<b>Nano-formulated curcumin restores hypothalamic–pituitary–ovarian axis disturbance in cadmium-induced female reproductive toxicity</b>

Background: Cadmium (Cd) is a pervasive environmental toxicant associated with female reproductive dysfunction through endocrine disruption and oxidative stress. Strategies that enhance antioxidant bioavailability may improve therapeutic efficacy against heavy metal-induced ovarian damage. Aim: To investigate the protective efficacy of polycaprolactone/polyvinyl alcohol-loaded curcumin nanoparticles (PCL/PVA/Cm NPs) against CdCl₂-induced reproductive toxicity in female rats, focusing on hormonal modulation and hypothalamic-pituitary-ovarian axis gene expression. Methods: Forty-eight adult female rats were allocated into six groups: control, CdCl₂, Cm, CdCl₂ + Cm, PCL/PVA/Cm NPs, and CdCl₂+PCL/PVA/Cm NPs. Body and reproductive organ weight, Serum gonadotropin-releasing hormone (GnRH), follicle stimulating-hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and prolactin (PRL) levels were assessed after 4 weeks. Ovarian (LHR, FSHR, and aromatase) and pituitary (LHβ, FSHβ, CYP450, and PRL) gene expression levels were quantified. Results: The results revealed that CdCl₂ exposure significantly reduced body, ovarian, and uterine weights and suppressed GnRH, FSH, LH, estradiol, and progesterone levels while elevating PRL levels. Ovarian and pituitary reproductive gene expression was markedly downregulated. Cm partially reversed these effects; however, nanoformulated Cm produced significantly greater restoration, normalizing hormonal profiles and gene expression patterns to near-control values. Conclusion: The nano-encapsulation markedly enhances Cm bioefficacy, effectively restoring endocrine balance and molecular signaling within the reproductive axis. PCL/PVA/Cm NPs represent a promising nanotherapeutic strategy for mitigating Cd-induced female reproductive toxicity.