GnRH Agonist Triptorelin Induces Hepatic Fibrosis via Sex-Specific Oxidative and Inflammatory Responses in Adolescent Rats

Recently, GnRHa puberty blockers have been under scrutiny, with newly identified risks of heart and brain damage and recurrent concerns about fertility, cancer risk, and bone health. This study explores the effects of GnRHa on liver morphology, function, and injury response. Peripubertal male and female Sprague-Dawley rats received daily GnRHa triptorelin (100 μg) subcutaneously. Liver oxidative stress, inflammation, and fibrosis were evaluated via malondialdehyde and 8-OHdG (oxidative damage), immunohistochemistry for CK19 (cholangiocytes) and CD45 (leukocytes), and collagen staining as well as áSMA (liver fibrogenesis) and TIMP1 (extracellular matrix breakdown) expression, respectively. Following GnRHa treatment, only male rats exhibited increased ductular reaction and oxidative stress. In contrast, GnRHa-treated female rats showed increased leukocyte infiltration. In both sexes, GnRHa-treated rats showed increased fibrosis, with significantly increased collagen deposition and áSMA expression. Interestingly, GnRHa-treated female rats exhibited increased TIMP1 expression, whereas male rats showed decreased TIMP1 expression. Overall, GnRHa puberty blocking leads to significantly increased liver injury in both sexes. Specifically, biological females are at increased risk of hepatic inflammation, while biological males are at increased risk of oxidative stress. Human clinical trials are crucial for further exploring these findings.