Surgical Castration for the Late Development of Resistance to Medical Castration with LHRH Agonists and Antagonists in Castrate-Resistant Prostate Cancert

Acquired resistance to GNRH agonists or antagonists used for the induction of medical castration for the treatment of metastatic prostate cancer has been rarely reported. To date, the mechanism(s) behind the development of apparent resistance to these agents has yet to be adequately defined while the impact of this refractoriness may possibly be detrimental even in Castrate-Resistant Prostate Cancer (CRPC). Here we describe two men with CRPC who were compliant with their GNRH agonist and who had documented low testosterone levels for years. They then developed rising testosterone levels despite documented continued receipt of these agents. Switching to the pure LHRH antagonist, degarelix, did not improve the testosterone suppression. Of interest, repeated determinations of luteinizing hormone were undetectable in both men suggesting the apparent resistance was not at the level of the hypothalamicpituitary axis. They did not have elevated Beta-HCG, prolactin or estrogen levels. The testosterone levels also did not respond to abiraterone given for their CRPC nor did them everhave sterile abscesses which have been associated with resistance to LHRH agonists. They therefore underwent surgical castration with bilateral orchiectomy and their testosterone levels returned to appropriate castrate levels againsuggesting that the failure of medical castration was not due to androgen production by the tumor cells but rather by the gonads. Understanding the endocrine mechanism for this failure remains unclear but the response to surgical castration suggests it is at the level of the gonads. These cases and others support the continued checking of testosterone levels while on long term medical castration agent since resistance can occur after many years of good control. Then, surgical castration becomes the treatment of choice.