madman
Super Moderator
Testosterone Treatment and the Risk of Prostate Adverse Events (2022)
Jason A. Levy, DO, MS, Arthur L. Burnett, MD, MBA, Adrian S. Dobs, MD, MHS
INTRODUCTION
Definition Hypogonadism is a clinical syndrome that results from failure of the testis to produce physiologic concentrations of testosterone (T).1 Various thresholds exist to define low total T ranging from 230 to 350 ng/dL. Peak T levels typically are measured between 3 and 8 AM with total T level decreasing during the first 30 minutes of waking.2Serum T decreases with age and has shown to have an association with diabetes, bone density loss, infertility, and other health disorders.3–5 Based on the most recent American Urologic Association (AUA) guidelines, clinicians should use a total T level of less than 300 ng/dL, or a free T below the normal range, as a reasonable cut-off in support of the diagnosis of low T.6 Further evaluation is often needed to determine the etiology of the hypogonadism. The intent of this article is to understand the effects T may have in the development and alteration of normal prostatic physiology and how it influences clinical applications in the hypogonadotropic male.
TESTOSTERONE AND THE PROSTATE
*The Prostate
The normal prostate gland develops from the urogenital sinus where circulating androgens produced by fetal testes play a critical role in its development. It is ovoid in shape and measures 3 cm in length, 4 cm in width, and 2 cm in depth with an estimated weight of 18 to 20 g. The base is situated at the bladder–prostate junction with the narrowed apex the most inferior portion of the prostate gland. It is divided into 3 distinct zones: the peripheral zone (the largest zone approximately 70% of tissue) and most susceptible to carcinoma, the transitional zone in which benign prostatic hyperplasia and ultimately obstruction may occur, and finally the central zone. The prostate is composed of both glandular elements (70%) as well as fibromuscular stroma (30%).7
The prostate depends on hormonal stimulation to develop, and previous studies have demonstrated that a lack of T has resulted in inability of the prostate to develop normally.8 T is converted to dihydrotestosterone via the enzyme 5-alpha reductase. Inhibiting this enzyme with pharmaceuticals such as finasteride and dutasteride decreases the amount of dihydrotestosterone available to the prostate and subsequently may result in not only cessation of growth, but also a shrinking of the gland as well. Exogenous T effects on the prostate remain controversial. Total prostate volume as well as transitional zone growth, as measured by ultrasound examination, were not significantly changed in patients undergoing T therapy. Numerous studies evaluating prostate-specific antigen (PSA) have demonstrated varying results as to whether PSA levels increase in T-deficient men.9 Kang and colleagues10 reviewed 15 studies with a total of 739 patients receiving T compared with 385 controls that demonstrated T therapy does not increase PSA levels in men being treated for hypogonadism, except when it is given by the intramuscular route, and even the increase with intramuscular administration is minimal.
*Benign Prostatic Hyperplasia and Testosterone
Lower urinary tract symptoms (LUTS), which include frequency, urgency, incomplete voiding, and slow stream, are common in both men and women with advancing age. The most common cause of LUTS in men is prostate enlargement and progression of BPH. Although there remains conflicting evidence about the benefits of T therapy in men with BPH and LUTS, the current body of literature demonstrates the safety of using T in men with BPH and LUTS.11 In regard to treating LUTS, numerous animal and human studies have been conducted to determine the effect of T on LUTS. T is hypothesized to improve LUTS via regulation of the expression of alpha-1 adrenergic receptors, phosphodiesterase type 5 activity, Rho-kinase activation, endothelin activity, and neuronal nitric oxide synthase.12,13 The effects of T on LUTS are not limited to overall effects on the prostate. In fact, in a rat model, T has been shown to improve bladder function via increasing bladder capacity and compliance by decreasing detrusor pressure.14 Similarly, Celayir15 measured baseline urodynamics and T levels in both control patients and those undergoing orchiectomy followed by treatment with or without T. Bladder capacity and compliance were increased on days 5 and 10 with T treatment, but decreased thereafter and returned to baseline levels on day 30, suggesting that T modulates bladder capacity and compliance.15
The aforementioned thought of T’s effects on LUTS transitioned similarly from animal models to human studies. T therapy has been reported to improve lower urinary tract function by increasing bladder capacity and compliance by decreasing detrusor pressure at maximal flow in men with T deficiency. Two separate studies, one with 30 men enrolled and another with 25 demonstrated statistically significant improvements in the International Prostate Symptom Score (IPSS) in addition to decreased mean detrusor pressure.16,17 Sixty Japanese men were recently enrolled in a clinical trial investigating the effects of T on various parameters. No statistical differences were observed regarding body mass index, postvoid residual urine volume, or prostate volume. However, similar to previous studies IPSS and International Index of Erectile Function scores improved significantly. Subgroup analysis demonstrated significant improvements in storage symptoms scores but not voiding symptoms scores.18
Last, the 2 largest studies to date involving 428 men with follow-up at 8 years and 999 men with follow-up at 3 years demonstrated conflicting results. Permpongkosol19 studied 428 men with late-onset hypogonadism, 120 of whom had 5 to 8 years of continuous T therapy. The study demonstrated a statistically significant improvement in the IPSS from a baseline of 8.54 6.6 to 6.78 5.44 and also statistically significantly increased the median PSA (0.96 mg/L).19 Conversely, the latter study by Debruyne and colleagues20 demonstrated mean baseline unadjusted PSA levels slightly higher for untreated men 2.2 9.1 ng/mL versus 1.1 1.7 ng/mL with treated men. Similarly, untreated men showed a slight increase in adjusted total IPSS over time, although little change was seen overall at baseline 5.13 on T therapy compared with 4.36, not on T therapy.20 Table 1 demonstrates a summary of T therapy on LUTS
A recent meta-analysis by Rastrelli and associates21 helped to reiterate previous findings that T “is not detrimental for the prostate, and treating hypogonadism could even produce relief from LUTS and limit prostatic inflammation, which generates and maintains the process leading to BPH.” Because of the significant number of studies regarding the effect of T and BPH, the most recent guidelines from the European Association of Urology state, there are no grounds to discourage T therapy in hypogonadal patients with BPH/LUTS and there is evidence of limited benefit from androgen administration.22
*Testosterone and Prostate Cancer
Prostate cancer (PCa) is the most commonly diagnosed cancer in men, with approximately 1 in 7 who will ultimately be diagnosed. In the United States, 170,000 men are diagnosed with PCa each year with a lifetime risk of death from PCa approximating nearly 2.8%. This totaled an estimated 31,620 PCa-related deaths in 2019. The pathogenesis of PCa is hormone-dependent, and it is thus important to assess the potential risks and benefits that exogenous T may have before a diagnosis of cancer and the role for T therapy after a cancer diagnosis.23–25
In 2017, Lopez and colleagues26 identified studies investigating the association of endogenous total T and use of T therapy with PCa events, ranging from 1990 to 2016. Most studies identified included observational studies as well as randomized controlled trials. The meta-analysis was subdivided into 3 parts. The first part demonstrated the association of endogenous total T with PCa in 31 observational studies (20 prospective and 11 prospective/retrospective). None of the 20 prospective studies demonstrated a relationship with PCa and 2 of 11 prospective/retrospective demonstrated an increased risk of PCa, whereas 2 demonstrated a decreased risk. Second, the relationship of categorical high versus low endogenous T was examined in 25 studies, 8 of which reported an increased risk of PCa in men with high T compared with low, but only 4 of these 8 were statistically significant. The remaining 17 studies showed a decreased risk of PCa after comparing high versus low, 11 of which were statistically significant. Finally, and perhaps most importantly in regards to T therapy were 2 meta-analyses of the randomized controlled trials (n=8 and n=11) involving associations with T therapy and PCa. These trials demonstrated a non-significant decreased risk of PCa.26 A more recent meta-analysis of 27 randomized controlled trials found no evidence of increased PSA levels after T therapy for 1 year. Included in the meta-analysis were 11 studies that found no evidence of increased risk of PCa.27
In conjunction with one another, both the AUA and European Association of Urology concluded that the current literature demonstrates an absence of evidence linking T to the development of PCa
*Testosterone Replacement in Men with a Prior Diagnosis of Prostate Cancer
T therapy can be considered in those men who have undergone radical prostatectomy with favorable pathology (ie, negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively. Three separate studies in patients undergoing T therapy demonstrated that patients who had undergone radical prostatectomy and had undetectable PSAs postoperatively demonstrated no cancer recurrence and maintained undetectable PSAs. The first study in 2004 included 7 hypogonadal men who underwent treatment with T therapy after undergoing radical prostatectomy, none of whom demonstrated recurrence. The next study in 2005 demonstrated similar results in 10 hypogonadal patients previously treated with radical prostatectomy and who had a median follow-up of 19 months after starting T therapy. Finally, the largest study in 2005 compared 103 hypogonadal men with PCa treated with radical prostatectomy and T therapy compared with 49 after radical prostatectomy in the reference group. Overall, 4 and 8 cases of recurrence were observed in the treatment group and reference groups, respectively.28–30
There remains a paucity of literature in patients treated with T therapy who were diagnosed with PCa previously and received radiation therapy as definitive treatment. Although scarce, retrospective studies of patients undergoing T therapy have been reported. In 2007, Sarosdy31 reported on 31 patients who had previously undergone brachytherapy for treatment of their PCa. T was started at a median of 4.5 years from brachytherapy treatment and, most notably, no patients stopped T therapy because of cancer recurrence or documented cancer progression, although 1 patient had transient increases in PSA.31 A similar retrospective study was published in 2014 with 20 patients who had previously undergone brachytherapy treatment for PCa.
Similarly, none of these patients had PCa progression or recurrence and no patient had an increasing serum PSA. They were also shown to have clinically significant benefits in both increase in T as well as improvements on the Sexual Health Inventory for Men questionnaire.32 A small case series of 5 patients who had previously been treated with external beam radiation after PSA nadir demonstrated marked clinical response to T therapy; however, 1 patient did have a transitory increase in the PSA.33
The final patient cohort that should be considered are those individuals who have been diagnosed previously with PCa but remain on an active surveillance protocol. The greatest concern patients and providers have regarding those individuals on active surveillance begs the question “will starting T therapy cause progression of previously diagnosed PCa?” In 2003, Rhoden and Morgentaler34 published a retrospective study of 75 patients previously diagnosed with prostatic intraepithelial neoplasia, but not PCa. They concluded at 1 year after treatment with T therapy that men with prostatic intraepithelial neoplasia do not have a greater increase in PSA or a significantly increased risk of cancer than men without prostatic intraepithelial neoplasia.34 In 2011, Morgentaler and colleagues35 retrospectively reviewed 13 men with untreated PCa and T deficiency who had received T therapy. They concluded that T therapy in men with untreated, low-volume, low to moderate grade PCa was not associated with progression in the short to medium term.35 More recently, a systematic review for T therapy in men with untreated PCa implied that T therapy might be harmful in men with advanced disease who undergo active surveillance.36
In practice, many men who have been diagnosed with and treated for PCa may have sufficiently low serum T levels and symptoms that may warrant T therapy. This may be particularly true in men who in the past were treated with androgen deprivation therapy and never fully regained activity of their hypothalamic-pituitary-gonadal axis. In this population, the resulting reduction in bone density, sexual function, and muscle mass may be particularly detrimental. Patients with T deficiency and a history of PCa should be informed that there is inadequate evidence to quantify the risk-benefit ratio of T therapy.6
*Clinical Evaluation and Initiation of Testosterone Replacement
Patients undergoing any type of hormone replacement therapy should undergo a comprehensive medical, surgical, and social history, as well as a physical examination. Obesity is strongly associated with hypogonadism, so body mass index, as well as measurement of waist circumference, are strongly recommended. When reviewing a patient’s LUTS, validated questionnaires such as the IPSS or AUA Symptom Index help not only to determine how bothersome an individual’s symptoms are but also how they are responding to treatment. Similar questionnaires are used to assess patients with erectile dysfunction, such as the International Index of Erectile Function questionnaire, which helps to discern erectile dysfunction severity and also can be helpful in assessing future improvements. In regards to a physical examination, components should include testicular size in addition to secondary sexual characteristics regarding overall androgen status. Finally, a digital rectal examination (DRE) should be performed to exclude any prostate abnormalities.22
PSA should be measured in men over 40 years of age before the commencement of T therapy to exclude a PCa diagnosis. In patients who have an elevated PSA at baseline, a second PSA test is recommended to rule out a spurious elevation. In patients who have 2 PSA levels at baseline that raise suspicion for the presence of PCa, a more formal evaluation should be conducted.6 Once a baseline PSA is established with no concern to pursue further testing for PCa, T supplementation may be started. Once patients who are started on T are maintained in the normal range, PSA testing should revert back to the AUA for PCa screening. Men aged 55 to 69 years undergo PSA screening via a shared decision-making process between the patient and their physician. Decisions in screening of men aged 40 to 54 years at higher risk for PCa should be individualized. The AUA defines men who may be at higher risk for PCa to include men of African American race, those with a family history of metastatic or lethal adenocarcinomas (ie, PCa, breast, ovarian, and pancreatic cancers), those affecting multiple first-degree relatives, and PCa that developed at younger ages.37
Although PSA remains the gold standard serum marker for diagnosis of PCa and DRE remains the gold standard physical examination, the amount of PCa missed in patients who have normal PSAs should be considered. Thompson and colleagues38 enrolled more than 18,000 men in a prevention trial and, among these, a cohort of 2950 men underwent prostate biopsy though they never had a PSA that was abnormal (>4.0 ng/mL) and never had an abnormal DRE. Of the 2950 men in the normal PSA/ DRE cohort, 449 (15.2%) had PCa, and 449 (14.9%) had a clinically significant PCa (Gleason grade 7 or higher).38 The DRE remains a common physical examination tool to help identify abnormalities in the prostate, which may prompt prostate biopsy owing to concerns for cancer. A further subanalysis of 35,350 men who underwent DRE from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) by Halpern and colleagues39 demonstrated that DRE has prognostic usefulness when the PSA was greater than 3 ng/mL, limited usefulness at less than 2 ng/ mL, and marginal usefulness for 2 to 3 ng/mL.39 Although new technologies (such as prostate MRI) and biomarkers are being used in practice more often, PSA and DRE remain the gold standard for PCa screening.
In the aforementioned study by Morgentaler and colleagues from 2011, patients who were treated with T therapy and had a previous diagnosis of PCa on active surveillance underwent PSA and DRE every 3 months with annual prostate biopsy. Furthermore, patients with high-risk or advanced PCa should not be candidates for T therapy. The authors remain in agreement with the following AUA guideline recommendations. For patients undergoing T therapy, T levels should be measured every 6 to 12 months. Finally, clinicians should discuss the cessation of T therapy 3 to 6 months after commencement of treatment in patients who experience normalization of total T levels but fail to achieve symptom or sign improvement.6
SUMMARY
The signs and symptoms of hypogonadism are becoming increasingly recognized and there is an increasing desire for both patients and providers to initiate T therapy to help mitigate issues with low libido, erectile function, anemia, bone mineral density, lean body mass, and even depressive symptoms. The benefit of T therapy remains a subject for debate, but the risk for adverse events on prostate health is likely minimal. As clinicians, it is important to weigh the benefits of prescribing any type of medication or hormone replacement therapy as well as understanding the risks associated with such. A substantial amount of literature regarding T therapy and its relation to both benign and malignant etiologies involving the prostate currently exists. However, most of this literature is not definitive and in fact, many studies contradict one another. Based on the currently available literature and in conjunction with current guidelines, T therapy should not be discouraged and may be of limited benefit in patients with BPH/ LUTS. Moreover, in relation to prostate malignancy, there is an absence of literature linking exogenous T to the development of PCa. Finally, in patients with a history of PCa, there remains inadequate evidence to quantify the risk-benefit ratio of exogenous T.
Jason A. Levy, DO, MS, Arthur L. Burnett, MD, MBA, Adrian S. Dobs, MD, MHS
INTRODUCTION
Definition Hypogonadism is a clinical syndrome that results from failure of the testis to produce physiologic concentrations of testosterone (T).1 Various thresholds exist to define low total T ranging from 230 to 350 ng/dL. Peak T levels typically are measured between 3 and 8 AM with total T level decreasing during the first 30 minutes of waking.2Serum T decreases with age and has shown to have an association with diabetes, bone density loss, infertility, and other health disorders.3–5 Based on the most recent American Urologic Association (AUA) guidelines, clinicians should use a total T level of less than 300 ng/dL, or a free T below the normal range, as a reasonable cut-off in support of the diagnosis of low T.6 Further evaluation is often needed to determine the etiology of the hypogonadism. The intent of this article is to understand the effects T may have in the development and alteration of normal prostatic physiology and how it influences clinical applications in the hypogonadotropic male.
TESTOSTERONE AND THE PROSTATE
*The Prostate
The normal prostate gland develops from the urogenital sinus where circulating androgens produced by fetal testes play a critical role in its development. It is ovoid in shape and measures 3 cm in length, 4 cm in width, and 2 cm in depth with an estimated weight of 18 to 20 g. The base is situated at the bladder–prostate junction with the narrowed apex the most inferior portion of the prostate gland. It is divided into 3 distinct zones: the peripheral zone (the largest zone approximately 70% of tissue) and most susceptible to carcinoma, the transitional zone in which benign prostatic hyperplasia and ultimately obstruction may occur, and finally the central zone. The prostate is composed of both glandular elements (70%) as well as fibromuscular stroma (30%).7
The prostate depends on hormonal stimulation to develop, and previous studies have demonstrated that a lack of T has resulted in inability of the prostate to develop normally.8 T is converted to dihydrotestosterone via the enzyme 5-alpha reductase. Inhibiting this enzyme with pharmaceuticals such as finasteride and dutasteride decreases the amount of dihydrotestosterone available to the prostate and subsequently may result in not only cessation of growth, but also a shrinking of the gland as well. Exogenous T effects on the prostate remain controversial. Total prostate volume as well as transitional zone growth, as measured by ultrasound examination, were not significantly changed in patients undergoing T therapy. Numerous studies evaluating prostate-specific antigen (PSA) have demonstrated varying results as to whether PSA levels increase in T-deficient men.9 Kang and colleagues10 reviewed 15 studies with a total of 739 patients receiving T compared with 385 controls that demonstrated T therapy does not increase PSA levels in men being treated for hypogonadism, except when it is given by the intramuscular route, and even the increase with intramuscular administration is minimal.
*Benign Prostatic Hyperplasia and Testosterone
Lower urinary tract symptoms (LUTS), which include frequency, urgency, incomplete voiding, and slow stream, are common in both men and women with advancing age. The most common cause of LUTS in men is prostate enlargement and progression of BPH. Although there remains conflicting evidence about the benefits of T therapy in men with BPH and LUTS, the current body of literature demonstrates the safety of using T in men with BPH and LUTS.11 In regard to treating LUTS, numerous animal and human studies have been conducted to determine the effect of T on LUTS. T is hypothesized to improve LUTS via regulation of the expression of alpha-1 adrenergic receptors, phosphodiesterase type 5 activity, Rho-kinase activation, endothelin activity, and neuronal nitric oxide synthase.12,13 The effects of T on LUTS are not limited to overall effects on the prostate. In fact, in a rat model, T has been shown to improve bladder function via increasing bladder capacity and compliance by decreasing detrusor pressure.14 Similarly, Celayir15 measured baseline urodynamics and T levels in both control patients and those undergoing orchiectomy followed by treatment with or without T. Bladder capacity and compliance were increased on days 5 and 10 with T treatment, but decreased thereafter and returned to baseline levels on day 30, suggesting that T modulates bladder capacity and compliance.15
The aforementioned thought of T’s effects on LUTS transitioned similarly from animal models to human studies. T therapy has been reported to improve lower urinary tract function by increasing bladder capacity and compliance by decreasing detrusor pressure at maximal flow in men with T deficiency. Two separate studies, one with 30 men enrolled and another with 25 demonstrated statistically significant improvements in the International Prostate Symptom Score (IPSS) in addition to decreased mean detrusor pressure.16,17 Sixty Japanese men were recently enrolled in a clinical trial investigating the effects of T on various parameters. No statistical differences were observed regarding body mass index, postvoid residual urine volume, or prostate volume. However, similar to previous studies IPSS and International Index of Erectile Function scores improved significantly. Subgroup analysis demonstrated significant improvements in storage symptoms scores but not voiding symptoms scores.18
Last, the 2 largest studies to date involving 428 men with follow-up at 8 years and 999 men with follow-up at 3 years demonstrated conflicting results. Permpongkosol19 studied 428 men with late-onset hypogonadism, 120 of whom had 5 to 8 years of continuous T therapy. The study demonstrated a statistically significant improvement in the IPSS from a baseline of 8.54 6.6 to 6.78 5.44 and also statistically significantly increased the median PSA (0.96 mg/L).19 Conversely, the latter study by Debruyne and colleagues20 demonstrated mean baseline unadjusted PSA levels slightly higher for untreated men 2.2 9.1 ng/mL versus 1.1 1.7 ng/mL with treated men. Similarly, untreated men showed a slight increase in adjusted total IPSS over time, although little change was seen overall at baseline 5.13 on T therapy compared with 4.36, not on T therapy.20 Table 1 demonstrates a summary of T therapy on LUTS
A recent meta-analysis by Rastrelli and associates21 helped to reiterate previous findings that T “is not detrimental for the prostate, and treating hypogonadism could even produce relief from LUTS and limit prostatic inflammation, which generates and maintains the process leading to BPH.” Because of the significant number of studies regarding the effect of T and BPH, the most recent guidelines from the European Association of Urology state, there are no grounds to discourage T therapy in hypogonadal patients with BPH/LUTS and there is evidence of limited benefit from androgen administration.22
*Testosterone and Prostate Cancer
Prostate cancer (PCa) is the most commonly diagnosed cancer in men, with approximately 1 in 7 who will ultimately be diagnosed. In the United States, 170,000 men are diagnosed with PCa each year with a lifetime risk of death from PCa approximating nearly 2.8%. This totaled an estimated 31,620 PCa-related deaths in 2019. The pathogenesis of PCa is hormone-dependent, and it is thus important to assess the potential risks and benefits that exogenous T may have before a diagnosis of cancer and the role for T therapy after a cancer diagnosis.23–25
In 2017, Lopez and colleagues26 identified studies investigating the association of endogenous total T and use of T therapy with PCa events, ranging from 1990 to 2016. Most studies identified included observational studies as well as randomized controlled trials. The meta-analysis was subdivided into 3 parts. The first part demonstrated the association of endogenous total T with PCa in 31 observational studies (20 prospective and 11 prospective/retrospective). None of the 20 prospective studies demonstrated a relationship with PCa and 2 of 11 prospective/retrospective demonstrated an increased risk of PCa, whereas 2 demonstrated a decreased risk. Second, the relationship of categorical high versus low endogenous T was examined in 25 studies, 8 of which reported an increased risk of PCa in men with high T compared with low, but only 4 of these 8 were statistically significant. The remaining 17 studies showed a decreased risk of PCa after comparing high versus low, 11 of which were statistically significant. Finally, and perhaps most importantly in regards to T therapy were 2 meta-analyses of the randomized controlled trials (n=8 and n=11) involving associations with T therapy and PCa. These trials demonstrated a non-significant decreased risk of PCa.26 A more recent meta-analysis of 27 randomized controlled trials found no evidence of increased PSA levels after T therapy for 1 year. Included in the meta-analysis were 11 studies that found no evidence of increased risk of PCa.27
In conjunction with one another, both the AUA and European Association of Urology concluded that the current literature demonstrates an absence of evidence linking T to the development of PCa
*Testosterone Replacement in Men with a Prior Diagnosis of Prostate Cancer
T therapy can be considered in those men who have undergone radical prostatectomy with favorable pathology (ie, negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively. Three separate studies in patients undergoing T therapy demonstrated that patients who had undergone radical prostatectomy and had undetectable PSAs postoperatively demonstrated no cancer recurrence and maintained undetectable PSAs. The first study in 2004 included 7 hypogonadal men who underwent treatment with T therapy after undergoing radical prostatectomy, none of whom demonstrated recurrence. The next study in 2005 demonstrated similar results in 10 hypogonadal patients previously treated with radical prostatectomy and who had a median follow-up of 19 months after starting T therapy. Finally, the largest study in 2005 compared 103 hypogonadal men with PCa treated with radical prostatectomy and T therapy compared with 49 after radical prostatectomy in the reference group. Overall, 4 and 8 cases of recurrence were observed in the treatment group and reference groups, respectively.28–30
There remains a paucity of literature in patients treated with T therapy who were diagnosed with PCa previously and received radiation therapy as definitive treatment. Although scarce, retrospective studies of patients undergoing T therapy have been reported. In 2007, Sarosdy31 reported on 31 patients who had previously undergone brachytherapy for treatment of their PCa. T was started at a median of 4.5 years from brachytherapy treatment and, most notably, no patients stopped T therapy because of cancer recurrence or documented cancer progression, although 1 patient had transient increases in PSA.31 A similar retrospective study was published in 2014 with 20 patients who had previously undergone brachytherapy treatment for PCa.
Similarly, none of these patients had PCa progression or recurrence and no patient had an increasing serum PSA. They were also shown to have clinically significant benefits in both increase in T as well as improvements on the Sexual Health Inventory for Men questionnaire.32 A small case series of 5 patients who had previously been treated with external beam radiation after PSA nadir demonstrated marked clinical response to T therapy; however, 1 patient did have a transitory increase in the PSA.33
The final patient cohort that should be considered are those individuals who have been diagnosed previously with PCa but remain on an active surveillance protocol. The greatest concern patients and providers have regarding those individuals on active surveillance begs the question “will starting T therapy cause progression of previously diagnosed PCa?” In 2003, Rhoden and Morgentaler34 published a retrospective study of 75 patients previously diagnosed with prostatic intraepithelial neoplasia, but not PCa. They concluded at 1 year after treatment with T therapy that men with prostatic intraepithelial neoplasia do not have a greater increase in PSA or a significantly increased risk of cancer than men without prostatic intraepithelial neoplasia.34 In 2011, Morgentaler and colleagues35 retrospectively reviewed 13 men with untreated PCa and T deficiency who had received T therapy. They concluded that T therapy in men with untreated, low-volume, low to moderate grade PCa was not associated with progression in the short to medium term.35 More recently, a systematic review for T therapy in men with untreated PCa implied that T therapy might be harmful in men with advanced disease who undergo active surveillance.36
In practice, many men who have been diagnosed with and treated for PCa may have sufficiently low serum T levels and symptoms that may warrant T therapy. This may be particularly true in men who in the past were treated with androgen deprivation therapy and never fully regained activity of their hypothalamic-pituitary-gonadal axis. In this population, the resulting reduction in bone density, sexual function, and muscle mass may be particularly detrimental. Patients with T deficiency and a history of PCa should be informed that there is inadequate evidence to quantify the risk-benefit ratio of T therapy.6
*Clinical Evaluation and Initiation of Testosterone Replacement
Patients undergoing any type of hormone replacement therapy should undergo a comprehensive medical, surgical, and social history, as well as a physical examination. Obesity is strongly associated with hypogonadism, so body mass index, as well as measurement of waist circumference, are strongly recommended. When reviewing a patient’s LUTS, validated questionnaires such as the IPSS or AUA Symptom Index help not only to determine how bothersome an individual’s symptoms are but also how they are responding to treatment. Similar questionnaires are used to assess patients with erectile dysfunction, such as the International Index of Erectile Function questionnaire, which helps to discern erectile dysfunction severity and also can be helpful in assessing future improvements. In regards to a physical examination, components should include testicular size in addition to secondary sexual characteristics regarding overall androgen status. Finally, a digital rectal examination (DRE) should be performed to exclude any prostate abnormalities.22
PSA should be measured in men over 40 years of age before the commencement of T therapy to exclude a PCa diagnosis. In patients who have an elevated PSA at baseline, a second PSA test is recommended to rule out a spurious elevation. In patients who have 2 PSA levels at baseline that raise suspicion for the presence of PCa, a more formal evaluation should be conducted.6 Once a baseline PSA is established with no concern to pursue further testing for PCa, T supplementation may be started. Once patients who are started on T are maintained in the normal range, PSA testing should revert back to the AUA for PCa screening. Men aged 55 to 69 years undergo PSA screening via a shared decision-making process between the patient and their physician. Decisions in screening of men aged 40 to 54 years at higher risk for PCa should be individualized. The AUA defines men who may be at higher risk for PCa to include men of African American race, those with a family history of metastatic or lethal adenocarcinomas (ie, PCa, breast, ovarian, and pancreatic cancers), those affecting multiple first-degree relatives, and PCa that developed at younger ages.37
Although PSA remains the gold standard serum marker for diagnosis of PCa and DRE remains the gold standard physical examination, the amount of PCa missed in patients who have normal PSAs should be considered. Thompson and colleagues38 enrolled more than 18,000 men in a prevention trial and, among these, a cohort of 2950 men underwent prostate biopsy though they never had a PSA that was abnormal (>4.0 ng/mL) and never had an abnormal DRE. Of the 2950 men in the normal PSA/ DRE cohort, 449 (15.2%) had PCa, and 449 (14.9%) had a clinically significant PCa (Gleason grade 7 or higher).38 The DRE remains a common physical examination tool to help identify abnormalities in the prostate, which may prompt prostate biopsy owing to concerns for cancer. A further subanalysis of 35,350 men who underwent DRE from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) by Halpern and colleagues39 demonstrated that DRE has prognostic usefulness when the PSA was greater than 3 ng/mL, limited usefulness at less than 2 ng/ mL, and marginal usefulness for 2 to 3 ng/mL.39 Although new technologies (such as prostate MRI) and biomarkers are being used in practice more often, PSA and DRE remain the gold standard for PCa screening.
In the aforementioned study by Morgentaler and colleagues from 2011, patients who were treated with T therapy and had a previous diagnosis of PCa on active surveillance underwent PSA and DRE every 3 months with annual prostate biopsy. Furthermore, patients with high-risk or advanced PCa should not be candidates for T therapy. The authors remain in agreement with the following AUA guideline recommendations. For patients undergoing T therapy, T levels should be measured every 6 to 12 months. Finally, clinicians should discuss the cessation of T therapy 3 to 6 months after commencement of treatment in patients who experience normalization of total T levels but fail to achieve symptom or sign improvement.6
SUMMARY
The signs and symptoms of hypogonadism are becoming increasingly recognized and there is an increasing desire for both patients and providers to initiate T therapy to help mitigate issues with low libido, erectile function, anemia, bone mineral density, lean body mass, and even depressive symptoms. The benefit of T therapy remains a subject for debate, but the risk for adverse events on prostate health is likely minimal. As clinicians, it is important to weigh the benefits of prescribing any type of medication or hormone replacement therapy as well as understanding the risks associated with such. A substantial amount of literature regarding T therapy and its relation to both benign and malignant etiologies involving the prostate currently exists. However, most of this literature is not definitive and in fact, many studies contradict one another. Based on the currently available literature and in conjunction with current guidelines, T therapy should not be discouraged and may be of limited benefit in patients with BPH/ LUTS. Moreover, in relation to prostate malignancy, there is an absence of literature linking exogenous T to the development of PCa. Finally, in patients with a history of PCa, there remains inadequate evidence to quantify the risk-benefit ratio of exogenous T.
