Serum testosterone suppression during androgen-deprivation therapy (ADT) has been reported to affect ADT efficacy. However, the factors impacting hormonal variations during ADT remain unclear. Therefore, in this study, we investigated the significance of missense polymorphisms in the gene encoding gonadotropin releasing hormone (GNRH) in men treated with primary ADT for metastatic prostate cancer.

This study included 80 Japanese patients with metastatic prostate cancer whose serum testosterone levels during ADT were available. The association of GNRH1 (rs6185, S20W) and GNRH2 gene polymorphisms (rs6051545, A16V) with clinicopathological parameters, including serum testosterone levels during ADT, as well as prognosis, including progression-free survival and overall survival, was examined.

The CT and CT/TT alleles in the GNRH2 gene (rs6051545) were associated with higher serum testosterone levels during ADT compared with those of the CC allele. Consequently, the CT alleles were associated with higher progression risk after adjustment for age and serum testosterone levels during ADT [hazard ratio (95% confidence interval), 1.73 (1.00-3.00), P = 0.049].

Taken together, these findings suggest that rs6051545 (GNRH2) genetic variation may result in an inadequate suppression of serum testosterone during ADT, which may lead to detrimental effects of ADT on prognosis in men with metastatic prostate cancer.