Developmental Stage Influences Metabolism and Gut Microbiome Community Structure in a Hyperandrogenic Mouse Model of Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous, polygenic disorder with an estimated prevalence of 6-15% in reproductive-aged women. In addition to infertility, many women with PCOS have metabolic dysfunction that results in an increased risk of obesity, type diabetes and cardiovascular disease. Given the limitations of current treatments for the metabolic symptoms of PCOS, there is a significant need to understand the etiology and pathophysiology of the PCOS metabolic phenotype. We previously developed a pubertal PCOS mouse model using the aromatase inhibitor, letrozole that recapitulated many of the reproductive and metabolic features of PCOS. This model also exhibited changes in the gut microbial community, including a decrease in bacterial alpha diversity and changes in specific taxa previously associated with metabolic disorders. Since PCOS often manifests in late adolescence, puberty may be a critical time for the development of this disorder. To further our understanding of the role of puberty in PCOS, we compared the effects of letrozole treatment in female mice initiated in puberty versus adulthood on reproductive and metabolic phenotypes.Results: Letrozole treatment of both pubertal and adult female mice resulted in reproductive hallmarks of PCOS, including hyperandrogenemia, anovulation and polycystic ovaries. However, unlike letrozole treatment of pubertal mice, treatment of adult female mice did not result in obesity or dysglycemia, nor did it decrease the alpha diversity of the gut microbiome or significantly change the relative abundances of specific bacterial genera (e.g., Allobaculum and Coprococcus) that were altered in the pubertal PCOS mouse model. Instead, letrozole treatment of adult female mice had no discernable effect on alpha diversity and altered the relative abundance of a distinct suite of bacterial taxa.Conclusions: Our results suggest that regulation of host metabolism and the gut microbiome by testosterone is influenced by the developmental stage of the host.