Systematic low-grade chronic inflammation and intrinsic mechanisms in polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder affecting 6-20% of women of childbearing age worldwide. Immune cell imbalance and dysregulation of inflammatory factors can lead to systematic low-grade chronic inflammation (SLCI), which plays a pivotal role in the pathogenesis of PCOS. A significant higher infiltration of immune cells such as macrophages and lymphocytes and pro-inflammatory factors IL-6 and TNF-α has been detected in PCOS organ systems, impacting not only the female reproductive system but also other organs such as the cardiovascular, intestine, liver, thyroid, brain and other organs. Obesity, insulin resistance (IR), steroid hormones imbalance and intestinal microecological imbalance, deficiencies in vitamin D and selenium, as well as hyperhomocysteinemia (HHcy) can induce systematic imbalance between pro-inflammatory and anti-inflammatory cells and molecules. The pro-inflammatory cells and cytokines also interact with obesity, steroid hormones imbalance and IR, leading to increased metabolic imbalance and reproductive-endocrine dysfunction in PCOS patients. This review aims to summarize the dysregulation of immune response in PCOS organ system and the intrinsic mechanisms affecting SLCI in PCOS to provide new insights for the systemic inflammatory treatment of PCOS in the future.

Keywords: chronic inflammation; intestinal microecological; intrinsic mechanisms; polycystic ovary syndrome; steroid hormones.

Figure 1

Immune dysfunction in PCOS and the intrinsic mechanisms influencing SLCI in PCOS. Immune dysfunction in PCOS affects not only the female reproductive system but also other organ systems, including the cardiovascular, intestinal, hepatic, thyroid, pancreatic, adrenal gland,brain and other organs. Obesity, IR, hyperandrogenism, and intestinal microecological imbalance, and hyperhomocysteinemia induce the secretion of systematic pro-inflammatory cells and cytokines. Conversely, deficiencies in progesterone, vitamin D, and selenium have the exert opposite effects.

Figure 2

In women with PCOS, there is a discernible imbalance in the inflammatory cells and cytokines in the peripheral blood, FF, ovaries, and adipose tissue. Inflammatory mediators interact with factors such as obesity, IR, hyperandrogenism, and intestinal microecological imbalances. This interplay may exaggerate the pathophysiological features of PCOS. In adipose tissues, peripheral blood, ovary/follicle fluid of PCOS, immune cells such as T cells, B cells, and neutrophils are activated, leading to the secretion of inflammation cytokines such as TNF-α, MCP-1, IL-17, IL-23 and IL-18. Subsequently, this inflammatory milieu may induce apoptosis in the ovarian GCs and impair oocyte maturation, contributing to the reproductive dysfunctions observed in PCOS.

Figure 3

Theory of dysbiosis of gut microbiota in PCOS. Both hyperandrogenism and high-fat diet increase the proportion of harmful gut bacteria, leading to increased intestinal permeability and the release of LPS, LPS-BP, zonulin, and activated macrophages from the colonic lumen into the circulation. SLCI disrupts glucolipid metabolism and increases insulin and testosterone secretion. Finally, SLCI induced changes in ovarian morphology, and reproductive hormone imbalances in PCOS.

Figure 4

Dysbiosis of the gut microbiota and bile acid metabolites in PCOS ovarian function through inflammation. (A) Bacteroides vulgatus were significantly elevated levels in the intestinal microbiota of individuals with PCOS-like mice, accompanied by reduced concentrations of bile acid metabolites GDCA and TUDCA. GDCA stimulates IL-22 secretion via GATA-binding protein 3(GATA3). The Bacteroides vulgatus metabolite agmatine activates the farnesoid X receptor (FXR) pathway, leading to the inhibition of glucagon-like peptide-1 (GLP-1) secretion in intestinal epithelial L cells. This contributes to IR and ovarian dysfunction in PCOS-like mice. (B) Elevated abundance of Akkermansia and desulfurization gut bacteria, as well as increased serum levels of LPS and interferon IFN-γ, were observed in DHEA-induced PCOS-like mice. IFN-γ has the potential to induce pyroptosis in macrophages within the ovaries, ultimately resulting in abnormal ovarian function. (C) SCFAs have the potential to modulate ovarian inflammation by reducing pro-inflammatory IL-6, TNF-α and NLRP3 inflammasome secretion in the ovaries.