Ketogenic diet restores hormonal, apoptotic/proliferative balance and enhances the effect of metformin on a letrozole-induced polycystic ovary model in rats

Abstract

Objective: Polycystic ovaries (PCO) is a hormonal disorder that is a leading cause of infertility. The formation of multiple persistent cysts and hormonal imbalance are hallmarks of PCO. Recent clinical studies reported a beneficial effect of the ketogenic diet (KD; high-fat, low-carbohydrate) on PCO. The aim of this study was to investigate the effect of the KD alone and in combination with metformin on letrozole-induced PCO in female rats. Methods: Female rats were grouped into control and PCO (letrozole; 1 mg/kg for 21 days). The PCO group was subdivided into PCO (non-treated), PCO-metformin (300 mg/kg), PCO rats fed with KD only, and PCO rats treated with metformin and fed with KD. All groups continued to receive letrozole during the 21-day treatment period. At the end of the experiment, serum and ovaries were collected for further analysis. Results: The untreated-PCO rats showed increased testosterone, LH/FSH ratio, and ovary weights. Disturbed apoptosis and proliferation balance were evident as a low caspase-3 activation and proliferating cell nuclear antigen expression and increased TGF-β expression. The KD improved the letrozole-induced effects, which was comparable to the effect of metformin. Combining the KD with metformin treatment additively enhanced the metformin effect. Conclusion: Our results indicate that the KD has a protective role against PCO in rats, especially when combined with metformin. This study reveals a potential therapeutic role of the KD in PCO, which could prompt valuable future clinical applications.