Testosterone and prostate cancer 2015, a Puke(TM) AudioPaper

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Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk.
Therapeutic Advances in Urology, 2015.
Jason Michaud, Kevin Billups and Alan Partin.
Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, USA.
DOI: 10.1177/1756287215597633

Abstract.
Testosterone plays a central role in male development and health. Likewise, androgen deficiency, or hypogonadism, is associated with a variety of symptoms including decreased energy, diminished libido and erectile dysfunction, among others. Male androgen levels steadily decline with age, and, in a subset of symptomatic older men, can result in late-onset hypogonadism. Over the last decade, increased awareness of hypogonadism among patients and providers has led to a significant rise in the use of testosterone replacement therapy for hypogonadism, and especially in late-onset hypogonadism. Accompanying the rise in testosterone replacement therapy are concerns of potential adverse effects, including cardiovascular risks and the promotion of prostate cancer. The androgen hypothesis asserts that prostate cancer development and progression is driven by androgens, and thus testosterone replacement therapy has the theoretical potential to drive prostate cancer development and progression. In this review, we examine existing data surrounding testosterone and prostate cancer. There is significant evidence that androgens promote prostate cancer in experimental systems. However, there is no clear evidence that elevations in endogenous testosterone levels promote the development of prostate cancer in humans. As a result of experimental and historical data on the progression of prostate cancer following testosterone replacement therapy, there has been widespread belief that testosterone replacement therapy will promote disease progression in prostate cancer patients. Despite these fears, there are a growing number of studies demonstrating no increase in prostate cancer incidence among men on testosterone replacement therapy. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on testosterone replacement therapy. While data from large, prospective, randomized, controlled trials are absent, testosterone replacement therapy in select prostate cancer patients is likely safe. In the end, the use of testosterone replacement therapy in prostate cancer patients is still considered experimental and should only be offered after well-informed shared decision making and with close monitoring.
Keywords: prostate cancer, testosterone, hypogonadism.

Introduction.
Androgen deficiency, or hypogonadism, is characterized by decreased serum testosterone and variable symptoms including decreased muscle mass, decreased energy, depressed mood, decreased libido and erectile dysfunction. As male androgen levels decline with age, a subset of symptomatic hypogonadal men develop so-called late-onset hypogonadism. Late-onset hypogonadism is associated with a variety of other disease states including hypertension, diabetes, hyperlipidemia and obesity. Although estimates vary, late-onset hypogonadism is a common condition and affects an estimated 2.4 million US men over 40 years of age.
Testosterone replacement therapy encompasses the administration of exogenous testosterone and other agents aimed at raising androgen levels in hypogonadal men. While testosterone replacement therapy has been used for decades by endocrinologists and urologists to treat men with hypogonadism, the last decade has seen a dramatic increase in the use of testosterone replacement therapy.

The percentage of men in the United States over 40 years of age prescribed TESTOSTERONE REPLACEMENT THERAPY increased from less than 1 percent in 2001 to nearly 3 percent in 2011. In 2011, global testosterone sales reached an estimated 1.8 billion dollars. With continued population growth of men over 65 years old, the number of men with late-onset hypogonadism who are candidates for testosterone replacement therapy can be expected to grow by over 400,000 per year.
The increase in testosterone replacement therapy and lack of data from large, long-term, randomized controlled trials, RCT’s, has raised concern for unrecognized adverse health risks, including potential increases in cardiovascular disease and prostate cancer. In this review we examine the effects of testosterone on Prostate Cancer pathogenesis and implications for testosterone replacement therapy and risk of progression in Prostate Cancer patients. We attempt to make important distinctions between patient populations and sources of testosterone. As such, we examine the role of endogenous testosterone in patients without Prostate Cancer, the role of endogenous testosterone in Prostate Cancer patients, and the potential oncologic risks of exogenous testosterone from testosterone replacement therapy in Prostate Cancer patients. Other aspects of testosterone replacement therapy, including the potential benefits to hypogonadal men and risk of adverse cardiovascular effects are beyond the scope of our review and have been expertly reviewed elsewhere.
Androgens and prostate physiology.
Androgens play a critical role in male sexual development and prostate physiology. The two principal androgens in men are testosterone, produced by testicular Leydig cells, and dihydrotestosterone, DHT), produced from testosterone in peripheral tissues by 5-alpha reductase. In circulation, testosterone is bound primarily to sex hormone-binding globulin (SHBG) while the unbound, or free testosterone, is the most bioavailable and active form. In the second trimester, fetal testosterone induces development of the epididymis, vas deferens and seminal vesicles, while DHT mediates development of the prostate, urethra and external genitalia. From birth through puberty, the prostate remains small and immature, while in postpubertal males the surge in androgens drives gland development and an increase in prostate volume up to 10 times its prepubertal size. DHT also plays a well-established role in promoting continued growth of the adult prostate, leading to benign prostatic hypertrophy, BPH.
Late-Onset hypogonadism.
Serum androgen levels in men steadily decline with age, beginning in the fourth decade of life. Accordingly, in the Baltimore Longitudinal Study on Aging, BLSA, roughly 10 percent of men in their forties and 25 percent of men in their seventies were hypogonadal, based on serum testosterone levels. While age related decline in testosterone is common among US populations it is not universal. For instance, Ellison and colleagues demonstrated young adult elevations in testosterone and subsequent age-related declines in US and Congo populations, but not in Nepal or Paraguay. In a subset of men, the age-related decline in androgens will lead to signs and symptoms of hypogonadism, termed late-onset hypogonadism or androgen deficiency in the aging male, ADAM.
Male hypogonadism may be caused by testicular, primary, or hypothalamic pituitary, secondary, dysfunction. Late-onset hypogonadism is typically characterized by mixed testicular and hypothalamic pituitary dysfunction. Testicular changes with aging include loss of Leydig cells, decreased testosterone production, and decreased responsiveness of the testes to luteinizing hormone. The resulting amplitude of peak morning testosterone is decreased in older men, making morning testosterone measurement a useful laboratory marker in the diagnosis of late-onset hypogonadism. Older men also demonstrate decreased amplitude and slowing of LH pulses and this hypothalamic dysfunction in late-onset hypogonadism is characterized by low-normal LH levels, even in the presence of low testosterone. The decline in total testosterone is further influenced by an increase in SHBG that occurs with aging, which may lower bioavailable testosterone.
An international consensus, including the International Society of Andrology, I S A, and the European Association of Urology, E A U, defines late-onset hypogonadism as a syndrome characterized by symptoms of hypogonadism and testosterone below the young adult reference range.

While common symptoms of hypogonadism in postpubertal men include decreased muscle mass, decreased energy, depressed mood, decreased libido, decreased spontaneous erections and erectile dysfunction, these symptoms can be considered subjective.
In a large, multi-institutional study of 3369 men aged 40 to 79 years, the European Male Aging Study (EMAS) attempted to better define the symptom complex of late-onset hypogonadism. Compared with constitutional symptoms, sexual symptoms of decreased morning erections, decreased libido and erectile dysfunction were most closely associated with low testosterone levels.
Prevalence estimates of late-onset hypogonadism vary widely depending on study methods, populations and diagnostic criteria used. The laboratory diagnosis of late-onset hypogonadism, including guideline recommendations, has been reviewed elsewhere. Importantly, the inclusion of symptoms in the diagnosis of late-onset hypogonadism helps to separate the pathologic condition of late-onset hypogonadism from normal, and expected, age-dependent declines in testosterone (Figure 1). For instance, in the Hypogonadism in Males, HIM, study, 38.7 percent of men over 45 years met criteria for androgen deficiency, defined as a morning total serum testosterone of less than 10.4 nano-moles per liter (300 nano-grams per deci liter). In contrast, in the European Male Aging Study (EMAS), using criteria of testosterone less than 11.1 nano-moles per liter (320 nano-grams per deci liter) combined with the presence of symptoms, an estimated 2.1 percent of men aged 40 to 79 years met these criteria. As expected, the prevalence of late-onset hypogonadism in EMAS increased with age, from 0.1 percent for men in their forties to 5.1 percent for men in their seventies. Using both laboratory and symptoms for diagnosis, the Massachusetts Male Aging Study estimated that 2.4 million US men met criteria for late-onset hypogonadism.
Endogenous testosterone and Prostate Cancer risk.
There is large body of both historic and modern data supporting a role for androgens in Prostate Cancer pathogenesis and progression, also known as the androgen hypothesis. In 1941, Huggins and Hodges proposed that Prostate Cancer growth was driven by androgens, after observing the benefits of castration in Prostate Cancer patients.
Current laboratory data demonstrate that many well-differentiated Prostate Cancer cell lines are androgen responsive and undergo programmed cell death upon androgen withdrawal. Likewise, androgens promote tumorigenesis and xenograft growth in animal models, and tumor regression is seen upon androgen deprivation. Clinically, androgen deprivation therapy (ADT) remains a mainstay in Prostate Cancer treatment, especially in advanced disease. Yet, despite basic science data supporting a role for androgens in Prostate Cancer pathogenesis, there are conflicting clinical data on the role of endogenous testosterone in human Prostate Cancer pathogenesis de novo. In reviewing the literature involving Prostate Cancer development in Prostate Cancer naive patients, there are studies implicating elevated testosterone, studies implicating lower testosterone, and studies with no association of testosterone and Prostate Cancer risk (Table 1).
Elevated testosterone and Prostate Cancer risk.
Several longitudinal studies have established a relationship between elevated testosterone and subsequent development of Prostate Cancer. Using serum samples and Prostate Cancer incidence data from the Physicians’ Health Study, Gann and colleagues identified 222 men with Prostate Cancer and 399 controls, matched for age, smoking status and follow up.
Compared with controls, men in the highest quartile of serum testosterone were more likely to develop Prostate Cancer, with an odds ratio of 2.6, 95 percent confidence interval (CI) 1.34 to 5.02, p equals 0.004. In another longitudinal analysis of a cohort of 781 patients enrolled in the BLSA, Pierorazio and colleagues examined the relationship between Prostate Cancer, serum testosterone, SHBG and free testosterone index (FTI), calculated as total serum testosterone divided by SHBG.

Figure 1.
Prevalence of symptomatic hypogonadism.
Percentage of hypogonadal men, with total serum testosterone of less than 11.3 nano moles per liter, 325 nano grams per deci-lliter, solid, or with both low testosterone and the listed sexual symptoms.

Of 145 cases of Prostate Cancer, 36 were categorized as high risk, based on modified D’Amico criteria. They found that high risk Prostate Cancer was associated with both FTI, with a hazard ratio, HR, of 1.91, 95 percent CI 1.10 to 3.32, p equals 0.02, and calculated free testosterone, HR 1.61, 95 percent CI 1.18 to 2.20, p equals 0.003. It should be noted that longitudinal studies of this kind are limited in that serum testosterone levels were not routinely drawn in the morning, and thus may not reflect the true peak circulating androgen levels. Lastly, Shaneyfelt and colleagues performed a meta-analysis of three prospective nested case-control studies, including the study by Gann and colleagues. Controlling for testosterone, estradiol, SHBG, age and body mass index (BMI), they demonstrated an increase in Prostate Cancer for men in the highest quartile of serum testosterone, with anOdds Ratio of 2.34, 95 percent CI 1.3 to 4.2, but no association of Prostate Cancer with DHT or estradiol.
Lower testosterone and Prostate Cancer risk.
While some longitudinal studies have demonstrated increased risk of Prostate Cancer with elevations in testosterone, smaller, well-designed studies have demonstrated the opposite, that is, increased Prostate Cancer risk in patients with lower testosterone levels.

Table 1. Endogenous testosterone and prostate cancer risk.

Columns are:
The study name, the number of patients, and the number with prostate cancer.
The Study design, the results with a 95 percent confidence interval, and comments.

A large study of untreated hypogonadal men with prostate-specific antigen (PSA) less than 4.0 nano grams per milli-liter revealed a relationship between low testosterone and Prostate Cancer , with anOdds Ratio of 2.02, 95 percent CI 1.10 to 3.72. A prospective cohort study of Korean men undergoing prostate biopsy for suspected Prostate Cancer compared biopsy results among men with low testosterone, defined as total testosterone levels below the median of 13.3 nano-moles per liter (385 nano-grams per deci liter). On multivariate analysis, low testosterone was associated with Prostate Cancer risk (OR 1.99, 95 percent Confidence Interval 1.25 to 3.16, p equals 0.003, but not Prostate Cancer grade.
No association of testosterone and Prostate Cancer.
Arguably the most robust data on the role of endogenous testosterone and Prostate Cancer risk comes from the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial which prospectively collected data on androgens and Prostate Cancer while comparing men treated with dutasteride or placebo. The placebo arm included 3242 patients between the ages of 50 and 75 years who all had at least one prior negative prostate biopsy.
Men had baseline androgen levels drawn and underwent prostate biopsy at 2 and 4 years, or for increases in PSA or abnormal digital rectal exam (DRE). In analyzing the placebo arm, researchers identified no association of testosterone or DHT with Prostate Cancer incidence or Gleason grade. Although information on the time of day for serum measurements was unknown and the study only included men with prior negative biopsy, the large number of patients and routine prostate biopsies make this population-based data in Prostate Cancer naive patients highly informative.
Similarly, in a large meta-analysis Roddam and colleagues examined the relationship between testosterone and Prostate Cancer in patients pooled from the Endogenous Hormones and Prostate Cancer Collaborative Group, which included data from 3886 Prostate Cancer patients and 6438 controls. They identified an inverse association of Prostate Cancer with SHBG, but not serum testosterone, with a relative risk (RR) of 0.86.
Testosterone and Prostate Cancer risk at biopsy.
There are a number of studies examining testosterone levels prior to prostate biopsy in men with suspected Prostate Cancer. Similar to studies on the general population, data are mixed on the relationship between testosterone and Prostate Cancer risk at biopsy. Yano and colleagues performed a prospective study in 420 men referred for prostate biopsy. They measured morning serum testosterone and examined the relationship to Prostate Cancer detection. There was no overall association of total testosterone with Prostate Cancer. However, in men with PSA levels of less than 10 micro grams per liter, there was a small but significant increase in Prostate Cancer risk among men with increased testosterone (HR 1.31, 95 percent CI 1.03 to 1.65, p equals 0.02.
Conversely, Mearini and colleagues examined the relationship between Prostate Cancer and testosterone among 206 men referred for evaluation of suspected Prostate Cancer or lower urinary tract symptoms (LUTS). They measured morning testosterone levels and compared 103 men diagnosed with BPH with 103 men diagnosed with Prostate Cancer. In multivariate analysis, lower testosterone levels were associated with Prostate Cancer, Odds Ratio of 0.70, 95 percent CI 0.55 to 0.89, p equals 0.004, especially in patients with total testosterone less than 8.3 nano-moles per liter (240 nano-grams per deci liter, with anOdds Ratio 0.134, 95 percent CI 0.039 to 0.453, p equals 0.001. An association of low testosterone and Prostate Cancer was also found in men with high grade prostatic intraepithelial neoplasia (HGPIN), where lower free testosterone was associated with Prostate Cancer diagnosis on re-biopsy (p equals 0.04).
There are several negative studies with mixed data on testosterone levels and associated Prostate Cancer risk at prostate biopsy. In a prospective study of 478 patients undergoing prostate biopsy for elevated PSA or abnormal DRE, testosterone levels were compared with biopsy results including cancer detection rates, PSA and Gleason grade.
Neither total testosterone nor free testosterone levels were associated with Prostate Cancer diagnosis or Gleason grade. Likewise, Botelho and colleagues examined total testosterone and biopsy results in a large study of 1570 patients referred for prostate biopsy for abnormal DRE or elevated PSA, and found no association between Prostate Cancer on biopsy and total testosterone.
Endogenous testosterone in Prostate Cancer patients.
Despite the large amount of basic science data implicating androgens in Prostate Cancer pathogenesis and progression, there is a lack of direct evidence that endogenous testosterone promotes Prostate Cancer progression in clinically localized disease. In fact, clinical studies have mainly associated lower testosterone levels with Prostate Cancer disease severity.

Several studies have implicated lower testosterone with higher Gleason grade at the time of prostatectomy. Lane and colleagues prospectively measured total testosterone levels of 455 patients with clinically localized Prostate Cancer undergoing radical prostatectomy. On multivariate analysis, low testosterone, defined as less than 7.6 nano-moles per liter (220 nano-grams per deci liter) was associated with the predominance of Gleason grades 4 and 5 (OR 2.4, 95 percent CI 1.01 to 5.7, p equals 0.048). Likewise, Dai and colleagues reported on preoperative testosterone levels in 110 Chinese men undergoing prostatectomy for clinically localized disease.
Men with Gleason 8 or greater had significantly lower serum testosterone, 14.2 nano-moles per liter (410 nano-grams per deci liter) versus 11.1 nano-moles per liter (320 nano-grams per deci liter) (p equals 0.028).
Furthermore, hypogonadal men, with total morning testosterone less than 8.6 nano-moles per liter (250 nano-grams per deci liter), were more likely to have Gleason 8 or greater disease (p equals 0.005). In addition to Gleason grade, low preoperative testosterone has been is associated with higher stage at prostatectomy. Xylinas and colleagues found that men with preoperative total testosterone less than 10.4 nano-moles per liter (300 nano-grams per deci liter) were more likely to have high-risk disease including Gleason grade greater than7 and stage pT3 to 4 on final pathology (p equals 0.01 and p equals 0.04). In a study of 673 men undergoing prostatectomy, Salonia and colleagues examined the association of morning testosterone with surgical pathology outcomes.
They identified no association between total testosterone and Gleason grade, but identified an increased risk of seminal vesicle invasion in severely hypogonadal men, defined as testosterone less than 3.4 nano-moles per liter (100 nano-grams per deci liter,Odds Ratio 3.11, p equals 0.006). In another study of men undergoing prostatectomy, lower pretreatment testosterone was associated with extraprostatic disease (p equals 0.046), but not biochemical recurrence. Finally, in examining total testosterone levels in patients undergoing prostatectomy, Imamoto and colleagues found that lower total testosterone was associated with non-organ confined disease (HR 2.16, 95 percent CI 1.29 to 3.63, p equals 0.003).
Testosterone therapy and Prostate Cancer.
Testosterone replacement therapy in patients without Prostate Cancer.
Androgens, including exogenous testosterone, have been shown to play a role in Prostate Cancer pathogenesis in cell lines and animal models. Despite this evidence, currently available data do not suggest an increased risk of Prostate Cancer in men undergoing testosterone replacement therapy.
Haider and colleagues reported on three prospective cohort studies comprising a total of 1023 hypogonadal men with PSA less than 4 micro-grams per liter who were treated with testosterone replacement therapy at three centers. With a median follow up of 5 years, the incidence of Prostate Cancer was lower in testosterone replacement therapy-treated populations than accepted incidence rates from large population-based studies with long-term follow up. Likewise, in a smaller study of men at increased risk of Prostate Cancer, testosterone replacement therapy appeared to be safe with respect to Prostate Cancer risk.
Rhoden and Morgentaler treated 20 men with HGPIN and 55 men with negative biopsies with 12 months of testosterone replacement therapy, and observed no changes in PSA or DRE.
This is in agreement with a separate study demonstrating higher incidence of Prostate Cancer on re-biopsy in men with HGPIN and lower serum testosterone levels.
The majority of studies on testosterone replacement therapy and Prostate Cancer are small and there have been no prospective studies on testosterone replacement therapy with sufficient power to determine increased Prostate Cancer risk. By one estimate, 6000 patients receiving 5 years of testosterone replacement therapy would be needed to detect a 30 percent increase in Prostate Cancer incidence. In a systematic review of 40 prospective studies of testosterone replacement therapy in men without Prostate Cancer, no study demonstrated an association between testosterone replacement therapy and Prostate Cancer risk. Furthermore, in a meta analysis of 19 placebo-controlled studies, comprising 651 men in the testosterone replacement therapy group and 433 men in the placebo group, there was no significant increase in Prostate Cancer, PSA greater than4 nano-grams per deci liter, or need for prostate biopsy.
Testosterone replacement therapy in patients with Prostate Cancer.
The androgen hypothesis and robust clinical data supporting ADT in advanced Prostate Cancer have helped foster the dogma that testosterone replacement therapy in Prostate Cancer patients is like feeding the fire. Historically, there are data supporting this concept. In 1982, Fowler and Whitemore reported on 52 men with metastatic Prostate Cancer patients with bone metastasis, with 65 percent having had a prior orchiectomy. With testosterone treatment there was elevation in prostatic acid phosphatase in 38 percent of men, two cases of measurable metastatic progression, and four deaths.

Importantly, these data are from the pre-PSA era in a mixture of patients with advanced disease that were either untreated, in remission or relapse, and many of whom had prior androgen deprivation. Thus, it would not be appropriate to apply these observations to men with clinically localized disease in the PSA era who commonly receive early primary treatment and PSA monitoring.
In contrast to historical data, a number of studies suggest that testosterone replacement therapy in selected Prostate Cancer patients does not lead to disease progression. Using Surveillance, Epidemiology, and End Results (SEER) Medicare data, Kaplan and colleagues reported on 149,354 men including 1181 men who received testosterone replacement therapy after a diagnosis with Prostate Cancer. Overall, testosterone replacement therapy was not associated with overall or cancer specific mortality. Similarly, Pastuszak and colleagues reported on 103 men treated with testosterone replacement therapy after prostatectomy. There was an overall increase in serum PSA, but no evidence of increased cancer recurrence over 36 months. Similarly, there was no evidence of disease progression following brachytherapy for clinically localized disease among 31 men who underwent testosterone replacement therapy for a median duration of 5 years.
It should be noted that there have been reports of Prostate Cancer patients who have progressed on testosterone replacement therapy.
Leibowitz and colleagues reported on 96 men with Prostate Cancer who began high-dose testosterone replacement therapy after undergoing primary Prostate Cancer treatment. After a median of 15 months on testosterone replacement therapy, men achieved a mean serum testosterone of 48 nano-moles per liter, 1391 nano-grams per deci liter, 43 percent had evidence of PSA progression, with seven patients showing radiographic progression and PSA decreasing in 59 percent of men after discontinuation. Whether the disease progression in this small number of patients was due to testosterone replacement therapy will remain unknown, but it should serve to highlight the need for close monitoring of Prostate Cancer patients who are offered testosterone replacement therapy.
Studies on testosterone replacement therapy in patients with Prostate Cancer enrolled in active surveillance (AS) programs provide valuable information on possible tumor progression in Prostate Cancer patients, given the frequency of exams, biopsies and close follow up in this population. In a review of 154 men enrolled in AS for very low risk Prostate Cancer, free testosterone was found to be associated with reclassification. Compared with men who remained on AS, men with free testosterone levels less than 1.56 nano-moles per liter (45 nano-grams per deci liter) were more likely to be reclassified, HR 2.40, 95 percent CI 1.13 to 5.10, p equals 0.02. Finally, in a smaller study, Morgentaler and colleagues examined 13 AS patients receiving testosterone replacement therapy. After a median follow up of 2.5 years, two men had upgrading on subsequent biopsy, but no cases of disease or PSA progression were seen.
There is an apparent disconnect between data supporting androgen-driven Prostate Cancer growth and the clinical data, although limited, demonstrating no increase in Prostate Cancer growth or progression in men on testosterone replacement therapy. In an effort to reconcile these differences, a saturation model was proposed which integrates data on androgen receptor responsiveness with clinical data on the effects of testosterone. The saturation model proposes a biologic saturation point for the maximal stimulation of prostate tissues by androgens, which falls in the lower range of serum testosterone levels, approximately 8.7 nano-moles per liter (250 nano-grams per deci liter). Androgen levels above the saturation point will have no further stimulatory effect, thus raising serum testosterone concentrations above the saturation point, as often seen with testosterone replacement therapy, fails to induce growth of prostate tissues. Although the merits of the saturation model are beyond the scope of this review, they recently been reviewed in detail elsewhere. Importantly, the model provides a framework for understanding the effects of testosterone in the context of androgen receptor responsiveness, and highlights the differences between testosterone replacement therapy in hypogonadal and eugonadal men.
Conclusion.
Overall, there remains no clear answer to the question Does testosterone promote Prostate Cancer pathogenesis in humans? There is good evidence that androgens can promote Prostate Cancer in animal models and that ADT is beneficial in Prostate Cancer patients.
However, after a large number of mostly retrospective studies, there remains no clear association with higher endogenous testosterone and the development or severity of Prostate Cancer. To the contrary, there are several studies associating lower testosterone levels with increased Prostate Cancer severity.
Whether hypogonadism promotes high-risk disease or is rather a symptom of high-risk disease remains unknown. With concerns that testosterone can stimulate cancer growth, testosterone replacement therapy in men with Prostate Cancer remains controversial.

Currently, there is a growing amount of evidence that testosterone replacement therapy is safe in wellselected men with clinically localized Prostate Cancer.
However, these results are based on testosterone replacement therapy in a small number of patients. Furthermore, the heterogeneity seen clinically in Prostate Cancer progression and aggressiveness may give rise to heterogeneity in the responsiveness of tumors to testosterone replacement therapy. As patients and providers continue to weigh the potential risks and benefits of testosterone replacement therapy, better defining the influence of testosterone on Prostate Cancer disease progression is of paramount importance. Thus, until the results of future RCTs are available, testosterone replacement therapy should only be offered to select patients who are carefully monitored and well-informed about the potential risks and benefits.

Funding.
This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement.
The authors declare no conflicts of interest in preparing this article.
References.