Dr. Ron’s Research Review – March 23, 2016

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This week’s research review focuses on low testosterone and prostate cancer.

For seventy years it has been axiomatic that high testosterone is risky for prostate cancer and low testosterone is protective. Yet recent work has shown this concept to be little more than a myth. (Morgentaler, 2011)

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. 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. There are, however, 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. (Michaud et al., 2015)

The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial included 8122 men. 4073 (50.1%) received placebo. Key entry criteria were PSA 2.5-10 ng/ml and one prior negative biopsy. Biopsies were performed at 2 and 4 yr; and for-cause biopsies at physician discretion. Of 4073 men, 3255 (79.9%) had at least one biopsy after randomization and were analyzed. Androgen levels tested continuously or by quintiles were generally unrelated to PCa detection or grade. PCa detection was similar among men with low compared with normal baseline testosterone levels (25.5% and 25.1%; p=0.831). In secondary analysis, higher testosterone levels at baseline were associated with higher PCa detection (odds ratio: 1.23; 95% confidence interval, 1.06-1.43; p=0.006) only if men had low baseline testosterone (<10nmol/l). For men with normal baseline testosterone (>/=10 nmol/l), higher testosterone levels at baseline were unrelated to PCa risk (p=0.33). No association was found for DHT and PCa (all p>0.85). Baseline serum testosterone and DHT levels were unrelated to PCa detection or grade. These findings of the lowest testosterone levels being associated with the lowest PCa risk with no further changes with higher testosterone support a saturation model where androgens may stimulate prostate growth at very low levels with no additional effects at higher levels. (Muller et al., 2012)

A second study examined serum hormones the day before surgery in a cohort of 724 candidates to radical prostatectomy. Low-, intermediate-, or high-risk prostate cancer was found in 251 (34.7%), 318 (43.9%), and 155 (21.4%) patients, respectively. Patients in the high-risk class showed the lowest tT, E(2), and tT-E(2) ratio values (all P ≤ 0.02). At univariate analysis, only age, tT, E(2), and tT-E(2) ratio values were significantly associated with high-risk prostate cancer (all P ≤ 0.006). At multivariate analyses considering model 1 variables, age (P = 0.03), serum tT (all P < 0.001), and E(2) (all P ≤ 0.01) were associated with high-risk prostate cancer; only tT-E(2) ratios achieved independent predictor status for high-risk prostate cancer (all P < 0.001) when considering model 2. Both the lowest and the highest tT, E(2), and tT-E(2) values depicted a nonlinear U-shaped significant association with high-risk prostate cancer. (Salonia et al., 2012)

Dr. Ron


 

Articles

Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk.
            (Michaud et al., 2015) Download
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 (LOH). 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 (TRT) for hypogonadism, and especially in LOH. Accompanying the rise in TRT 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 TRT 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 TRT, there has been widespread belief that TRT 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 TRT. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on TRT. While data from large, prospective, randomized, controlled trials are absent, TRT in select prostate cancer patients is likely safe. In the end, the use of TRT in prostate cancer patients is still considered experimental and should only be offered after well-informed shared decision making and with close monitoring.

Turning conventional wisdom upside-down: Low Serum testosterone and high-risk prostate cancer
            (Morgentaler, 2011) Download
For seventy years it has been axiomatic that high testosterone (T) is risky for prostate cancer (PCa) and low T is protec- tive. Yet recent work has shown this concept to be little more than a myth,1 based on what the fictional detective Sherlock Holmes might have called circumstantial evidence. In this issue of Cancer, Salonia et al2 explore a totally different idea, namely whether low T may be associated with high-risk PCa.

Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial
         (Muller et al., 2012) Download
BACKGROUND: Findings of studies on the association between androgens and prostate cancer (PCa) are mixed. Androgens may affect prostate-specific antigen (PSA) levels, thereby influencing biopsy recommendations. Also, androgens may stimulate prostate growth at very low levels with no additional effects at higher levels (saturation model). OBJECTIVE: To test whether androgens were associated with PCa risk in the placebo arm of a prospective study in which biopsies were performed regardless of PSA level. DESIGN, SETTING, AND PARTICIPANTS: Of 8122 men in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, 4073 men (50.1%) received placebo. Key entry criteria were PSA 2.5-10 ng/ml and one prior negative biopsy. INTERVENTION: Per-protocol biopsies at 2 and 4 yr; for-cause biopsies at physician discretion. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable logistic regression was used to test the association between baseline log-transformed testosterone and dihydrotestosterone (DHT) levels and the risk of detecting either PCa or low-grade PCa (Gleason score <6) compared with high-grade PCa (Gleason score >7). In secondary analysis, we stratified the analysis by low baseline androgen levels (testosterone <10 nmol/l; DHT <0.76 nmol/l) compared with normal baseline androgen levels. RESULTS AND LIMITATIONS: Of 4073 men, 3255 (79.9%) had at least one biopsy after randomization and were analyzed. Androgen levels tested continuously or by quintiles were generally unrelated to PCa detection or grade. PCa detection was similar among men with low compared with normal baseline testosterone levels (25.5% and 25.1%; p=0.831). In secondary analysis, higher testosterone levels at baseline were associated with higher PCa detection (odds ratio: 1.23; 95% confidence interval, 1.06-1.43; p=0.006) only if men had low baseline testosterone (<10nmol/l). For men with normal baseline testosterone (>/=10 nmol/l), higher testosterone levels at baseline were unrelated to PCa risk (p=0.33). No association was found for DHT and PCa (all p>0.85). CONCLUSIONS: Baseline serum testosterone and DHT levels were unrelated to PCa detection or grade. Our findings of the lowest testosterone levels being associated with the lowest PCa risk with no further changes with higher testosterone support a saturation model but must be confirmed in future studies using an a priori defined hypothesis. CLINICALTRIALS.GOV IDENTIFIER: NCT00056407.

Preoperative hypogonadism is not an independent predictor of high-risk disease in patients undergoing radical prostatectomy.
            (Salonia et al., 2011) Download
BACKGROUND:  A study was undertaken to assess the association between either preoperative serum total testosterone (TT) or hypogonadism (defined as TT <3 ng/mL) with high-risk prostate cancer (PCa) (defined as patients with pathological extracapsular extension [ECE], seminal vesicle invasion [SVI], or Gleason grades ≥4 + 3 [high-grade PCa]) at radical prostatectomy (RP). METHODS:  A cohort of 673 consecutive Caucasian-European patients who underwent RP at a single institute was used. None of the patients had taken any hormonal neoadjuvant treatment or other hormonal preparations during the previous 12 months. Serum TT was measured the day before surgery (8-10 AM) in all cases. Logistic regression models tested the associations among predictors (eg, prostate-specific antigen, clinical stage, biopsy Gleason sum, body mass index, and TT) and ECE, SVI, and high-grade PCa. RESULTS:  Median TT was 4.5 ng/mL (mean, 4.5; range, 0.02-13.6). Hypogonadism was found in 144 (21.4%) patients, and severe hypogonadism (defined as TT <1 ng/mL) was observed in 37 (5.5%) men. Extracapsular extension, SVI, and high-grade PCa were found in 96 (14.6%), 88 (13.1%), and 153 (22.7%) patients, respectively. Patients with high-risk PCa had median TT comparable to those with low-risk disease. At multivariate analysis, TT did not achieve independent predictor status for ECE, SVI, and high-grade PCa. Only circulating TT <1 ng/mL was an independent predictor of SVI (odds ratio, 3.11; P = .006). CONCLUSIONS:  In contrast with previous reports, preoperative circulating TT levels were not associated with high-risk PCa. Likewise, hypogonadism did not achieve independent predictor status for high-risk PCa.

Serum sex steroids depict a nonlinear u-shaped association with high-risk prostate cancer at radical prostatectomy.
            (Salonia et al., 2012) Download
PURPOSE:  To assess the association between preoperative serum total testosterone (tT), 17β-estradiol (E(2)), sex hormone-binding globulin (SHBG), and tT-E(2) ratio values with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network practice guidelines) at radical prostatectomy. EXPERIMENTAL DESIGN:  Serum E(2), tT, and SHBG were dosed the day before surgery (7:00-11:00 am) in a cohort of 724 candidates to radical prostatectomy. Restricted cubic spline functions tested the association between predictors (i.e., model 1: age, body mass index, and serum tT, E(2), and SHBG levels; model 2: tT-E(2) values instead of tT and E(2) levels) and high-risk prostate cancer. RESULTS:  Low-, intermediate-, or high-risk prostate cancer was found in 251 (34.7%), 318 (43.9%), and 155 (21.4%) patients, respectively. Patients in the high-risk class showed the lowest tT, E(2), and tT-E(2) ratio values (all P ≤ 0.02). At univariate analysis, only age, tT, E(2), and tT-E(2) ratio values were significantly associated with high-risk prostate cancer (all P ≤ 0.006). At multivariate analyses considering model 1 variables, age (P = 0.03), serum tT (all P < 0.001), and E(2) (all P ≤ 0.01) were associated with high-risk prostate cancer; only tT-E(2) ratios achieved independent predictor status for high-risk prostate cancer (all P < 0.001) when considering model 2. Both the lowest and the highest tT, E(2), and tT-E(2) values depicted a nonlinear U-shaped significant association with high-risk prostate cancer. CONCLUSIONS:  These data showed that preoperative serum sex steroids are independent predictors of high-risk prostate cancer, depicting a nonlinear U-shaped association.

 

 

 

References

Michaud, JE, KL Billups, and AW Partin (2015), ‘Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk.’, Ther Adv Urol, 7 (6), 378-87. PubMed: 26622322
Morgentaler, A. (2011), ‘Turning conventional wisdom upside-down: Low Serum testosterone and high-risk prostate cancer’, Cancer, PubMed: 21365620
Muller, R. L., et al. (2012), ‘Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial’, Eur Urol, 62 (5), 757-64. PubMed: 22658758
Salonia, A, et al. (2011), ‘Preoperative hypogonadism is not an independent predictor of high-risk disease in patients undergoing radical prostatectomy.’, Cancer, 117 (17), 3953-62. PubMed: 21365624
Salonia, A, et al. (2012), ‘Serum sex steroids depict a nonlinear u-shaped association with high-risk prostate cancer at radical prostatectomy.’, Clin Cancer Res, 18 (13), 3648-57. PubMed: 22589393