Abstract
Polycystic ovary syndrome (PCOS), which affects 5–10% of women of reproductive age, is associated with reproductive and metabolic disorders, such as chronic anovulation, infertility, insulin resistance, and type 2 diabetes. However, the mechanism of PCOS is still unknown. Therefore, this study used a letrozole-exposed mouse model in which mice were orally fed letrozole for 20 weeks to investigate the effects of letrozole on the severity of reproductive and metabolic consequences and the expression of cysteine–cysteine motif chemokine receptor 5 (CCR5) in letrozole-induced PCOS mice. The letrozole-treated mice showed a disrupted estrous cycle and were arrested in the diestrus phase. Letrozole treatment also increased plasma testosterone levels, decreased estradiol levels, and caused multicystic follicle formation. Furthermore, histological analysis of the perigonadal white adipose tissue (pgWAT) showed no significant difference in the size and number of adipocytes between the letrozole-treated mice and the control group. Further, the letrozole-treated mice demonstrated glucose intolerance and insulin resistance during oral glucose and insulin tolerance testing. Additionally, the expression of CCR5 and cysteine-cysteine motif ligand 5 (CCL5) were significantly higher in the pgWAT of the letrozole-treated mice compared with the control group. CCR5 and CCL5 were also significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR). Finally, the mechanisms of insulin resistance in PCOS may be caused by an increase in serine phosphorylation and a decrease in Akt phosphorylation.
Highlights
Polycystic ovary syndrome (PCOS) is a common endocrine metabolic disease that affects 5–10% of women of reproductive age [1,2]; it is associated with chronic anovulation, hyperandrogenism, and the development of multiple small subcapsular cystic follicles in the ovary [3,4]
chemokine receptor 5 (CCR5) and cysteine-cysteine motif ligand 5 (CCL5) expression in multiple organs or tissues of the letrozole-treated mice were assessed to understand the role of CCR5 in PCOS pathogenesis
CCR5 and CCL5 expression in the perigonadal white adipose tissue (pgWAT) was significantly higher in the letrozole-treated mice compared with the control mice
Summary
Polycystic ovary syndrome (PCOS) is a common endocrine metabolic disease that affects 5–10% of women of reproductive age [1,2]; it is associated with chronic anovulation, hyperandrogenism, and the development of multiple small subcapsular cystic follicles in the ovary (shown by ultrasonography) [3,4]. Continuous administration of letrozole at 200 μg/d starting before puberty induces reproductive abnormalities and metabolic disturbances in female rats, mimicking the symptoms of women with PCOS [26] These rats exhibited increased body weight and inguinal fat accumulation, anovulation, larger ovaries with follicular atresia and multiple cysts, endogenous hyperandrogenemia, and lower estrogen levels [26]. Letrozole-treated rats showed insulin re of 15 sistance and enlarged adipocytes in perirenal and visceral fat depots, increased circulating levels of luteinizing hormone, decreased levels of follicle-stimulating hormone (FSH), and increased ovarian expression of Cyp17a1 mRNA [28]. These data indicated that letrozoleincreased ovarian of Cyp17a1.
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