Dulaglutide, a long-acting GLP-1 receptor agonist, can improve hyperandrogenemia and ovarian function in DHEA-induced PCOS rats

The purpose of this study was to explore the effect of dulaglutide on DHEA induced PCOS rats and its mechanism, to provide new drugs and research directions for clinical treatment of PCOS. In this study, the PCOS model was established by giving female SD rats subcutaneous injection of DHEA for 21 consecutive days. After modeling, the treatment group was injected subcutaneously with three doses of dulaglutide for 3 weeks. The model group was injected with sterile ultrapure water, and the normal group did not get any intervention. The body weight changes of rats in each group were recorded from the first day when rats received the administration of dulaglutide. Three weeks later, the rats were fasted the night after the last treatment, determined fasting insulin and fasting glucose the next day. After the rats were anesthetized by chloral hydrate, more blood was collected from the heart of the rat. The serum insulin, testosterone and sex hormone binding globulin (SHBG) levels were detected by the enzyme-linked immunoassay method. After removing the adipose tissue, the obtained rat ovary tissue was used for subsequent experimental detection, using HE staining for morphology and follicular development analysis; qRT-PCR for the detection of 3βHSD, CYP17α1, CYP19α1, and StAR gene expression in ovarian tissue; and western blotting analysis of CYP17α1, CYP19α1, StAR protein expression and insulin level to verify whether dulaglutide has a therapeutic effect on PCOS in rats. After treated with different concentrations of dulaglutide, we found that the body weight of rats in the treatment groups were reduced. Compared with the rats in PCOS group, the serum androgen level of rats in the treatment groups was significantly decreased, and the serum sex hormone binding protein content was significantly increased, and there was statistically significant difference between these groups and PCOS group. In terms of protein expression and gene regulation, the expression of 3βHSD, CYP19α1 and StAR in the ovarian tissue of rats in treatment groups were decreased significantly after received the treatment of dulaglutide, and there was statistically significant difference between these groups and PCOS group. In addition, dulaglutide reduced the insulin content in the ovarian tissue of PCOS rats. Dulaglutide may reduce the hyperandrogenemia of PCOS rats by regulating the content of serum SHBG and the expression of 3βHSD, CYP19α1, and StAR related genes and proteins, thereby inhibiting the excessive development of small follicles and the formation of cystic follicles in the ovaries of PCOS rats, thereby improving polycystic ovary in PCOS rats. In addition, dulaglutide may reduce the weight of PCOS rats, further reducing the level of high androgen in PCOS rats, and improving the morphology of their polycystic ovaries.