INSL3 Preserves Male Reproductive Function Under Inflammatory and Glucocorticoid Stress in Rats

Rheumatoid arthritis and its glucocorticoid-based treatment may adversely affect male reproductive function by disrupting spermatogenesis, steroidogenesis, and testicular homeostasis. Insulin-like peptide 3 (INSL3), a Leydig cell-derived peptide hormone and marker of Leydig cell functional capacity, may contribute to the maintenance of testicular function through its steroidogenic and anti-inflammatory effects. In the present study, we investigated the effects of prednisolone and INSL3, administered alone or in combination, on testicular structure and function in rats with adjuvant-induced arthritis. Adult male rats were allocated to seven groups: control, prednisolone, INSL3, arthritis, arthritis + prednisolone, arthritis + INSL3, and arthritis + prednisolone + INSL3. Testicular alterations were evaluated using histological, morphometric, immunohistochemical, ultrastructural, testosterone, and sperm analyses. Arthritis was associated with reduced testicular weight, decreased seminiferous tubule diameter and epithelial thickness, impaired sperm parameters, lower serum and intratesticular testosterone levels, increased testicular tumor necrosis factor-α and interleukin-6 immunoreactivity, and reduced 3β-hydroxysteroid dehydrogenase and proliferating cell nuclear antigen immunoreactivity. In arthritic rats, prednisolone or INSL3 alone was associated with partial improvement in selected testicular parameters, whereas combined treatment was associated with improvement across several inflammatory, morphometric, steroidogenic, and sperm-related parameters. These findings suggest that INSL3 treatment is associated with partial attenuation of inflammation-related testicular injury and improvement in selected reproductive parameters under inflammatory and glucocorticoid stress. Further studies are required to clarify whether these effects are mediated by direct intratesticular mechanisms or indirect systemic pathways.