Toll-like receptor 4 knockout mice are protected against PMOS-like pathogenesis.

In brief: Polyendocrine metabolic ovarian syndrome (PMOS) is associated with metabolic, reproductive, and immune dysfunction, yet the mechanisms driving these abnormalities remain unclear. This study identifies Toll-like receptor 4 (TLR4) as a key contributor of PMOS-like pathology in mice, linking gut barrier disruption and endotoxin-associated immune activation to impaired metabolic and reproductive function. Abstract: Polyendocrine metabolic ovarian syndrome (PMOS), formerly termed polycystic ovary syndrome (PCOS), is a reproductive disorder with heterogeneous symptoms and severity. Despite extensive research documenting chronic immune dysfunction as a hallmark of PMOS, the specific mechanisms of immune activation remain poorly understood. Emerging evidence suggests that gut-derived bacterial endotoxins, particularly lipopolysaccharide (LPS), can breach intestinal barriers and trigger systemic inflammation via Toll-like receptor 4 (TLR4). This study examined the role of TLR4 in PMOS-like pathology using a letrozole (LET)-induced mouse model. In LET-treated wild-type female mice, serum LPS and its carrier protein lipopolysaccharide-binding protein (LBP) were elevated compared with LET-treated TLR4-/- mice. Additionally, TLR4 deficiency attenuated multiple PMOS-like features, including elevated luteinizing hormone, anovulation, and metabolic dysfunction. The LET-treated TLR4-/- mice also preserved estrous cycling and fertility, maintained gut barrier integrity, and reduced inflammatory markers. These findings support TLR4 as an important contributor to multiple features of PMOS-like pathology. This novel work highlights TLR4-mediated inflammation as a potential target for anti-inflammatory treatments in women with PMOS.