Research
Inflammation and Endometrial Function in PCOS
Chronic inflammation disrupts endometrial function in PCOS, impacting fertility and increasing long-term health risks. Explore solutions and management strategies.
June 8, 2025
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Chronic inflammation disrupts endometrial function in PCOS, impacting fertility and increasing long-term health risks. Explore solutions and management strategies.
PCOS affects up to 21% of women worldwide, and chronic inflammation is a hidden factor disrupting fertility and reproductive health. Here's how inflammation impacts the endometrium, the uterine lining crucial for pregnancy:
Key Solutions:
Managing inflammation is essential for improving reproductive health and reducing long-term risks in PCOS. Read on for detailed insights into how inflammation affects the endometrium and actionable strategies to address it.
In individuals with PCOS, the endometrium faces disruptions caused by immune cells and inflammatory molecules, which interfere with its normal function. This heightened state of inflammation not only impacts menstrual cycles but also alters how the uterine lining responds to hormones and prepares for pregnancy.
Studies show that people with PCOS have elevated levels of immune cells - such as lymphocytes, neutrophils, monocytes, macrophages, and eosinophilic granulocytes - in their peripheral blood. These cells can migrate to the endometrial tissue, disrupting its role in reproduction.
This inflammatory activity often creates a harmful cycle. Elevated androgens can trigger the production of pro-inflammatory molecules, which in turn activate additional inflammatory pathways. This cycle disrupts the balance needed for normal endometrial function and successful embryo implantation. Below, we’ll explore specific immune cell changes and the effects of pro-inflammatory cytokines.
The behavior of immune cells in PCOS reveals distinct abnormalities that contribute to endometrial dysfunction. The immune response in the PCOS endometrium differs significantly from that of healthy individuals, even in women with PCOS who are of normal weight. Research by Piltonen et al. found that endometrial stromal fibroblasts from women with PCOS showed impaired progesterone-driven decidualization and abnormal cytokine profiles. These factors promote increased immune cell migration in vitro.
In PCOS, the usual progesterone withdrawal that regulates menstrual inflammation is often absent. This disrupts the normal influx of leukocytes and the production of chemokines and matrix metalloproteinases, which are essential for tissue remodeling. Without these processes, inflammatory debris can accumulate, creating a chronically inflamed environment that is unfavorable for embryo implantation.
Cytokine imbalances in PCOS directly impair endometrial function. Pro-inflammatory cytokines - chemical messengers that drive inflammation - are elevated in individuals with PCOS. Markers such as hs-CRP, IL-18, TNF-α, IL-6, MCP-1, and MIP-1α are found at higher levels in the peripheral blood of PCOS patients. For example, IL-18 interferes with the endometrium’s response to estrogen during the proliferative phase, while TNF-α and IFN-γ disrupt key receptivity markers during the secretory phase.
Research by Oróstica et al. highlighted how these cytokines affect cellular function. TNF-α increased the phosphorylation of insulin receptor substrate-1 (IRS1) at S270, while IL-6 reduced phosphorylation at IRS1-Y612 in endometrial cells. These changes disrupt insulin signaling in endometrial tissue, which may contribute to the insulin resistance commonly seen in PCOS.
Additionally, the activation of the NF-κB signaling pathway by these cytokines intensifies inflammation by promoting the expression of inflammatory genes. Elevated NF-κB levels have been associated with reduced progesterone receptor expression and function, leading to progesterone resistance. This resistance further disrupts endometrial function and embryo implantation. The connection between endometrial inflammation and broader metabolic issues highlights the need to address inflammation to improve both fertility and overall health.
Chronic inflammation and hormonal imbalances in polycystic ovary syndrome (PCOS) cause significant disruptions in the cellular makeup of the endometrium. These changes not only affect how cells function and interact but also have serious implications for fertility and overall health risks.
Endometrial biopsies from individuals with PCOS reveal an imbalance in cell composition - there’s an increase in epithelial cells and a decrease in stromal and lymphoid cells, creating an environment less conducive to implantation. Endometrial fibroblasts in PCOS also show impaired decidualization, a process crucial for pregnancy. These disruptions largely stem from the effects of unopposed estrogen and a resistance to progesterone.
Hormonal imbalances in PCOS also lead to irregularities in cytokine and chemokine profiles, which are essential for maintaining a healthy endometrial environment. These fluctuations further destabilize the conditions needed for successful implantation.
The cellular changes in PCOS extend to the molecular level, where altered gene expression further hinders embryo implantation. For instance, inflammatory markers like IL-6 and TNF-α are elevated in endometrial cells, creating a less favorable environment. Additionally, higher levels of Rel A (endometrial NF-κB p65) have been linked to increased serum testosterone levels in PCOS, which contributes to a hostile setting for embryo development.
Cytokine expression also varies abnormally throughout the menstrual cycle in PCOS. During the proliferative phase, IL-18 levels are elevated, while the secretory phase shows reduced levels of CXCL10, IL-15, and IL-18. These disruptions interfere with the molecular processes critical for implantation.
Metabolic issues add another layer of complexity. Hyperinsulinemia, a common feature in PCOS, disrupts insulin receptor substrates, impairing glucose metabolism and reducing endometrial receptivity. Insulin resistance is observed in about 30% of PCOS patients with endometrial lesions, further complicating their reproductive health.
These cellular and molecular changes have profound effects on pregnancy outcomes. Women with PCOS are 3–4 times more likely to experience gestational hypertension and preeclampsia, and they face twice the risk of preterm birth compared to women without PCOS. Professor Elisabet Stener-Victorin from the Department of Physiology and Pharmacology at Karolinska Institutet explains:
"These results show that the growth of the cells is affected, which may explain why it can take longer for affected women to become pregnant and why they are more likely to miscarry, as well as contributing to the increased risk of endometrial cancer".
The long-term risks are equally concerning. Women with PCOS have a threefold increased risk of developing endometrial cancer. A 2021 study led by Xue et al. found that 97% of PCOS patients in the study did not ovulate, and 41% had endometrial hyperplasia. This suggests that prolonged estrogen exposure due to anovulation plays a significant role in these outcomes.
Chronic inflammation in PCOS disrupts essential fertility processes, leading to both immediate challenges with conception and long-term reproductive health concerns.
One of the significant ways inflammation impacts fertility in PCOS is by interfering with ovulation and implantation. As a result, PCOS accounts for up to 56% of infertility cases, making it one of the top causes of reproductive difficulties for women of childbearing age. Women with PCOS are also 8–10 times more likely to need assisted reproductive technology (ART) and face a fivefold increased risk of pregnancy complications, even when ovulation occurs naturally.
On a cellular level, elevated pro-inflammatory cytokines hinder progesterone's effectiveness, which is critical for preparing the endometrium for implantation. Additionally, immune system imbalances, like reduced levels of T regulatory cells (Tregs) in the bloodstream, disrupt the immune tolerance needed for a successful pregnancy.
"Inflammatory dysregulations are associated with infertility diseases and, therefore, have been shown to affect ovarian function, oocyte quality, and endometrium receptivity."
– Dr. Leandro M. Velez, Department of Biological Chemistry, University of California, Irvine
Insulin resistance and hyperinsulinemia further complicate matters by impairing glucose metabolism in the endometrium, reducing its ability to support implantation. Over time, this chronic inflammatory state can also lead to pathological changes in the endometrium, compounding fertility challenges.
The same inflammatory mechanisms that disrupt fertility also increase the risk of developing endometrial hyperplasia and cancer. Women with PCOS are three times more likely to develop endometrial carcinoma compared to those without the condition. For Caucasian women with PCOS, this translates to a 9% lifetime risk of endometrial cancer, compared to a 3% risk for women without PCOS.
Chronic anovulation, a hallmark of PCOS, results in prolonged exposure to estrogen without the balancing effects of progesterone. This hormonal imbalance causes the endometrium to thicken, increasing the risk of hyperplasia and cancer. Hyperandrogenism and insulin resistance further disrupt normal endometrial cell growth and metabolism, creating conditions that favor abnormal cell changes.
Premalignant and malignant endometrial polyps are also more common in women with PCOS. A study found that 2.15% of premenopausal women undergoing hysteroscopic polypectomies had these types of polyps, with PCOS identified as a significant risk factor. Dr. Ling Lu and colleagues emphasize the importance of monitoring and managing these risks:
"PCOS is associated with a higher risk of premalignant and malignant endometrial polyps in premenopausal women. Therefore, it is important to evaluate the endometrium in PCOS patients with ultrasonography or hysteroscopy, and active management involving hysteroscopic polypectomy should be offered to PCOS patients diagnosed with endometrial polyps regardless of symptoms."
– Dr. Ling Lu and colleagues
Inflammatory markers like TNF-α and IL-6 also play a role by promoting endometrial cell proliferation and disrupting normal cell turnover. Additionally, progesterone resistance reduces the hormone's ability to counteract estrogen's effects, further increasing the risk of hyperplasia and cancer.
Dr. Chaitra Shetty and colleagues highlight these risks:
"Women with PCOS have three times more probability of developing endometrial carcinoma as compared to those without PCOS. This corresponds to a 9% lifetime risk of endometrial carcinoma among Caucasian women with PCOS versus a 3% lifetime risk in women without PCOS."
– Dr. Chaitra Shetty and colleagues
The clear connection between chronic inflammation and endometrial disorders underscores the need for a comprehensive approach to PCOS management. Addressing inflammation not only improves fertility outcomes but also helps reduce long-term risks like endometrial cancer. For more expert insights and resources on managing PCOS-related inflammation, visit PCOSHelp.
Effectively managing inflammation in PCOS involves a blend of medications and lifestyle adjustments. Tackling the root inflammatory processes can lead to better endometrial health and improved fertility outcomes for women dealing with this condition.
Metformin is a cornerstone treatment for PCOS-related endometrial issues. It works by inhibiting glucose production in the liver, enhancing the body's sensitivity to insulin, and reducing glucose absorption in the intestines. A 16-week study conducted at the Karolinska Institutet in 2025 revealed that metformin can restore gene expression in pathways related to cell adhesion and cancer risk, such as ITGA2 and ITGA3.
"We can show that metformin seems to have many more functions in women with PCOS than lowering blood sugar. In the study, all the women were overweight, but it is likely that metformin has similar effects in affected women who are not overweight but insulin resistant if they have problems getting pregnant or have repeated miscarriages."
– Dr. Elisabet Stener-Victorin, Principal Investigator, Karolinska Institutet
Metformin's benefits extend beyond blood sugar regulation. It enhances fertility, reduces the risk of miscarriage, promotes ovulation, and increases menstrual regularity. It can be administered on its own or paired with clomifene for ovulation induction. When combined with lifestyle changes, the medication's impact on reducing systemic inflammation is even more pronounced.
Lifestyle adjustments are a fundamental part of managing PCOS and its effects on the endometrium. These changes not only reduce inflammation but also address many of the condition's underlying symptoms.
"If you are diagnosed with polycystic ovary syndrome, it doesn't mean that you are destined to have poor health. There is a lot you can do to take charge, minimize symptoms and keep yourself healthy."
– Amanda Stathos, M.S., R.D., L.D.N.
A comprehensive strategy that combines medication with lifestyle interventions is widely recommended for managing PCOS. International guidelines advocate for lifestyle changes as the first line of treatment. Research shows that combining herbal medicine with lifestyle modifications leads to better results than relying on lifestyle changes alone. Additionally, lifestyle interventions are often more cost-effective than surgical or pharmacological options.
This integrated approach involves regular physical activity to improve insulin resistance, a balanced anti-inflammatory diet, stress reduction techniques, and appropriate medical treatments. Behavioral and educational programs can further enhance adherence to treatment plans, addressing both physical and mental health challenges associated with PCOS.
Collaboration between healthcare providers and patients is essential. Open communication ensures that women are actively involved in their care decisions, creating a more personalized and effective approach to managing PCOS. By addressing inflammation through this combined strategy, women can significantly improve their fertility and long-term reproductive health.
For more information on managing PCOS-related inflammation and staying updated on the latest treatment options, visit PCOSHelp.
Inflammation plays a significant role in the development of endometrial dysfunction for individuals with PCOS, impacting both reproductive and overall health. Studies indicate that those with PCOS are more likely to show signs of chronic, low-grade inflammation. This is linked to serious health risks, including the fact that over half of individuals with PCOS develop type 2 diabetes before the age of 40, along with an elevated risk of cardiovascular disease.
This chronic, low-grade inflammation stems from an imbalance between immune cells and inflammatory cytokines found in the serum, ovaries, and other organs. This imbalance is associated with worsening obesity, insulin resistance, and disruptions in ovulatory and hormonal functions.
The good news? Specific lifestyle changes can make a big difference. Following an anti-inflammatory diet and committing to at least 120 minutes of vigorous exercise each week can significantly reduce inflammation, improve insulin resistance, and aid in maintaining a healthy weight. Experts widely agree that these lifestyle modifications are essential for improving both metabolic and reproductive health outcomes. These changes set the stage for better reproductive health and overall well-being.
Chronic inflammation plays a major role in affecting fertility for those with Polycystic Ovary Syndrome (PCOS). People with PCOS often show higher levels of inflammatory markers like C-reactive protein (CRP) and interleukin-6 (IL-6). These elevated markers are tied to problems such as poor egg quality, disrupted follicle development, and hormonal imbalances. Together, these issues can interfere with ovulation and make the uterine lining less receptive for implantation.
Inflammation also exacerbates insulin resistance and hyperandrogenism, two key features of PCOS that further disrupt reproductive health. However, managing chronic inflammation through lifestyle adjustments, medical interventions, and effective treatment strategies can help improve fertility and support better reproductive outcomes for individuals with PCOS.
To help reduce inflammation and support endometrial health in those with PCOS, making targeted lifestyle changes can have a powerful impact.
Start with a diet rich in anti-inflammatory foods. Include plenty of high-fiber vegetables, lean proteins, whole grains, and healthy fats like those found in nuts, seeds, and avocados. Cutting back on refined carbs and added sugars is equally important, as it helps regulate insulin levels - something especially vital for managing PCOS, given the frequent link to insulin resistance.
Adding regular physical activity into your routine is another key step. Aerobic exercises like walking or cycling, paired with resistance training, can help reduce inflammation, improve insulin sensitivity, and encourage hormonal balance. Maintaining a healthy weight further enhances these benefits, supporting both symptom management and endometrial health.
By focusing on these changes, you can take proactive steps to better manage PCOS and improve overall well-being.
Managing Inflammation in PCOS to Lower Endometrial Cancer Risk
Controlling inflammation is key to reducing the chances of endometrial cancer in individuals with Polycystic Ovary Syndrome (PCOS). Chronic inflammation, a frequent issue in PCOS, disrupts hormone levels and affects endometrial health. This imbalance can lead to conditions like hyperplasia, which heighten the risk of cancer. On top of that, common PCOS-related factors such as obesity and insulin resistance further increase this risk.
Research suggests that people with PCOS face a two to six times higher risk of developing endometrial cancer compared to those without the condition. However, taking steps to manage inflammation - whether through lifestyle adjustments, medical interventions, or addressing symptoms effectively - can significantly reduce these risks and contribute to better overall health.
