Impact of elevated estrogen on the testis with potential implications for prostate carcinogenesis

Abstract

Loss of the androgen-regulated gene Nkx3.1 leads to prostatic intraepithelial neoplasia (PIN), a precursor to prostate cancer (PCa). Elevated testicular estrogen may disrupt hormonal balance in the prostate and downregulate Nkx3.1 expression by indirectly suppressing androgen production via the hypothalamic-pituitary-gonadal axis. Previous research has shown that increased levels of estrogen within the prostate can induce PIN. However, the effects of elevated estrogen levels in the testis, particularly when Nkx3.1 is absent and their potential downstream impact on prostate carcinogenesis remain unknown. This study investigates the effects of systemically elevated 17β-estradiol (E2) levels on the testis in the absence of Nkx3.1. Testicular morphology and connective tissue organisation were assessed by histological analysis following prolonged exposure to elevated E2 via subcutaneous implantation of 90-day extended-release pellets. Cancer-related gene expression was analysed by RT-qPCR after acute administration of elevated E2 by subcutaneous injection. Alterations in testicular morphology and connective tissue organisation were observed; however, no significant changes in gene expression were detected in Nkx3.1-deficient mice in response to E2 treatment. Nkx3.1-intact mice exhibited reduced Esr1, increased Esr2, increased Myc and unchanged Trp53 expression levels following E2 treatment. These findings show that elevated testicular E2 induces tissue abnormalities in the absence of Nkx3.1 and regulates cancer-related gene expression when Nkx3.1 is present, suggesting that Nkx3.1 may modulate testicular response to estrogen, with potential implications for prostate carcinogenesis.