BERKELEY, CA (UroToday.com) - Androgens and the androgen receptor (AR) play a role in the progression of prostate cancer.> Androgen deprivation therapy (ADT) is a mainstay in the treatment of metastatic prostate cancer. ADT is expected to reduce serum testosterone levels from a normal level of about 500 to 600 ng/dl (17.3-20.8 nmol) down to castration levels. Traditionally, castration was considered to be achieved if testosterone levels were lowered to a threshold of 50 ng/dl (1.73 nmol/l), a definition determined more by measurement methods derived from the use of old assay methods than evidence. Serum testosterone levels in three-quarters of patients after surgical castration drop to less than 20 ng/dl (0.69 nmol/l).
The optimum serum castration levels of testosterone to be achieved with ADT are still debated. Lowering the testosterone level as much as possible might be associated with better prognostic significance in metastatic prostate cancer. Testosterone breakthrough greater than castration level and the acute-on-chronic effects of administration of a gonadotropin-releasing hormone (GnRH) agonist may cause testosterone levels to periodically rise, sometimes to non-castrate levels. A spontaneous rise in testosterone level over 20 ng/dl (0.69 nmol/l) and the acute on chronic effect are not well understood.
Ineffective suppression of testosterone is currently poorly recognized and may possibly have an impact of prostate cancer mortality. The clinical significance of the different levels of testosterone yielded during ADT is still unknown and long-term data on the occurrence of castration-resistant prostate cancer and cancer-specific survival are not available. Persistent levels of serum testosterone after castration are mainly derived from adrenal androgens. Pituitary-gonadal, pituitary-adrenal, and pituitary-intratumoral androgen axis have critical roles during ADT. The desirable treatment goal in patients with advanced prostate cancer will achieve the selective lowering of intraprostatic and intratumoral androgen levels and androgens and the AR activity, with new classes of drugs such as abiraterone and enzalutamide to inhibit biosynthesis of androgens and the conversion from androgen precursors to dihydrotestosterone and AR activity.
Randomized clinical trials assessing the impact of further hormonal manipulation in patients with testosterone levels in the range of 20-50 ng/dl (0.69-1.73 nmol/l) as well as in those patients failing to reach the standard castration level during GnRH agonist monotherapy would be desirable. However, such studies are very hard to conduct, due to the large number of patients needed to achieve a sufficient statistical power and the required long-term follow-up.
Written by:
Tsutomu Nishiyama, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Associate Professor
Division of Urology
Department of Regenerative and Transplant Medicine
Niigata University Graduate School of Medical and Dental Sciences
Asahimachi 1-757, Chuo-ku, Niigata 951-8510, Japan
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