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Safety of androgen therapy in men with prostate cancer (2022)
Prabhakar Rajan, Ph.D., FRCS (Urol), FHEA, Clinical Senior Lecturer in Urology, Tharu Tharakan, MBBS, BSc, MRCS, Urology Registrar, Runzhi Chen, BSc., Medical student
Prostate cancer is one of the most frequently diagnosed malignancies in men worldwide and the life expectancy for men with prostate cancer is improving due to advancements in diagnostics and treatment. Male hypogonadism is associated with obesity, diabetes, and other comorbidities and also has been linked with increasing age; the primary therapy modality for this condition is testosterone replacement therapy (TRT). There are concerns that testosterone therapy may cause prostate cancer disease progression. However, contemporary evidence suggests that testosterone replacement therapy may be safe in specific groups of patients with prostate cancer. This chapter will summarise the contemporary literature regarding TRT use in hypogonadal men with prostate cancer, including limitations and future research goals.
Introduction
Male hypogonadism is characterized 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, anemia, and metabolic disorders [3-6]. Longitudinal studies have shown that testosterone progressively decreases with age [7-9]. 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-center cross-sectional study that 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 in 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. Global testosterone sales have increased by 100-fold over the last three decades and represent 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 optimization of medical co-morbidities specifically in patients with LOH remains weak [1]. Thus, LOH and exogenous testosterone utilization represents a growing public health issue [15]
Globally, prostate cancer is one of the most frequently diagnosed malignancies specific to the male sex and the 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 have 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 [21-23]. 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.
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 phosphatase activity in 8 men with metastatic prostate cancer. The authors reported that the mean acid phosphatase activity in four men decreased from 31.25 to 5.5 units within 12 days following bilateral orchidectomy [19]. This study demonstrated that androgen deprivation by surgical castration caused regression of metastatic prostate cancer with respect to serum enzymes [19]. In addition, subsequent exogenous testosterone administration resulted in an increase of acid phosphatase activity above precastration levels [19,28]. These study findings are supported by observational data reporting that eunuchs have impalpable prostate glands and rarely develop prostate cancer due to a deficiency in androgenic activity [29].
Androgen deprivation therapy (ADT) functions to suppress the AR pathway to prevent the growth of prostatic tumor cells [30]. It is the primary therapy for men with metastatic prostate cancer. ADT utilizes the effects of gonadotrophin-releasing hormone analogs to suppress the production of gonadotropins and endogenous testosterone, thereby conferring to medical castration [31]. However, the majority of prostate cancers treated with ADT will eventually progress to a castration-resistant form of the disease. Although the definitive pathophysiological mechanisms have not been fully elucidated, it has been postulated that the development of castration-resistant prostate cancer is largely due to ligand-independent AR activity. The proposed mechanisms include increased sensitivity of the AR to transcription cofactors, mutations in the AR causing resistance to anti-androgens, and overexpression of the AR [32,33]. There are an increasing number of studies that advocate for the use of intermittent ADT to reduce the risk of disease progression whilst maintaining oncological outcomes [34-36]. Such studies have also highlighted the benefits of intermittent ADT on morbidity [37], symptom profile [35], and cost savings [36]. However, there is a lack of prospective studies and the optimal regimen has not yet been clearly established [38].
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 prospective multi-center cohort study of 1023 hypogonadal men and reported that TRT did not increase the risk of prostate cancer. In a prospective cohort study by Feneley et al. [41] which included 1365 men, the authors reported that the incidence of prostate cancer during long-term TRT was equivalent to that of the general population. In light of this evidence, Morgentaler and Traish [27] postulated the androgen saturation theory which proposes that androgenic activity on prostate growth is limited by AR availability once maximal androgen-AR binding saturation has been reached. Hence, testosterone supplementation above the threshold level will not stimulate prostate growth [42]. This model suggests that prostatic ARs become saturated at serum testosterone concentrations below the physiological range [27]. The AR in prostatic tissue is postulated to become unreceptive to further increases in serum testosterone at concentrations above 8.3 nmol/L [27,43,44].
Despite the previous consensus that higher serum testosterone levels promote prostate cancer growth [19], the androgen saturation theory (Fig. 2) has provided a rationale for why higher serum testosterone levels seem unrelated to prostate cancer risk in the general population. Studies have corroborated this theory by demonstrating the lack of correlation between the endogenous total serum testosterone levels and serum prostate-specific antigen (PSA) in the general population, suggesting that the relationship between prostate cellular activity and testosterone is not linear [45]. Moreover, a randomized placebo-controlled trial in 44 men [46] concluded that whilst TRT was shown to normalize serum androgen levels in men with LOH (median testosterone 9.8 nmol/L to 22.2 nmol/L after 6 months of treatment), there were minimal effects on the intraprostatic tissue composition and cell proliferation seen on biopsy specimens. Further proteomic and genomic analysis of these specimens also revealed no statistically significant changes in gene expression of prostate-specific androgen-regulated biomarkers associated with the prostatic epithelium and prostate cancer [46].
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.
Testosterone replacement therapy in men with treated prostate cancer
There is increasing data showing the safety of TRT in hypogonadal patients who have undergone curative treatment of prostate cancer (Table 1). Teeling et al. [47] performed a meta-analysis comprising of 13 studies and included a total of 608 patients. The authors observed a negligible risk of biochemical recurrence (BCR) (recurrence risk 0.00, 95% CI [0.00, 0.005]) in men with cured high-risk prostate cancer when given TRT. However, the authors reported that the available evidence was of very low quality [47]. In a large, national comparative study (n = 69,984) where 1,012 patients received TRT after curative treatment of prostate cancer, no differences were observed between cohorts in BCR rates, prostate cancer-specific mortality, or overall mortality [48]. The median follow-up was 6.95 years (83.5 months) [48]. The authors concluded that TRT did not increase the risk of BCR or mortality in patients who had received curative treatment and thus appropriate for this cohort [48].
The majority of studies investigating the use of TRT in patients with prostate cancer who underwent curative management are small, retrospective cohort studies (Table 1). Agarwal and Oefelein [49] reported a significant improvement in symptoms of testosterone deficiency and quality of life (p = 0.00005) in 10 symptomatic hypogonadal men who previously underwent curative radical prostatectomy (RP) and were subsequently treated with TRT [49]. The authors also observed that after a median follow-up period of 19 months, there were no increases in serum PSA greater than 0.1 ng/mL [49]. Khera et al. [50] investigated the serum PSA levels in 57 men started on TRT following curative treatment of prostate cancer with RP. The authors reported no significant increases in PSA values despite significant increases in serum T levels [50]. However, a limitation to this study was that the median follow-up time was only 13 months, which may have been insufficient to detect possible BCR [50]. Ahlering et al. [51] performed a case-control study comparing BCR rates in 152 men who had undergone RP and were treated with TRT compared to those not treated with TRT. The authors reported BCR rates of 7.2% and 12.6% for TRT and non-TRT men, respectively. This study suggests that TRT does not significantly increase the risk of BCR in men treated with RP. In a retrospective study [52] of 109 hypogonadal men treated with RP who were given TRT, the authors reported a significantly lower BCR recurrence rate in men given TRT compared to a reference group of 49 men who had not received TRT (3.7% vs. 16.3%, p = 0.015). The authors postulated that the lower BCR rate in the treatment group may be due to increases in testosterone levels in the peripheral circulation without changes in residual prostate tissue levels [52].
Pastuszak et al. [53] investigated the effects of TRT in 98 hypogonadal men treated previously with radical radiotherapy (RT). The authors reported that TRT was associated with a small non-significant increase in median serum PSA levels at follow-up after a median of 40.8 months (0.08 ng/mL to 0.09 ng/mL, p = 0.051), and six patients (6.1%) fulfilled BCR criteria [53]. However, the authors note that the observed rate of BCR was lower than published rates in similar cohorts treated with RT without TRT administration [53,54].
Table 1 summarises the studies investigating the biochemical or clinical recurrence of prostate cancer after the use of TRT in men who had undergone RT or RP. The majority of studies suggest that TRT is not associated with BCR in men treated with radical treatments for prostate cancer. However, it must be recognized that the current data is limited by a paucity of long-term follow-up data and large prospective studies.
Testosterone replacement therapy in men with untreated/active surveillance prostate cancer
In men diagnosed with low-risk prostate cancer (typically defined as either a Gleason score of 6 or less, non-palpable disease, or low grade and stage), active surveillance (AS) and deferment of curative treatment is offered due to the relatively indolent nature of low-risk disease and risk of side effects associated with treatment [60]. In this cohort of patients, the safety of TRT has been disputed given the assumption that testosterone supplementation may increase the risk of disease progression. However, there is increasing evidence showing no significant association between TRT and prostate cancer diagnosis in the general population. A large retrospective study of 12,779 patients with LOH observed that the use of TRT did not result in an increased risk of prostate cancer (hazard ratio 0.97, 95% CI [0.71, 1.32]) after a mean follow-up of 4.6 years [61]. A meta-analysis of 22 randomized controlled trials involving 2351 patients reported no difference in prostate cancer diagnosis between TRT and placebo groups (OR 0.99, 95% CI [0.24, 4.02], p = 0.99) [22]. The authors also reported that short-term TRT use was more likely to be associated with increased PSA levels (mean difference 0.33, 95% CI [0.21, 0.44], p < 0.00001) but no apparent differences were reported in long-term TRT use [22]. Loeb et al. performed a nested case-control study from data from the National Prostate Cancer Register of Sweden and analyzed 38,570 men diagnosed with prostate cancer and 192,838 men without prostate cancer [39]. The authors reported no significant differences in prostate cancer risk between patients who had received TRT compared to those who had not received TRT (OR 1.03, 95% CI [0.91, 1.17]). Therefore, it is unclear whether TRT increases the risk of disease progression, especially given that there is no association between TRT use and prostate cancer incidence [62].
In summary, the current evidence investigating the risks and benefits of TRT in men with untreated prostate cancer is of low quality, with an absence of large-scale randomized controlled trials. Thus, the use of TRT in men with untreated prostate cancer can only be advocated in a clinical trial setting.
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 randomized 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 mortality rates. For example, hypogonadal men are at higher risk of cardiovascular disease [4] and therefore it would be interesting to identify whether TRT mitigates overall mortality by reducing the risk of cardiovascular disease despite a potential risk of prostate cancer disease progression. It must also be recognized that even in men with seemingly cured prostate cancer from RP or RT, there is an estimated 10-20% risk of clinical recurrence or biochemical failure within 15 years which is due to the presence of undetectable micro-metastases [66]. Therefore, randomized controlled trials are needed to mitigate this variable as the BCR rate could be artificially elevated in men undergoing TRT, who might already have micrometastases [66,67].
A limitation of the current evidence is that most studies report serum PSA levels as a marker of prostate cancer activity, but not mortality or metastatic progression rates. PSA is prostate but not cancer-specific, and therefore may not be a specific marker of disease progression. Moreover, a recent meta-analysis highlighted that serum PSA screening demonstrated no effect on overall mortality [68]. It is important to recognize that serum PSA monitoring has a role in the confirmation of curative treatment and indicator of prostate activity [69]. However, consideration should also be given to the patient quality of life cardiovascular disease status, and other markers of health, since hypogonadism may cause more morbidity and mortality than prostate cancer.
Whilst there is a growing body of evidence for TRT in men with either treated or untreated prostate cancer, there is a lack of evidence for patients currently undergoing treatment (for example, during radiotherapy treatment). Similarly, there is minimal evidence for patients with advanced or metastatic disease [70]. This is most likely due to concerns regarding the putative role of androgens in driving disease progression. Thus, better evidence is needed to address the safety and cancer risk profile to help guide counseling. It is important to note that cardiovascular disease constitutes to substantial mortality risk in men with prostate cancer [71], likely due to the increased risk of metabolic comorbidities associated with decreased testosterone levels [72]. This highlights that further research is needed to evaluate the optimal management of prostate cancer in terms of disease progression but also competing risks and overall health. Large-scale, randomized studies with a focus on quality-of-life metrics are needed to address the paucity of evidence in this aspect of prostate cancer management. Future studies focusing on the safety profile of TRT should analyze the type of treatment, grading and stage of cancer, serum PSA levels, BCR status, hypogonadal symptoms, serum testosterone levels, preexisting metabolic disorders such as diabetes, and cardiovascular disease status. Secondary outcomes should include metastasis and mortality risks and complications associated with prostate cancer as well as hypogonadism. It is important to recognize that existing literature has described the association between low testosterone levels and increased risk of seminal vesicle invasion [70], increased positive surgical margins after surgery [73], and metastasis [70].
Within this context, there is emerging evidence for the administration of exogenous testosterone with finasteride to improve symptoms of hypogonadism but also minimize increases in prostate size observed with TRT [74,75]. In the Prostate Cancer Prevention Trial (PCPT), the authors reported that finasteride reduced the relative risk of prostate cancer by 24.8%, but increased the relative risk of developing high-grade prostate cancer by 26.9% [76]. A recent meta-analysis which included 8 cohort studies by Wang et al. [77] reported that the use of finasteride in a chemoprevention setting was shown to reduce the risk of prostate cancer (OR 0.70, 95% CI [0.51, 0.96], p = 0.03) but may increase the risk of high-grade tumors (OR 2.10, 95% CI [1.85, 2.38], p < 0.00001). The reasons for these observations are unclear but might be due to the fact that finasteride use is associated with morphological changes that are similar to high-grade cancer, that high-grade tumors are resistant to finasteride therapy, or that finasteride treatment actually drives high-grade prostate cancer. However, longer-term follow-up of the PCPT did not identify any increased mortality risk in men diagnosed with high-grade prostate cancer who received finasteride treatment compared to placebo after 18 years (hazard ratio 0.94, 95% CI [0.70, 1.27], p = 0.68) [78,79]. Therefore, therapies such as finasteride should be investigated to assess the most optimal method of treating hypogonadal symptoms whilst reducing the risk of prostate cancer development or progression.
There has been an increased interest in the role of selective androgen receptor modulators (SARMs) as a treatment modality for hypogonadism in men with prostate cancer. SARMs function by exerting both agonistic and antagonistic effects on AR in specific tissues. Nyquist et al. observed that SARMs repressed oncoprotein expression and inhibited the growth of prostate cancer in vitro and in vivo [80]. Similarly, Chisamore et al. reported that the SARM MK-4541 inhibited prostate tumor growth and reduced plasma testosterone levels in murine studies [81]. Whilst SARMs represent a promising therapy for men with prostate cancer, there is an absence of prospective randomized controlled human studies. Therefore, until high-grade evidence is available, this treatment should be considered experimental.
There is also evidence that supports the role of conservative management such as diet and exercise for LOH, especially in patients with comorbidities such as obesity. Corona et al. [82] performed a meta-analysis of 22 studies investigating lifestyle modifications and testosterone levels and reported that both a low-calorie diet and bariatric surgery were associated with a significant increase in total testosterone levels compared to baseline values (p < 0.0001). The authors noted that the androgen rise was more pronounced with higher weight loss [82]. A recent retrospective study of 71 obese men with LOH [83] reported that a bodyweight loss greater than 10% correlated to total testosterone levels above 10.4 nmol/L (from a mean baseline level of 9.2 nmol/L, p < 0.01). Future studies should investigate the effects of conservative management, in patients with LOH and a history of prostate cancer as a lower-risk alternative to TRT.
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 prostate cancer, but this is based on low-quality evidence. There is also a lack of long-term data regarding disease progression and recurrence, mortality from cardiovascular disease, and other complications from hypogonadism in men with prostate cancer. Men with prostate cancer and symptomatic hypogonadism who have undergone curative management may potentially be suitable candidates for TRT at minimal testosterone doses to meet replacement needs, alongside monitoring for disease progression or recurrence. The use of TRT in all other cohorts of prostate cancer should be considered experimental and adequate patient counseling should be performed with a discussion regarding the risks of prostate cancer disease progression as well as hypogonadal symptoms and complications. The authors advocate the use of lifestyle changes and conservative therapies (weight loss, optimization of medical co-morbidities) in all patients with hypogonadism and prostate cancer, as this will mitigate the risks of hypogonadal symptoms, but also reduce the morbidity from other diseases such as cardiovascular disease. Moreover, lifestyle changes can be a safe alternative to TRT in men with prostate cancer.
Prabhakar Rajan, Ph.D., FRCS (Urol), FHEA, Clinical Senior Lecturer in Urology, Tharu Tharakan, MBBS, BSc, MRCS, Urology Registrar, Runzhi Chen, BSc., Medical student
Prostate cancer is one of the most frequently diagnosed malignancies in men worldwide and the life expectancy for men with prostate cancer is improving due to advancements in diagnostics and treatment. Male hypogonadism is associated with obesity, diabetes, and other comorbidities and also has been linked with increasing age; the primary therapy modality for this condition is testosterone replacement therapy (TRT). There are concerns that testosterone therapy may cause prostate cancer disease progression. However, contemporary evidence suggests that testosterone replacement therapy may be safe in specific groups of patients with prostate cancer. This chapter will summarise the contemporary literature regarding TRT use in hypogonadal men with prostate cancer, including limitations and future research goals.
Introduction
Male hypogonadism is characterized 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, anemia, and metabolic disorders [3-6]. Longitudinal studies have shown that testosterone progressively decreases with age [7-9]. 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-center cross-sectional study that 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 in 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. Global testosterone sales have increased by 100-fold over the last three decades and represent 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 optimization of medical co-morbidities specifically in patients with LOH remains weak [1]. Thus, LOH and exogenous testosterone utilization represents a growing public health issue [15]
Globally, prostate cancer is one of the most frequently diagnosed malignancies specific to the male sex and the 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 have 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 [21-23]. 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.
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 phosphatase activity in 8 men with metastatic prostate cancer. The authors reported that the mean acid phosphatase activity in four men decreased from 31.25 to 5.5 units within 12 days following bilateral orchidectomy [19]. This study demonstrated that androgen deprivation by surgical castration caused regression of metastatic prostate cancer with respect to serum enzymes [19]. In addition, subsequent exogenous testosterone administration resulted in an increase of acid phosphatase activity above precastration levels [19,28]. These study findings are supported by observational data reporting that eunuchs have impalpable prostate glands and rarely develop prostate cancer due to a deficiency in androgenic activity [29].
Androgen deprivation therapy (ADT) functions to suppress the AR pathway to prevent the growth of prostatic tumor cells [30]. It is the primary therapy for men with metastatic prostate cancer. ADT utilizes the effects of gonadotrophin-releasing hormone analogs to suppress the production of gonadotropins and endogenous testosterone, thereby conferring to medical castration [31]. However, the majority of prostate cancers treated with ADT will eventually progress to a castration-resistant form of the disease. Although the definitive pathophysiological mechanisms have not been fully elucidated, it has been postulated that the development of castration-resistant prostate cancer is largely due to ligand-independent AR activity. The proposed mechanisms include increased sensitivity of the AR to transcription cofactors, mutations in the AR causing resistance to anti-androgens, and overexpression of the AR [32,33]. There are an increasing number of studies that advocate for the use of intermittent ADT to reduce the risk of disease progression whilst maintaining oncological outcomes [34-36]. Such studies have also highlighted the benefits of intermittent ADT on morbidity [37], symptom profile [35], and cost savings [36]. However, there is a lack of prospective studies and the optimal regimen has not yet been clearly established [38].
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 prospective multi-center cohort study of 1023 hypogonadal men and reported that TRT did not increase the risk of prostate cancer. In a prospective cohort study by Feneley et al. [41] which included 1365 men, the authors reported that the incidence of prostate cancer during long-term TRT was equivalent to that of the general population. In light of this evidence, Morgentaler and Traish [27] postulated the androgen saturation theory which proposes that androgenic activity on prostate growth is limited by AR availability once maximal androgen-AR binding saturation has been reached. Hence, testosterone supplementation above the threshold level will not stimulate prostate growth [42]. This model suggests that prostatic ARs become saturated at serum testosterone concentrations below the physiological range [27]. The AR in prostatic tissue is postulated to become unreceptive to further increases in serum testosterone at concentrations above 8.3 nmol/L [27,43,44].
Despite the previous consensus that higher serum testosterone levels promote prostate cancer growth [19], the androgen saturation theory (Fig. 2) has provided a rationale for why higher serum testosterone levels seem unrelated to prostate cancer risk in the general population. Studies have corroborated this theory by demonstrating the lack of correlation between the endogenous total serum testosterone levels and serum prostate-specific antigen (PSA) in the general population, suggesting that the relationship between prostate cellular activity and testosterone is not linear [45]. Moreover, a randomized placebo-controlled trial in 44 men [46] concluded that whilst TRT was shown to normalize serum androgen levels in men with LOH (median testosterone 9.8 nmol/L to 22.2 nmol/L after 6 months of treatment), there were minimal effects on the intraprostatic tissue composition and cell proliferation seen on biopsy specimens. Further proteomic and genomic analysis of these specimens also revealed no statistically significant changes in gene expression of prostate-specific androgen-regulated biomarkers associated with the prostatic epithelium and prostate cancer [46].
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.
Testosterone replacement therapy in men with treated prostate cancer
There is increasing data showing the safety of TRT in hypogonadal patients who have undergone curative treatment of prostate cancer (Table 1). Teeling et al. [47] performed a meta-analysis comprising of 13 studies and included a total of 608 patients. The authors observed a negligible risk of biochemical recurrence (BCR) (recurrence risk 0.00, 95% CI [0.00, 0.005]) in men with cured high-risk prostate cancer when given TRT. However, the authors reported that the available evidence was of very low quality [47]. In a large, national comparative study (n = 69,984) where 1,012 patients received TRT after curative treatment of prostate cancer, no differences were observed between cohorts in BCR rates, prostate cancer-specific mortality, or overall mortality [48]. The median follow-up was 6.95 years (83.5 months) [48]. The authors concluded that TRT did not increase the risk of BCR or mortality in patients who had received curative treatment and thus appropriate for this cohort [48].
The majority of studies investigating the use of TRT in patients with prostate cancer who underwent curative management are small, retrospective cohort studies (Table 1). Agarwal and Oefelein [49] reported a significant improvement in symptoms of testosterone deficiency and quality of life (p = 0.00005) in 10 symptomatic hypogonadal men who previously underwent curative radical prostatectomy (RP) and were subsequently treated with TRT [49]. The authors also observed that after a median follow-up period of 19 months, there were no increases in serum PSA greater than 0.1 ng/mL [49]. Khera et al. [50] investigated the serum PSA levels in 57 men started on TRT following curative treatment of prostate cancer with RP. The authors reported no significant increases in PSA values despite significant increases in serum T levels [50]. However, a limitation to this study was that the median follow-up time was only 13 months, which may have been insufficient to detect possible BCR [50]. Ahlering et al. [51] performed a case-control study comparing BCR rates in 152 men who had undergone RP and were treated with TRT compared to those not treated with TRT. The authors reported BCR rates of 7.2% and 12.6% for TRT and non-TRT men, respectively. This study suggests that TRT does not significantly increase the risk of BCR in men treated with RP. In a retrospective study [52] of 109 hypogonadal men treated with RP who were given TRT, the authors reported a significantly lower BCR recurrence rate in men given TRT compared to a reference group of 49 men who had not received TRT (3.7% vs. 16.3%, p = 0.015). The authors postulated that the lower BCR rate in the treatment group may be due to increases in testosterone levels in the peripheral circulation without changes in residual prostate tissue levels [52].
Pastuszak et al. [53] investigated the effects of TRT in 98 hypogonadal men treated previously with radical radiotherapy (RT). The authors reported that TRT was associated with a small non-significant increase in median serum PSA levels at follow-up after a median of 40.8 months (0.08 ng/mL to 0.09 ng/mL, p = 0.051), and six patients (6.1%) fulfilled BCR criteria [53]. However, the authors note that the observed rate of BCR was lower than published rates in similar cohorts treated with RT without TRT administration [53,54].
Table 1 summarises the studies investigating the biochemical or clinical recurrence of prostate cancer after the use of TRT in men who had undergone RT or RP. The majority of studies suggest that TRT is not associated with BCR in men treated with radical treatments for prostate cancer. However, it must be recognized that the current data is limited by a paucity of long-term follow-up data and large prospective studies.
Testosterone replacement therapy in men with untreated/active surveillance prostate cancer
In men diagnosed with low-risk prostate cancer (typically defined as either a Gleason score of 6 or less, non-palpable disease, or low grade and stage), active surveillance (AS) and deferment of curative treatment is offered due to the relatively indolent nature of low-risk disease and risk of side effects associated with treatment [60]. In this cohort of patients, the safety of TRT has been disputed given the assumption that testosterone supplementation may increase the risk of disease progression. However, there is increasing evidence showing no significant association between TRT and prostate cancer diagnosis in the general population. A large retrospective study of 12,779 patients with LOH observed that the use of TRT did not result in an increased risk of prostate cancer (hazard ratio 0.97, 95% CI [0.71, 1.32]) after a mean follow-up of 4.6 years [61]. A meta-analysis of 22 randomized controlled trials involving 2351 patients reported no difference in prostate cancer diagnosis between TRT and placebo groups (OR 0.99, 95% CI [0.24, 4.02], p = 0.99) [22]. The authors also reported that short-term TRT use was more likely to be associated with increased PSA levels (mean difference 0.33, 95% CI [0.21, 0.44], p < 0.00001) but no apparent differences were reported in long-term TRT use [22]. Loeb et al. performed a nested case-control study from data from the National Prostate Cancer Register of Sweden and analyzed 38,570 men diagnosed with prostate cancer and 192,838 men without prostate cancer [39]. The authors reported no significant differences in prostate cancer risk between patients who had received TRT compared to those who had not received TRT (OR 1.03, 95% CI [0.91, 1.17]). Therefore, it is unclear whether TRT increases the risk of disease progression, especially given that there is no association between TRT use and prostate cancer incidence [62].
In summary, the current evidence investigating the risks and benefits of TRT in men with untreated prostate cancer is of low quality, with an absence of large-scale randomized controlled trials. Thus, the use of TRT in men with untreated prostate cancer can only be advocated in a clinical trial setting.
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 randomized 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 mortality rates. For example, hypogonadal men are at higher risk of cardiovascular disease [4] and therefore it would be interesting to identify whether TRT mitigates overall mortality by reducing the risk of cardiovascular disease despite a potential risk of prostate cancer disease progression. It must also be recognized that even in men with seemingly cured prostate cancer from RP or RT, there is an estimated 10-20% risk of clinical recurrence or biochemical failure within 15 years which is due to the presence of undetectable micro-metastases [66]. Therefore, randomized controlled trials are needed to mitigate this variable as the BCR rate could be artificially elevated in men undergoing TRT, who might already have micrometastases [66,67].
A limitation of the current evidence is that most studies report serum PSA levels as a marker of prostate cancer activity, but not mortality or metastatic progression rates. PSA is prostate but not cancer-specific, and therefore may not be a specific marker of disease progression. Moreover, a recent meta-analysis highlighted that serum PSA screening demonstrated no effect on overall mortality [68]. It is important to recognize that serum PSA monitoring has a role in the confirmation of curative treatment and indicator of prostate activity [69]. However, consideration should also be given to the patient quality of life cardiovascular disease status, and other markers of health, since hypogonadism may cause more morbidity and mortality than prostate cancer.
Whilst there is a growing body of evidence for TRT in men with either treated or untreated prostate cancer, there is a lack of evidence for patients currently undergoing treatment (for example, during radiotherapy treatment). Similarly, there is minimal evidence for patients with advanced or metastatic disease [70]. This is most likely due to concerns regarding the putative role of androgens in driving disease progression. Thus, better evidence is needed to address the safety and cancer risk profile to help guide counseling. It is important to note that cardiovascular disease constitutes to substantial mortality risk in men with prostate cancer [71], likely due to the increased risk of metabolic comorbidities associated with decreased testosterone levels [72]. This highlights that further research is needed to evaluate the optimal management of prostate cancer in terms of disease progression but also competing risks and overall health. Large-scale, randomized studies with a focus on quality-of-life metrics are needed to address the paucity of evidence in this aspect of prostate cancer management. Future studies focusing on the safety profile of TRT should analyze the type of treatment, grading and stage of cancer, serum PSA levels, BCR status, hypogonadal symptoms, serum testosterone levels, preexisting metabolic disorders such as diabetes, and cardiovascular disease status. Secondary outcomes should include metastasis and mortality risks and complications associated with prostate cancer as well as hypogonadism. It is important to recognize that existing literature has described the association between low testosterone levels and increased risk of seminal vesicle invasion [70], increased positive surgical margins after surgery [73], and metastasis [70].
Within this context, there is emerging evidence for the administration of exogenous testosterone with finasteride to improve symptoms of hypogonadism but also minimize increases in prostate size observed with TRT [74,75]. In the Prostate Cancer Prevention Trial (PCPT), the authors reported that finasteride reduced the relative risk of prostate cancer by 24.8%, but increased the relative risk of developing high-grade prostate cancer by 26.9% [76]. A recent meta-analysis which included 8 cohort studies by Wang et al. [77] reported that the use of finasteride in a chemoprevention setting was shown to reduce the risk of prostate cancer (OR 0.70, 95% CI [0.51, 0.96], p = 0.03) but may increase the risk of high-grade tumors (OR 2.10, 95% CI [1.85, 2.38], p < 0.00001). The reasons for these observations are unclear but might be due to the fact that finasteride use is associated with morphological changes that are similar to high-grade cancer, that high-grade tumors are resistant to finasteride therapy, or that finasteride treatment actually drives high-grade prostate cancer. However, longer-term follow-up of the PCPT did not identify any increased mortality risk in men diagnosed with high-grade prostate cancer who received finasteride treatment compared to placebo after 18 years (hazard ratio 0.94, 95% CI [0.70, 1.27], p = 0.68) [78,79]. Therefore, therapies such as finasteride should be investigated to assess the most optimal method of treating hypogonadal symptoms whilst reducing the risk of prostate cancer development or progression.
There has been an increased interest in the role of selective androgen receptor modulators (SARMs) as a treatment modality for hypogonadism in men with prostate cancer. SARMs function by exerting both agonistic and antagonistic effects on AR in specific tissues. Nyquist et al. observed that SARMs repressed oncoprotein expression and inhibited the growth of prostate cancer in vitro and in vivo [80]. Similarly, Chisamore et al. reported that the SARM MK-4541 inhibited prostate tumor growth and reduced plasma testosterone levels in murine studies [81]. Whilst SARMs represent a promising therapy for men with prostate cancer, there is an absence of prospective randomized controlled human studies. Therefore, until high-grade evidence is available, this treatment should be considered experimental.
There is also evidence that supports the role of conservative management such as diet and exercise for LOH, especially in patients with comorbidities such as obesity. Corona et al. [82] performed a meta-analysis of 22 studies investigating lifestyle modifications and testosterone levels and reported that both a low-calorie diet and bariatric surgery were associated with a significant increase in total testosterone levels compared to baseline values (p < 0.0001). The authors noted that the androgen rise was more pronounced with higher weight loss [82]. A recent retrospective study of 71 obese men with LOH [83] reported that a bodyweight loss greater than 10% correlated to total testosterone levels above 10.4 nmol/L (from a mean baseline level of 9.2 nmol/L, p < 0.01). Future studies should investigate the effects of conservative management, in patients with LOH and a history of prostate cancer as a lower-risk alternative to TRT.
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 prostate cancer, but this is based on low-quality evidence. There is also a lack of long-term data regarding disease progression and recurrence, mortality from cardiovascular disease, and other complications from hypogonadism in men with prostate cancer. Men with prostate cancer and symptomatic hypogonadism who have undergone curative management may potentially be suitable candidates for TRT at minimal testosterone doses to meet replacement needs, alongside monitoring for disease progression or recurrence. The use of TRT in all other cohorts of prostate cancer should be considered experimental and adequate patient counseling should be performed with a discussion regarding the risks of prostate cancer disease progression as well as hypogonadal symptoms and complications. The authors advocate the use of lifestyle changes and conservative therapies (weight loss, optimization of medical co-morbidities) in all patients with hypogonadism and prostate cancer, as this will mitigate the risks of hypogonadal symptoms, but also reduce the morbidity from other diseases such as cardiovascular disease. Moreover, lifestyle changes can be a safe alternative to TRT in men with prostate cancer.
