and improving quality of life in some men [1]. Within the last century there has been an increasing interest into both LOH and TRT; the cause of this phenomenon is unclear but it has been attributed to a recent vogue for male rejuvenation [13]. There has been an exponential increase in exogenous testosterone use which has been primarily driven by off-label prescribing. The global testosterone sales have increased by 100-fold over the last three decades and represents an estimated $1.8 billion market [14]. Within this context, the evidence demonstrating the clinical efficacy of TRT in improving quality of life, life expectancy, and optimisation of medical co-morbidities specifically in patients with LOH remains weak [1]. Thus, LOH and exogenous testosterone utilisation represents a growing public health issue [15].
Globally, prostate cancer is one of the most frequently diagnosed malignancies specific to the male sex and third highest diagnosed cancer overall in 2020 [16]. Worldwide, prostate cancer was diagnosed in 1,414,259 men and contributed to 3.8% of all new cancer deaths in 2020 [16]. Prostate cancer was most frequently diagnosed among men aged between 65 and 74 years, with the median age being 67 years at diagnosis [17]. Despite the relatively high incidence rates of prostate cancer, the 5-year survival rate has been shown to be 76–88% [18]. The growth and progression of prostate cancer has been postulated to be reliant on androgens [19] and one of the main therapies to treat metastatic prostate cancer is androgen deprivation therapy [20]. Within this context, it is unclear whether men with prostate cancer and symptomatic hypogonadism should be treated with TRT, and there is a lack of consensus in the current literature [[21], ∗[22], [23]]. Historically, there were concerns that TRT increased the risk and progression of prostate cancer based on the pro-oncogenic effect of androgens in prostate cancer disease pathophysiology [19]. However, there is emerging evidence to suggest that exogenous testosterone use may be safe in certain prostate cancer cohorts, and could ameliorate the symptoms and complications of hypogonadism [24,25].
This chapter will discuss the pathophysiological mechanisms between testosterone and prostate cancer, the contemporary literature regarding the safety of androgen therapy in prostate cancer, and the limitations in current evidence and need for future work.
Section snippets
Pathophysiological mechanisms
The embryological development of the prostate gland is regulated by androgen activity through the androgen receptor (AR) (Fig. 1). Testosterone is converted to 5 alpha-dihydrotestosterone (DHT) via 5alpha-reductase, which binds to the AR to induce transcriptional activity within the prostate [26]. The AR modulates both cell proliferation and apoptosis within the prostate [27]. Huggins and Hodges [19] investigated the effects of androgen deprivation by surgical castration on serum prostatic acid
Androgen saturation theory
The work of Huggins and Hodges [19] has dissuaded many clinicians from prescribing TRT in hypogonadal men with prostate cancer. However, there is emerging data to suggest that in some cohorts of men with prostate cancer TRT may be safe [24,25]. Loeb et al. [39] performed a large case–control study containing 1662 men and observed no overall increase in the risk of prostate cancer with TRT use (odds ratio (OR) 1.03, 95% confidence interval (CI) [0.90, 1.17]). Haider et al. [40] performed a
Contemporary literature
We will discuss the current evidence regarding TRT in men who have undergone curative management of prostate cancer and those who have not been treated or cured of prostate cancer.
Limitations of current evidence and future work
The current evidence for TRT in men with a history of, or concurrent, prostate cancer is predominantly retrospective studies with small cohort sizes. Thus, the quality of evidence is low, and a focus of future research should be the development of large-scale, multicentre randomised controlled trials. In most studies the median follow up is less than five years, and thus future studies should include longer study periods to allow for the recognition of disease progression but also overall
Summary
The role and safety of androgen therapy in men with prostate cancer remains an area of controversy, primarily due to the shift in our understanding of the interplay between androgens and prostate cancer. Moreover, the high incidence of LOH in men with a history of prostate cancer in addition to the lack of evidence and consensus for the safety of TRT in this population has created a clinical dilemma.
The current literature suggests that TRT may be safe in hypogonadal men with previously cured
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