Dehydroepiandrosterone stimulates inflammation and impairs ovarian functions of polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in child-bearing age women. It is characterized by ovulation dysfunction, polycystic ovaries, and hyperandrogenism. Inflammation is likely to be a crucial contributor to the pathogenesis of PCOS. However, the association between the inflammatory cytokines and the development of PCOS has not been reported. To explore the relationship between the inflammatory cytokines and PCOS, alterations of serum proteins in dehydroepiandrosterone (DHEA)-induced PCOS rats were screened by protein array, and the concentration of IFN-γ was further measured by using enzymelinked immunosorbent assay (ELISA). DHEA-induced PCOS rats had a decreased level of IFN-γ compared with the control rats, which was restored partly in flutamide (an androgen receptor antagonist) treated rats. Moreover, the level of IFN-γ in serum of patients with PCOS was also lower than that in healthy women. Using the ovarian granulosa cells (KGN), we demonstrated that DHEA downregulated the expression and secretion of IFN-γ in dose-and time-dependent manners, which could be restored to some extent by treating with flutamide. Furthermore, flutamide ameliorated the inhibitory effect on cell proliferation and promotive effect on cell apoptosis by DHEA.The results also revealed that IFN-γ promoted the proliferation but inhibited the apoptosis of KGN cells, which was suppressed by DHEA via activating the downstream PI3K/AKT signaling pathway. Taken together, these results showed that DHEA inhibited the proliferation and promoted the apoptosis of ovarian granulosa cells through downregulating the expression of IFN-γ which could be restored by flutamide, and IFN-γ may serve as a potential inflammatory biomarker for PCOS detection.

Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10

“…6 g). Several inflammatory regulators, such as IL-10, IFN-γ, and TIMP-2, have been found to be lower in PCOS patients compared with healthy women [ 42 , 60 – 62 ]. We tested mouse serum using an antibody-based membrane assay and found that these cytokines were significantly lower in the untreated PCOS group (IL-10: 0.50 ± 0.08 fold, INF-γ: 0.79 ± 0.05 fold, TIMP-2: 0.82 ± 0.13 fold) compared with control mice (Fig.…”

“…The published studies reported that both TIMP-2 and IFN-gamma are decreased in PCOS patients [ 60 , 61 ]. Our serum analysis in our mouse model also confirmed that these two immunomodulatory factors were decreased in PCOS mice and successfully reversed after MSC treatment.…”

DHEA and polycystic ovarian syndrome: Meta-analysis of case-control studies

“…Studies have shown that DHEA when induced in rat models stimulates inflammation and oxidative stress causing large follicular cysts to develop in ovaries. This finding mimics human PCOS including added effects of glucose intolerance and androgen excess [ 13 ].…”

Elevated ovarian pentraxin 3 in polycystic ovary syndrome

“…Ovary acts as the main androgen supplier in women, and is also an androgen-sensitive tissue [ 34 ]. Studies have indicated that androgen excess in vivo and in vitro induces a proinflammatory response in PCOS women [ 35 , 36 ]. In our study, the univariable association analysis and multivariable regression analysis revealed remarkable positive associations between follicular PTX3 level and ovarian androstenedione concentration.…”