title: Elucidation of the mechanism of suppressed steroidogenesis during androgen deprivation therapy of prostate cancer patients using a mouse model.
abstract: Androgen deprivation therapy (ADT) is the standard medical approach to the management of prostate cancer. Patients switched from a GnRH antagonist to a GnRH agonist, did not experience a testosterone surge in spite of the occurrence of luteinizing hormone (LH) surge in our protocol of clinical study. To clarify this observation, male mice pre-treated with two different doses of the GnRH antagonist degarelix for 28 days were further administered the GnRH agonist leuprolide or chorionic gonadotropin, and testosterone production of the mice was studied. Serum LH and testosterone levels, the size of Leydig cells, and expression level of steroidogenesis-related genes in the testis were analyzed. Treatment of mice with a high dose of degarelix (0.1 μg/mouse; HDG), but not a low dose (0.05 μg/mouse; LDG), for 28 days reproduced declined steroidogenesis observed in prostate cancer patients during ADT switched from a GnRH antagonist to a GnRH agonist. The size of the Leydig cells in the HDG mice was not significantly different from that in naive mice. Although expression levels of StAR, P450scc, and 17β HSD increased significantly in the LDH testis, those in the HDG testis did not change. Treatment of mice with a high dose of degarelix for 28 days reproduced the decline in steroidogenesis observed in prostate cancer patients during ADT. In this animal model, we demonstrated that initial ADT may inhibit the ability of Leydig cells to produce testosterone by suppressing the expression of genes involved in steroidogenesis, such as StAR, P450scc, and 17βHSD.
authors.affiliation: Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan.|Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Taniguchi
authors.affiliation: Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Katano
authors.affiliation: Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Department of Medical Chemistry, Kansai Medical University, Hirakata, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ito
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D004195:Disease Models, Animal; D006727:Hormone Antagonists / Q000494:pharmacology*; D016729:Leuprolide / Q000494:pharmacology*; D007985:Leydig Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013737:Testis / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D018931:Antineoplastic Agents, Hormonal; D006063:Chorionic Gonadotropin; D006727:Hormone Antagonists; D009842:Oligopeptides; D010750:Phosphoproteins; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; D007986:Luteinizing Hormone; D015067:17-Hydroxysteroid Dehydrogenases; D016729:Leuprolide
keywords: GnRH antagonist; androgen deprivation therapy; prostate cancer; steroidogenesis; testis