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Potential Protective Effects of Testosterone Therapy on Prostate Cancer (2022)
Angeline Johny, Pratik Kanabur, and Mohit Khera
Abstract
This review article encompasses the historical perspective of androgen deprivation therapy by first reviewing the
early research conducted by Huggins and Hodge, followed by a cellular biological discussion of androgen receptors in prostate cancer (PCa) physiology, leading to a subsequent discussion of the risk and potential therapeutic role of testosterone therapy in localized, oligometastatic, and metastatic PCa.
Introduction
Hypogonadism is a constellation of symptoms, including fatigue, low energy state, decreased libido, erectile dysfunction, and low muscle/bone mass, and is a clinical syndrome associated with aging.1 The overall incidence of male hypogonadism is *5.6–30% and an estimated 500,000 Americans are reported to have male hypogonadism annually.1
Testosterone also decreases with age, with an annual decrease of *1% in free testosterone levels after the age of 30. Given that hypogonadism is predominantly a disease of the aging man, there is a significant possibility of an overlapping diagnosis of prostate cancer (PCa) along with hypogonadism, which can occur at any stage of the disease course. PCa currently has >200,000 new cases diagnosed in 2020 alone.2 The current mainstay for PCa therapy includes active surveillance (AS), radical prostatectomy, local radiation, or systemic therapy, with subsequent adjunct therapies designed to mitigate biochemical recurrence, noted to be as high as 53% who have received radiation, and up to 30% in patients who had undergone surgery.3
The initial relationship between PCa and testosterone was first investigated by Huggins and Hodge in the 1940s when serum phosphatases were demonstrated to significantly change with exposure to hormones, including testosterone.4,5 This was the first established relationship between hormonal effects within an oncological context and set the current paradigm of PCa therapy: targeting testosterone availability to minimize PCa proliferation. However, in 1965, Huggins, later on, went on to propose that hormonal excess might be used for therapeutic benefit, a proposal that has now regained renewed significant clinical interest.6
Although androgen deprivation has remained the mainstay of advanced PCa therapy, this discovered relationship was made before the advent of prostatic specific antigen (PSA) measurements and before the availability of reliable serum testosterone measurements, thus limiting its clinical applicability.7 Nonetheless, the relationship between testosterone and PCa remains complex and highly controversial. Androgens are the initial signal for DNA synthesis; however, extracellular factors and additional gene expression pathways exist within PCa physiology, convoluting therapy targets with regard to PCa.
No conclusive data have been demonstrated that testosterone therapy (TTh) increases PCa risk; however, clinical professional societies, including the Endocrine Society and the American Urological Association, advise against TTh in hypogonadal patients with PCa. In addition, existing clinical guidelines do not address nuances on TTh with respect to clinically localized PCa, locally advanced disease, and metastatic prostatic cancer.
The focus of this chapter is to demonstrate the evolution of the relationship between androgens and PCa, the prostate saturation model, and the potential protective effects of TTh on PCa.
*An Overview of the Relationship of Androgens and PCa
*The Advent of the Prostate Saturation Model
Potential Protective Effects of TTh on PCa—Clinical Studies
The relationship of low endogenous testosterone and increased rates and severity of PCa
Thus, these studies underscore the clinical relevance of the saturation model hypothesis in that low testosterone levels can impact prostate carcinogenesis. Given this physiological phenomenon, the relevance of treating hypogonadism is clinically relevant in the context of PCa and directly argues against previously understood relationships of androgens and PCa. The protective effect of the eugonadal state in the setting of PCa argues that TTh could mitigate the risk of PCa and may not yield that controversial risk once previously held.
PCa development in patients on TTh
The plethora of existing data investigating TTh, and the risk of de novo PCa development suggests that (1) the risk is comparable with that of eugonadal males who do not receive TTh and (2) TTh has shown protective effects with overall lower rates of higher risk aggressive PCa subtypes. The mechanisms behind these associations are not fully understood, yet they suggest that untreated hypogonadism is not only a detriment to the quality of life but could also potentially result in worse oncological outcomes.
Low testosterone levels linked to worse outcomes post radical prostatectomy for localized PCa
Thus, the association of worsening local oncological outcomes and recurrence among hypogonadal patients again underscores the importance of maintaining a eugonadal state and avoiding the potential role of the androgen receptor activity at ‘‘saturation point.’’ The existing literature also illustrates the potential clinical value of serum total and free testosterone in predicting postoperative outcomes and in guiding closer postoperative surveillance.
Bipolar androgen therapy and its role in advanced castrate-resistant PCa
The study demonstrates the safety of BAT and raises an exciting physiological concept in which BAT could potentially sensitize mCRPC to existing therapies thereby increasing the efficacy of the drug. Future studies will help elucidate this therapy and this cellular relationship, but preliminary studies have demonstrated that supraphysiological testosterone provides a safe potentially efficacious treatment option in a clinically challenging treatment landscape.
Conclusions
The current landscape of TTh in the setting of PCa has gone through several paradigm shifts from viewing testosterone as potentially dangerous (the proverbial ‘‘fuel to the fire’’) to generally safe, and now to a protective measure and potential therapy.
The prior dogmas of PCa as a hormonally mediated cancer responding to TTh have shifted after the advent of the prostate saturation model noted that prostatic activity is in response to a myriad of biochemical factors, and androgen levels are only clinically relevant at near castrate and castrate levels.
Clinical corroboration of this model has illustrated that TTh is not only safe but also can protect patients from developing aggressive progressive forms of PCa. This role is ever evolving and requires further exploration as patients could not only have improvements in quality of life but also in oncological outcomes.
Angeline Johny, Pratik Kanabur, and Mohit Khera
Abstract
This review article encompasses the historical perspective of androgen deprivation therapy by first reviewing the
early research conducted by Huggins and Hodge, followed by a cellular biological discussion of androgen receptors in prostate cancer (PCa) physiology, leading to a subsequent discussion of the risk and potential therapeutic role of testosterone therapy in localized, oligometastatic, and metastatic PCa.
Introduction
Hypogonadism is a constellation of symptoms, including fatigue, low energy state, decreased libido, erectile dysfunction, and low muscle/bone mass, and is a clinical syndrome associated with aging.1 The overall incidence of male hypogonadism is *5.6–30% and an estimated 500,000 Americans are reported to have male hypogonadism annually.1
Testosterone also decreases with age, with an annual decrease of *1% in free testosterone levels after the age of 30. Given that hypogonadism is predominantly a disease of the aging man, there is a significant possibility of an overlapping diagnosis of prostate cancer (PCa) along with hypogonadism, which can occur at any stage of the disease course. PCa currently has >200,000 new cases diagnosed in 2020 alone.2 The current mainstay for PCa therapy includes active surveillance (AS), radical prostatectomy, local radiation, or systemic therapy, with subsequent adjunct therapies designed to mitigate biochemical recurrence, noted to be as high as 53% who have received radiation, and up to 30% in patients who had undergone surgery.3
The initial relationship between PCa and testosterone was first investigated by Huggins and Hodge in the 1940s when serum phosphatases were demonstrated to significantly change with exposure to hormones, including testosterone.4,5 This was the first established relationship between hormonal effects within an oncological context and set the current paradigm of PCa therapy: targeting testosterone availability to minimize PCa proliferation. However, in 1965, Huggins, later on, went on to propose that hormonal excess might be used for therapeutic benefit, a proposal that has now regained renewed significant clinical interest.6
Although androgen deprivation has remained the mainstay of advanced PCa therapy, this discovered relationship was made before the advent of prostatic specific antigen (PSA) measurements and before the availability of reliable serum testosterone measurements, thus limiting its clinical applicability.7 Nonetheless, the relationship between testosterone and PCa remains complex and highly controversial. Androgens are the initial signal for DNA synthesis; however, extracellular factors and additional gene expression pathways exist within PCa physiology, convoluting therapy targets with regard to PCa.
No conclusive data have been demonstrated that testosterone therapy (TTh) increases PCa risk; however, clinical professional societies, including the Endocrine Society and the American Urological Association, advise against TTh in hypogonadal patients with PCa. In addition, existing clinical guidelines do not address nuances on TTh with respect to clinically localized PCa, locally advanced disease, and metastatic prostatic cancer.
The focus of this chapter is to demonstrate the evolution of the relationship between androgens and PCa, the prostate saturation model, and the potential protective effects of TTh on PCa.
*An Overview of the Relationship of Androgens and PCa
*The Advent of the Prostate Saturation Model
Potential Protective Effects of TTh on PCa—Clinical Studies
The relationship of low endogenous testosterone and increased rates and severity of PCa
Thus, these studies underscore the clinical relevance of the saturation model hypothesis in that low testosterone levels can impact prostate carcinogenesis. Given this physiological phenomenon, the relevance of treating hypogonadism is clinically relevant in the context of PCa and directly argues against previously understood relationships of androgens and PCa. The protective effect of the eugonadal state in the setting of PCa argues that TTh could mitigate the risk of PCa and may not yield that controversial risk once previously held.
PCa development in patients on TTh
The plethora of existing data investigating TTh, and the risk of de novo PCa development suggests that (1) the risk is comparable with that of eugonadal males who do not receive TTh and (2) TTh has shown protective effects with overall lower rates of higher risk aggressive PCa subtypes. The mechanisms behind these associations are not fully understood, yet they suggest that untreated hypogonadism is not only a detriment to the quality of life but could also potentially result in worse oncological outcomes.
Low testosterone levels linked to worse outcomes post radical prostatectomy for localized PCa
Thus, the association of worsening local oncological outcomes and recurrence among hypogonadal patients again underscores the importance of maintaining a eugonadal state and avoiding the potential role of the androgen receptor activity at ‘‘saturation point.’’ The existing literature also illustrates the potential clinical value of serum total and free testosterone in predicting postoperative outcomes and in guiding closer postoperative surveillance.
Bipolar androgen therapy and its role in advanced castrate-resistant PCa
The study demonstrates the safety of BAT and raises an exciting physiological concept in which BAT could potentially sensitize mCRPC to existing therapies thereby increasing the efficacy of the drug. Future studies will help elucidate this therapy and this cellular relationship, but preliminary studies have demonstrated that supraphysiological testosterone provides a safe potentially efficacious treatment option in a clinically challenging treatment landscape.
Conclusions
The current landscape of TTh in the setting of PCa has gone through several paradigm shifts from viewing testosterone as potentially dangerous (the proverbial ‘‘fuel to the fire’’) to generally safe, and now to a protective measure and potential therapy.
The prior dogmas of PCa as a hormonally mediated cancer responding to TTh have shifted after the advent of the prostate saturation model noted that prostatic activity is in response to a myriad of biochemical factors, and androgen levels are only clinically relevant at near castrate and castrate levels.
Clinical corroboration of this model has illustrated that TTh is not only safe but also can protect patients from developing aggressive progressive forms of PCa. This role is ever evolving and requires further exploration as patients could not only have improvements in quality of life but also in oncological outcomes.
