6 The introduction of PSA testing has increased the prevalence of prostate cancer patients diagnosed at earlier stages. The consequent

increase in ADT utilization highlights the importance of strategies to help reduce side effects associated with T suppression, as well as strategies to avoid unnecessary screening, overdetection, and overtreatment. Some of the above controversies related to ADT in the management of prostate cancer are addressed, specifically, PSA screening for prostate cancer and its impact upon ADT utilization; new insights related to the adverse-event profile associated with Inhibitors,research,lifescience,medical ADT; the role of intermittent hormone therapy (IHT); measuring T levels and Inhibitors,research,lifescience,medical whether the level of T suppression following GnRH agonists influences survival; and differences between GnRH agonists. In addition, this article assesses the potential future role of GnRH agonists in prostate cancer therapy. Novel strategies to minimize the risk of adverse effects of T suppression are also reviewed. GnRH Agonists GnRH is a decapeptide that is produced by the hypothalamus Inhibitors,research,lifescience,medical and regulates serum T levels through its effects on LH release by the pituitary gland.7 The various

commercially available GnRH agonists are all modifications of the GnRH decapeptide by amino acid substitutions or chemical alterations of existing amino acids. GnRH agonists can cause a T flare in response to increased stimulation of LH; selleck kinase inhibitor continuous stimulation of the GnRH Inhibitors,research,lifescience,medical receptors promotes desensitization of the GnRH receptors, resulting in T suppression.8

Commercially available GnRH agonists differ in their duration of action (1 month to 1 year), route of administration (intramuscular or subcutaneous injection or subcutaneous implant), and requirement Inhibitors,research,lifescience,medical for reconstitution. It is generally thought that GnRH agonists have similar efficacy and side effects because all of the commercially available agents have been shown to effectively reduce serum T levels to < 50 ng/dL, which historically was the level thought to be consistent with surgical castration.9 Using modern assay techniques, it is now recognized that the median T level achieved following AV-951 surgical castration is ~15 ng/dL, with a range between 10 to 30 ng/dL.9 In a review of the literature, Perachino and colleagues10 reported that between 13% and 42% of men with prostate cancer fail to achieve castrate levels of androgens (< 20 ng/dL as per the study, as compared with standard < 50 ng/dL) after initiating leutinizing hormone-releasing hormone (LHRH) therapy, depending on the upper limit of serum T. The clinical benefits of maintaining T levels < 20 ng/dL versus < 50 ng/dL have not been prospectively studied. A prospective, randomized, and carefully designed trial contemplating clinical progression and specific mortality is necessary as the primary endpoint would be required to confirm these findings and reassess the cutoff level.