SAT024 Contribution of 11-Ketotestosterone and 11-Ketodihydrotestosterone to Castration-Resistant Prostate Cancer

Abstract

Abstract Disclosure: H.S. Abu-Lebdeh: None. H.M. Heshmati: None. Background: Prostate cancer is among the most common malignancy in men and represents the second most common cause of cancer-related mortality among men in the US. Androgen-deprivation therapy with surgical or medical castration is widely used to treat hormone-sensitive prostate cancer. Disease progression despite androgen-deprivation therapy is a state defined as castration-resistant prostate cancer that is associated with poor survival rate. This review presents an update on the contribution of two adrenal androgens, 11-ketotestosterone and 11-ketodihydrotestosterone, to the castration-resistant prostate cancer. Methods: A systematic search of literature was conducted using the search terms prostate cancer, testosterone, dihydrotestosterone, adrenal androgens, 11-ketotestosterone, 11-ketodihydrotestosterone, androgen-deprivation therapy, castration, and castration-resistant prostate cancer. Results: In 2022, around 268,490 new cases of prostate cancer were diagnosed in the US with a mortality of 34,500 cases. Although androgen-deprivation therapy with castration is efficient at the beginning, most patients develop a state of castration resistance usually after 2-3 years as a result of the reactivation of androgen-receptor signaling despite low testosterone levels. The adrenal glands produce significant amounts of steroid hormones and metabolites. Among them, 11-ketotestosterone and 11-ketodihydrotestosterone are potent and efficacious androgens with potentially longer activity compared to testosterone and dihydrotestosterone because they are metabolized at a lower rate. Dihydrotestosterone derived from the metabolism of adrenal androgens (e.g., androstenedione and dehydroepiandrosterone) and especially 11-ketotestosterone and 11-ketodihydrotestosterone are important contributors to castration-resistant prostate cancer. In these cases, adrenal suppression with drugs causing a decrease in adrenal androgen production may improve the effectiveness of the androgen-deprivation therapy. Conclusion: In most patients with prostate cancer, androgen-deprivation therapy loses its effectiveness after 2-3 years leading to a state of castration-resistant prostate cancer. Two potent and highly efficacious androgen-receptor agonists of adrenal origin, 11-ketotestosterone and 11-ketodihydrotestosterone, are predominant androgens after castration and play an important role in the development and progression of castration-resistant prostate cancer. Their measurement in blood can be of clinical value during androgen-deprivation therapy. Concomitant treatment aimed to block the production of adrenal androgens is of potential interest in the management of these patients, but more studies are necessary to further investigate the benefits and adverse effects of this approach. Presentation: Saturday, June 17, 2023