What Actually Causes PCOS? A Mechanistic Reading of Polycystic Ovary Syndrome — The five mechanistic drivers of PCOS

Driver 1: Gut dysbiosis and the DOGMA hypothesis The Dysbiosis of Gut Microbiota (DOGMA) hypothesis was proposed by Tremellen and Pearce in 2012. The hypothesis posited that gut dysbiosis drives systemic inflammation through bacterial translocation, that the systemic inflammation produces insulin resistance, and that the insulin resistance combined with inflammation drives the ovarian hyperandrogenism and follicular arrest characteristic of PCOS. The hypothesis has been substantially supported by subsequent research. Multiple studies have now documented specific microbial signatures in PCOS patients compared to healthy controls. The work of Liu and colleagues, Lindheim and colleagues, Zeng and colleagues, and others has consistently shown reduced alpha diversity, expansion of Bacteroides species, depletion of obligate anaerobic core taxa (particularly Faecalibacterium prausnitzii and Akkermansia muciniphila), and elevated lipopolysaccharide (LPS) levels in serum. The pattern parallels what is seen in the recurrent SIBO and IBD frameworks described in the recurrent SIBO article and the IBD article. The mechanism connecting gut dysbiosis to PCOS is direct. The barrier failure that accompanies the dysbiosis allows LPS translocation. The translocated LPS activates Toll-like receptor 4 (TLR4) on innate immune cells, producing chronic low-grade systemic inflammation. The inflammation