The development of PCOS with IR is significantly influenced by genetic factors (Luo et al., 2024; Stamou et al., 2024). Gene polymorphism and epigenetics are the specific topics of discussion in this paragraph.

HA is a complex clinical condition characterized by elevated androgen levels, affecting a majority of individuals with PCOS (Stewart and Edwards, 1994; Azziz et al., 2004; Rosenfield and Ehrmann, 2016). This disorder is both a contributing factor and a clinical manifestation of PCOS. Early research by Burghen et al., in 1980 established a close relationship between IR and HA in PCOS (Burghen et al., 1980). Later research on human intervention provided more evidence in favor of the idea that anti-androgenic actions are essential for reducing IR (Elkind-Hirsch et al., 1993; Moghetti et al., 1996). Current understanding suggests that androgens contribute to the development of IR by directly or indirectly affecting the insulin signaling pathway (Cussen et al., 2025). Excessive androgens can directly influence insulin signaling through androgen receptors, while HA may also indirectly disrupt insulin signaling by promoting inflammation (Ignjatović et al., 2023; Su et al., 2025).

According to recent research, HA can also induce the occurrence and development of IR in PCOS by causing abnormalities in other indirect pathways (Zhai et al., 2020; Yuan et al., 2021; Aflatounian et al., 2022; Misra et al., 2024; Farhadi-Azar et al., 2025). HA reduces the level of Kisspeptin through the action of androgen receptor (AR), thereby disrupting the protective function of Kisspeptin in inhibiting the PERK/eIF2α pathway and calcium overload, leading to endoplasmic reticulum homeostasis and ultimately resulting in the occurrence of IR (Yuan et al., 2021). Zhai et al. (2020) noted that HA downregulates the levels of the circadian clock gene BMAL1 in the liver and adipose tissue, thereby inhibiting the function of the NAMPT/NAD/SIRT1 pathway, reducing the expression of glucose transporter4 (GLUT4), and finally results in the development of IR in an animal model of PCOS. The study by Aflatounian et al. (2022) found that the NAD⁺ level in skeletal muscle tissue mediates HA-induced IR. In addition, recent studies have proposed that prenatal androgen exposure is also one of the important pathophysiological factors for the formation and progression of IR. After constructing an environment of prenatal hyperandrogen exposure by injecting 5 mg of free testosterone into pregnant female rats on the 20th day of pregnancy, it was discovered that the corpulence of their female offspring increased significantly after birth, impaired glucose tolerance occurred at 3 months of age, and it gradually developed into insulin resistance with age (Farhadi-Azar et al., 2025). Interestingly, we found that not all studies seem to propose the theory that androgens are associated with impaired insulin sensitivity. A recent cross-sectional study showed that Dehydroepiandrosterone sulfate (DHEAS) and androstenedione in lean PCOS patients were positively related to insulin sensitivity. This suggests that androgens may protect insulin sensitivity in lean PCOS (Misra et al., 2024). However, the experimental sample was from a single region, and further studies are needed for the extrapolation of the conclusion.

In fact, the pathophysiology of HA in PCOS patients is significantly influenced by IR as well (Cussen et al., 2025; Su et al., 2025). Mechanistically, compensatory HI brought on by IR can increase the ovary’s luteinizing hormone (LH) receptors, making it more receptive to LH and encouraging the release of androgen (Cara and Rosenfield, 1988; Zhang et al., 2000; Rosenfield and Ehrmann, 2016). A key player in androgen biosynthesis, the CYP17-encoded enzyme P450c17α is increased in response to IR and HI, which increases androgen production (Rosenfield and Ehrmann, 2016; Wang et al., 2019; Sanchez-Garrido and Tena-Sempere, 2020; Zhang et al., 2020a). Additionally, HI linked to IR can inhibit the liver’s production of sex hormone-binding globulin (SHBG), increasing free testosterone and androgen biological activity (Deswal et al., 2018). Furthermore, “tissue-selective sensitivity” to insulin in the adrenal gland has been seen in PCOS-IR patients. As a result of IR, HI interacts with the adrenal gland’s insulin receptors, boosting CYP11B1 enzyme activity and subsequently raising the production of 11-oxygenated androgens generated from the adrenal gland (Walzer et al., 2022). The existence of this harmful loop is supported by recent studies. IR and HA in PCOS have a bidirectional pathological link, according to a recent network meta-analysis, and improving insulin sensitivity is essential to breaking this cycle (Xing et al., 2020).

Actually, PCOS has long been thought to as a low-grade, chronic inflammation (Zhang Q. et al., 2024). The onset and progression of IR in PCOS individuals are significantly influenced by this persistent low-grade inflammation (Deng et al., 2024; Su et al., 2025). Through a case-control research, Kelly et al. hypothesized as early as 2001 that PCOS patients had a chronic low-grade inflammatory state that is inversely connected with insulin sensitivity (Kelly et al., 2001). A later prospective controlled study also revealed a strong correlation between IR and the inflammatory state in PCOS patients (González et al., 2006). Insulin signaling is primarily impacted by inflammation at the cellular and molecular levels via a variety of mechanisms (Hotamisligil et al., 1994; Yu et al., 2022; Olaniyi et al., 2024). First, by preventing the tyrosine phosphorylation of IRS, the inflammatory factor TNF-α reduces cellular sensitivity to insulin by blocking the downstream transmission of insulin signals (Hotamisligil et al., 1994). Through the JAK-STAT, HIF-1, and PI3K-Akt signaling pathways, inflammatory factors drive the development of PCOS-IR in overweight PCOS patients (Yu et al., 2022). Through the NrF2/HIF1-α pathway, hypothalamic inflammation and pyroptosis also contribute to PCOS-IR episodes (Olaniyi et al., 2024). According to a recent study, monocytes (MNC) from PCOS patients with saturated fat activate the NF-κB pathway, causing an overabundance of TNFα, IL-6, and IL-1β to be secreted. These inflammatory molecules then suppress insulin signaling, which results in PCOS-IR (González et al., 2020; Li X. et al., 2024). Therefore, moderately limiting saturated fat consumption can be a useful strategy for PCOS-IR patients to avoid the onset and progression of PCOS-IR.

The diverse microbial population found in the human gut is referred to as the gut microbiota. In areas including immune system modulation, gastrointestinal mucosal barrier protection, and nutritional absorption and digestion, these microbial populations coexist harmoniously with the human body (Noverr and Huffnagle, 2004; Bäckhed et al., 2005). Thus, preserving the gut microbiota’s homeostasis is crucial to preserving the body’s regular physiological processes. Recent research has revealed that the structure and function of the gut microbiota are typically aberrant in PCOS patients (Morris, 2020; Li P. et al., 2023). Furthermore, some research has revealed that PCOS patients with IR and those without IR have quite different gut microbiotas (He and Li, 2021). As a result, there has been a lot of interest in the connection between the gut microbiota and IR, the main pathogenic characteristic of PCOS.

The pathogenic theory of “gut barrier-endotoxemia-inflammation” was put forth by Tremellen and Pearce (2012) in 2012. According to this view, intestinal mucosa tight junction protein function is initially compromised by gut microbial dysbiosis, which permits lipopolysaccharide (LPS) to pass from the gut into the bloodstream. After entering the bloodstream, LPS attaches itself to receptors on target cells, triggering intracellular signaling cascades that increase the release of cytokines that promote inflammation. In the end, this harms the insulin signaling system, which results in IR (Tremellen and Pearce, 2012). According to further research, Bacteroides vulgatus inhibits the production of interleukin-22 (IL-22) by lowering certain bile acids (such glycodeoxycholic acid) that cause the stomach to produce IL-22, which in turn causes PCOS with IR (Qi et al., 2019). According to Yang et al. (2021), there was a notable rise in Bacteroides abundance in PCOS patients and PCOS model mice, which was associated by a drop in cholic acid and an increase in farnesol. Insulin resistance results from this because the farnesoid X receptor (FXR) in the ileum is not sufficiently activated. By attaching to the aryl hydrocarbon receptor (AhR) on the surface of type 3 innate lymphoid cells (ILC3s), Aspergillus tubingensis and its secondary metabolite AT-C1 prevent endogenous ligand activation, suppress IL-22 release, and ultimately cause IR (Wu J. et al., 2025). Apart from the previously described microfunctional abnormalities, it has been established that PCOS-IR is intimately linked to macroabnormalities in the ecological structure of the microbiota and their metabolites. In PCOS patients, the degree of IR is positively connected with a decline in Prevotella_9 abundance (Chen J. et al., 2021). Impaired glucose tolerance is linked to an increase in the Firmicutes/Bacteroidetes ratio and a decrease in the gut microbiota’s α-diversity (Yue et al., 2022). The HOMA-IR and the amount of propionic acid in PCOS patients’ feces have a favorable correlation (Dong et al., 2024). But not every type of gut microbiota causes PCOS-IR to develop. By restoring gut microbiota diversity, increasing the abundance of beneficial bacteria (like Bifidobacterium, Lactobacillus, and Butyricoccus), decreasing the abundance of harmful bacteria (like Helicobacter and Bacteroides), and significantly lowering the levels of pro-inflammatory factors (like IL-6 and TNF-α), Bifidobacterium longum subsp. longum BL21 has recently been demonstrated to significantly improve IR in PCOS mice (Dong et al., 2025). Because the gut microbiota is diverse, strains within the same species may affect diseases differently, and future research into the precise pathogenic pathways is necessary.

Emerging research shows microbiota affects neuroendocrine signaling involved in PCOS. The gut microbiota plays a crucial role in regulating neuroendocrine signals via the “gut-brain axis”, contributing to the pathogenesis of PCOS and associated metabolic disorders, including insulin resistance (Babu et al., 2024; Gautam et al., 2024). Microbial metabolites, such as short-chain fatty acids and tryptophan derivatives, can modulate the central nervous system by circulating in the bloodstream (Eepho et al., 2023; Longo et al., 2023; Monroy et al., 2024). These metabolites influence the secretion pattern of gonadotropin-releasing hormone (GnRH) and disrupt the homeostasis of the hypothalamic-pituitary-ovarian axis (Eepho et al., 2023; Longo et al., 2023; Monroy et al., 2024). Consequently, they trigger metabolic dysregulations like energy metabolism perturbations and IR (Eepho et al., 2023; Longo et al., 2023; Monroy et al., 2024). This pathway of the “gut-brain axis” offers a novel perspective on the link between gut microbiota and PCOS with IR.

As an emerging area that has attracted much attention in the research on the mechanism of IR in PCOS in recent years, the exploration of mitochondrial dysfunction and its molecular regulatory mechanism provides a new perspective for understanding the pathology of the disease (Zhou et al., 2024). Specifically, mitochondrial gene polymorphisms, abnormal gene expression, and dysfunction form a cascading regulatory network that jointly promotes the occurrence and development of the disease (Deer et al., 2025; Kobayashi et al., 2025).

Firstly, in terms of mitochondrial gene polymorphism, specific polymorphisms in the mtDNA D-loop region may be involved in the occurrence and development of IR in patients with PCOS by influencing the association between body mass index and IR (He et al., 2023). Secondly, at the gene expression level, the reduced expression of nuclear-encoded genes in the mitochondrial oxidative phosphorylation (OXPHOS) system may mediate the occurrence and development of insulin resistance in the skeletal muscle tissue of PCOS patients, and the decreased expression of PGC-1α may be a key mediating factor (Skov et al., 2007). A recent study constructed an animal model of PCOS with IR and intervened with the mitochondrial-targeted antioxidant MitoQ (Ding et al., 2019). It was found that mitochondrial DNA (mtDNA) mutations, reduced ATP production, decreased membrane potential, and excessive reactive oxygen species (ROS) could promote the occurrence and development of IR in PCOS by triggering oxidative stress and abnormal apoptosis (Ding et al., 2019). This indicates that abnormal mitochondrial function also plays an important role in the occurrence and development of PCOS complicated with IR.

However, the relationship between mitochondrial dysfunction and IR is not unidirectional. IR, in turn, can exacerbate mitochondrial damage, forming an intertwined vicious cycle. A recent human study on women with PCOS found that compared with healthy women, the mtDNA content in PCOS patients was significantly reduced, accompanied by more obvious metabolic abnormalities (Rojo et al., 2024). After adjusting for the HOMA index, the differences in mtDNA content and oxidation levels between PCOS patients and healthy women lost statistical significance (Rojo et al., 2024). This suggests that IR may be the main driving factor for mitochondrial abnormalities in PCOS patients. Another study indicated that mitochondrial dysfunction (manifested as mtDNA deletion, decreased metabolic flexibility, etc.) is closely related to the occurrence and development of PCOS with IR and may form a vicious cycle through interaction with obesity and IR (Varhegyi et al., 2024). Human studies have shown that the high platelet reactivity in PCOS patients is closely related to mitochondrial dysfunction (impaired integrity, imbalance of fission - fusion) (Randriamboavonjy et al., 2015). After treating them with metformin, it was found that metformin can improve mitochondrial integrity through AMPKα1 - dependent Drp - 1 regulation, thereby reducing high platelet reactivity, and this effect is only observed in PCOS patients with IR (Randriamboavonjy et al., 2015). This provides a new perspective on the cardiovascular risk and mitochondrial dysfunction in PCOS with IR patients. Animal studies have also confirmed the negative effect of IR on mitochondrial function. IR leads to a decrease in the mtDNA copy number in mouse metaphase II (MII) oocytes, disordered mitochondrial distribution in germinal vesicle (GV) and MII oocytes, and abnormal mitochondrial inner membrane potential (increased in the GV stage and decreased in the MII stage), ultimately resulting in damage to mouse oocytes (Ou et al., 2012).

Under normal circumstances, the tyrosine residues of the β-subunit of the insulin receptor undergo autophosphorylation upon the binding of insulin to its receptor, activating the receptor (Sun et al., 1991). IRS proteins are then recruited and phosphorylated by the active insulin receptor, resulting in their activation (Sun et al., 1991). PI3K is bound to and activated by the active IRS. The transformation of phosphatidylinositol 4,5 bisphosphate (PIP2) on the cell membrane into phosphatidylinositol 3,4,5 trisphosphate (PIP3) is then catalyzed by PI3K. AKT is drawn to the cell membrane by PIP3 (Folli et al., 1992; Hers et al., 2011). Phosphatidylinositol-dependent kinase-1 (PDK1) and mammalian target of rapamycin complex 2 (mTORC2) then work in concert to phosphorylate AKT’s Thr308 and Ser473 sites, which activates the protein (Hers et al., 2011; Huang et al., 2018). Phosphorylation of downstream target proteins is how the activated AKT carries out its actions. To lower blood glucose levels, AKT can also phosphorylate the AS160 protein, which encourages GLUT4 to move from the intracellular compartment to the cell membrane (Xu et al., 2016). This improves cellular glucose uptake and permits blood glucose to enter cells for storage or use. Conversely, GSK-3β is phosphorylated by AKT, which renders it inactive. This relieves the inhibition of GSK-3β, hence facilitating the synthesis of glycogen. Furthermore, AKT phosphorylates the target of rapamycin (mTOR) to stimulate protein synthesis (Cheatham and Kahn, 1995; Saltiel and Kahn, 2001; James et al., 2021).

According to recent studies, PCOS-IR develops and occurs as a result of anomalies at several locations along the insulin signaling pathway. As CPXM1 damages the insulin signaling system, it lowers the expression of IRS-1/2 and INSR while also downregulating the phosphorylation of Akt, a crucial component of the pathway (Pervaz et al., 2023). This results in IR in the ovary and adipose tissue. The primary mechanisms of IR in PCOS, as demonstrated by a recent animal study, are increased serine phosphorylation of IRS-1 and decreased phosphorylation of Akt in the insulin signaling pathway of perigonadal white adipose tissue (pgWAT). This abnormality is closely linked to the inflammatory response mediated by C-C chemokine receptor 5 (CCR5) (Seow et al., 2021). In liver tissue, targeting the reduction of neutrophil extracellular traps (NETs) is the key to improving their negative effect on the phosphorylation of AKT, a downstream signaling molecule of the insulin signaling pathway, and ultimately enhancing insulin sensitivity in the liver tissue (Lin et al., 2025). Src-associated in mitosis, 68 kDa (Sam68) in ovarian granulosa cells lowers the phosphorylation level of IRS-1, which results in inadequate activation of the downstream insulin signaling pathway and, eventually, IR (Vilariño-García et al., 2022).

Another important step in fostering the advancement of PCOS with IR is the activation of the classical NF-κB signaling pathway, which is mediated by tumor necrosis factor-α (TNF-α) (Moller, 2000; Shoelson et al., 2006). The NF-κB dimer is inactive in the cytoplasm and firmly binds to Inhibitor of NF-κB alpha (IκBα) under normal physiological conditions. The downstream IκB kinase (IKK) complex is activated in pathological conditions when TNF-α secretion rises sharply and binds to its receptor (TNFR). It then quickly attracts TNF receptor-associated death domain protein (TRADD) and TNF receptor-associated factor 2 (TRAF2) to form a membrane-bound signaling complex (Leong and Karsan, 2000; Oeckinghaus and Ghosh, 2009). When IKK phosphorylates the IκBα protein, it releases the active NF-κB dimer (like p50/p65) and causes the protein to be ubiquitinated and degraded. Following its translocation into the nucleus, NF-κB attaches itself to the κB site in the target gene’s promoter region and starts the transcription of pro-inflammatory proteins like IL-6 and IL-1β (Leong and Karsan, 2000; Oeckinghaus and Ghosh, 2009). These inflammatory factors, in turn, can further stimulate the secretion of TNF-α, forming an inflammatory cascade amplification effect.

From an IR perspective, IKKβ within the NF-κB signaling pathway phosphorylates Ser307 on IRS-1, reducing its capacity for insulin-triggered tyrosine phosphorylation. Consequently, insulin signal transduction is impeded, culminating in IR (Gao et al., 2002; de Alvaro et al., 2004; Liu et al., 2011). Inflammatory mediators like TNF-α, prompted by NF-κB activation, impede PI3K-AKT signaling, hindering GLUT4 translocation to the cell membrane and diminishing peripheral tissue sensitivity to insulin (Hotamisligil et al., 1996; Baker et al., 2011). Prolonged NF-κB activation can exacerbate IR, perturb glucose and lipid metabolism, fostering a detrimental cycle of “TNF-α-NF-κB-inflammation-IR” (Tan et al., 2024).

Following its binding to target cell receptors, insulin triggers the receptors’ tyrosine kinase activity, which phosphorylates the tyrosine residues of the downstream adapter protein Shc in the pathological process of PCOS with IR (Diamanti-Kandarakis and Dunaif, 2012). Phosphorylated Shc binds to Grb2 and further recruits SOS, which promotes the activation of Ras. Subsequently, the Ras - MAPK cascade reaction composed of Raf - MEK - ERK is activated. Finally, the activated ERK enters the nucleus to phosphorylate transcription factors, thereby regulating the expression of genes related to cell growth and proliferation (de La Fernandes et al., 1999; Corbould et al., 2006; Rajkhowa et al., 2009; Makker et al., 2012; Zhao et al., 2015).

By further activating the pathway, HI in the presence of IR can worsen the development of the disease. After the MAPK pathway is activated, ERK phosphorylates serine sites on IRS-1/2, which prevents IRS from becoming tyrosine phosphorylated and lowers PI3K recruitment (Tanti and Jager, 2009). As a result, the PI3K-AKT pathway’s ability to regulate glucose uptake is impaired, which aids in the development and advancement of IR (Dunaif et al., 2001).

IR causes an array of health hazards and worsens clinical characteristics in adolescent PCOS patients. Mechanistically, IR and compensatory HI increase the hypothalamic gonadotropin-releasing hormone (GnRH) pulsatile frequency, which causes the pituitary gland to secrete too much LH (Patel et al., 2003). It exacerbates pre-existing issues such high androgen levels, irregular ovulation, and menstrual cycle disorders by increasing ovarian androgen synthesis and ovulation disorders at the same time (Dunaif, 1997; Venkatesan et al., 2001; Diamanti-Kandarakis and Dunaif, 2012). Furthermore, biochemical hyperandrogenism may exacerbate the clinical manifestations of hyperandrogenism, including acne and hirsutism (Taketani and Mizuno, 1990; Stanczyk, 2006; Guo et al., 2023). As early as 2001, a clinical study demonstrated that most patients’ normal menstrual cycle and the hypothalamic-pituitary-ovarian axis function could be successfully restored, androgen levels could be decreased, after improving insulin sensitivity in white adolescent girls with PCOS with metformin and a high-protein, low-carb diet (Glueck et al., 2001). A retrospective observational study of adolescents with PCOS then examined metabolic markers of several menstruation types, such as oligomenorrhea (OM), secondary amenorrhea (SA), and primary amenorrhea (PA) (Javed et al., 2015). It was discovered that the PA group had a considerably higher HOMA-IR value and fasting insulin level than the SA and OM groups, and that the PA and SA groups had a significantly greater prevalence of metabolic syndrome than the OM group (Javed et al., 2015). This implies that IR is linked to a higher metabolic risk and may be particularly noticeable in teenage PCOS patients who have severe irregularities in their menstrual cycles, such amenorrhea. According to a recent meta-analysis and systematic review, the incidence of amenorrhea in adolescents with PCOS increases with body mass index (BMI) (Zuchelo et al., 2024). This indirectly reflects the correlation between abnormal glucose and lipid metabolism and abnormal menstrual cycles in adolescent PCOS patients.

IR is intimately linked to obesity and poor glucose metabolism in adolescents with PCOS (Bayramoğlu et al., 2021; Gupta et al., 2022; Fu et al., 2023). In adolescents with PCOS, elevated blood glucose and lipid levels are also strongly linked to the onset and progression of a number of metabolic disorders (Huang et al., 2010). Adolescent females with PCOS had higher triglyceride, cholesterol, and IR levels than do those without the condition (Patel-Sanchez et al., 2023). The incidence of non-alcoholic liver disease is greater in adolescents with PCOS who go on to develop diabetes (Patel-Sanchez et al., 2023). This indicates that IR is one of the major pathogenic causes for non-alcoholic liver disease in adolescents with PCOS, in addition to being intimately linked to aberrant glucose and lipid metabolism in these patients. Furthermore, a cross-sectional investigation of obese teenage PCOS patients revealed a strong correlation between fasting IR and the pancreatic fat fraction in teenage girls, which is unrelated to PCOS (Ware et al., 2022). Moreover, IR is significantly linked to poorer sleep quality (including sleep-disordered breathing and decreased sleep efficiency) in obese teenage PCOS patients, indicating that doctors should focus on the holistic care of both (Simon et al., 2020).

However, the psychological problems caused by metabolic disorders are also worthy of attention. Teenagers and young women with PCOS have higher levels of anxiety and sadness than those without the condition, according to a recent systematic review and meta-analysis (Nasiri-Amiri et al., 2023). The causes of negative psychology, including depression and anxiety, in adolescents with PCOS were then investigated in a number of clinical studies that used assessment techniques like questionnaire scale evaluation, group comparative analysis, and correlation analysis. These studies suggested that the presence of negative emotions in adolescents with PCOS may be connected to clinical symptoms like obesity, hirsutism, and irregular menstrual cycles linked to IR (Kara et al., 2022; Saei Ghare Naz et al., 2023). Therefore, the mental health of adolescents with PCOS-IR should be taken into consideration when treating their organic disorders in the future.

In women with PCOS who are of reproductive age, IR can lead to both metabolic problems and malfunction of the reproductive system (Vatier et al., 2022). This disorder includes infertility, which is defined by anovulatory infertility and aberrant oocyte development, as well as pregnancy problems, such as decreased live birth rates and an increased chance of threatening miscarriage (Dumesic and Abbott, 2008; Sakumoto et al., 2010; Vatier et al., 2022).

On the one hand, IR can cause infertility in women of reproductive age with PCOS through multiple mechanisms. Heightened expression of miR-181d-5p in PCOS patients compared to healthy individuals has been observed (Sang et al., 2024). This upregulation of miR-181d-5p can impede granulosa cell proliferation by inhibiting SIRT1 activity, thereby compromising oocyte quality in PCOS-IR individuals (Sang et al., 2024). In terms of ovulation, IR stimulates the production of androgens (such as testosterone) by inducing compensatory hyperinsulinemia and acting synergistically with the elevated LH level on hypersensitive ovarian theca cells (Graham and Selgrade, 2017). The elevated testosterone induces the synthesis of LH in the pituitary gland and inhibits the function of FSH. Meanwhile, it increases the sensitivity of follicles to LH and causes premature luteinization, ultimately impairing ovulation ability (Graham and Selgrade, 2017). Furthermore, IR can reduce the sensitivity of the ovaries to gonadotropins in PCOS patients, obstructing the follicle development and ovulation processes and thus leading to ovulation disorders (Ezeh et al., 2021; Li Y. et al., 2023).

On the other hand, in women of reproductive age with PCOS, IR may lower the live birth rate and raise the frequency of pregnancy problems. By blocking the PI3K/AKT pathway and inhibiting glycolytic enzymes such as HK2 and PKM2, IR prevents embryo implantation by upsetting endometrial balance and energy supply (Zhang et al., 2024d). Patients with PCOS are therefore more likely to experience miscarriage and unsuccessful embryo implantation. Additionally, IR increases the endometrial inflammatory milieu by promoting the activation of natural killer (NK) cells and skewing macrophages toward the M2 anti-inflammatory phenotype (Liu S. et al., 2021). This chain reaction further hinders the implantation of embryos and jeopardizes the continuation of pregnancy. IR and the rate of prenatal abortions in PCOS are also tightly related. According to an examination of a retrospective cohort study, IR plays a significant role in early abortion in PCOS patients’ first embryo transfer cycle (Chen et al., 2022). According to another study, insulin resistance is linked to a higher risk of preterm delivery in PCOS patients, and PCOS is an independent risk factor for late abortion (Jie et al., 2022). Nevertheless, other research has also demonstrated that IR’s detrimental impact on the late pregnancy outcomes of induced pregnant women is not specific to PCOS patients (Yang T. et al., 2022). By interfering with endometrial homeostasis and energy availability, IR mechanistically reduces pregnancy stability (Zhang et al., 2024d). Additionally, IR can cause and exacerbate endometrial chronic inflammation, increasing the chance of miscarriage in PCOS patients (Liu S. et al., 2021). Additionally, the combined effects of IR and HA cause abnormal mitochondrial shape and function in the placenta and gravid uterus. By blocking the Nrf2/GPX4 pathway, this combination also upsets the balance between oxidation and antioxidation, which leads to unusual cell death pathways like ferroptosis and miscarriage (Hu et al., 2019; Zhang et al., 2019; Zhang Y. et al., 2020). The final result of the multi-link damage described above is a decrease in the live birth rate. Research has indicated that in patients with PCOS, IR is a risk factor in and of itself for the lower live birth rate following frozen-thawed embryo transfer (Jiang et al., 2021). According to another clinical investigation, pregnant women with metabolic syndrome are more likely to develop gestational diabetes and give birth to babies who are macrosomic, and metabolic syndrome has a detrimental effect on the clinical pregnancy rate and live birth rate in obese PCOS patients (Arya et al., 2021). These results highlight the negative effects of metabolic abnormalities, like IR, on the live birth rates and reproductive outcomes of women with PCOS who are of reproductive age.

As mentioned above, IR affects oocyte development, ovulation function, and pregnancy outcomes in women of reproductive age with PCOS through the aforementioned multiple mechanisms, ultimately leading to infertility or increasing the risk of miscarriage. The various regulatory mechanisms discussed above are summarized in (Figure 2).

In patients with PCOS, IR is not only one of the core pathogenic factors in the pre-menopausal period but also continuously affects the health status after menopause, significantly increasing the risk of various long - term complications (Lambrinoudaki, 2011; Xu and Qiao, 2022). In fact, there are few studies on the multiple disease states of post - menopausal PCOS patients caused by single insulin resistance, and more studies focus on the synergistic effect of IR and other factors such as HA. The core mechanism of the synergistic effect between IR and HA lies in the vicious cycle of their interaction.

IR induced by HA worsens postmenopausal PCOS in rat models, resulting in significant abnormalities in glucose and lipid metabolism as well as cardiovascular and renal damage, including hypertension, decreased glomerular filtration rate, proteinuria, and tubular injury (Dalmasso et al., 2016). The negative effects of IR on postmenopausal cardiac health and glucose-lipid metabolism were highlighted by a recent study that used a postmenopausal PCOS rat model to show that treatment with a GLP-1 receptor agonist (liraglutide) effectively mitigated multiple cardiometabolic risk factors and improved IR (Torres Fernandez et al., 2019). More significantly, compared to people without PCOS, those with PCOS appear to be at a higher risk of developing cancer. With evidently aberrant glucose and lipid metabolism, postmenopausal PCOS patients have a larger chance of developing certain cancers than premenopausal PCOS patients (Meczekalski et al., 2020; Frandsen et al., 2023; Frandsen et al., 2024). The mechanism behind this could be linked to pathological diseases such adipokine imbalance and chronic inflammation brought on by IR alone or in conjunction with hyperandrogenism (Esposito et al., 2014; Slopien et al., 2018; Elibol et al., 2025).