In stressed mice, chronic restraint triggers a specific stress pathway (PERK) in the testicles, leading to poorer sperm and damage to testicular tissue. Giving the drug ISRIB, which blocks this pathway, fixes the tissue, improves sperm quality, and restores hormone balance, but the study does not involve gonadorelin.

Although endoplasmic reticulum stress (ERS) is known to be associated with spermatogenesis, there is limited information about the role and impact of ERS on chronic stress-induced male infertility. To determine the alteration in ERS-related proteins after chronic restraint stress (CRS), these male C57BL/6J mice were randomly divided into the control or CRS group. An ERS inhibitor, integrated stress response inhibitor (ISRIB), was used to establish the causal relationship between ERS and CRS-induced testicular damage, for which male C57BL/6J mice were randomly divided into the following three groups: normal + normal saline (NS), CRS + NS, and CRS + ISRIB. The ERS pathway-related proteins, sperm parameters, testicular structure, spermatogenic cell markers, enzymes involved in steroid biosynthesis, serum corticosterone (CORT) and gonadotropin-releasing hormone (GnRH) levels, and c-fos expression in the hypothalamic paraventricular nucleus (PVN) were evaluated. CRS primarily activated the pancreatic endoplasmic reticulum kinase (PERK)-mediated ERS pathway in the testis. ISRIB administration improved histology structure, low semen quality, expression of spermatogenic cell markers, and the level of enzymes related to steroid biosynthesis in CRS mice. ISRIB administration also reduced serum CORT levels and normalized hypothalamic PVN neuronal activation, accompanied by increased serum GnRH levels in CRS mice. CRS increased p-PERK expression in the testis. However, treatment with the PERK blocker ISRIB improved sperm quality, preserved testis structure, and rescued the expression of steroidogenesis genes in CRS mice, which might be due to the restoration of the hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-gonadal function.