785 PITUITARY-ADRENAL AXIS IS CLOSELY ASSOCIATED WITH THE REGULATION OF ANDROGEN-RESPONSIVE KALLIKREINS DURING CONVENTIONAL ANDROGEN DEPRIVATION THERAPY

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2012785 PITUITARY-ADRENAL AXIS IS CLOSELY ASSOCIATED WITH THE REGULATION OF ANDROGEN-RESPONSIVE KALLIKREINS DURING CONVENTIONAL ANDROGEN DEPRIVATION THERAPY Noboru Hara, Tatsuhiko Hoshii, Itsuhiro Takizawa, and Tsutomu Nishiyama Noboru HaraNoboru Hara Niigata, Japan More articles by this author , Tatsuhiko HoshiiTatsuhiko Hoshii Niigata, Japan More articles by this author , Itsuhiro TakizawaItsuhiro Takizawa Niigata, Japan More articles by this author , and Tsutomu NishiyamaTsutomu Nishiyama Niigata, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.873AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although the pituitary-adrenal axis has been associated with the progression of castration-resistant prostate cancer, their role/contribution remains unclear. This study was performed to elucidate the regulatory mechanism of adrenal androgen synthesis and influence of the pituitary-adrenal axis on adrenal androgens and androgen-responsive kallikreins (KLKs) including KLK3/PSA during conventional androgen deprivation therapy (ADT). METHODS Ninety patients with localized prostate cancer were prospectively studied based on their blood samples before and after ADT using GnRH agonists for 6 months. Serum levels of testosterone/Dihydrotestosterone (DHT), adrenal androgens, and adrenocorticotropic hormone (ACTH) were quantified with highly sensitive assays. Developing an experimental model with LNCaP, 22Rv1, VCaP, PC3, and DU145 cells, the expression levels of KLK 1 to 15 were quantified using Real-time PCR under various androgen concentrations. RESULTS Before ADT, no correlation was found between pituitary hormones and androgens or PSA levels. After ADT, the serum ACTH level was closely correlated with the serum levels of testosterone (p<0.001), dehydroepiandrosterone sulfate (DHEA-S) (p<0.001), androstenedione (p = 0.002), and PSA (p <0.001); both serum DHEA-S and androstenedione levels were also correlated with the serum PSA level (p <0.001 in both). After ADT, androgens and PSA levels decreased compared with those at the baseline (p < 0.001 in all). No difference was noted between the serum levels before and after ADT in ACTH (p = 0.232). With the experimental model using prostate cancer cells, androgen-responsive LNCaP, 22Rv1, and VCaP shared expressions of androgen-dependent KLK2, KLK3/PSA, KLK4, and KLK15, whereas androgen receptor-inactive PC3 and DU145 were deficient in these KLKs. In LNCaP, 22Rv1, and VCaP cells, the transcription of these 4 KLKs was upregulated by DHEA in a concentration-dependent manner (p<0.05 in all). CONCLUSIONS In patients treated with ADT, the pituitary-adrenal axis mediated by ACTH plays a central role in the regulation of androgen synthesis. Both serum ACTH and adrenal androgen concentrations were correlated with the post-treatment PSA level. In androgen receptor-active prostate cancer cells, transcription levels of androgen-responsive KLKs were upregulated by adrenal androgens in a concentration-dependent manner. The present study verified that androgen synthesis mediated by the pituitary-adrenal axis is a potential target for advanced ADT. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e321 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Noboru Hara Niigata, Japan More articles by this author Tatsuhiko Hoshii Niigata, Japan More articles by this author Itsuhiro Takizawa Niigata, Japan More articles by this author Tsutomu Nishiyama Niigata, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...