Comparative effectiveness of equol on estrogen and androgen disruption and metabolic parameters in adult male Sprague-Dawley rats

Previous research has investigated the biological activities of equol (EQ), but no experiments have been carried out with positive estrogenic and anti-androgenic animal models to disclose the accurate biological actions of EQ in male rats. This research aimed to investigate the mechanisms of EQ action compared to estradiol valerate (E2V) and anti-androgenic drug flutamide (FLUT) on pituitary-testicular (PT) axis hormonal profiles, metabolic parameters, histopathological and histomorphological changes in male rat pituitary and reproductive organs, and fertility. Three-month-old male Sprague-Dawley rats (n = 12/group) were treated for five days with either EQ (0.25, 2.5, 30, 100, 250 mg/kg/day), E2V (0.6 mg/kg/day), or FLUT (100 mg/kg/day). Key findings revealed that EQ exerted estrogen agonism on PT axis and lipid parameters, resulting in upregulation of pituitary estrogen receptor (ER)-alpha protein expression and decreased levels of plasma luteinizing hormone (LH), testosterone (T), total cholesterol (TC), and lipoproteins, whereas FLUT had opposite effects. Underlying histopathological mechanisms involved in EQ and E2V versus FLUT actions on (i) reductions of seminal vesicle weight and epithelial thickness, tubular/acini, epithelial and luminal areas of prostate and epididymis, and vas deferens, (ii) changes in the frequency of seminiferous epithelial cycle stages, (iii) occurrence of germ cell debris in epididymal tubule, and (iv) enlargement of prostatic stroma, were different due to opposing changes in LH/T profiles, Leydig cell morphology, and relative weights of epididymides and vas deferens. EQ treatment did not result in detectable changes in pituitary cell nuclear size, hepatic injury, and infertility rate, suggesting the potential of EQ as a safe pituitary-ER alpha modulator for promoting beneficial effects on male rat reproductive endocrine and hepatic tissues.