Treatment with Luteinizing Hormone-ReleasingHormone Antagonists: is Serum TestosteroneReduction the Only Mechanism?

Background: Androgen deprivation therapy (ADT) by surgical or medical castration is recommended for advanced or metastatic prostate cancer. Recent literature suggests that medical castration by luteinizing hormone receptor hormone (LHRH) antagonists might have advantages over treatment with LHRH agonists in patients with metastatic prostate cancer when prostate specific antigen (PSA) progression free survival and overall survival are concerned. Using a state-of-the-art method to assess levels of testosterone, we investigated whether a potential difference in clinical outcome between different forms of ADT might be related to differences in serum testosterone concentrations. We further searched for evidence in literature for other biochemical pathways explaining a potential benefit of LHRH antagonists over LHRH agonists. Methods: Patients underwent surgical castration (n=34) or received an LHRH antagonist (n=25). Serum samples were obtained more that 3 months after initiation of ADT. Testosterone levels were determined using isotope dilution-liquid chromatography tandem mass spectrometry. Dehydroepiandrosterone sulphate (DHEAS), androstenedione, sex hormone-binding globulin (SHBG) and inhibin B levels were determined. Results: All surgically castrated subjects and all but one subject in the LHRH antagonist group had serum testosterone values less than 50 ng/dL. No difference was found between groups in serum testosterone, DHEAS, androstenedione and SHBG. Patients who underwent surgical castration had significantly lower levels of inhibin B compared to patients treated with degarelix Conclusion: Using a highly sensitive and specific technique of testosterone determination, no difference was found between patients after surgical castration and patients on LHRH antagonists. Thus, differences in clinical outcome between different forms of ADT are accounted for by testosterone independent pathways or mechanisms. Abbreviations: ADT: Androgen Deprivation Therapy; CV: Coefficient of Variation; DHEAS: Dehydroepiandrosterone Sulphate; EGF: Epidermal Growth Factor; EGFR: Epidermal Growth Factor Receptor; FSH: Follicle Stimulating Hormone; ID-LC-MS/MS: Isotope Dilution-Liquid Chromatography-Tandem Mass Spectrometry; LH: Luteinizing Hormone; LHRH: Luteinizing Hormone-Releasing Hormone; LHRH-R: Luteinizing Hormone-Releasing Hormone Receptor; LOQ: Limit Of Quantification; LUTS: Lower Urinary Tract Symptoms; PSA: Prostate-Specific Antigen; RIA: Radio Immuno Assay; s.c.: Subcutaneously; SHBG: Sex Hormone-Binding Globulin.