LOW SYSTEMIC TESTOSTERONE LEVELS INDUCE ANDROGEN MAINTENANCE IN BENIGN RAT PROSTATE TISSUE

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 338-357-Steroid Hormone Actions
Basic/Translational
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-347
Ye Zhou*, Maya Otto-Duessel, Miaoling He and Jeremy Jones
City of Hope, Duarte, CA
Background: Prostate cancer (PC) is both an age- and 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, many studies have shown that systemic androgen levels do not reflect the levels of androgen in prostate tissue. Furthermore, experiments in mice indicate that sustained exposure to low testosterone (T) can promote, rather than prevent, PC. We hypothesized that low blood androgen levels puts pressure on the healthy prostate to mutate in such a way to maintain androgen levels and that this mutation leads to increased risk of developing prostate cancer. To test our hypothesis, we treated rodents to achieve castrate, normal, sub- and supra-physiological levels of T and quantified the DHT and testosterone levels in the serum as well as in the prostate. We also compared the changes in the AR signaling axis in response to different levels of androgens and correlated the changes with the intraprostatic level of T and DHT.

Methods: 24 male rats were divided in 4 groups; intact, castrate, castrate+ low T, castrate+ medium T, castrate + high T and treated for 6 weeks. After treatment, animals were euthanized, serum and prostates were harvested. QRT-PCR was used to evaluate transcriptional levels of the genes that are involved in androgen/AR signaling pathways. LC-MS/MS was used to determine the levels of T and DHT in both serums and prostates.

Results: Rats in low T group only had 23% as much T in serum as the intact group while they had 63% as much DHT and 71% as much T in the prostate compared to the rats in the intact group, demonstrating the ability of healthy rat prostate tissue to maintain androgen levels despite low systemic levels. Low T treatment resulted in significant alterations in expression of androgen axis genes, while these changes were not as strong with mid and high T treatments.

Conclusions: Our study suggested that regardless of the serum level of T and DHT, the prostate could work as buffer system to maintain a functional level of T and DHT. Long exposure to low T could promote upregulation of genes that participate in steroidogenesis and induce overexpression of AR, suggesting that intracrine steroidogenesis as well as increased androgen responsiveness might contribute to the sustained levels of T and DHT in the prostate. However, long-term study is needed to investigate whether low systemic T has a causal relationship with the onset of PC and whether changes in the androgen/AR signaling axis in response to low circulating T may contribute to prostate tumorigenesis.

Nothing to Disclose: YZ, MO, MH, JJ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm