Effects of Short- and Long-Term Vortioxetine Administration on Reproductive Function in Female Rats

Background/Objectives: Vortioxetine is a multimodal antidepressant that modulates serotonergic, noradrenergic, and dopaminergic systems, yet its effects on female reproductive physiology remain incompletely defined. This study investigated how short- and long-term vortioxetine exposure influences reproductive function in female rats, integrating measurements of oxidative-stress biomarkers, catecholamines, and endocrine endpoints (prolactin and corticosterone). Methods: Forty-two female Wistar albino rats were randomized into seven groups (n = 6): healthy control; short-term vortioxetine; long-term vortioxetine; and the same two regimens each combined with metyrosine or metyrapone. Metyrosine and metyrapone (50 mg/kg, oral gavage) were given 1 h before vortioxetine (10 mg/kg). Treatments lasted one week (short-term) or four weeks (long-term). Serum MDA, tGSH, SOD, CAT, adrenaline, noradrenaline, dopamine, serotonin, prolactin, and corticosterone were measured. Fertility outcomes were assessed by co-housing females with males for one month. Results: Vortioxetine increased MDA, catecholamines, and serotonin and decreased antioxidant markers and prolactin versus controls (p < 0.001). Long-term vortioxetine produced a marked rise in corticosterone that coincided with infertility and delayed parturition. Metyrosine lowered oxidative stress and catecholamines but did not reverse infertility. In contrast, metyrapone blunted corticosterone elevation and preserved reproductive capacity. Conclusions: Long-term vortioxetine induced infertility in female rats, likely mediated by corticosterone elevation consistent with hypothalamic-pituitary-adrenal axis dysregulation. These findings suggest the need to monitor reproductive risk when considering vortioxetine in women of reproductive age and warrant further mechanistic and translational studies.