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Elucidation of the mechanism of suppressed steroidogenesis during androgen deprivation therapy of prostate cancer patients using a mouse model
Author(s) -
Taniguchi H.,
Katano T.,
Nishida K.,
Kinoshita H.,
Matsuda T.,
Ito S.
Publication year - 2016
Publication title -
andrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.947
H-Index - 43
eISSN - 2047-2927
pISSN - 2047-2919
DOI - 10.1111/andr.12213
Subject(s) - testosterone (patch) , prostate cancer , medicine , androgen deprivation therapy , endocrinology , agonist , leydig cell , human chorionic gonadotropin , antagonist , luteinizing hormone , cholesterol side chain cleavage enzyme , androgen , hormone , cancer , receptor , cytochrome p450 , metabolism
Summary Androgen deprivation therapy ( ADT ) is the standard medical approach to the management of prostate cancer. Patients switched from a Gn RH antagonist to a Gn RH 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 Gn RH antagonist degarelix for 28 days were further administered the Gn RH 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 Gn RH antagonist to a Gn RH agonist. The size of the Leydig cells in the HDG mice was not significantly different from that in naive mice. Although expression levels of St AR , 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 St AR , P450scc, and 17β HSD .