Chronic Inflammation in Polycystic Ovarian Syndrome: Examining Biomarker–Driven Control Strategies to Reduce Population–Level Disease Burden

INTRODUCTION

METHODS

RESULTS

Initially, the search retrieved 112 documents [Figure 2]. After a thorough analysis of every study published on the topic (n = 23) and following general observational reporting methodology, a total of 29 articles were chosen for this review that also includes six cross-referenced articles from earlier studies identified through a directed citation search.

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Figure 2:

PRISMA flow-chart diagram of the review work.

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Overall, it is evident that low levels of inflammation termed also as “chronic inflammation” are linked to PCOS development, an immunological and hereditary disease that is crucial to the genesis, development, and incidence of the disease. Additionally, infertile PCOS patients receiving ART exhibit abnormal ovulatory activity, elevated oxygen free radical concentrations in granulosa cells, and elevated follicular fluid. It appears that the combination of three primary factors—high dietary carbohydrate intake, insulin resistance, and hyperandrogenism—could be responsible for oxidative stress and low-grade inflammation in PCOS patients.^[12–17] Anti-inflammatory medications and antioxidant supplements may help these patients’ infertility treatment cycles improve, but ultimately, lifestyle changes are important.

DISCUSSION

The objective of the study was to delineate various biochemical factors responsible for creating long-term chronic, low-grade inflammation in the human body that can form the basis of early detection and prevention of PCOS. A pilot study in 2017 by Lindheim and colleagues compared the gut permeability, inflammatory conditions, and stool microbiome of women with PCOS with those of healthy controls. The study showed that patients with PCOS had a stool microbiome with reduced diversity and a different phylogenetic composition.^[11] This added “gut health” as a third dimension besides low-grade inflammation and reproductive hormonal changes in women with PCOS. However, it remains to be deciphered what propels the progression of the disease in a sequential manner within gut-immune-brain axis of things, thus representing a critical knowledge gap. Further, in PCOS patients, the relative abundance of bacteria from the phylum Tenericutes, the order ML615J-28 within that phylum, and the family S24-7 within the phylum Bacteroidetes was much lower when uncommon taxa were examined.^[11] Therefore, gut microbiota itself can now be used as a biomarker to detect disease early. Regarding overall gut microbiome composition, for any taxon with a relative abundance greater than 1%, no discernible changes were found. Although they did not cause clinical phenomena in the patient cohort, endotoxemia and gut barrier disruption might have contributed to the persistent low-grade inflammation identified in the pathophysiology of PCOS. Certain markers of endotoxemia and gut barrier function were altered in the patients, but not all of them. These findings were also linked to reproductive parameters. The authors concluded that the stool microbiome of PCOS patients has a changed phylogenetic profile and decreased diversity, which are linked to clinical characteristics. Independent of obesity, a dietary trigger such as glucose from carbohydrate dietary sources can cause oxidative stress and an inflammatory response in the mononuclear cells (MNCs) of women with PCOS.^[10–13] This finding is significant because MNC-derived macrophages are the main source of cytokine production in adipose tissue and are abundant, and these cells stimulate cytokine production in adipocytes in a paracrine manner. TNFa, a proinflammatory cytokine, is recognized as an insulin resistance mediator. In PCOS, TNFa production from MNCs induced by glucose and inflammatory molecular markers is linked to insulin resistance. Under fasting conditions, hyperandrogenism can activate MNCs, which increases their sensitivity to glucose.^[5] Inflammation and oxidative stress have been increasingly studied in the etiology of polycystic ovarian syndrome in recent years. The assessment of extant research concerning the impact of inflammatory mediators and oxidative stress on ovarian function in individuals diagnosed with PCOS highlights the pivotal function of these variables in the advancement and emergence of complications associated with the disease.^[13] The goal of the current review was to provide an overview of the existence and function of inflammatory mediators as well as the impact of contemporary therapeutic modalities, such as the use of anti-inflammatory drugs and antioxidant supplements, on patients’ ability to respond better to infertility treatment cycles.

Increased C-reactive protein (CRP) concentrations, a sign of low-grade chronic inflammation, are an independent predictor of type 2 diabetes and coronary heart disease (CHD) risk. There are currently no data on the indicators of inflammation in women with polycystic ovarian syndrome (PCOS), even though these women are insulin resistant and at increased risk for type 2 diabetes and CHD.^[7] Another pilot study involved 17 PCOS-afflicted women (identified by increased testosterone and oligomenorrhea) and 15 healthy women who were matched for body mass index. CRP levels were measured using an extremely sensitive technique. Insulin resistance was measured using the hyperinsulinemia euglycemic clamp technique. In comparison to those in controls, the CRP concentrations in PCOS-afflicted women were noticeably greater than those in healthy women (geometric means, 2.12 and 0.67 mg/L, respectively).^[3]

PCOS patients have considerably higher levels of inflammatory factors in their peripheral blood, including human serum-CRP (hsCRP), IL-1R, IL-6, IL-17A, IL-17F, IL-18, IL-23, TNF-a, a-1 acid glycoprotein, monocyte chemoattractant protein-1 (MCP-1), adipokines, and their paralogs.^[15] PCOS patients had significantly reduced levels of anti-inflammatory cytokines in their peripheral blood, including IL-10, IL-17E, IL-27, IL-35, IL-37, Omentin-1, and secreted frizzled-related protein 5 (SFRP5).^[19] Furthermore, a pooled analysis of 63 studies found that PCOS women (n = 4,086) had substantially higher circulating CRP levels than controls (n = 3,120), with a standardized mean difference (SMD 1.26, 95% CI = 0.99, 1.53).^[15] A sensitivity meta-analysis of 35 high-quality studies involving nonobese women found that PCOS patients had significantly higher circulating CRP levels than controls (SMD 1.80, 95% CI = 1.36, 2.25). The systemic inflammation underlying PCOS is thought to interact with comorbidities such as obesity, insulin resistance (IR), and hyperandrogenism. Ayurvedic and Traditional Chinese Medicine (TCM) are multitarget treatments for PCOS that involve anti-inflammatory and antioxidant agents and lifestyle modifications that can benefit women by alleviating inflammatory responses. However, the evidence for this link remains inconclusive, and its causal nature remains unclear.

A systematic review of studies investigating CRP and other inflammatory markers in PCOS patients versus healthy controls revealed significantly greater circulating CRP levels in PCOS patients than in controls.^[15] A sensitivity meta-analysis of 35 high-quality studies including nonobese women showed significantly greater circulating CRP levels in PCOS patients than in controls. Thus, evidently, low-grade inflammation and inflammatory indicators are associated with PCOS.^[21] Further, dietary modifications have been shown to significantly reduce inflammation and prevent disease progression.^[21,22] Examining the inflammatory mediators and processes that lead to the onset and progression of PCOS can be a vital first step toward comprehending the pathophysiology of this rampant disease and helpful in developing strategies for treating it by blocking or regulating relevant signaling pathways. We address the pathophysiological roles of chronic low-grade inflammatory mediators, including cytokines linked to inflammasome formation, interleukin-1β (IL-1β), and IL-18, in PCOS development in the current review.

As per a WHO report, Metformin, the oldest oral antidiabetic drug, has been shown to improve the coexisting complications of diabetes, prevent or alleviate cardiovascular diseases, and ameliorate obesity, PCOS,^[2] osteoporosis, cancer, periodontitis, neuronal damage and neurodegenerative diseases, inflammation, inflammatory bowel disease (IBD), tuberculosis, and even COVID-19. Therefore, it has been proposed to be an anti-aging “elixir” and has numerous mechanisms involved in its protective effects. However, there are long-term side effects and resistance phenomena to be wary of continuous therapy with metformin.

According to earlier researches,^[23–25] oxidative stress and inflammation in the ovarian microenvironment might affect the physiological state of granulosa cells (GCs), which in turn can lead to abnormal follicular growth associated with PCOS. Thus, improving the ovarian microenvironment can be a practical way to boost the capacity for development of PCOS-related oocytes. GCs were obtained from control and PCOS patients to measure the expression of factors related to oxidative stress (HIF-1a and VEGFA) and inflammation (TGF-β1, IL-10, TNFa, and IL-6), as well as the ability of GCs to proliferate and increase the degree of apoptosis.^[25] Next, the human ovarian granulosa cell line (KGN) was treated to confirm the anti-inflammatory and antioxidative stress properties of chitosan oligosaccharide (COS) so as to investigate the ideal culture duration.^[25] Symptoms of polycystic ovarian morphology (PCOM), oligoanovulation, and hyperandrogenism are combined to cause PCOS. It is not confounding that the levels of certain inflammatory cytokines were always found elevated in PCOS, a condition marked by chronic inflammation. Hu et al. in 2023 found that increased expression of HMGB1, TLR2, and TLR4 proteins led to inflammation-related signaling pathways in the gravid uterus exposed to 5a-dihydrotestosterone and insulin. This mimicked the clinical features of PCOS, including hyperandrogenism and insulin resistance. Authors further delineate that elevated levels of HMGB1 and its receptors, as well as alteration of the pro-/anti-inflammatory balance in the gravid uterus, may contribute to the pathophysiology of PCOS-associated pregnancy loss.^[26-29]

CONCLUSION AND IMPLICATIONS FOR TRANSLATION

In conclusion, while the precise mechanisms underlying inflammation in patients with PCOS remain unclear, obesity, insulin resistance, and elevated testosterone levels are believed to play significant roles in mediating this chronic inflammatory state. Persistent inflammatory conditions in the ovaries and uterus of PCOS patients adversely affect both the quality of life and the likelihood of developing additional health issues. Subsequently, developing strategies to reduce such inflammation albeit being low-grade, in adolescent and young women is crucial. Further, it may be concluded that circulating CRP is moderately but significantly elevated in PCOS women independent of obesity, which is indicative of low-grade, chronic inflammation and therefore stimulates the production of inflammatory cytokines, proteins that attract circulating monocytes, and other immune cell recruitment to elicit an inflammatory response that sustains the inflammatory state within adipocytes. Elevated circulating levels of hsCRP in PCOS women, independent of obesity, also suggest its potential as a biomarker for identifying low-grade chronic inflammation. Interventions targeting the kynurenine metabolic pathway, which feeds the patients’ health towards a low risk of chronic inflammation, may therefore mitigate and control PCOS progression. Hence, we draw following implications for translation and healthcare policy framework from the study:

1. Biomarkers such as CRP and IL6 and metabolites such as kynurenic acid to quinolinic acid ratio using tryptophan metabolite assays can serve as important analytes to detect PCOS early in order to identify kynurenine pathway dysfunction.

2. Recommendations for an anti-inflammatory diet and regular physical exercise present a potential non-pharmacological intervention strategy for susceptible individuals post-early diagnosis.