UC Irvine

Polycystic ovary syndrome (PCOS), is the most common endocrine disorder affecting both the reproduction and metabolism of females. Characteristics of this heterogeneous disorder include anovulation, biochemical hyperandrogenemia, insulin resistance, and obesity, which can be recapitulated with a letrozole-induced PCOS mouse model. Immune abnormalities have also been reported in PCOS human patients, including pro-inflammatory factor secretion imbalance and endothelial cell dysfunction. The extent to which the letrozole-induced mouse model for PCOS can represent these immune dysregulations remain unclear, specifically its relevance to disrupting hormone-regulating centers, such as the pituitary gland. Using a PCOS mouse model developed via letrozole induction, we performed single-cell mRNA sequencing (scRNA-seq) on the pituitaries to study impairment in hormone activity and immune regulation. A multiplexed immunoassay was also carried out on stimulated splenocytes to profile cytokines under different immune cell stimulation conditions. The scRNA-seq on the pituitaries revealed microglia and B cells, including sub-populations of macrophages, neutrophils, and T memory cells. Gene set enrichment analysis revealed an association of differentially expressed genes, including Prl, in the total immune cell population of PCOS mice with inflammatory response and positive regulation of cytokine production. Pituitary neuroendocrine cell types also exhibited dysregulated expression, including lactotropes, corticotropes, somatotropes, and two separate clusters of gonadotropes. Interestingly, the lactotrope population decreased in PCOS mice, which could indicate an effect on the total prolactin secretion. Differences in cytokine expression from the multiplex immunoassays also allowed the distinction of mice treated with or without letrozole via partial least square discriminate analysis. Altogether, the letrozole-treated mice presented disrupted immune responses and hormonal imbalances in their transcription and cytokine profiles that provided additional insight to their ability to model the PCOS immune system.