The impact of fluoxetine treatment on reproductive organs in male rats following peripubertal PTSD-like stress exposure

Fluoxetine (FLX) is the primary treatment for childhood posttraumatic stress disorder (PTSD); however, it may exacerbate the impact of stress on the development of the male reproductive system. In this study, using a PTSD rat model, we evaluated the long-term effects of peripubertal stress and FLX treatment on the morphophysiological parameters of the testes and epididymis, as well as the levels of hormones that regulate male reproduction. Male 40-day-old rats were subjected to a stress-restress paradigm, followed by 21 days of FLX treatment (10 mg/kg). Behavioral testing confirmed PTSD-like anxiety in stressed rats. The PTSD rats exhibited significant reductions in serum testosterone and follicle-stimulating hormone (FSH) levels irrespective of FLX treatment. Although stress alone did not significantly reduce the sperm count, stressed and FLX-treated rats exhibited decreased sperm numbers, lower epididymis weights, and greater gonadosomatic indices. Histological analyses revealed testicular damage, including peritubular edema, disrupted seminiferous epithelium, and vascular congestion, in both PTSD and PTSD+FLX rats. These effects were more pronounced in the testes of the FLX-treated group, as evidenced by a significant reduction in the numbers of Sertoli cells and spermatogonia and an increase in the number of vacuoles. RNA sequencing revealed only modest gene expression alterations, which were primarily limited to the effects of stress. Thus, our results highlight the detrimental impact of FLX on male reproductive function, particularly in the context of PTSD-induced hormonal dysregulation. Although FLX is widely used for treating PTSD and other psychiatric disorders, its effects on reproductive health underscore the need for a cautious approach when prescribing the drug to adolescents.