Low systemic testosterone levels induce androgen maintenance in benign rat prostate tissue

Prostate cancer (PC) is both an age- and an androgen-dependent disease. Paradoxically, systemic levels of androgens decline with age as the risk of PC rises. While there is no correlation between systemic androgen levels and the risk of PC, systemic androgen levels do not reflect the levels of androgens in prostate tissue. In metastatic PC, changes in the androgen biosynthesis pathway during hormone therapy result in increased levels of androgens in cancer tissue and contribute to continued androgen receptor (AR) signaling. It is possible that similar changes occur in normal prostate tissue as androgen levels decline with age and that this contributes to tumorigenesis. In the present study, we sought to determine whether the rat prostate is able to maintain functional levels of androgens despite low serum testosterone levels. Rats were castrated and implanted with capsules to achieve castrate, normal, sub-physiological, and supra-physiological levels of testosterone. After 6 weeks of treatment, LC–MS/MS was used to quantify the levels of testosterone and dihydrotestosterone (DHT) in the serum and prostate tissue. Quantitative RT-PCR was used to quantify the expression of genes involved in the androgen/AR signaling axis. Despite significantly different levels of testosterone and DHT being present in the serum, testosterone and DHT concentrations in prostate tissue from different testosterone-treatment groups were very similar. Furthermore, the expression of androgen-regulated genes in the prostate was similar among all the testosterone-treatment groups, demonstrating that the rat prostate can maintain a functional level of androgens despite low serum testosterone levels. Low-testosterone treatment resulted in significant alterations in the expression of androgen biosynthesis genes, which may be related to maintaining functional androgen levels.

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Testosterone Treatment Is Associated with Reduced Mortality in Men with Low Serum Testosterone Levels

10.1210/endo-meetings.2011.part2.p20.p1-772 ◽

2011 ◽

pp. P1-772-P1-772

Author(s):

Molly M Shores ◽

Nicholas L Smith ◽

Christopher W Forsberg ◽

Bradley D Anawalt ◽

Alvin M Matsumoto

Keyword(s):

Serum Testosterone ◽

Testosterone Treatment ◽

Testosterone Levels ◽

Low Serum

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Low serum testosterone levels are predictive of prostate cancer

World Journal of Urology ◽

10.1007/s00345-011-0793-x ◽

2011 ◽

Vol 31 (2) ◽

pp. 247-252 ◽

Cited By ~ 27

Author(s):

Luigi Mearini ◽

Alessandro Zucchi ◽

Elisabetta Nunzi ◽

Tommaso Villirillo ◽

Vittorio Bini ◽

...

Keyword(s):

Prostate Cancer ◽

Serum Testosterone ◽

Testosterone Levels ◽

Low Serum

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Effect of testosterone treatment on the trabecular bone score in older men with low serum testosterone

Osteoporosis International ◽

10.1007/s00198-021-06022-1 ◽

2021 ◽

Author(s):

J. A. Cauley ◽

S. S. Ellenberg ◽

A. V. Schwartz ◽

K. E. Ensrud ◽

T. M. Keaveny ◽

...

Keyword(s):

Trabecular Bone ◽

Trabecular Bone Score ◽

Serum Testosterone ◽

Older Men ◽

Testosterone Treatment ◽

Low Serum

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MP04-04 RELATIONSHIP OF TESTOSTERONE TREATMENT AND INCIDENT PROSTATE CANCER RISK AMONG U.S. VETERANS WITH LOW SERUM TESTOSTERONE

The Journal of Urology ◽

10.1016/j.juro.2016.02.1939 ◽

2016 ◽

Vol 195 (4S) ◽

Author(s):

Thomas Walsh ◽

Molly Shores ◽

Nicholas Smith ◽

Mary Lou Thompson ◽

Alexandra Fox ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Risk ◽

Prostate Cancer Risk ◽

Serum Testosterone ◽

Testosterone Treatment ◽

Relationship Of ◽

Low Serum

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Influence of ischemia on tissue androgens in eugonadal and androgen-deprived men treated with prostatectomy.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.118 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 118-118 ◽

Cited By ~ 2

Author(s):

Robert B. Montgomery ◽

Michael Christopher Risk ◽

Daniel W. Lin ◽

Alvin M. Matsumoto ◽

Brett Marck ◽

...

Keyword(s):

Linear Trend ◽

Clinical Trial Design ◽

Prostate Tissue ◽

Lhrh Agonist ◽

Time Intervals ◽

Stable Measure ◽

Ischemic Time ◽

Treatment Groups ◽

One Way Anova ◽

Androgen Levels

118 Background: Optimizing tissue androgen suppression may provide a higher rate of complete pathologic response in patients with localized prostate cancer (PCa). The ability to accurately assess tissue androgens may be influenced by ischemic time and catabolism after devascularization. This study was performed to determine if ischemia influences tissue androgen in eugonadal men and in men treated with various types of neoadjuvant androgen deprivation (ADT). Methods: Eugonadal men (n=12) or men treated with neoadjuvant ADT using LHRH agonist and Casodex or LHRH agonist with Dutasteride, Casodex or all three with Ketoconazole (n=34) underwent prostatectomy for localized PCa. Tissue was acquired by needle biopsy at the time of ligation of the vascular pedicles, at prostate removal and at 30 minutes after prostate removal. Prostate tissue was flash-frozen and tissue dihydrotestosterone (DHT) and testosterone (T) were determined by LC/MS/MS. Change in tissue androgens from clamp was assessed at each time point. Trends in androgen levels were assessed by ANOVA for eugonadal men and within each treatment group Results: Average time from clamp to removal was 23 minutes (± 8) and from removal to subsequent biopsy 32 minutes (± 2). There was no evidence for a significant change in T or DHT over the time intervals tested (one way ANOVA p>0.05 for all measures) except in patients treated with LHRH agonist and Casodex alone. In this group of patients, T declined by 34%by the time of prostate removal, and by 83% at 30 minutes after removal when compared to levels at clamp (one way ANOVA p=0.017, test for linear trend =0.007). In all other treatment groups, both T and DHT were stable for 60 minutes. Conclusions: Assessment of DHT levels in prostate tissue at prostatectomy is not compromised by ischemia. Tissue sampling from 30-60 minutes after vascular clamping yields a stable measure of tissue DHT in the majority of patients. In the absence of SRD5A blockade, testosterone sampling in castrate men is sensitive to ischemia, and delayed sampling underestimates tissue androgen levels due to ischemia-related metabolism. These results lend important insight into clinical trial design and translational endpoints.

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Serum testosterone level and overall survival in first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17545 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17545-e17545

Author(s):

Maysa Tamara Silveira Vilbert ◽

Marcelle Goldner Cesca ◽

Natasha Carvalho Pandolfi ◽

Vinicius Fernando Calsavara ◽

Bruno Cezar de Mendonça Uchôa ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Testosterone Level ◽

Serum Testosterone ◽

Serum Testosterone Level ◽

Castration Resistant Prostate Cancer ◽

First Line ◽

Testosterone Levels ◽

Castration Resistant ◽

Low Serum

e17545 Background: Androgen receptor-targeted agents Abiraterone and Enzalutamide (Abi/Ez) prolonged overall survival in metastatic castration resistant prostate cancer (mCRPC). Patients with very-low serum testosterone levels seem to have less benefit from these therapies as well as more aggressive prostate cancer. Methods: A retrospective observational cohort study was conducted to evaluate whether a serum testosterone measured at time of start first-line therapy with Abi/Ez is related to overall survival (OS) and time-to-treatment failure (TTF) in mCRPC patients. Kaplan-Meier survival estimates and Cox-regression models were used for time-to-event analyses. The best cut-off for testosterone was defined using Log-rank statistics (Lausen and Schumacher). X² test and Mann-Whitney U-test were applied to compare categorical and continuous variables, respectively. Logistic regression was used to assess characteristics related to serum testosterone levels. Statistical significance was fixed at 0.05. Results: From May 2012 to February 2017, 100 patients were assessed. Median follow-up was 27.8 months (range 2.23 to 68.26). Pts with a high testosterone level ( > 28.2; n = 20) achieved a significantly higher OS (median 66.0 vs 31.9 mo, testosterone > 28.2 HR: 0.206, 95% CI 0.074 to 0.571, p = 0.002) and TTF (median 30.6 vs 11.8 mo, testosterone > 28.2 HR: 0.408, 95%CI 0.219 to 0.762, p = 0.005) than pts with a low serum testosterone level ( < 28.2; n = 80), regardless of receiving therapy with either Abi (n = 69) or Ez (n = 31). Pts with a higher testosterone level were younger (median 67.7 vs 73.6 years; p = 0.026), had a higher body mass index (BMI) (28.5 vs 25.9, p = 0.023) and a lower PSA at start Abi/Ez (12 vs 26, p = 0.031) than pts with lower values. Age (OR 0.93, 95%CI 0.8 to 0.9, p = 0.021), BMI (OR 1.21, 95%CI 1.1 to 1.4, p = 0.006) and baseline PSA (OR 1.2, 95%CI 1.03 to 1.4, p = 0.020) were significantly associated with testosterone > 28.2. After 4 months of Abi/Ez treatment, PSA decrease > 50% of baseline was seen more frequently in high testosterone levels group than in low testosterone levels pts (90% vs 57.5% of pts, respectively, p = 0.007). Conclusions: Pts with high levels of testosterone ( > 28.2) achieved a better OS and TTF when treated with Abi/Ez in first-line mCRPC than those with low levels. Testosterone can be considered a prognostic and predictive biomarker in this scenario, and could be used in treatment decision for this population.

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