Abstract
Women with polycystic ovary syndrome (PCOS) have been reported to have an elevated serum advanced glycation end product (AGE) level. However, the effect of AGEs on the pathophysiological ovarian granulosa cells of PCOS is still unclear. In this study, five indented BSA-derived AGE products were used to evaluate their effect on the function of human granulosa cells. We found that the proliferation of both primary human ovarian granulosa (hGC) cells and human granulosa-like tumor (KGN) cells were inhibited by treatment with these five AGE products. The progesterone secretion level was also reduced in both hGC and KGN cells by treatment with these AGE products through downregulation of LH receptor/cAMP regulatory activity. The granulosa cell layer and serum progesterone level were reduced in rats by treatment with MG-BSA; moreover, an increased number of follicle cysts and an irregular estrous cycle were observed. MG-BSA treatment had a similar effect on the phenotypes of the DHEA-induced PCOS model. Additionally, the insulin resistance and hepatic lesions seen in the DHEA-induced PCOS model were observed in the MG-BSA treatment group. Taken together, we found that AGEs exert a toxic effect on ovarian granulosa cells, ovarian morphology, and the estrous cycle that mimics the DHEA-induced PCOS phenotypes.
Highlights
Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders, leading to several complications [1]
The results showed that the follicle-stimulating hormone (FSH) receptor was intensively expressed in human granulosa cells (hGC) cells (Figure 1A)
We found that the cell proliferation of hGC cells was inhibited by treatment with GA-BSA and GO-BSA for four days; when treated for eight days, all five advanced glycation end product (AGE) products inhibited hGC cell proliferation (Figure 1B)
Summary
Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders, leading to several complications [1]. The presence of hyperandrogenism is positively correlated with ovarian dysfunction (anovulation and/or polycystic ovaries) in PCOS patients [6,7], and this phenotype is observed in DHEA-induced PCOS animal models [8,9]. The diagnosis of PCOS has been linked to metabolic disorders that encompass insulin resistance, type II diabetes, steatosis, and nonalcoholic steatohepatitis [10,11]. A previous study reported that local excessive androgen levels from the follicular fluid are positively correlated with insulin resistance in PCOS patients, despite normal circulating androgen levels [13]. The pathophysiology of PCOS remains unclear, but there is emerging evidence suggesting that it is a complex trait arising from familial heritable influences, intra- and extrauterine environmental factors, variations in insulin resistance, alterations in steroidogenesis/steroid metabolism, and alternative adaptations to energy excess [14,15]. We investigated the effect of AGEs on ovarian granulosa cell growth and hormone secretion; a DHEA-induced PCOS animal model was generated for evaluation of the role of AGEs on PCOS
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