Synergistic Impact of Obesity and PCOS on Immune Dysregulation: A Review of Systemic and Local Inflammatory Profiles.

The immune-inflammatory microenvironment in PCOS with obesity exerts profound and complex effects on the function of ovarian granulosa cells. Research indicates that chronic low-grade inflammation is one of the core mechanisms underlying PCOS pathogenesis. Multiple inflammatory factors directly interfere with granulosa cell proliferation, apoptosis, and steroid hormone production by activating key signaling pathways, thereby disrupting normal follicular development and maturation. For example, the pro-inflammatory cytokine interleukin-15 (IL-15) is overexpressed in patients with PCOS. 63 In vitro experiments confirmed that this substance inhibits granulosa cell proliferation and promotes apoptosis, partially mediated through the activation of multiple inflammation-related signaling pathways, including p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and NF-kappaB 63 Upregulation of leptin exacerbates granulosa cell inflammation in PCOS, leading to reduced cell proliferation, increased apoptosis, and intensified inflammatory responses. This process involves the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) pathway, revealing the critical role of inflammatory mediators in regulating NF-kappaB, JAK/STAT, and MAPK signaling pathways. 64 The inflammatory environment seriously interferes with the synthesis of steroid hormones in granulosa cells, especially the expression and activity of aromatase (CYP19A1), leading to insufficient estrogen synthesis and androgen/estrogen imbalance, which is one of the key mechanisms of arrested follicular development in PCOS. 63 The expression of androgen synthesis related gene CYP17A1 is up-regulated and CYP19A1 is inhibited in granulosa cells of women with PCOS. The expression of adipokine spexin is decreased in obese and PCOS women. Exogenous SPX can negatively regulate steroidogenesis and reduce estradiol secretion through its receptor and kinase. 65 Another study showed that α1AMP-activated protein kinase (α1AMPK) subunit could induce a hyperandrogenism response in KGN cells, up-regulate the expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) and P450scc, and promote androgen production. 66 These evidences suggest that inflammatory signaling reshapes the steroidogenic profile of granulosa cells through multiple molecular mechanisms, exacerbating hyperandrogenism in PCOS. The inflammatory state also impairs the sensitivity of granulosa cells to FSH, affecting the selection and maturation of dominant follicles. Insulin resistance is a common feature of PCOS. Even in PCOS with obesity women who lack clinical signs of insulin resistance, the insulin signaling pathway in cumulus granulosa cells is dysregulated. 67 Overexpression of multiple genes in this pathway is associated with abnormal cumulus cell proliferation and differentiation, suggesting functional insulin resistance in the follicular microenvironment that may impair FSH signaling. 67 In addition, the adipokine vaspin was found to be able to enhance steroidogenesis, proliferation and viability of human granulosa cells in a concentration dependent manner, which was mediated through its receptor glucose-regulated protein 78 (GRP78). 22 In obese and women with simple polycystic ovary morphology, the expression of vaspin and GRP78 changes, which may indirectly affect the responsiveness of granulosa cells to gonadotropins. 22 In summary, the immune-inflammatory microenvironment associated with obesity impairs the function of granulosa cells through multiple pathways, including interfering with hormone synthesis, altering the activity of signaling pathways, and affecting the cells’ response to FSH. All these factors jointly lead to ovulatory disorders and abnormal follicular development in PCOS. The decline in oocyte quality in patients with PCOS with obesity is closely related to their low fertility, and this is mainly influenced by the local immune-inflammatory microenvironment of the ovary. Studies have shown that the levels of inflammatory factors in follicular fluid are negatively correlated with the quality of oocytes. 68 The hyperandrogenism and insulin resistance in patients with PCOS with obesity can lead to chronic low-grade inflammation of the ovaries, increase oxidative stress, and disrupt follicular development. 23 This inflammatory environment leads to an increase in the oxidative stress level of oocytes, impairment of mitochondrial function, and an increase in DNA damage. Some researchers have found in the PCOS mouse model that an increase in androgen levels can cause abnormal mitochondrial structure in oocytes, an increase in reactive oxygen species (ROS), and problems with adenosine 5’-triphosphate (ATP) production. These functional impairments exacerbate oxidative stress and cell damage. 69 In the lean PCOS mouse model, mitochondrial dysfunction and ultrastructural abnormalities were also observed in oocytes, accompanied by increased ROS levels and transcriptional changes. 70 These mitochondrial dysfunctions not only affect the energy supply of oocytes, but also aggravates oxidative stress, leading to increased cell damage and apoptosis. 71 Furthermore, lipid metabolites in follicular fluid, such as neurophosphatidic acid (NA), can further damage ovarian function by inducing mitochondrial oxidative stress and activating inflammatory pathways. 72 Therefore, the chronic inflammation and oxidative stress of the ovary jointly create a microenvironment that is unfavorable for the maturation of oocytes. This directly confirms that although patients with PCOS obtain a large number of eggs during the IVF process, the number of fertilized eggs, the number of high-quality embryos, and the pregnancy rate do not have any advantages. Moreover, as BMI increases, these indicators further decline. Clinical research data support this view. A study on patients with PCOS found that the number of dominant follicles, the number of retrieved oocytes, and the number of mature oocytes in patients with PCOS were higher than those in non-PCOS patients. However, there were no differences in the number of fertilized eggs, the number of high-quality embryos, the pregnancy rate, the implantation rate, and the live birth rate. This suggests that the quality of the oocytes in patients with PCOS may be impaired. 73 Another large retrospective study further confirmed that as BMI increased, the total number of eggs, the number of MII oocytes, the number of 2PN fertilized eggs, and the number of high-quality embryos in patients with PCOS all significantly decreased. Moreover, the live birth rate and implantation rate of patients with BMI ≥ 23 kg/m 2 also significantly decreased. 24 Obesity itself is regarded as a significant risk factor for poor oocyte quality and is associated with adverse reproductive outcomes. 74 , 75 The mechanism involves changes in the microenvironment of the follicular fluid, such as increased inflammation and oxidative stress, which impairs the development of oocytes. 25 In contrast, non-PCOS women may exhibit protective metabolic and inflammatory adaptations when dealing with obesity, which helps them maintain the quality of oocytes better. 25 These findings indicate that the local immune-inflammatory microenvironment of the ovaries in obese patients with PCOS impairs mitochondrial function and increases oxidative stress, thereby reducing the developmental potential of oocytes. This is the key pathological basis for the suboptimal success rate of ART in these patients. The ovulation and luteal function of patients with PCOS with obesity are affected by the immune-inflammatory microenvironment. Obesity is accompanied by metabolic syndrome, which leads to a decrease in the success rate of inducing ovulation and an increased risk of adverse pregnancy outcomes. A study involving 750 women with PCOS and infertility found that women with metabolic syndrome had significantly lower clinical pregnancy rates and live birth rates, and a higher incidence of pregnancy complications. 76 Metabolic syndrome has an independent negative impact on live birth rate, independent of obesity. It may be related to the chronic low-grade inflammatory state associated with obesity, which interferes with normal follicular development, ovulation, and luteal function. 26 Oxidative stress interacts with hyperandrogenemia, insulin resistance and obesity, forming a vicious cycle, and participates in the occurrence and development of PCOS and ovulatory disorders. 26 Furthermore, in women with PCOS with obesity, the expression of growth differentiation factor-8 (GDF-8) in the serum is elevated, which affects the function of granulosa cells. The blockade of its signaling pathway is considered a potential target for treating ovulation disorders in PCOS. 77 At the clinical treatment level, obesity significantly affects the therapeutic effect of ovulation-promoting drugs. Especially for women with PCOS with obesity who have poor response to the induction of ovulation with letrozole. 78 Obesity also reduces the effectiveness of coenzyme Q10 treatment. 79 Obesity-related metabolic and inflammatory disorders impair follicular development, ovulation, and luteal function, thereby affecting pregnancy. Therefore, lifestyle intervention to improve metabolic and inflammatory status before ovulation induction is essential for patients with PCOS with obesity.

In an obese state, adipose tissue, particularly visceral fat, undergoes a series of pathophysiological changes, transforming it from a primarily endocrine organ into an active pro-inflammatory organ. 30 The core mechanisms of this transformation include hypertrophy and hyperplasia of fat cells, local hypoxia, and infiltration of immune cells. 31 Excessive expansion of adipose tissue leads to changes in the microenvironment, exacerbating cellular stress and dysfunction. 32 In this pathological state, adipose tissue is no longer merely an energy storage depot, but rather becomes a continuous source of inflammatory signals. The fat cells themselves, as well as the infiltrating immune cells, particularly the pro-inflammatory M1-type macrophages, start to excessively secrete a series of pro-inflammatory factors. 33 These factors include TNF-alpha, IL-6, and monocyte chemoattractant protein-1 (MCP-1), among others. 32 Meanwhile, the secretion of adipokines with anti-inflammatory and insulin-sensitizing effects, such as adiponectin, is significantly reduced. 34 This imbalance between pro-inflammatory and anti-inflammatory factors constitutes the core mechanism driving obesity-related metabolic disorders. 35 This systemic chronic low-grade inflammation driven by adipose tissue is a crucial bridge linking obesity to metabolic abnormalities in patients with PCOS. 33 The abnormal release of adipokines and cytokines directly participates in the development and progression of insulin resistance and hyperandrogenemia. 36 Excessive TNF-alpha and IL-6 can impair the insulin signaling pathway by interfering with the phosphorylation of insulin receptor substrate (IRS), leading to insulin resistance in peripheral tissues such as muscle and liver. 37 Elevated leptin not only aggravates insulin resistance, but also directly impairs the function of the reproductive axis through multiple mechanisms. At the hypothalamic level, it inhibits the pulsatile secretion of gonadotropin-releasing hormone (GnRH). At the pituitary and ovarian level, it impairs luteinizing hormone (LH) / follicle-stimulating hormone (FSH) signaling through its receptors, and directly inhibits steroid hormone synthesis in granulosa cells and follicular development. Thus, leptin constitutes a direct molecular bridge between metabolic disorders and reproductive dysfunction. 38 In addition, inflammatory mediators derived from adipose tissue can also affect other organs, including the ovaries, through the bloodstream. 31 In the context of PCOS, this systemic inflammatory state lays the foundation for localized inflammatory responses in the ovaries, potentially exacerbating the pathological manifestations of PCOS by affecting follicular development, hormone synthesis, and the ovulation process. 39 Therefore, a deep understanding of the role of adipose tissue as a source of inflammation is of crucial clinical significance for elucidating the pathogenesis of PCOS with obesity. The complex bidirectional interaction between insulin resistance and chronic low-grade inflammation serves as the core pathological basis for metabolic diseases such as PCOS with obesity. On the one hand, chronic inflammation is a key driver of insulin resistance. In an obese state, immune cells infiltrate and activate in insulin-sensitive tissues such as adipose tissue, liver, and skeletal muscle, leading to a persistent, low-grade inflammatory state. 40 , 41 This inflammation directly interferes with insulin signaling by activating multiple intracellular signaling pathways. 42 The activation of these pathways inhibits the normal tyrosine phosphorylation of IRS, leading to impaired insulin signaling in the liver, muscle, and adipose tissue, and ultimately causing systemic insulin resistance. 42 In addition, epigenetic regulation, such as hypomethylation in the promoter regions of inflammatory genes or alterations in histone modifications, may also play crucial roles in inflammation-induced insulin resistance. 43 On the other hand, hyperinsulinemia accompanying insulin resistance itself also has a pro-inflammatory effect, driving and exacerbating a self-reinforcing vicious cycle. Hyperinsulinemia can stimulate ovarian theca cells and the adrenal glands to produce more androgen. Elevated androgens, especially in conjunction with visceral fat accumulation, can further exacerbate local and systemic inflammatory states and insulin resistance. 44 Meanwhile, high insulin levels can directly activate inflammatory pathways, exacerbate insulin resistance, and together with high androgen levels, form a vicious triangle of “inflammation-insulin resistance-high androgen” 44 In patients with PCOS, adipose tissue dysfunction, macrophage infiltration and increased secretion of pro-inflammatory factors are not only the key links of this cycle, but also the “fuel” for its continuous operation. 1 , 36 For example, M1 polarization of adipose tissue macrophages secretes large amounts of TNF-alpha and IL-6, which not only impair insulin sensitivity in local adipose tissue but also enter the circulation to affect the function of distant organs such as the ovaries and liver. 37 Therefore, a deep understanding of this interaction is crucial for uncovering the mechanisms of PCOS and developing new therapies.

In the clinical management of PCOS with obesity, it is essential to construct a multi-parameter inflammation assessment model to accurately stratiize the patient’s inflammation risk. Traditional single index, such as CRP or IL-6, cannot fully capture the complex metabolic-immune interaction of PCOS. 91 SII combined with traditional inflammatory markers and metabolic indicators (such as homeostasis model assessment of insulin resistance (HOMA-IR) can more comprehensively evaluate the state of metabolic inflammation in patients with PCOS. Compared with a single marker such as CRP that only reflects the acute phase response, SII integrates neutrophil, lymphocyte and platelet count, so as to achieve a multi-dimensional assessment of innate immune activation, adaptive immune status and thromboinflammatory tendency. SII can more comprehensively reflect the low-grade chronic inflammation of PCOS. This integrated advantage of SII enables it to reveal the “inflammation-coagulation-immunity” interaction that is easily ignored by traditional indicators, such as platelet activation driven by hyperinsulinemia and the formation of neutrophil extracellular traps (NETs). These processes have been shown to be directly related to granulosa cell dysfunction and follicular atresia. This “inflammation-coagulation-immunity” interaction constitutes a key mechanism pathway for metabolic abnormalities to damage the local ovarian microenvironment. Studies have shown that coenzyme Q10 supplementation can reduce the levels of TNF-alpha, high-sensitivity C-reactive protein (hs-CRP) and IL-6 and improve endothelial function in overweight/obese PCOS women, suggesting that the integration of inflammatory markers and HOMA-IR can more comprehensively evaluate the intervention effect. 91 In addition, emerging marker like serum amyloid A (SAA) and Endocan, linked to hyperandrogenism, obesity, and insulin resistance in PCOS, offer new evidence for evaluating inflammation. 92 , 93 Machine learning methods can identify key genes (such as CLDN11, HLA-DMA), which are involved in inflammatory pathways such as IL-17, and provide molecular targets for the construction of multi-parameter models. 94 This multi-dimensional model can help to distinguish different PCOS phenotypes and thus provide a basis for individualized risk prediction and treatment strategies. The inflammatory factor profile of follicular fluid is the key to evaluate the ovarian microenvironment and predict the quality of oocytes. The local inflammatory state of the ovary is subject to unique regulation and is not a simple reflection of systemic inflammation. Proteomic analysis showed that the follicular fluid protein composition of patients with PCOS was significantly changed, involving the abnormal expression of protease inhibitors and immune-related proteins, suggesting that inflammation and immune dysregulation play a key role in the ovarian microenvironment of PCOS. 28 For example, in PCOS patients with normal body mass index, granulosa cell proteomic analysis revealed enhanced immune and inflammatory responses and significantly increased levels of macrophage inflammatory protein-1 beta (MIP-1 beta) and stromal cell-derived factor-1alpha (SDF-1alpha) in follicular fluid. Importantly, follicular fluid MIP-1 beta levels were negatively correlated with the number of good-quality embryos and the rate of good-quality blastocysts in patients with PCOS, suggesting that it may be a potential local biomarker affecting embryo quality. 95 Metabolite methylglyoxal and exosomal microRNA(miRNA) are involved in the regulation of inflammation, 96 and become indicators reflecting the local state of the ovary. Studies have shown that ex-miRNAs are differentially expressed in women with obesity-related PCOS and are involved in the regulation of inflammation, glucose metabolism, and folliculogenesis and growth. 97 These profiling of inflammatory factors, metabolites, and non-coding RNAs present in the follicular fluid can more directly assess the inflammation and oxidative stress in the follicular microenvironment, thereby predicting the developmental potential of oocytes and the quality of embryos after fertilization, and providing key information for optimizing embryo selection and improving pregnancy success in assisted reproductive technology.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in women of reproductive age, with a complex pathophysiology involving multiple factors such as genetics, endocrine disruptions, and metabolic imbalances. 1 Obesity is one of the most common features of PCOS, with approximately 40–80% of patients being overweight or obese. 2 Obesity not only exacerbates the clinical manifestations of PCOS but also plays a crucial role in its immune-inflammatory dysregulation. Excessive adipose tissue, particularly visceral fat, releases a large amount of pro-inflammatory cytokines and adipokines, leading to systemic chronic low-grade inflammation. 3 This chronic inflammatory state is closely related to the core features of PCOS, such as hyperandrogenemia, insulin resistance, and ovulatory dysfunction, forming a vicious cycle. 1 , 4 Studies have shown that patients with PCOS exhibit systemic low-grade chronic inflammation, characterized by increased levels of pro-inflammatory cytokines (such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), Interleukin-18 (IL-18)) in circulation, as well as changes in the number and function of immune cells (such as neutrophils, lymphocytes, monocytes). 5 , 6 This inflammatory state is not a simple accompanying phenomenon of PCOS, but an important participant in its pathogenic mechanism. In PCOS with obesity, insulin resistance (IR) and its induced hyperinsulinemia are the initial and core factors driving the vicious cycle of “inflammation-hyperandrogenism”. Hyperinsulinemia can directly up-regulate the expression of IL-1β in target tissues such as ovary. At the same time, activated IL-1β can exacerbate local insulin resistance, forming a self-perpetuating positive feedback loop between metabolism and inflammation. The central effect of this loop is that IL-1β activates inflammatory pathways such as nuclear factor kappaB (NF-kappaB), which directly induce the expression of rate-limiting enzymes of androgen synthesis, such as CYP17A1, leading to hyperandrogenism. 1 , 7 Therefore, the central pathological effect of insulin resistance is that it links metabolic defects to hyperandrogenism through the activation of IL-1β, an inflammatory hub. Meanwhile, obesity itself acts as an amplifier of PCOS, and its associated adipose tissue dysfunction releases more pro-inflammatory mediators, exacerbating the systemic and local inflammatory microenvironment in the ovaries. 8 In recent years, given the heterogeneity of PCOS, there is an urgent need for a biomarker that can comprehensively reflect various inflammatory information. The systemic immune-inflammation index (SII) has emerged, which integrates neutrophil, lymphocyte, and platelet counts to provide a more comprehensive assessment of the body’s inflammatory and immune balance status. 9 SII, as an emerging and easily accessible inflammatory marker, has demonstrated significant prognostic value in various chronic inflammatory diseases. 9 The association between SII and disease severity, metabolic syndrome risk, and adverse pregnancy outcomes in PCOS with obesity is increasingly becoming a research focus. 10 , 11 The abnormal inflammatory state suggested by the elevated SII level is considered to directly target the local ovarian microenvironment. Studies have shown that high SII is closely related to abnormal follicular development, decreased oocyte quality, and decreased ovarian responsiveness to ovulation induction drugs in patients with PCOS. 10 Systemic inflammation can disrupt the local ovarian microenvironment by interfering with paracrine signals, inducing granulosa cell dysfunction and oxidative stress, thereby impairing the normal maturation and ovulation of follicles. Therefore, SII is not only an inflammatory index, but also an important early signal to predict “local” inflammatory damage and potential decline in ovarian reserve function. Moreover, composite inflammatory markers such as SII have shown potential in distinguishing different clinical phenotypes of PCOS (such as those with oligomenorrhea/amenorrhea or polycystic ovarian morphology), potentially aiding in the identification of patient subgroups with higher cardiovascular metabolic risks. 12 , 13 Understanding how systemic inflammatory signals are “transmitted” and alter the local microenvironment of the ovary is crucial for exploring the mechanisms of folliculogenesis, ovulation, and luteal dysfunction. The ovary is not an immunologically privileged organ, and its normal function relies on the delicate microenvironmental balance formed by immune cells (such as macrophages, T cells) and cytokines. 6 , 14 In the state of PCOS, systemic chronic low-grade inflammation can disrupt the local immune homeostasis of the ovaries. Studies have shown that there is an increase in macrophage infiltration and abnormal polarization (tending towards the pro-inflammatory M1 phenotype) in the ovarian tissue of patients with PCOS, which directly contributes to granulosa cell dysfunction, follicular arrest, and ovulation disorders. 14 , 15 In addition, PCOS related systemic inflammation and metabolic disorders also affect endometrial receptivity. Studies suggest that there is an abnormal immune microenvironment in the endometrium of patients. 16 This may be independent of obesity and potentially affect embryo implantation success. Therefore, summarizing the research progress on the immune-inflammatory microenvironment in PCOS with obesity from the axis of “systemic inflammation (represented by SII) - ovarian local response” not only deepens our understanding of the disease’s mechanisms but also provides theoretical foundations and clinical insights for the development of novel therapeutic strategies targeting inflammatory pathways, such as immune regulation, targeted macrophage polarization, and gut microbiota modulation. 14 , 17 , 18 This article aimed to provide a systematic review of the characteristics of the immune-inflammatory microenvironment in PCOS with obesity. Table 1 lists important references containing key information in these fields. Table 1 Important References on Review of the Immune-Inflammatory Microenvironment in Polycystic Ovary Syndrome with Obesity Titles of Publications Journal, Year of Publication; Authors Type of study; Study Subjects; Methods Major Findings Comments Correlation and predictive value of systemic immune-inflammation index for dyslipidemia in patients with polycystic ovary syndrome BMC Womens Health 2024 Zhou X et al 10 Clinical study; Patients with PCOS aged 20–35 years (according to the Rotterdam criteria); The relationship between lipid metabolism abnormalities and inflammation in patients with PCOS. SII remains associated with an increased incidence of dyslipidemia in PCOS. Elevated SII levels correlate with the occurrence of dyslipidemia in patients with PCOS, making it valuable for the early diagnosis of PCOS. The association between systemic immune-inflammation index and in vitro fertilization outcomes in women with polycystic ovary syndrome: a cohort study J Ovarian Research 2023 Li X et al 11 Clinical study; Women with PCOS undergoing IVF procedures; Evaluating the correlation between SII and assisted reproductive outcomes in patients with PCOS. The logarithm of SII was negatively correlated with the available embryo rate. SII may affect assisted reproductive outcomes in patients with PCOS. Association between the systemic immune-inflammation index and obesity among adults: Insights from the NHANES 2017–2018 PLoS One 2024 Yu Y et al 19 Clinical study; A total of 4395 participants aged ≥20 years were included in the 2017–2018 National Health and Nutrition Examination Survey; Association between SII and obesity. SII showed a significant positive correlation with BMI, most pronounced in adults under 60 years of age without hypertension or diabetes. SII are positively correlated with body weight in American adults. Icariin and its phosphorylated derivatives alleviate intestinal epithelial barrier disruption caused by enterotoxigenic Escherichia coli through modulate p38 MAPK in vivo and in vitro Faseb j 2020 Xiong W et al 20 Basic research; Regulatory mechanisms of the p38 MAPK signaling pathway; Systematic Evaluation of the Protective Effects of ICA/Pica. p38 MAPK is a key regulatory target for the barrier function of IPEC-J2 cells. ICA and pICA modulate inflammatory responses and oxidative stress in intestinal epithelial cells by suppressing p38 MAPK expression, thereby mitigating ETEC K88-induced intestinal barrier disruption and increased permeability. Shared diagnostic genes and potential mechanism between PCOS and recurrent implantation failure revealed by integrated transcriptomic analysis and machine learning Front Immunol 2023 Chen W et al 21 Clinical prediction model research; The data sets related to PCOS and RIF; Collect granulosa cells from healthy women and infertile women with PCOS, as well as endometrial tissue from healthy patients and RIF patients, and validate the reliability of key genes using RT-PCR. GLIPR1 and MAMLD1 may serve as potential diagnostic markers for PCOS and RIF, aiding in early screening and prognosis assessment. Abnormal TCA cycle metabolism and immune activation may represent a key mechanism underlying their co-occurrence, providing novel targets for the targeted treatment of PCOS and RIF. Vaspin, a novel adipokine in woman granulosa cells physiology and PCOS pathogenesis? J Endocrinol 2021 Bongrani A et al 22 Basic research; Infertile women undergoing in vitro fertilization procedures; Detection of vaspin and GRP78 in granulosa cells and follicular fluid using RT-qPCR and ELISA. Vaspin is highly expressed in human ovaries. Vaspin enhances granulosa cell steroid production, proliferation, and viability in a GRP78 concentration-dependent manner. Vaspin levels are significantly elevated in obese women and in the simple polycystic ovarian morphology group among normal-weight women. Vaspin may represent a novel regulator of human granulosa cell physiology and could be involved in the pathogenesis of PCOS. Chronic low-grade inflammation and ovarian dysfunction in women with polycystic ovarian syndrome, endometriosis, and aging Front Endocrinol (Lausanne) 2023 Orisaka M et al 23 Review; The ovarian microenvironment; The ovarian microenvironment is critical for follicular development and oocyte maturation. Chronic low-grade inflammation elevates pro-inflammatory cytokine levels, induces oxidative stress and fibrosis, and disrupts the ovarian microenvironment and follicular development. A framework for the association between inflammation and ovarian dysfunction was proposed by integrating existing studies. Overweight and obesity determined by body mass index criteria for Asian populations adversely affect assisted reproductive outcomes among Chinese women with polycystic ovary syndrome Int J Obes (Lond) 2024 Zhao R et al 24 Clinical study; Women with PCOS undergoing IVF treatment; Evaluating the impact of BMI on clinical and embryological outcomes. Increased BMI was significantly associated with a reduction in the total number of retrieved oocytes, metaphase II oocytes, 2PN fertilized oocytes, and the number of good-quality oocytes. PCOS patients with a BMI ≥ 23 kg/m 2 exhibit reduced pregnancy rates and live birth rates. Impact of obesity on proteomic profiles of follicular fluid-derived small extracellular vesicles: A comparison between PCOS and non-PCOS women J Ovarian Research 2025 Chang Q et al 25 Basic research; PCOS group and non-PCOS control group; Follicular fluid collected for proteomics analysis using DIA technology. Significant associations exist between specific differentially expressed proteins and IVF/ICSI outcomes. Obesity exacerbates inflammation and oxidative stress in women with PCOS, thereby impairing oocyte development and IVF/ICSI outcomes. Oxidative stress and antioxidant imbalance in ovulation disorder in patients with polycystic ovary syndrome Front Nutr 2022 Li W et al 26 Review; PCOS; The Impact of Interactions Between oxidative stress, and Hyperandrogenemia, Insulin Resistance, or Overweight/Obesity on Ovulatory Dysfunction in PCOS. Hyperandrogenism interacts with insulin resistance and overweight/obesity to form a mutually reinforcing vicious cycle, collectively contributing to the onset and progression of PCOS. Oxidative stress, combined with hyperandrogenism, insulin resistance, or overweight/obesity, exerts a negative effect on ovulation in PCOS. Sinapic acid modulates oxidative stress and metabolic disturbances to attenuate ovarian fibrosis in letrozole-induced polycystic ovary syndrome SD rats Food Sci Nutr 2024 Lan H et al 27 Basic research; Six‐week‐old SD rats; Performed to evaluate the antifibrotic properties of SA in rats with letrozole-induced PCOS-related ovarian fibrosis. Erucic acid significantly improves metabolic dysfunction and oxidative stress. Erucic acid reduces ovarian fibrosis in PCOS rats induced by letrozole. Proteomic Analysis of Follicular Fluid in Polycystic Ovary Syndrome: Insights into Protein Composition and Metabolic Pathway Alterations Int J Mol Sci 2024 Przewocki J et al 28 Basic research; The proteomic composition of follicular fluid; Proteomics analysis using machine learning to compare whether there are differences in protein composition between PCOS and the control group. Protease inhibitors and immune-related proteins involved in the pathophysiology of PCOS. Myosin light chain peptide 6 may serve as a novel independent biomarker for PCOS. Polycystic ovary syndrome and obesity: clinical aspects and nutritional management Minerva Endocrinol (Torino) 2022 Frias-Toral E et al 29 Review; PCOS and obesity; Clinical characteristics and nutritional management of PCOS. The close interaction between oxidative stress, low-grade inflammation, and PCOS. PCOS complications can be managed through a comprehensive approach and treatment. Abbreviations : PCOS, polycystic ovary syndrome; SII, systemic immune-inflammation index; IVF, in vitro fertilization; BMI, body mass index; MAPK, mitogen-activated protein kinase; ICA, ictal central apnea; ETEC, enterotoxigenic Escherichia coli; RT-PCR, reverse transcription-polymerase chain reaction; RIF, recurrent implantation failure; RT-PCR, reverse transcription-polymerase chain reaction; GLIPR1, Glioma Pathogenesis-Related Protein 1; MAMLD1, mastermind-like domain-containing 1; TCA, Trichloroacetic acid; GRP78, glucose-regulated protein 78; RT-qPCR, Reverse transcription quantitative PCR; ELISA, enzyme-linked immunosorbent assay; 2PN, two-pronuclear; DIA, data-independent acquisition; ICSI, intra cytoplasmic sperm injection; SD, Sprague-Dawley. Important References on Review of the Immune-Inflammatory Microenvironment in Polycystic Ovary Syndrome with Obesity Abbreviations : PCOS, polycystic ovary syndrome; SII, systemic immune-inflammation index; IVF, in vitro fertilization; BMI, body mass index; MAPK, mitogen-activated protein kinase; ICA, ictal central apnea; ETEC, enterotoxigenic Escherichia coli; RT-PCR, reverse transcription-polymerase chain reaction; RIF, recurrent implantation failure; RT-PCR, reverse transcription-polymerase chain reaction; GLIPR1, Glioma Pathogenesis-Related Protein 1; MAMLD1, mastermind-like domain-containing 1; TCA, Trichloroacetic acid; GRP78, glucose-regulated protein 78; RT-qPCR, Reverse transcription quantitative PCR; ELISA, enzyme-linked immunosorbent assay; 2PN, two-pronuclear; DIA, data-independent acquisition; ICSI, intra cytoplasmic sperm injection; SD, Sprague-Dawley.

Although a large number of studies have revealed that PCOS is closely related to systemic and local ovarian immune inflammatory states, the current evidence is mostly based on correlation observation, and the clear causal mechanism is still unclear. Future research is urgently needed to use tools such as gene-edited animal models and organoids to further explore the causal role of specific inflammatory pathways in PCOS ovarian lesions. The NLRP3 inflammasome pathway has been identified as a key driver in a variety of chronic inflammatory diseases. 112 In the context of PCOS, obesity and insulin resistance can induce a chronic low-grade inflammatory state, activate the inflammasome including NLRP3, and lead to the maturation and release of pro-inflammatory cytokines such as IL-1β. 113 However, whether the activation of NLRP3 inflammasome is the “cause” or “effect” of PCOS ovarian dysfunction (such as follicular arrest and granulosa cell apoptosis) still needs to be verified by conditional knockout or overexpression of NLRP3 related genes in PCOS animal models. Such studies will clarify whether targeted inhibition of NLRP3 can reverse or ameliorate the reproductive phenotype of PCOS, thus providing direct evidence for the development of causal therapeutic strategies. At the same time, studies need to pay attention to how elevated systemic inflammatory indicators (such as SII) regulate the local ovarian microenvironment remotely and interfere with follicular development and hormone production through mechanisms such as immune cell infiltration, inflammatory factor action and adipokine release. The use of organoid co-culture or tracing models is expected to elucidate the specific signal transduction chain from systemic inflammation to ovarian dysfunction. The establishment of an accurate classification system based on inflammatory biomarkers is the key to individualized treatment of PCOS with obesity. The core pathophysiology of PCOS involves excessive androgens, and obesity interacts with PCOS in a variety of ways, such as exacerbating insulin resistance and altering the production of adipokines and inflammatory cytokines. 114 Studies have shown that the inflammatory state is an important bridge connecting obesity with the severity of the PCOS phenotype. 114 In both obese and non-obese PCOS patients, the alternative pathway of the complement system is over-expressed, and this disorder is further aggravated in obese patients. 115 In addition, novel inflammatory markers such as neutrophil index were also significantly increased in patients with PCOS, supporting the hypothesis that PCOS has inflammation independent of obesity. 116 Therefore, integrating systemic immune inflammation index, complement system specific proteins, adipokines, etc., can construct a multi-dimensional inflammatory biomarker, which can more precisely distinguish subtypes characterized by high inflammatory burden, thus providing a basis for the selection of anti-inflammatory therapy or targeted metabolism therapy, and realizing individualized treatment strategies. 29 Prospective cohort studies to dynamically monitor the changes of systemic immune inflammation index and other indicators are essential for objective evaluation of efficacy and prediction of prognosis. Lifestyle intervention targeting weight loss is the first-line treatment strategy for overweight or obese women with PCOS. 114 Dynamic monitoring can evaluate the improvement effect of interventions on the immune-inflammatory microenvironment. For example, bariatric surgery can eliminate the effects of chronic low-grade inflammation by significantly reducing fat mass and improving metabolic parameters, thereby restoring ovulation and menstrual cycle in obese women with PCOS. 117 Prospective studies can systematically track the changes of systemic immune inflammation index, C-reactive protein, specific complement factors and other indicators of patients before and after lifestyle intervention, drug therapy or surgery. 115 , 118 Decreases in these inflammatory markers may be associated with improved insulin sensitivity, reduced androgen levels, and recovery of ovulation. The inclusion of dynamically changing inflammatory measures in the assessment of efficacy could provide earlier and more sensitive data than weight change alone. In addition, baseline or early inflammation levels may have prognostic predictive value, and patients with a higher inflammatory burden may respond poorly to conventional treatment or have a higher risk of long-term metabolic complications such as type 2 diabetes, cardiovascular disease. 119 , 120 Therefore, establishing an efficacy evaluation model based on dynamic inflammation monitoring is an important direction to achieve accurate management and improve long-term prognosis. The exploration of precision drug delivery systems targeting local immune inflammation in the ovary, such as nanovector-based delivery technology, is a cutting-edge strategy to improve the therapeutic effect while reducing systemic side effects. There are local macrophage enrichment and inflammatory microenvironment changes in POSC ovary, which are related to endometrial receptivity, embryo implantation and other reproductive process abnormalities. 61 Current systemic drug therapy may cause systemic side effects such as gastrointestinal reactions, and has limited drug concentration and targeting to the ovary. Nano-carrier systems can be actively targeted through surface modification to specifically deliver anti-inflammatory drugs or genetic tools to the site of ovarian inflammation, thereby increasing local drug concentrations, regulating immune cells, inhibiting androgen overproduction and follicular dysplasia, and reducing systemic toxicity. 121 Molecular imaging techniques can be used to track the distribution and release of nanocarriers in vivo for therapeutic visualization. 121 , 122 Combined with wearable or implantable sensor devices for continuous monitoring of systemic inflammatory markers, a closed-loop system of “local targeted therapy-systemic response monitoring” can be formed to provide real-time feedback for adjusting the dosing regimen. 123 This strategy of precise drug delivery targeting the local ovary represents a potential new treatment mode for the future treatment of PCOS with obesity, especially for patients with refractory ovulation disorder and low ovarian function.

In patients with PCOS with obesity, chronic low-grade inflammation of the ovaries is central to driving fibrosis and is often induced by hyperandrogenism and insulin resistance. This inflammation stimulates the transformation of fibroblasts into myofibroblasts in the ovarian stroma, leading to excessive deposition of extracellular matrix such as collagen and destruction of ovarian structure. 23 Animal models have shown that reproductive tract fibrosis, which is associated with metabolic disorders and inflammation, occurs in a PCOS-like rat model induced by a high-refined carbohydrate diet. 80 This fibrotic change is not limited to the ovary, and may also have a similar pathological mechanism to liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD), which is often associated with PCOS patients, suggesting that systemic metabolic inflammation has a broad impact on multi-organ fibrosis. 81 Transforming growth factor-beta 1 (TGF-beta1), a key molecule linking inflammation and fibrosis, is up-regulated in PCOS ovaries. 82 TGF-beta1 drives the differentiation of fibroblasts through the small mothers against decapentaplegic (SMAD) signaling pathway and enhances the gene transcription and synthesis of extracellular matrix proteins such as collagen, thus directly promoting the occurrence of fibrosis. 82 Therefore, targeting this pathway is considered as a potential therapeutic strategy. In PCOS related MASLD, insulin resistance and hyperandrogenism may also aggravate liver fibrosis through TGF-beta and other factors, forming a vicious cycle of reproductive and metabolic systems. 81 As an important member of the innate immune system, macrophages play a complex and contradictory dual role in the ovarian fibrosis microenvironment. Under the continuous stimulation of chronic inflammation, macrophages are recruited and activated. They secrete pro-fibrotic factors such as TGF-beta1 and platelet-derived growth factor (PDGF), which promote myofibroblast activation and extracellular matrix deposition. 23 At the same time, it regulates extracellular matrix remodeling by secreting a variety of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and affects the progression of fibrosis. 23 In systemic inflammation in PCOS, the macrophage-mediated inflammation-fibrosis axis may be amplified. For example, in the pathogenesis of MASLD, liver inflammation and fibrosis also involve the activation of macrophages, which aggravates systemic and ovarian insulin resistance and endocrine disorders. 81 Therefore, an in-depth understanding of the specific phenotypic and functional switching of macrophages in PCOS ovarian fibrosis is essential for the development of novel therapies that can interrupt the vicious cycle of inflammation and fibrosis. Ovarian interstitial fibrosis is the key structural pathological change of PCOS with obesity, which leads to sclerosis and decreased elasticity of ovarian tissue, hindering the normal development of follicles and ovulation. 83 This is an important structural basis leading to follicular development arrest, long-term anovulation and disease prolongation in patients with PCOS. 27 , 84 Studies have shown that the upregulation of fibrosis markers in PCOS ovaries is directly related to ovulation disorders. 85 , 86 Therefore, ovarian fibrosis is not only the pathological result of PCOS, but also the core link driving the persistence of reproductive dysfunction. The fibrotic ovaries contribute to the decreased clinical responsiveness to gonadotropins. Normal ovarian function depends on the effective feedback of follicles to FSH and LH, and the fibrotic ovarian microenvironment will make the positive and negative feedback abnormal. 83 For example, the persistent activation of fibrosis-related PDGF / SMAD signaling pathway inhibits the normal function of granulosa cells and interferes with gonadotropin receptor signaling, resulting in poor follicle recruitment and maturation even in response to exogenous gonadotropin stimulation. 84 , 87 Therefore, assessing the degree of ovarian fibrosis is expected to be a new research direction to predict the response of patients with PCOS to ovulation induction therapy (such as clomiphene or gonadotropin). At present, serum anti-Mullerian hormone (AMH) and antral follicle count (AFC) are mainly relied on to assess ovarian reserve function, but these indicators cannot reflect the quality of ovarian stroma. Emerging imaging techniques, such as shear wave elastography, can noninvasively quantify tissue stiffness and provide potential tools for the assessment of ovarian fibrosis. 88 In the future, a combination of biomarkers (eg., serum plasminogen activator inhibitor-1 (PAI-1) levels) and imaging assessment may allow more comprehensive models to be constructed to identify patients with PCOS who are likely to have a poor response to treatment due to severe ovarian fibrosis before treatment, thereby allowing for individualized treatment. 89 , 90

The core pathophysiological feature of PCOS with obesity is the disorder of systemic and ovarian immune inflammatory microenvironment. As an integrated inflammation index, SII can effectively reflect this chronic low-grade inflammation state, and has been confirmed to be significantly associated with metabolic risks such as insulin resistance, dyslipidemia, and adverse reproductive outcomes such as ovulation disorder and low pregnancy rate. This suggests that inflammation is not only a concomitant phenomenon of PCOS, but also a key pathological link driving reproductive and metabolic dysfunction. Most current studies have shown a “whole-ovary” inflammatory transmission. Systemic inflammatory factors can directly act on the ovary through blood circulation, or indirectly by inducing insulin resistance, oxidative stress and other ways to remodel the local ovarian microenvironment. Specifically, inflammatory signals originating from visceral adipose tissue can breach the blood-follicle barrier and directly induce the polarization of intra-ovarian macrophages toward a proinflammatory phenotype through activation of pathways such as NF-kappaB. It is important to clarify that hyperandrogenism is the central driver of this process. It stimulates monocyte / macrophage infiltration and proliferation, thus forming a self-sustaining vicious cycle with obesity-related inflammation. This remodeling is characterized by impaired granulosa cell function, abnormal follicular development, decreased oocyte quality, and ovarian interstitial fibrosis, which eventually lead to ovulation disorder and reduced fertility. However, there are still differences in the key inflammatory pathways, dominant cell types and core effector molecules. For example, some studies have emphasized the central role of macrophage polarization, while others have focused on the activation of specific cytokines or inflammosomes such as TNF-alpha and IL-6. Due to the high heterogeneity of PCOS, inflammation may act as a common upstream mechanism and manifest a dominant pattern of differentiation in different subtypes or individuals through different downstream pathways. Therefore, combined analysis of comprehensive indicators such as SII with specific pathway markers may be more conducive to reveal individualized inflammation profiles. Based on the current evidence, clinical management strategies are in urgent need of innovation. The evaluation of inflammatory state indexes such as SII has been promoted to the same important status as hormone levels and metabolic indicators. Of particular note, patients in the highest quantile of SII had significantly lower embryo implantation and live birth rates in ART cycles, which were mainly attributed to the adverse effects of factors such as dyslipidemia on the endometrial microenvironment. In terms of treatment, anti-inflammation should no longer be regarded as an auxiliary means, but as a fundamental strategy throughout. The first-line lifestyle intervention itself has a strong anti-inflammatory effect. In the drug treatment, in addition to the traditional insulin sensitizing agents, it is necessary to explore or rationally apply drugs with clear anti-inflammatory effect, and to implement precise treatment stratification according to different clinical phenotypes of patients, so as to achieve higher clinical accuracy and individualized efficacy and consider the regulation of inflammation in the assisted reproductive technology cycle to improve egg quality and endometrial receptivity. Looking forward to the future, more in-depth and precise research is needed in this field. First, it is necessary to use cutting-edge technologies such as single-cell sequencing and spatial transcriptomomics to clarify the interaction between immune cells and parenchymal cells in the ovary at higher resolution, and to clarify the precise details of the initiation and maintenance of inflammation. Second, translational research is focused on the development of highly targeted and safe novel anti-inflammatory therapies, such as biologics or small molecule drugs targeting specific inflammatory pathways or cytokines, and the evaluation of their efficacy in PCOS. The ultimate goal is to establish a multi-dimensional integrated classification system based on SII, specific inflammatory markers, genetic background and clinical phenotypes, and realize the paradigm shift from “one size fits all” to “individualized” treatment. Only through this pathway of precision medicine can we fundamentally intervene in the inflammatory core of PCOS, effectively improve the reproductive prognosis and long-term metabolic health of patients, and reduce the overall burden of this disease.

Lifestyle intervention, especially comprehensive management with weight loss as the core, is the first-line anti-inflammatory treatment for PCOS with obesity. Weight loss, especially visceral fat loss, is the most effective way to reduce systemic and ovarian inflammation. 29 Obesity is closely linked to the pathophysiology of PCOS, and the accumulation of visceral fat can exacerbate insulin resistance, chronic inflammation, and oxidative stress. 29 Weight loss through lifestyle intervention significantly improved insulin sensitivity, regulated sex hormone levels, and reduced systemic inflammatory states. 29 A systematic review clearly indicates that lifestyle changes including dietary modification, exercise, and behavioral changes can improve the reproductive, metabolic, and psychological outcomes of PCOS. 98 Dietary modification is the core of lifestyle intervention, and anti-inflammatory dietary pattern has shown the potential to improve the clinical symptoms of PCOS in studies. 99 Pro-inflammatory dietary patterns are associated with PCOS related adverse outcomes, highlighting the importance of anti-inflammatory dietary interventions. 100 In addition, a low glycemic index diet has been shown to improve symptoms of hyperandrogenism. 101 These dietary interventions not only act directly on metabolic and inflammatory pathways, but also synergistically promote weight loss and create a favorable microenvironment for the recovery of ovarian function. The importance of regular exercise in lifestyle intervention cannot be ignored, and exercise itself has an independent anti-inflammatory effect. Exercise can induce muscle secretion of actin, which has anti-inflammatory effects. 29 In women with PCOS, both aerobic and resistance exercise can enhance insulin sensitivity, aid weight loss, and improve metabolic and reproductive outcomes. 98 Exercise indirectly reduces the release of proinflammatory factors by improving body composition and reducing fat accumulation. 102 Comprehensive lifestyle intervention, combined with diet and exercise, can significantly improve insulin resistance, achieve sustained weight loss, and increase ovulation rate, which is widely recommended as the first-line treatment for PCOS management. 29 Therefore, individualized lifestyle program with weight loss, anti-inflammatory diet and regular exercise is the most fundamental and effective treatment strategy to regulate the immune and inflammatory microenvironment of PCOS and improve clinical outcomes. Metformin, an insulin sensitizer, is not only used in the treatment of PCOS with obesity to improve glucose metabolism and insulin resistance, but has also been proven to have clear anti-inflammatory properties. It can effectively reduce the levels of inflammatory markers in patients with PCOS and improve the systemic low-grade inflammatory state. 103 This anti-inflammatory effect is crucial for patients with PCOS, as chronic inflammation is a key pathophysiological link connecting insulin resistance, obesity and ovulatory dysfunction. New hypoglycemic drugs, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, are gradually becoming the treatment of choice for PCOS due to their advantages in weight loss, insulin resistance improvement and cardiovascular benefits. 103 In addition, phytochemicals, such as quercetin, can also treat PCOS by regulating steroidogenic activity and correcting hormonal imbalance to improve metabolic disorders. 104 These drugs regulate the metabolic and immune-inflammatory microenvironment through multi-target effects, which provides more possibilities for the comprehensive management of PCOS. Based on the above drug evidence, the treatment strategy of PCOS is moving toward individualization and precision. Hierarchical management based on the dominant phenotype is the key to improve the efficacy. A phenotype dominated by metabolic abnormalities was characterized by a high BMI and a significantly elevated systemic inflammatory index. In such patients, glucagon-like peptide-1 (GLP-1) receptor agonists are preferred because of their potent weight loss and comprehensive improvement of glucose and lipid metabolism. 105 In contrast, phenotypes characterized by hyperandrogenism and / or insulin resistance have a relatively low metabolic burden, such as normal or low BMI. Inositol combined with resveratrol can provide a targeted alternative strategy by regulating local ovarian steroidogenesis and improving peripheral insulin sensitivity. 106 Statins may help to improve dyslipidemia, obesity and insulin resistance and reduce cardiovascular risk due to their lipid-lowering and anti-inflammatory effects, thus bringing additional benefits to PCOS patients with severe metabolic disorders. 107 Although there are relatively few specific studies on the use of statins in PCOS, their role in improving metabolic syndrome related indicators has been widely recognized. Notably, treatment strategies for PCOS are evolving toward individualization and multi-targeting, such as drugs targeting neuroendocrine pathways, 108 which may be more comprehensively used to correct multi-system abnormalities of the disease in the future. Biological agents targeting specific inflammatory pathways, such as anti-tumor necrosis factor-alpha antibodies, have shown potential to ameliorate the disease phenotype in animal models of PCOS. For example, in DHEA-induced PCOS rat model, apigenin treatment significantly suppressed the levels of inflammatory cytokines TNF- alpha and IL-6 and improved ovarian function. 109 This provides non-clinical research data for targeting inflammatory pathways in the treatment of PCOS. Human studies of this class of biologics in patients with PCOS are still in the early stages of exploration. The benefits and risks need to be carefully weighed, especially regarding long-term safety in women of reproductive age. Currently, more attention is paid to anti-inflammatory strategies based on natural products or novel drug delivery systems, such as quercetin hydrogels 104 or spironolactone-loaded metal gel particles, 110 aiming to achieve local and sustained drug release, enhance efficacy while reducing systemic side effects. These studies represent an important shift from systemic anti-inflammatory treatment to local, targeted modulation of the inflammatory response in the ovarian microenvironment, opening new avenues for the development of safer and effective PCOS therapies in the future. In assisted reproductive technology cycles, inflammation management in patients with PCOS with obesity is a key link to optimize pregnancy outcomes. Obesity can exacerbate inflammation and oxidative stress in women with PCOS, which has a negative impact on ART outcomes. 25 Therefore, PCOS patients, especially obese PCOS patients, need to receive weight loss and anti-inflammatory interventions before cycle treatment to optimize reproductive outcomes. This precision medicine and evidence-based approach is essential to improve fertility outcomes. 111