madman
Super Moderator
Testosterone therapy in prostate cancer: is it still a controversy? (2022)
Alex S. Barta , Alexander Van Hoofa , Ryan Badre-Humea , Joshua Selvarajaha , Kristian Robillarda and David M. Albala
Purpose of review
The benefits of testosterone therapy (TTh) in the hypogonadal male can be dramatic. Historically, TTh has been contraindicated in prostate cancer (PCa). Current evidence has redefined our understanding of the influence serum testosterone has on prostatic androgen activity. Increasing numbers of hypogonadal men with coexisting PCa emphasize the importance of describing those who may safely receive TTh. This review aims to present literature that evaluates the efficacy and safety of TTh in men with coexisting PCa.
Recent findings
Our study, a comprehensive review of published literature regarding TTh in men with a history of PCa, consisted of studies conducted from the 1940s to 2022. Our review discusses evidence in accordance with previous studies that TTh has a role in patients with localized PCa as it has not been reported to increase rates of recurrence or progression of PCa.
Summary
The use of TTh in hypogonadal men with a localized PCa has been shown to have positive clinical outcomes without increasing the rate of disease progression or recurrence. Further research, in a randomized controlled setting, is warranted.
INTRODUCTION
As the global population has aged, there has been an increase in testosterone prescriptions in men [1]. This has led to an improved understanding of the disease, the breadth of symptoms, and ways to better treat men who suffer from testosterone deficiency (hypogonadism) while also assessing prostate cancer (PCa) risk [2,3]. It is estimated that 10–40% of men experience testosterone deficiency with prevalence increasing with age [4–7]. Twelve percent of men in their 50s and 49% of men in their 80s have biochemical hypogonadism [8]. However, there is no universally agreed upon testosterone calibration standard, so clinicians typically consider testosterone deficiency as serum T (testosterone) levels below a value of 200–400 ng/dl [9–12]. Testosterone therapy (TTh) has been shown to be an effective treatment in alleviating symptoms of testosterone deficiency [13–15]. The symptoms of testosterone deficiency are broad, contributing to decreased energy and fatigue, depression and poor quality of life, insulin resistance, visceral obesity, sexual dysfunction, and more [16]. As such the clinical and lifestyle benefits of successful TTh can be dramatic. Despite this, many men with testosterone deficiency are denied exogenous testosterone administration because of their concurrent or previous diagnosis of prostate cancer (PCa), which has been a contraindication to TTh. Recently, TTh use in men with PCa has begun to be re-evaluated because of various studies reporting benefits to exogenous testosterone administration.
The finding that exogenous testosterone administration increased acid phosphatase activity and susceptibility to PCa progression date back to the 1940s. Urologists Charles Huggins and Clarence V. Hodges were awarded the Nobel Prize for their ‘androgen hypothesis’, which demonstrated that androgens play a role in the progression of PCa [17]. This established the belief that PCa development and growth were directly associated with androgenic levels in the body. Subsequent studies have supported this hypothesis in which untreated and previously treated PCa patients have suffered adverse effects of TTh [18,19]. Thus, it was concluded that androgens ‘activated’ PCa, which led to the unchallenged view that increasing serum androgen levels through exogenous testosterone administration would increase disease progression and cancer growth in PCa patients.
Over the past two decades, evidence has emerged that challenges the ‘androgen hypothesis’. Studies have shown that testosterone does not initiate PCa growth or result in disease progression following administration [3,20,21]. Additionally, long-acting testosterone injections have not been reported to increase serum prostate-specific antigen (PSA) or result in recurrence [22]. Although it was previously believed that PCa was caused by high levels of serum T, researchers have determined that there is no clear evidence to support this belief [23,24& ]. Nonetheless, TTh has remained controversial amongst clinicians because of the concern that increased androgen activity may promote PCa progression or recurrence. The purpose of this review is to compile and analyze the literature evaluating the safety of TTh in patients with a history of PCa.
RESULTS
Historical outline In a 1941 study, Huggins and Hodges discovered that serum acid phosphatase activity decreased in men with metastatic PCa when treated with orchiectomy or estrogen administration. Both treatments were shown to reduce serum T. They also reported that testosterone injections resulted in an increase in acid phosphatase levels [17]. Fowler and Whitmore [18] found that 45 out of 52 men with metastatic PCa experienced unfavorable responses within 30 days of testosterone administration. Prout and Brewer [19] reported that about 50% of men who had been castrated prior to exogenous testosterone administration experienced rapid progression or death. In a longitudinal study, Gann et al. [25] reported that men in the highest quartile of serum testosterone were more likely to develop PCa compared with the controls. Given these findings, it became widely accepted that testosterone administration triggered PCa growth [16]. The notion that an increase in testosterone levels equates to greater PCa progression has subsequently been taught to medical students for nearly seven decades.
Surgical castration became the standard treatment for men with metastatic PCa. However, castration through androgen-deprivation therapy (ADT) eventually superseded bilateral orchiectomy. The promising results of ADT led medical professionals to believe that exogenous androgen should not be administered to men with PCa [15]. In recent years, the risks of testosterone administration in men with PCa have begun to be re-evaluated. Morgentaler and Collins noted that Huggins and Hodges only reported information for one hormonally intact individual who received testosterone injections. According to Morgentaler et al. [26], this individual had inconsistent, unpredictable acid phosphatase results following testosterone administration. In Fowler and Whitmore’s study, all but four men were androgen deprived prior to receiving testosterone injections. Three of the four hormonally intact men who received exogenous testosterone did not experience rapid progression or unfavorable outcomes [18]. Hormonally intact men who received testosterone treatment in Prout and Brewer’s [19] study did not experience the negative outcomes that their castrated counterparts did. These findings suggested that TTh led to rapid progression in androgen-deprived men but not in men with normal serum testosterone concentrations. This difference between hormonally intact and androgen-deprived men led to the development of Morgentaler’s saturation model.
*The saturation model
The saturation model presented in Morgenthaler and Conners’ literature review shows the previous viewpoints and notions on serum testosterone concentration and PCa growth as well as a more modern outlook. Overall, the model is a description of the behavior of the androgen-driven prostate growth in relation to serum testosterone. The premise of the modern model describes two seemingly contradictory proposals: in the normal concentration range, benign and malignant prostate tissues appear indifferent to variation in serum androgen concentration and at very low concentrations, there is extreme sensitivity to variation in serum androgen concentrations. The saturation model resolves this paradox by postulating that there is a point at which increases in serum testosterone have no effect on the level of androgen-driven growth [15,26].
Recent studies have produced evidence that supports Morgentaler’s model. In a 2006 randomized, double-blind, placebo-controlled trial, Marks et al. reported on 44 patients who either received 150 mg of intramuscular testosterone enanthate (n = 21) or were in the placebo group (n = 19) for 6 months. While on treatment, patients had blood drawn and prostate tissue biopsied to look at serum and prostatic tissue levels of testosterone. Serum testosterone levels rose in men receiving TTh; however, no rise in testosterone levels was seen within the prostate tissue itself. In addition, TTh did not affect prostate tissue histology, biomarkers, gene expression, and cancer incidence or severity [27]. A saturation point at which serum testosterone concentration does not cause any further appreciable growth exists near 250 ng/dl or 8 nmol/l. Additionally, there have been several studies, which have documented that a baseline serum testosterone concentration greater than 250 ng/dl does not result in increasing PSA levels [28–30].
*Clinical recommendations from the American Urology Association and European Association of Urology
The most recent guidelines by the American Urology Association (AUA) suggest that a reasonable cutoff for testosterone deficiency is serum testosterone levels below 10.4 nmol/l or 300 ng/dl. In addition, the diagnosis of low testosterone requires two total testosterone measurements taken on separate occasions with both occurring in the morning. A clinical diagnosis can only be made if a patient has both low testosterone levels and symptoms of testosterone deficiency [31]. The AUA guidelines for initiating TTh in men with PCa are considered to be relatively liberal, with a few notable restrictions. Subject to risk stratification on a case-by-case basis, any man with a history of PCa treated with curative intent by radical prostatectomy or radiation may be considered for treatment with TTh. Clinicians are advised to use caution in men with PCa risk and conduct a shared decision-making approach with a discussion of the risks and benefits prior to starting TTh. More specifically, the recommendations suggest the clinician state that there is an overall lack of data to sufficiently quantify the risk of testosterone therapy after PCa treatment, especially with regard to long-term follow-up. Prior to initiation of TTh, a baseline digital rectal examination (DRE) and PSA should be obtained. Additionally, PSA levels are recommended to be monitored on the same schedule as men without testosterone deficiency. Close follow-up after TTh initiation is recommended to ensure testosterone levels are within the normal physiological range of 450–600 ng/dl. After achieving stable testosterone levels and symptomatic improvement, the AUA guidelines recommend monitoring patients every 6–12 months. Cessation should occur after 3–6 months of no response to TTh [31,32&&].
According to guidelines from the European Association of Urology (EAU), the threshold for testosterone deficiency is serum testosterone levels below 12.1 nmol/l or 349 ng/dl [33]. Prior to TTh, the EAU recommends calculation of free testosterone in men with symptoms of hypogonadism and normal testosterone, border-line total testosterone [between 8 and 12 nmol/l (231–346 ng/dl)], and elevated sex hormone-binding globulin levels [34]. Short-acting preparations are recommended when initiating TTh to allow for adjustment of treatment if side effects occur. However, clinicians should take caution when administering short-acting injections because of fluctuations in serum testosterone levels. Routine PSA monitoring is recommended for all patients on TTh. The EAU suggests that TTh be ‘cautiously considered’ at a minimum of 1 year following treatment of low-risk PCA with no signs of recurrence [35]. Similar to the recommendations of the AUA, the EAU recommends that patients follow up with serum testosterone testing at 3, 6, and 12 months after the onset of TTh, and every 6–12 months thereafter to monitor serum testosterone levels [36].
*Testosterone therapy in men with prostate cancer on active surveillance
Active surveillance combines PSA-level testing, DREs, and prostate biopsies to mitigate overtreatment and prevent side effects of curative treatment [37, 38&,39,40& ]. Although no randomized control trials have assessed the risk of TTh in patients with untreated PCa, there are reviews and retrospective studies that have addressed this concept [41]. In a 2005 study, Calof et al.reviewed 19 randomized trials (1966–2004) that required participants to undergo TTh for at least 90 days, including men that were at least 45 years old, and had low or low-to-normal testosterone levels. The authors found that rates of PCa, PSA greater than 4 ng/ml, and prostate biopsies were not significantly different in the treatment group than in the control group [42]. In a 2011 study, Morgentaler et al.reported that 13 symptomatic hypogonadal men with untreated PCa underwent TTh for a median of 30 months. The mean serum testosterone concentration of the patients changed from 238 to 664 ng/dl (P < 0.001), while there was no change in PSA or prostate volume. No cancer was observed in 54% of follow-up biopsies and no local or distant disease progression occurred [43].
In a more recent study, Jenkins et al. [44] reported on 24 patients who were on TTh and active surveillance with a mean follow-up of 29.2 months. The mean pretreatment PSA (3.79 2.65 ng/ml) was not significantly higher than the mean PSA while on TTh (4.23 2.42 ng/ml). Hashimoto et al. retrospectively reviewed 12 patients who underwent multiparametric prostate MRI (mpMRI) before and after TTh while under active surveillance. Following TTh, there was a significant increase in serum testosterone, PSA, and prostate volume. However, Prostate Imaging Reporting and Data System Version 2 (PI-RADSv2) scores remained the same in 10 of 12 patients after TTh [45]. In a 2016 study, Kacker et al. concluded that biopsy growth remained unaffected after 36 months for 28 men undergoing TTh while on active surveillance. Additionally, biopsy progression rates were similar for the treatment groups and historical controls [46]. In 2022, Flores et al. conducted a study with 82 patients on TTh and active surveillance. Prior to treatment, the median pre-TTh PSA levels were 4.6 ng/ml while the mean baseline serum testosterone levels were 305 ng/dl. Following TTh, the median PSA rose to 4.9 ng/ml and the mean serum testosterone levels rose to 553 ng/dl [47&&].
*Testosterone therapy in men with prostate cancer post radical prostatectomy
Although there is limited clinical evidence regarding the effect of testosterone use in men treated for PCa, the evidence that does exist suggests it is possible to achieve positive outcomes in these men. Specifically, the literature demonstrates that some men undergoing TTh have little-to-no PCa recurrence following radical prostatectomy (Table 1). In a 2004 study, Kaufman and Graydon reported that seven hypogonadal men who underwent radical prostatectomy experienced no biochemical or clinical evidence of recurrence. No PSAs were detectable prior to surgery and after testosterone administration [48]. The following year, Agarwal and Oefelein [49] reported similar findings in which 10 hypogonadal men with a history of PCa had no recurrence and experienced significant improvement in hypogonadal symptoms following TTh. In a study of 57 men treated with radical prostatectomy, Khera et al. found no increase in PSA values following testosterone administration. The median follow-up after TTh was 13 months and no biochemical recurrence (BCR) was reported [52]. Several other studies have shown that men treated with radical prostatectomy experience little-to-no BCR or disease progression [50,51,53,54–59].
More recent studies have reported similar results to those published nearly two decades ago. In a 2018 study, Morgentaler et al. [60] reported their series of 92 hypogonadal men who were treated with radical prostatectomy and underwent TTh. The median follow-up occurred 19 months following testosterone administration and BCR was observed in 6 men (6.5%). In 2020, Ahlering et al. examined the rates of BCR in 850 patients who underwent radical prostatectomy. After a median follow-up of 42 months, BCR was observed in 11 out of 152 (7.2%) and 53 out of 419 (12.6%) patients in the TTh and control groups, respectively. TTh was reported to be an independent predictor of recurrence-free survival and the patients prescribed TTh was about 54% less likely to recur (hazard ratio 0.54, 95% (CI) 0.292–0.997). Additionally, TTh appeared to delay recurrence by an average of 18 months [61,62& ]. In one of the largest studies to date, Shahine et al.reported the rates of BCR in 1303 men treated with robotic-assisted radical radical prostatectomy (RARP). The median follow-up was 48 months. Three out of 47 (6.4%) men treated with TTh and 157 (12.56%) of the control group experienced BCR. TTh was not found to be a predictor of BCR and serum testosterone levels significantly changed before and 6 months after the initiation of TTh [63&&].
*Testosterone therapy in men with prostate cancer post-radiation therapy
Recent advances in radiation therapy delivery have allowed for the use of ultrahypofractionated radiation therapy which uses a high dose per fraction through the use of the technique stereotactic body radiation therapy (SBRT). SBRT may be more well tolerated and efficacious for localized PCa when used alone or in conjunction with conventionally fractionated radiation therapy (CFRT). Both of these treatments fall under the broader umbrella of external beam radiation therapy (EBRT). In Haque et al.’s [64] review, the authors indicated that hypofractionation EBRT as opposed to conventionally fractionated EBRT was more favorable because of convenience to patients through decreasing time spent during treatment. Additionally, the authors indicated that there was radiobiological data indicating that hypofractionated radiation treatment could potentially improve the relationship between PCa cells killed and normal organ toxicity [64,65].
In terms of widely used treatments, approximately 50% of men with localized PCa undergo radical prostatectomy whereas 25% receive EBRT and brachytherapy [66]. In a 2007 study, Sarosdy reported on 31 men who received TTh after prostate brachytherapy for 6–102 months (median, 54 months), with a median follow-up of 24 months. Median serum total testosterone levels were 188 ng/ dl before TTh and rose to 498 ng/dl on TTh. PSA level was less than 0.1 ng/ml in 74.2% of patients studied (23 patients), less than 0.5 ng/ml in 96.7% of patients (30 patients), and less than 1 ng/ml in 100% of patients (31 patients). The authors indicated that none of the patients stopped TTh because of cancer recurrence or documented cancer progression [67]. In Morales et al.’s study, five men with poignant signs of testosterone deficiency underwent EBRT to treat localized PCa once their PSA levels had reached a nadir. The mean testosterone level prior to EBRT was 5.2 nmol/l, with a mean follow-up of 14.5 months. The mean testosterone level after treatment was 17.6 nmol/l and none of the men experienced PSA levels of more than 1.5 ng/ml [68].
In a 2013 study, Pastuszak et al. performed a retrospective review of 13 hypogonadal men with PCa who were treated with EBRT and subsequently received TTh between 2006 and 2011. Serum testosterone and PSA levels were evaluated about every 3 months. Median initial testosterone and PSA were 178.0 ng/dl and 0.30 ng/ml, respectively. Median follow-up after TTh initiation was 29.7 months (2.3–67.3 months). A significant increase in mean testosterone [368.0 (281.3–591.0) ng/dl, P = 0.012] was observed, with no significant increases in PSA [0.66 (0.16–1.35) ng/ml, P = 0.345]. Moreover, no significant increases in PSA or PCa recurrences were observed at any follow-up interval [69]. In the following study, Pastuszak et al. investigated 98 men who were treated for PCa with RT. Median baseline testosterone and PSA were 209 ng/dl and 0.08 ng/ml, respectively. Median follow-up after TTh initiation was 40.8 months (1.5–147 months). Serum testosterone increased to a median of 420 ng/dl during follow-up (P < 0.001). PSA rose to 0.09 ng/ml on TTh. Six men (6.1%) met criteria for biochemical recurrence [70].
DISCUSSION
Testosterone deficiency is a common and likely underdiagnosed condition with well described and significant impact on health and quality of life. The use of TTh is equally well described as a well-tolerated and effective treatment of this condition, with a growing body of evidence suggesting an increasingly wide array of benefits. The incidence of PCa and testosterone deficiency are both increased with age, and subsequently, it is increasingly common for the two conditions to co-exist in older men [4,5,6,7]. Testosterone has historically been contraindicated in men with a history of PCa secondary to the Huggins dogma that testosterone fuels PCa growth in a linear fashion. A large number of men suffering from testosterone deficiency in the setting of PCa fail to be offered or receive TTh and are, thus, deprived of the potential health and quality-of-life benefits. Although this practice was a reasonable standard 80 years ago when the ‘androgen hypothesis’ was developed, it is no longer supported by modern evidence.
At present, our improved understanding of the pathophysiological impact of androgens and serum testosterone on prostate cells (both benign and cancerous) have proven the ‘androgen hypothesis’ and a number of associated beliefs to be inaccurate. Some have argued this was an overly broad application of conclusions from an incomplete interpretation of Huggins and Hodges’ findings. The ‘androgen hypothesis’ was easily propagated without further inquiry secondary to the central role of androgen deprivation. In its place, the saturation model, initially described by Abraham Morganteller, has increasingly gained support from experts in the field. From a physiologic perspective, there is high-quality evidence in support of the saturation model. Data from in-vitro studies and randomized placebo-controlled trials have demonstrated androgen activity in prostatic tissue to be independent of changes in serum testosterone levels at normal physiological levels [27]. Furthermore, the evidence presented in this review suggests that PCa patients receiving curative treatments and undergoing TTh do not experience increased risks of disease progression, BCR, or treatment failure.
CONCLUSION
In this review, we presented evidence that treating hypogonadal men with a history of PCa with TTh does not cause significant increases in PCa progression. By changing the notion that testosterone drives PCa, many men with a history of PCa will have the opportunity to be treated for testosterone deficiency. This will allow for prodigious improvements in the quality of life of men with PCa. However, clinicians must still assess the risks of TTh for individual patients to ensure their disease is not exacerbated. Unfortunately, a randomized control study investigating the risks of TTh in men with a history of PCa has yet to be published, so clinicians need to use their best judgment when initiating TTh. We recommend more research efforts in this field that aim to find a standardized course of action that balances improving quality of life without worsening patient prognosis.
Alex S. Barta , Alexander Van Hoofa , Ryan Badre-Humea , Joshua Selvarajaha , Kristian Robillarda and David M. Albala
Purpose of review
The benefits of testosterone therapy (TTh) in the hypogonadal male can be dramatic. Historically, TTh has been contraindicated in prostate cancer (PCa). Current evidence has redefined our understanding of the influence serum testosterone has on prostatic androgen activity. Increasing numbers of hypogonadal men with coexisting PCa emphasize the importance of describing those who may safely receive TTh. This review aims to present literature that evaluates the efficacy and safety of TTh in men with coexisting PCa.
Recent findings
Our study, a comprehensive review of published literature regarding TTh in men with a history of PCa, consisted of studies conducted from the 1940s to 2022. Our review discusses evidence in accordance with previous studies that TTh has a role in patients with localized PCa as it has not been reported to increase rates of recurrence or progression of PCa.
Summary
The use of TTh in hypogonadal men with a localized PCa has been shown to have positive clinical outcomes without increasing the rate of disease progression or recurrence. Further research, in a randomized controlled setting, is warranted.
INTRODUCTION
As the global population has aged, there has been an increase in testosterone prescriptions in men [1]. This has led to an improved understanding of the disease, the breadth of symptoms, and ways to better treat men who suffer from testosterone deficiency (hypogonadism) while also assessing prostate cancer (PCa) risk [2,3]. It is estimated that 10–40% of men experience testosterone deficiency with prevalence increasing with age [4–7]. Twelve percent of men in their 50s and 49% of men in their 80s have biochemical hypogonadism [8]. However, there is no universally agreed upon testosterone calibration standard, so clinicians typically consider testosterone deficiency as serum T (testosterone) levels below a value of 200–400 ng/dl [9–12]. Testosterone therapy (TTh) has been shown to be an effective treatment in alleviating symptoms of testosterone deficiency [13–15]. The symptoms of testosterone deficiency are broad, contributing to decreased energy and fatigue, depression and poor quality of life, insulin resistance, visceral obesity, sexual dysfunction, and more [16]. As such the clinical and lifestyle benefits of successful TTh can be dramatic. Despite this, many men with testosterone deficiency are denied exogenous testosterone administration because of their concurrent or previous diagnosis of prostate cancer (PCa), which has been a contraindication to TTh. Recently, TTh use in men with PCa has begun to be re-evaluated because of various studies reporting benefits to exogenous testosterone administration.
The finding that exogenous testosterone administration increased acid phosphatase activity and susceptibility to PCa progression date back to the 1940s. Urologists Charles Huggins and Clarence V. Hodges were awarded the Nobel Prize for their ‘androgen hypothesis’, which demonstrated that androgens play a role in the progression of PCa [17]. This established the belief that PCa development and growth were directly associated with androgenic levels in the body. Subsequent studies have supported this hypothesis in which untreated and previously treated PCa patients have suffered adverse effects of TTh [18,19]. Thus, it was concluded that androgens ‘activated’ PCa, which led to the unchallenged view that increasing serum androgen levels through exogenous testosterone administration would increase disease progression and cancer growth in PCa patients.
Over the past two decades, evidence has emerged that challenges the ‘androgen hypothesis’. Studies have shown that testosterone does not initiate PCa growth or result in disease progression following administration [3,20,21]. Additionally, long-acting testosterone injections have not been reported to increase serum prostate-specific antigen (PSA) or result in recurrence [22]. Although it was previously believed that PCa was caused by high levels of serum T, researchers have determined that there is no clear evidence to support this belief [23,24& ]. Nonetheless, TTh has remained controversial amongst clinicians because of the concern that increased androgen activity may promote PCa progression or recurrence. The purpose of this review is to compile and analyze the literature evaluating the safety of TTh in patients with a history of PCa.
RESULTS
Historical outline In a 1941 study, Huggins and Hodges discovered that serum acid phosphatase activity decreased in men with metastatic PCa when treated with orchiectomy or estrogen administration. Both treatments were shown to reduce serum T. They also reported that testosterone injections resulted in an increase in acid phosphatase levels [17]. Fowler and Whitmore [18] found that 45 out of 52 men with metastatic PCa experienced unfavorable responses within 30 days of testosterone administration. Prout and Brewer [19] reported that about 50% of men who had been castrated prior to exogenous testosterone administration experienced rapid progression or death. In a longitudinal study, Gann et al. [25] reported that men in the highest quartile of serum testosterone were more likely to develop PCa compared with the controls. Given these findings, it became widely accepted that testosterone administration triggered PCa growth [16]. The notion that an increase in testosterone levels equates to greater PCa progression has subsequently been taught to medical students for nearly seven decades.
Surgical castration became the standard treatment for men with metastatic PCa. However, castration through androgen-deprivation therapy (ADT) eventually superseded bilateral orchiectomy. The promising results of ADT led medical professionals to believe that exogenous androgen should not be administered to men with PCa [15]. In recent years, the risks of testosterone administration in men with PCa have begun to be re-evaluated. Morgentaler and Collins noted that Huggins and Hodges only reported information for one hormonally intact individual who received testosterone injections. According to Morgentaler et al. [26], this individual had inconsistent, unpredictable acid phosphatase results following testosterone administration. In Fowler and Whitmore’s study, all but four men were androgen deprived prior to receiving testosterone injections. Three of the four hormonally intact men who received exogenous testosterone did not experience rapid progression or unfavorable outcomes [18]. Hormonally intact men who received testosterone treatment in Prout and Brewer’s [19] study did not experience the negative outcomes that their castrated counterparts did. These findings suggested that TTh led to rapid progression in androgen-deprived men but not in men with normal serum testosterone concentrations. This difference between hormonally intact and androgen-deprived men led to the development of Morgentaler’s saturation model.
*The saturation model
The saturation model presented in Morgenthaler and Conners’ literature review shows the previous viewpoints and notions on serum testosterone concentration and PCa growth as well as a more modern outlook. Overall, the model is a description of the behavior of the androgen-driven prostate growth in relation to serum testosterone. The premise of the modern model describes two seemingly contradictory proposals: in the normal concentration range, benign and malignant prostate tissues appear indifferent to variation in serum androgen concentration and at very low concentrations, there is extreme sensitivity to variation in serum androgen concentrations. The saturation model resolves this paradox by postulating that there is a point at which increases in serum testosterone have no effect on the level of androgen-driven growth [15,26].
Recent studies have produced evidence that supports Morgentaler’s model. In a 2006 randomized, double-blind, placebo-controlled trial, Marks et al. reported on 44 patients who either received 150 mg of intramuscular testosterone enanthate (n = 21) or were in the placebo group (n = 19) for 6 months. While on treatment, patients had blood drawn and prostate tissue biopsied to look at serum and prostatic tissue levels of testosterone. Serum testosterone levels rose in men receiving TTh; however, no rise in testosterone levels was seen within the prostate tissue itself. In addition, TTh did not affect prostate tissue histology, biomarkers, gene expression, and cancer incidence or severity [27]. A saturation point at which serum testosterone concentration does not cause any further appreciable growth exists near 250 ng/dl or 8 nmol/l. Additionally, there have been several studies, which have documented that a baseline serum testosterone concentration greater than 250 ng/dl does not result in increasing PSA levels [28–30].
*Clinical recommendations from the American Urology Association and European Association of Urology
The most recent guidelines by the American Urology Association (AUA) suggest that a reasonable cutoff for testosterone deficiency is serum testosterone levels below 10.4 nmol/l or 300 ng/dl. In addition, the diagnosis of low testosterone requires two total testosterone measurements taken on separate occasions with both occurring in the morning. A clinical diagnosis can only be made if a patient has both low testosterone levels and symptoms of testosterone deficiency [31]. The AUA guidelines for initiating TTh in men with PCa are considered to be relatively liberal, with a few notable restrictions. Subject to risk stratification on a case-by-case basis, any man with a history of PCa treated with curative intent by radical prostatectomy or radiation may be considered for treatment with TTh. Clinicians are advised to use caution in men with PCa risk and conduct a shared decision-making approach with a discussion of the risks and benefits prior to starting TTh. More specifically, the recommendations suggest the clinician state that there is an overall lack of data to sufficiently quantify the risk of testosterone therapy after PCa treatment, especially with regard to long-term follow-up. Prior to initiation of TTh, a baseline digital rectal examination (DRE) and PSA should be obtained. Additionally, PSA levels are recommended to be monitored on the same schedule as men without testosterone deficiency. Close follow-up after TTh initiation is recommended to ensure testosterone levels are within the normal physiological range of 450–600 ng/dl. After achieving stable testosterone levels and symptomatic improvement, the AUA guidelines recommend monitoring patients every 6–12 months. Cessation should occur after 3–6 months of no response to TTh [31,32&&].
According to guidelines from the European Association of Urology (EAU), the threshold for testosterone deficiency is serum testosterone levels below 12.1 nmol/l or 349 ng/dl [33]. Prior to TTh, the EAU recommends calculation of free testosterone in men with symptoms of hypogonadism and normal testosterone, border-line total testosterone [between 8 and 12 nmol/l (231–346 ng/dl)], and elevated sex hormone-binding globulin levels [34]. Short-acting preparations are recommended when initiating TTh to allow for adjustment of treatment if side effects occur. However, clinicians should take caution when administering short-acting injections because of fluctuations in serum testosterone levels. Routine PSA monitoring is recommended for all patients on TTh. The EAU suggests that TTh be ‘cautiously considered’ at a minimum of 1 year following treatment of low-risk PCA with no signs of recurrence [35]. Similar to the recommendations of the AUA, the EAU recommends that patients follow up with serum testosterone testing at 3, 6, and 12 months after the onset of TTh, and every 6–12 months thereafter to monitor serum testosterone levels [36].
*Testosterone therapy in men with prostate cancer on active surveillance
Active surveillance combines PSA-level testing, DREs, and prostate biopsies to mitigate overtreatment and prevent side effects of curative treatment [37, 38&,39,40& ]. Although no randomized control trials have assessed the risk of TTh in patients with untreated PCa, there are reviews and retrospective studies that have addressed this concept [41]. In a 2005 study, Calof et al.reviewed 19 randomized trials (1966–2004) that required participants to undergo TTh for at least 90 days, including men that were at least 45 years old, and had low or low-to-normal testosterone levels. The authors found that rates of PCa, PSA greater than 4 ng/ml, and prostate biopsies were not significantly different in the treatment group than in the control group [42]. In a 2011 study, Morgentaler et al.reported that 13 symptomatic hypogonadal men with untreated PCa underwent TTh for a median of 30 months. The mean serum testosterone concentration of the patients changed from 238 to 664 ng/dl (P < 0.001), while there was no change in PSA or prostate volume. No cancer was observed in 54% of follow-up biopsies and no local or distant disease progression occurred [43].
In a more recent study, Jenkins et al. [44] reported on 24 patients who were on TTh and active surveillance with a mean follow-up of 29.2 months. The mean pretreatment PSA (3.79 2.65 ng/ml) was not significantly higher than the mean PSA while on TTh (4.23 2.42 ng/ml). Hashimoto et al. retrospectively reviewed 12 patients who underwent multiparametric prostate MRI (mpMRI) before and after TTh while under active surveillance. Following TTh, there was a significant increase in serum testosterone, PSA, and prostate volume. However, Prostate Imaging Reporting and Data System Version 2 (PI-RADSv2) scores remained the same in 10 of 12 patients after TTh [45]. In a 2016 study, Kacker et al. concluded that biopsy growth remained unaffected after 36 months for 28 men undergoing TTh while on active surveillance. Additionally, biopsy progression rates were similar for the treatment groups and historical controls [46]. In 2022, Flores et al. conducted a study with 82 patients on TTh and active surveillance. Prior to treatment, the median pre-TTh PSA levels were 4.6 ng/ml while the mean baseline serum testosterone levels were 305 ng/dl. Following TTh, the median PSA rose to 4.9 ng/ml and the mean serum testosterone levels rose to 553 ng/dl [47&&].
*Testosterone therapy in men with prostate cancer post radical prostatectomy
Although there is limited clinical evidence regarding the effect of testosterone use in men treated for PCa, the evidence that does exist suggests it is possible to achieve positive outcomes in these men. Specifically, the literature demonstrates that some men undergoing TTh have little-to-no PCa recurrence following radical prostatectomy (Table 1). In a 2004 study, Kaufman and Graydon reported that seven hypogonadal men who underwent radical prostatectomy experienced no biochemical or clinical evidence of recurrence. No PSAs were detectable prior to surgery and after testosterone administration [48]. The following year, Agarwal and Oefelein [49] reported similar findings in which 10 hypogonadal men with a history of PCa had no recurrence and experienced significant improvement in hypogonadal symptoms following TTh. In a study of 57 men treated with radical prostatectomy, Khera et al. found no increase in PSA values following testosterone administration. The median follow-up after TTh was 13 months and no biochemical recurrence (BCR) was reported [52]. Several other studies have shown that men treated with radical prostatectomy experience little-to-no BCR or disease progression [50,51,53,54–59].
More recent studies have reported similar results to those published nearly two decades ago. In a 2018 study, Morgentaler et al. [60] reported their series of 92 hypogonadal men who were treated with radical prostatectomy and underwent TTh. The median follow-up occurred 19 months following testosterone administration and BCR was observed in 6 men (6.5%). In 2020, Ahlering et al. examined the rates of BCR in 850 patients who underwent radical prostatectomy. After a median follow-up of 42 months, BCR was observed in 11 out of 152 (7.2%) and 53 out of 419 (12.6%) patients in the TTh and control groups, respectively. TTh was reported to be an independent predictor of recurrence-free survival and the patients prescribed TTh was about 54% less likely to recur (hazard ratio 0.54, 95% (CI) 0.292–0.997). Additionally, TTh appeared to delay recurrence by an average of 18 months [61,62& ]. In one of the largest studies to date, Shahine et al.reported the rates of BCR in 1303 men treated with robotic-assisted radical radical prostatectomy (RARP). The median follow-up was 48 months. Three out of 47 (6.4%) men treated with TTh and 157 (12.56%) of the control group experienced BCR. TTh was not found to be a predictor of BCR and serum testosterone levels significantly changed before and 6 months after the initiation of TTh [63&&].
*Testosterone therapy in men with prostate cancer post-radiation therapy
Recent advances in radiation therapy delivery have allowed for the use of ultrahypofractionated radiation therapy which uses a high dose per fraction through the use of the technique stereotactic body radiation therapy (SBRT). SBRT may be more well tolerated and efficacious for localized PCa when used alone or in conjunction with conventionally fractionated radiation therapy (CFRT). Both of these treatments fall under the broader umbrella of external beam radiation therapy (EBRT). In Haque et al.’s [64] review, the authors indicated that hypofractionation EBRT as opposed to conventionally fractionated EBRT was more favorable because of convenience to patients through decreasing time spent during treatment. Additionally, the authors indicated that there was radiobiological data indicating that hypofractionated radiation treatment could potentially improve the relationship between PCa cells killed and normal organ toxicity [64,65].
In terms of widely used treatments, approximately 50% of men with localized PCa undergo radical prostatectomy whereas 25% receive EBRT and brachytherapy [66]. In a 2007 study, Sarosdy reported on 31 men who received TTh after prostate brachytherapy for 6–102 months (median, 54 months), with a median follow-up of 24 months. Median serum total testosterone levels were 188 ng/ dl before TTh and rose to 498 ng/dl on TTh. PSA level was less than 0.1 ng/ml in 74.2% of patients studied (23 patients), less than 0.5 ng/ml in 96.7% of patients (30 patients), and less than 1 ng/ml in 100% of patients (31 patients). The authors indicated that none of the patients stopped TTh because of cancer recurrence or documented cancer progression [67]. In Morales et al.’s study, five men with poignant signs of testosterone deficiency underwent EBRT to treat localized PCa once their PSA levels had reached a nadir. The mean testosterone level prior to EBRT was 5.2 nmol/l, with a mean follow-up of 14.5 months. The mean testosterone level after treatment was 17.6 nmol/l and none of the men experienced PSA levels of more than 1.5 ng/ml [68].
In a 2013 study, Pastuszak et al. performed a retrospective review of 13 hypogonadal men with PCa who were treated with EBRT and subsequently received TTh between 2006 and 2011. Serum testosterone and PSA levels were evaluated about every 3 months. Median initial testosterone and PSA were 178.0 ng/dl and 0.30 ng/ml, respectively. Median follow-up after TTh initiation was 29.7 months (2.3–67.3 months). A significant increase in mean testosterone [368.0 (281.3–591.0) ng/dl, P = 0.012] was observed, with no significant increases in PSA [0.66 (0.16–1.35) ng/ml, P = 0.345]. Moreover, no significant increases in PSA or PCa recurrences were observed at any follow-up interval [69]. In the following study, Pastuszak et al. investigated 98 men who were treated for PCa with RT. Median baseline testosterone and PSA were 209 ng/dl and 0.08 ng/ml, respectively. Median follow-up after TTh initiation was 40.8 months (1.5–147 months). Serum testosterone increased to a median of 420 ng/dl during follow-up (P < 0.001). PSA rose to 0.09 ng/ml on TTh. Six men (6.1%) met criteria for biochemical recurrence [70].
DISCUSSION
Testosterone deficiency is a common and likely underdiagnosed condition with well described and significant impact on health and quality of life. The use of TTh is equally well described as a well-tolerated and effective treatment of this condition, with a growing body of evidence suggesting an increasingly wide array of benefits. The incidence of PCa and testosterone deficiency are both increased with age, and subsequently, it is increasingly common for the two conditions to co-exist in older men [4,5,6,7]. Testosterone has historically been contraindicated in men with a history of PCa secondary to the Huggins dogma that testosterone fuels PCa growth in a linear fashion. A large number of men suffering from testosterone deficiency in the setting of PCa fail to be offered or receive TTh and are, thus, deprived of the potential health and quality-of-life benefits. Although this practice was a reasonable standard 80 years ago when the ‘androgen hypothesis’ was developed, it is no longer supported by modern evidence.
At present, our improved understanding of the pathophysiological impact of androgens and serum testosterone on prostate cells (both benign and cancerous) have proven the ‘androgen hypothesis’ and a number of associated beliefs to be inaccurate. Some have argued this was an overly broad application of conclusions from an incomplete interpretation of Huggins and Hodges’ findings. The ‘androgen hypothesis’ was easily propagated without further inquiry secondary to the central role of androgen deprivation. In its place, the saturation model, initially described by Abraham Morganteller, has increasingly gained support from experts in the field. From a physiologic perspective, there is high-quality evidence in support of the saturation model. Data from in-vitro studies and randomized placebo-controlled trials have demonstrated androgen activity in prostatic tissue to be independent of changes in serum testosterone levels at normal physiological levels [27]. Furthermore, the evidence presented in this review suggests that PCa patients receiving curative treatments and undergoing TTh do not experience increased risks of disease progression, BCR, or treatment failure.
CONCLUSION
In this review, we presented evidence that treating hypogonadal men with a history of PCa with TTh does not cause significant increases in PCa progression. By changing the notion that testosterone drives PCa, many men with a history of PCa will have the opportunity to be treated for testosterone deficiency. This will allow for prodigious improvements in the quality of life of men with PCa. However, clinicians must still assess the risks of TTh for individual patients to ensure their disease is not exacerbated. Unfortunately, a randomized control study investigating the risks of TTh in men with a history of PCa has yet to be published, so clinicians need to use their best judgment when initiating TTh. We recommend more research efforts in this field that aim to find a standardized course of action that balances improving quality of life without worsening patient prognosis.
