Hormonal Therapy for Advanced Prostate Cancer

Decades ago, Nobel Laureate Charles Huggins demonstrated that the growth dependence of normal canine prostate on hormones had significant therapeutic implications for men with prostate cancer (1). Since then, androgen ablation therapy has provided effective palliation for patients with advanced disease. Synthesis of testosterone is regulated by the hypothalamic-pituitary-testicular axis. Testosterone is intracellularly converted to dihydrotestosterone, which binds to the cytoplasmic androgen receptor of the prostate cancer cell. The hormone-receptor complex binds to nuclear DNA, stimulating protein synthesis. The adrenal glands also produce androgens, which contribute to intraprostatic dihydrotestosterone.

Androgen ablation may be achieved surgically (with bilateral orchiectomy) or pharmacologically, usually with the luteinizing hormone-releasing hormone (LHRH) agonists. The LHRH agonists initially stimulate a release of luteinizing hormone that increases testosterone, followed by downregulation of pituitary receptors and suppression of testosterone to castration levels. The exogenous estrogen diethylstilbestrol also reduces testosterone to castration levels, but it is associated with cardiovascular complications and is no longer commercially available in the United States. Antiandrogens, agents that block androgen receptors, have been studied as monotherapy and in conjunction with surgical or pharmacologic castration to inhibit the effects of adrenal androgens (a treatment known as combined androgen blockade). After years of clinical investigation and experience, the optimal approach to hormonal therapy in men with advanced prostate cancer is still being defined.

In this issue, …