1448 ORAL ADMINISTRATION OF GTX-758, A SELECTIVE ERα AGONIST, INDUCES CHEMICAL CASTRATION BUT NOT GYNECOMASTIA IN MALE MONKEYS (2011)

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 20111448 ORAL ADMINISTRATION OF GTX-758, A SELECTIVE ERα AGONIST, INDUCES CHEMICAL CASTRATION BUT NOT GYNECOMASTIA IN MALE MONKEYS Amanda Jones, Robert H. Getzenberg, James T. Dalton, and Karen A. Veverka Amanda JonesAmanda Jones Memphis, TN More articles by this author , Robert H. GetzenbergRobert H. Getzenberg Baltimore, MD More articles by this author , James T. DaltonJames T. Dalton Memphis, TN More articles by this author , and Karen A. VeverkaKaren A. Veverka Memphis, TN More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1361AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Gynecomastia is a psychologically distressing and sometimes painful estrogen-related side effect experienced by men on androgen deprivation therapy (ADT) for prostate cancer (PCa). Gynecomastia affects 40–80% of men on estrogen therapy (e.g. diethylstilbesterol; DES) and is of high incidence in men on antiandrogen monotherapy and in combination with a luteinizing hormone releasing hormone (LHRH) agonist. GTx-758 is a novel oral selective estrogen receptor alpha (ERα) agonist designed as first or second line therapy for advanced PCa. We evaluated and compared the effects of GTx-758 and DES on serum hormones, prostate specific antigen (PSA) and male breast development (gynecomastia) in male nonhuman primates. METHODS Male monkeys (n = 4–7 /group, ≥ 4 years of age), received daily gavage with vehicle, DES (0.05 or 2 mg/kg) or GTx-758 (1, 10, or 100 mg/kg) for a period of at least 56 days. Nipple diameter and prepuce were examined at necropsy. Mammary gland thickness was measured as the greatest thickness of glandular elements perpendicular to skin from histologic sections. Serum testosterone and PSA concentrations were determined by enzyme immunoassay. RESULTS GTx-758 and DES reduced serum testosterone to castrate levels (i.e., ≤ 50 ng/dL) and GTx-758 markedly suppressed PSA. Treatment with DES produced signs of hyperestrogenicity, including a highly significant bilateral increase in nipple diameter as well as swollen prepuce in 4/4 (100%) monkeys within 22 days of treatment initiation with 2 mg/kg DES. Nipple diameter was 1.6 and 2 fold (P < 0.01) higher for 0.05 and 2 mg/kg DES, respectively, compared to vehicle control. Mammary gland hypertrophy was also evident by a 5.3 to 5.8 fold increase in thickness for DES-treated monkeys compared to vehicle control. Monkeys treated with GTx-758 did not exhibit similar magnitudes of change in mammary or scrotal tissue. CONCLUSIONS Oral administration of GTx-758 and DES significantly reduced serum testosterone to castrate levels and GTx-758 lowered serum PSA. However, unlike DES, monkeys treated with GTx-758 did not exhibit significant signs of hyperestrogenicity including gynecomastia. Future phase II clinical trials are designed to demonstrate the efficacy and safety of GTx-758 and provide evidence that GTx-758 is an attractive option for first-line hormone therapy in advanced prostate cancer. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e581 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Amanda Jones Memphis, TN More articles by this author Robert H. Getzenberg Baltimore, MD More articles by this author James T. Dalton Memphis, TN More articles by this author Karen A. Veverka Memphis, TN More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...