Male Fertility Suppression by Piper nigrum: Insights from In Vivo and In Silico Analysis
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Piper nigrum L. (black pepper) is a widely used spice known for its diverse pharmacological effects, including potential activity on male reproductive function. This study aimed to explore the anti-fertility mechanisms of ethanolic extract of P. nigrum through a combination of in vivo and in silico molecular docking evaluation. Phytocompounds identified via GC-MS were docked against key reproductive targets, including the androgen receptor, follicle-stimulating hormone receptor (FSHR), follicle-stimulating hormone (FSH), testosterone, proprotein convertase subtilisin/kexin type 4 (PCSK4), mothers against decapentaplegic signaling (SMAD3) proteins, and cAMP-responsive element modulator (CREM). Compounds such as hinokinin (-9.9 kcal/mol) and piperine (-8.2 kcal/mol) exhibited strong binding affinities, particularly with the androgen receptor, SMAD3, and CREM, suggesting disruption of hormonal signaling and spermatogenic regulation. In vivo analysis in male rats confirmed these predictions, revealing dose-dependent alterations in sperm quality parameters. Lower to moderate doses (KP1 and KP2) significantly reduced sperm motility and viability and increased abnormality rates, indicating compromised fertility potential. However, the highest dose Group IV (KP3) showed a partial recovery trend, with the greatest increase in sperm concentration, motility levels comparable to the control group, and improved viability, though abnormalities remained elevated. These findings suggest a hormetic effect, where high doses may trigger adaptive protective mechanisms after initial impairment at lower doses. Overall, the results demonstrate that P. nigrum contains bioactive compounds capable of modulating male reproductive health through both molecular and physiological pathways. The combined approach highlights its potential as a reversible male contraceptive, warranting further research on dose optimization, treatment duration, and long-term safety. These findings also underscore the relevance of regional phytochemical variability in determining biological activity.
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