IDO Inhibition by 1-Methyltryptophan: Unlocking New Paths to Treat Ovarian Dysfunction and Hormonal Imbalance in PCOS.

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic inflammation, as well as metabolic and reproductive dysfunction. While insulin resistance affects many tissues, ovarian tissue exhibits insulin hypersensitivity, which promotes androgen excess and worsens PCOS symptoms. The kynurenine pathway (KP), a major route of tryptophan metabolism regulated by indoleamine 2,3-dioxygenase (IDO), is implicated in ovarian dysfunction in PCOS. Objectives: To investigate the effects of IDO inhibition on ovarian morphology and insulin signaling in a PCOS rat model, evaluating its potential as a therapeutic approach compared to metformin. Methods: Twenty-four female rats were randomly assigned to four groups: Control, PCOS, 1-methyltryptophan (1-MT, IDO inhibitor) (10 mg/kg), and metformin (100 mg/kg). The PCOS was induced by subcutaneous testosterone injections at 21 days of age. Outcomes measured included luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio, ovarian weight, follicle and corpus luteum counts, granulosa and theca layer thickness, fasting blood glucose, and ovarian expression of insulin receptor substrate 1 (IRS-1) and phosphoinositide 3-kinase (PI3K). Results: The results indicated that both treatments, 1-MT and metformin, significantly reduced the LH/FSH ratio, with metformin showing a more substantial effect. Additionally, 1-MT increased ovarian weight and the number of healthy follicles (HFs), unlike metformin. Both treatments increased the number of corpora lutea (CL), indicating restored ovulation. The IRS-1 expression decreased with both treatments, whereas PI3K levels remained unchanged. Conclusions: The IDO inhibition by 1-MT improves ovarian function and hormonal balance in PCOS more effectively than metformin, likely by reducing inflammation and modulating insulin signaling. These findings support 1-MT as a promising therapeutic candidate for PCOS management and improving ovarian function. However, these results are from a short-term animal study, and further clinical trials are necessary to assess long-term efficacy and safety.