The interplay of obesity, microbiome dynamics, and innovative anti-obesity strategies in the context of endometrial cancer progression and therapeutic approaches.

Weight loss interventions hold promise in curbing EC's rising incidence and mortality and provide innumerable additional health benefits. As previously mentioned, many of those inflicted with EC will succumb to other comorbid conditions rather than their cancer. Thus, attaining and sustaining a healthy weight is expected to improve overall mortality in EC survivors, mainly related to the risk of cardiovascular disease ( 90 ). In addition, intentional weight loss in those with obesity is associated with a lower risk of EC ( 91 ). The mechanism in which weight loss reduces EC incidence is thought to be through a reversal in the risk factors associated with obesity and their complex contributions to the development of EC. For example, weight loss in patients with obesity has been shown to improve insulin sensitivity, reduce systemic inflammatory biomarkers, and increase infiltration of protective immune cells in the endometrium ( 92 ). Weight loss could modify specific inflammation-related biomarkers linked to obesity and EC, particularly, CRP, leptin, and IL-6, as previously discussed. Findings from Linkov et al. demonstrated that patients who experienced substantial weight loss from bariatric surgery exhibited significant decreases in C-peptide, insulin, CRP, leptin, IL-1Rα, and IL-6. Conversely, levels of SHBG, IGFBP1 (IGF1 binding protein), and adiponectin significantly increased following weight loss ( 93 ). Furthermore, data from the non-obese control group suggests biomarkers of obese patients approached near similar levels to the control group after the intervention ( 93 ). These results support the idea that weight loss may positively influence inflammation-related biomarkers, thereby offering insights into preventive measures for EC within the context of obesity management. Adopting lifestyle interventions for weight loss with multidisciplinary teams is being introduced in the clinical setting for patients diagnosed with EC. As weight loss is critical pre-operatively for EC patients who undergo gynecological surgical treatment, it is also vital to maintain weight loss post-surgery for increased survival from obesity-related co-morbidities, such as cardiovascular disease ( 94 , 95 ). Research examining diet and exercise interventions on inflammatory biomarkers of obesity, such as cytokines and adipokines, demonstrates that weight loss can drastically affect biomarker expression, in support of positive health outcomes ( 96 ). Furthermore, improving diet quality pre-and post-surgery has shown to promote EC-free survival, leading to improved overall well-being ( 94 ). Importantly, patient education on the benefits of diet and exercise and supportive care to reduce the risk of EC recurrence is warranted. As physician education about the obesity link to EC can raise awareness and increase patient interest in weight loss programs, the disadvantage is poor attendance in these weight loss programs possibly related to emotional stress and inadequate support systems ( 95 ). For these reasons, EC survivors may be less inclined to adopt and maintain the changes necessary for long-term survival. Current data suggest that successful lifestyle changes can have approximately a 5% effect on weight reduction, followed by anti-obesity medications at 10%, with both treatment approaches challenging to achieve sustainable results. In contrast, bariatric surgery has been more successful in more appreciable and sustainable weight loss, with results beyond ten years following surgery showing an approximate 20% reduction in total weight ( 97 – 100 ). The two most common bariatric surgery procedures are the Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), both with similar efficacy ( 97 ). Bariatric surgery also reduces cancer incidence, with the most significant benefit being obesity-related cancers such as EC ( 101 , 102 ). In a recent retrospective cohort study of over 30,000 patients in which 5,053 underwent bariatric surgery via RYGB or SG, a significant reduction in obesity-associated cancers, particularly EC, was found in those who had bariatric surgery compared with the control cohort ( 103 ). Another retrospective cohort study reported an impressive relative risk reduction in EC incidence following bariatric surgery at 71% in those who underwent bariatric surgery compared to those who did not ( 104 ). Furthermore, if the weight loss following bariatric surgery was maintained, this resulted in an even higher reduction of EC at 81% ( 104 ). Similar to the complex mechanisms attributing an increase in cancer risk in those with obesity, the reversal of this risk through bariatric surgery is analogously complex and not fully understood. Both RYGB and SG create anatomical modifications contributing to their weight loss outcomes. RYGB bypasses the majority of the stomach and a portion of the duodenum. At the same time, SG removes approximately 80% of the stomach. However, the weight loss achieved through surgical intervention rather than their distinct physiologic effects is thought to contribute to both procedure's success ( 103 , 105 , 106 ). However, metabolic improvements are noticed before achieving appreciable weight loss following bariatric surgery. Nearly one third of patients with type II diabetes mellitus who underwent gastric bypass were discharged from the hospital after their surgery with normal glucose levels and not requiring antidiabetic medications ( 107 ). In addition to improving insulin sensitivity and reducing hyperinsulinemia, bariatric surgery lessens obesity-associated inflammation, improves sex hormone levels, improves adipokine levels, and reverses neoplastic changes of the endometrium ( 108 , 109 ). Even the favorable changes bariatric surgery produces on the endometrium are not solely weight-loss dependent, asbariatric surgery alone can produce rapid normalization of the endometrium before achieving a normal body weight in those with EC precursor lesions ( 109 ). Additionally, within two months following surgery, significant reductions in endometrial tissue biomarkers of proliferation, PI3K/AKT/mTOR pathway signaling, ER, and circulating biomarkers of insulin resistance, inflammation, and SHBG are seen ( 109 ). Therefore, explaining both the weight-loss-independent effects of bariatric surgery and its ability to achieve sustainable weight-loss outcomes is an area of active research, with recent evidence suggesting the gut microbiota as a key factor ( 105 , 106 , 110 , 111 ). Several systematic reviews demonstrate notable changes in the microbiome, including a healthier microbial diversity and increased Bacteroidetes to Firmicutes ratio, mirroring that of non-obese individuals ( 105 , 106 ). Thus, a reduction in EC risk through bariatric surgery may be explained through correcting gut dysbiosis remedying its altered dietary energy intake and inflammatory pathways ( 112 , 113 ). While bariatric surgery remains the gold standard in achieving and sustaining weight loss, not all patients have access to or meet the eligibility criteria for bariatric surgery. Unfortunately, the less efficacious but more broadly available non-surgical weight loss interventions have yet to demonstrate similar results in maintaining a reduction in EC risk ( 114 ). Improvements in non-surgical interventions to achieve and sustain a healthy weight for those with obesity are needed if a reduction in EC incidence is to be seen at the global population level. Dietary and lifestyle interventions have only produced modest results, with low dietary adherence rates ( 115 , 116 ). Caloric restriction with an associated weight reduction does appear to reduce the risk of cancer ( 117 ). It also displays anti-tumorigenic properties, but its ability for broad implementation is limited by adherence challenges, prompting interest in achieving the beneficial effects of energy restriction through intermittent energy intake ( 118 ). Intermittent energy restriction (IER) is achieved through recurrent alternating periods of normal energy intake interrupted by extended periods of minimal to no energy intake ( 119 ). IER has also garnered interest as a dietary treatment for obesity as it may be better tolerated and achieve greater metabolic and anti-inflammatory changes than calorie restricted diets ( 118 , 119 ). Additionally, the beneficial effects of IER through its specific cellular adaptive responses that render cancer cells more susceptible to cytotoxic treatment while protecting normal cells may have a role as an adjunct therapy in obesity-driven cancers ( 119 – 121 ). The utility of IER as a preventative or adjunct treatment in EC has yet to be sufficiently explored, but early pre-clinical studies show potential promise. In a mouse model of obesity-driven EC comparing a switch from a high-fat diet to either a low-fat or IER diet, IER resulted in a lower tumor incidence, improved inflammatory and metabolic profiles, and a more robust reduction in tumor size, especially when combined with paclitaxel chemotherapy ( 122 ). While IER is an attractive dietary intervention for EC prevention and adjuvant treatment, future studies are needed to understand better the underlying biology of IER on the endometrium and tumor microenvironment. Further incentive for investigating the role of IER in EC is based on results of recent studies investigating the role of IER in breast cancer, another obesity-driven cancer. These phase II clinical trials suggest a beneficial role of utilizing IER as an adjunct dietary intervention, improving the efficacy of chemotherapy and hormonal treatment of breast cancer and limiting treatment-related adverse events ( 120 , 121 ). When weight loss is not achieved through dietary and lifestyle interventions, patients may be candidates for pharmacotherapy. Historically, efficacy in pharmacotherapy interventions to achieve and sustain weight loss has been underwhelming. However, recent phase III trials of incretin receptor agonists—semaglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, and tirzepatide, a dual-acting GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonist, have shown promise as efficacious pharmacotherapy options for treating obesity ( 123 – 125 ). GLP-1 was first targeted for the treatment of type 2 diabetes, as GLP-1 is a major regulator of insulin secretion in response to caloric intake ( 126 ). Agonists of the GLP-1 receptor achieve weight loss by reducing energy intake ( 127 ). GIP regulates lipid metabolism and can reduce energy intake, particularly when combined with GLP-1 ( 128 ). When semaglutide was compared to placebo in adults who were overweight or obese, at 68 weeks, 86% of patients taking semaglutide achieved 5% or more weight loss compared to 32% of those treated with placebo ( 123 ). Semaglutide also showed a mean reduction in weight of nearly 15% compared to the 2.4% reduction with placebo ( 123 ). At 72 weeks of treatment, >85% of patients taking tirzepatide had a 5% or more reduction in their weight, with a mean 15–20% decrease in weight compared to 34.5% of patients assigned to placebo who had a mean weight loss of about 3% ( 125 ). Tirzepatide and semaglutide both show efficacy in the management of type II diabetes, with both demonstrating an approximately two percentage point reduction in hemoglobin A1c level ( 129 ). In patients with type II diabetes, treatment with GLP-1 receptor agonists results in a 12% reduction in all-cause mortality, a 12% reduction of major adverse cardiovascular events, and a 17% reduction in adverse renal outcomes ( 130 ). In addition to the beneficial health outcomes expected with the reduction of obesity-associated comorbidities following weight loss from these novel therapeutics, early pre-clinical studies based on the understanding of hyperinsulinemia contributing to EC carcinogenesis through activation of the PI3K/AKT/mTOR pathway may indicate a potential role of incretin receptor agonists as an adjunct therapy in EC ( 131 , 132 ). Using Ishikawa EC cell xenografts in a nude mouse model, Zhang et al. treated the intervention group with exenatide, a GLP-1 receptor agonist, and found that the tumor growth rate slowed compared to the control and its effects were through inhibition of the PI3K/AKT/mTOR pathway and promotion of apoptosis ( 132 ). Kanda et al. treated Ishikawa EC cells with liraglutide, another GLP-1 receptor agonist, with findings supporting that of Zhang et al., and also found that a greater expression of GLP-1 receptor expression may be associated with a better prognosis in EC patients ( 131 ). Further investigation regarding the role of GLP-1 receptor agonists and dual-acting GLP-1 and GIP receptor agonists in obesity management for EC patients as well as specific anti-tumorigenic effects is undoubtedly warranted in EC, as these drugs may be beneficial for both improving cancer outcomes as well as obesity-related co-morbidities. As 96% of patients diagnosed with EC have shown an interest in losing weight, many grapple with the complex challenges of maintaining weight loss through common weight-loss strategies ( 133 ). A survey conducted by Wilson et al. indicated that only a small number of EC patients considered bariatric surgery either due to lack of awareness, fear of complications, or concerns about qualifying for insurance purposes ( 133 , 134 ). The same is true for weight-loss medications, like semaglutide or tirzepatide, due to limited data on the effects of anti-obesity medications in the EC population. These findings further amplify the importance of patient education and discussions about weight management strategies and the need for comprehensive support systems that address healthy physical, emotional, and psychological aspects ( 134 ).

Endometrial cancer (EC) is expected to be diagnosed in 66,200 women in the United States with 13,030 dying from the disease in 2023, making it the most common gynecologic malignancy and the fourth most common cancer in women ( 1 ). Despite advancements in preventing and treating other gynecologic malignancies, EC incidence and mortality continue to rise ( 1 ). EC incidence and deaths in the United States are expected to pass that of colon cancer within the next two decades ( 2 ). The concerning lack of progress in EC may best be exemplified when comparing to what has historically been the deadliest gynecologic malignancy, ovarian cancer (OC). In the early 1990s, the mortality rate of OC was twice that of EC, but today, that survival difference has been eliminated as EC and OC have nearly equivalent mortality rates ( 3 ). The obesity epidemic has undoubtedly contributed to the alarming trends in EC as obesity, diabetes, and insulin resistance are all well-established risk factors ( 4 , 5 ). Notably, the proportion of EC incidence and mortality attributed to obesity is greater than any other cancer, and nearly 75% of EC can be attributed to obesity and physical inactivity ( 4 ). Furthermore, there is a direct correlation between increasing body mass index (BMI) and EC incidence in pre-and post-menopausal women ( 6 , 7 ). EC presents with abnormal uterine bleeding, allowing most patients to be diagnosed early with a good prognosis. However, many patients diagnosed and treated for EC will succumb to other obesity-related comorbidities (e.g., cardiovascular disease) rather than cancer ( 8 , 9 ). Improvements in the incidence and all-cause mortality associated with EC can be expected by preventing and treating obesity. Due to the increasing mortality rates of EC related to obesity in the United States, this review aims to emphasize the strong association between these two serious health issues by examining crucial risk factors, such as diabetes, hormones, and insulin resistance. In addition to reviewing the mechanisms involved in these metabolic disturbances, gut dysbiosis is a developing area demonstrating a link to stimulated cellular proliferation in the endometrium and resulting carcinogenesis. As diet and exercise alone are challenging for patients to maintain long enough to make significant metabolic changes, emerging research in novel obesity treatments can provide practical, less invasive approaches to combat obesity-related EC mortality, as shown in Fig. 1 .

At least 100 trillion microbial cells reside on and in the human body along with their associated genomes constituting the microbiome. Most of these microbes reside in the gut; however, distinct communities have been described in other organs, including the genitourinary tract ( 45 , 46 ). The healthy gut microbiome demonstrates a symbiotic relationship with its human host, where macronutrient digestion provides microbes with an energy source, providing the host with vitamins, nutrients, and other metabolism products vital for the hosťs health ( 47 ). In order to maintain this symbiotic relationship, the composition and function of the microbes making up the gut microbiome need to be conserved. Numerous host factors influence the composition and functionality of the gut microbiota including, diet, genetics, immune response, medications, infections, and environmental exposures ( 48 – 54 ). Disruptions in the gut microbiota composition lead to dysbiosis, associated with many diseases ( 54 , 55 ). One such example with pertinent importance to this review is the gut dysbiosis associated with obesity. Obesity may be associated with a decrease in gut microbial diversity and alterations in its composition of Bacteroidetes and Firmicutes —which contribute to >90% of its microbiota ( 56 ). However, all studies have not uniformly demonstrated this ( 57 ). In the obese state, Firmicutes is believed to be overrepresented, resulting in a decreased ratio of Bacteroidetes to Firmicutes. This imbalance leads to an increased capacity to harvest dietary energy—a favorable environment for carcinogenesis ( 58 ). While how the gut dysbiosis associated with obesity contributes to EC has yet to be fully elucidated, there appears to be significant interplay. One critical function of the gut microbiome that contributes to its relationship with EC is its role in modulating systemic estrogen levels through the estrobolome—microbes whose production of deconjugating enzymes, β-glucuronidase and β-glucosidase, allow for reabsorption of bioavailable estrogen ( 59 – 61 ). A disruption in the estrobolome, which may occur due to the gut dysbiosis seen with obesity, results in elevated estrogen levels ( 59 , 62 ). In addition to the increase in bioavailable estrogen, gut dysbiosis contributes to the chronic inflammatory state associated with obesity ( 56 ). Obesity is coupled with gut dysbiosis with pro-carcinogenic effects beyond the enteral tract, prompting an investigation into the inter-relationship of obesity and the gut microbiome in concert with the local microenvironment, such as the uterus. In addition to the gut microbiome's role in carcinogenesis, the microbiome of the local tumor microenvironment may also be an important contributor. Emerging evidence demonstrates the impact microbes play in modulating the tumor microenvironment, including avoiding immune detection and destruction, resisting apoptosis, and activating invasion and metastasis ( 63 , 64 ). Comparisons of the human tumor microbiome in seven cancer types (breast, lung, ovarian, pancreatic, melanoma, bone, and brain cancers) showed that each type has a distinct microbial composition ( 65 ). Correlations were found between specific intra-tumoral bacteria and smoking status for lung cancer and estrogen receptor positive or negative status for breast cancer ( 65 ). Correlations have also been found between molecular subtypes, particular cancer mutations, and distinct bacterial species in colon cancer ( 66 , 67 ). This correlation suggests an inter-relationship between cancer sub-types dictated by varying tumor genomics and the microbiome may exist. The endometrium was once considered a sterile environment, but recent work has begun characterizing its microbial composition. Not surprisingly, it is lower in bacterial abundance when compared to the gut, but a distinct community has been described as predominantly comprised of Bacteriodetes, Firmicutes, Proteobacteria, and Actinobacteria ( 45 ). Differing microbial compositions of the uterus have been associated with poor reproductive outcomes, endometriosis, and an inflammatory milieu, which may be implicated in EC carcinogenesis ( 68 – 70 ). In contrast to what is seen in the gut, a greater microbial diversity in the reproductive tract is associated with poor reproductive health, such as seen in obesity and with the presence of EC ( 71 , 72 ). This finding is opposite to what is found in the gut, where high microbial diversity is a sign of a healthy gut, and obesity and diabetes affect the guťs health by decreasing its diversity ( 71 ). In addition to the differing microbiomes between the gut, uterus, and other organs, different tumors have their distinct microbial composition ( 65 ). While some malignancies can be attributed to a single microbial species, such as Helicobacter pylori in gastric cancer ( 73 ), Salmonella enterica serovar Typhi in gallbladder cancer ( 74 ), and Borrelia burgdorferi in B-cell lymphoma ( 75 ), global changes in the microbiome are more likely the driver in a majority of microbial induced carcinogenesis ( 76 ). The literature in characterizing the EC microbiome could be more extensive. Walsh et al. prospectively investigated the reproductive tract microbiome and its association with EC via a sterile prospective collection of swabs from the lower (i.e., vagina and cervix) and upper (i.e., uterus and ovaries/fallopian tubes) reproductive tracts ( 71 ). One hundred forty-one patients undergoing a hysterectomy for EC or benign conditions were enrolled. Of the 66 patients with EC, significant differences were seen in the lower reproductive tract microbiome, including an increase in diversity and significant enrichment of 17 taxa, with Porphyromonas somerae as the most enriched species. When looking specifically at the uterine microbiome in those with EC, no statistically significant differences were seen compared to the benign uterus. However, only a fraction of those who enrolled had uterine or intra-tumoral tissue available for investigation—possibly contributing to an underpowered analysis with an inability to detect a significant difference. This observation prompted our recent investigation using a larger uterine sample size to help characterize the EC microbiome ( 77 ). We assessed banked hysterectomy specimens of 96 ECs and 16 benign lesions, with one of our aims investigating differences in the EC microbiome between obese and non-obese patients. We found a greater microbial diversity in the EC samples from obese versus non-obese women. Additionally, greater microbial diversity was seen in EC compared to the benign specimens, further supporting the association of increased microbial diversity with obesity and the presence of EC ( 77 ). Our study's limitations include its retrospective nature using banked tumor specimens, which raises the potential concern for specimen contamination through processing and handling. Prospective studies addressing sterility concerns of uterine specimens and the role of the gut microbiome in EC development and treatment are underway, including our institutional prospective study of the intra-tumoral and gut microbiome in endometrial cancer patients. Further understanding of the gut and EC microbiome will provide additional insight into EC carcinogenesis and the efficacy of treatment modalities. Unfortunately, the excellent outcomes seen in localized EC are in stark contrast to the limited prognosis of unresectable metastatic and multifocal recurrent EC ( 16 ). Standard treatment in this setting includes a combination of a platinum and taxane doublet ( 78 ). Microbes may contribute to variations in chemotherapeutic outcomes in treating EC, as pre-clinical and clinical studies in other cancers have suggested alterations in the gut microbiome can modulate platinum efficacy and toxicity ( 79 – 81 ). While cytotoxic treatment currently remains the standard modality in treating EC, immunotherapies, mainly through blockade of program cell death 1 (PD-1), have quickly moved to the first and second-line treatment of advanced and recurrent endometrial cancer ( 82 – 84 ). The gut microbiome appears to alter the efficacy of anti-PD-1 therapies as a greater alpha diversity and abundance of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium results in improved efficacy and outcomes in metastatic melanoma treated with anti-PD-1 therapies, and similar studies are certainly warranted for EC ( 85 , 86 ). It is also important to note that some studies have reported a surprisingly positive association between obesity and response to cancer immunotherapy ( 87 , 88 ). Naik et al. researched the complex ‘obesity paradox’ of anti-PD-1 agents alone (i.e., pembrolizumab or nivolumab) or in combination. They showed that overall survival was lower in non-overweight melanoma patients (BMI 35 kg/m 2 ) compared to overweight and class I obese patients (BMI 25–35 kg/m 2 ) ( 89 ). As obese individuals may have reduced microbial diversity and imbalances in their gut microbiota, this alteration can contribute to metabolic dysfunction and inflammation. For obese patients with EC, the tumor microenvironment has a role in carcinogenesis, suggesting that microbes within and around tumors can impact critical processes, such as immune evasion, apoptosis resistance, invasion, and metastasis. Weight loss strategies for EC patients that target the gut microbiome, such as dietary modifications, bariatric surgery, lifestyle interventions, and pharmacotherapies, aid in weight management and may be able to reverse imbalances in microbiota, leading to lower estrogen levels, a reduction in inflammation, and improved insulin sensitivity. Thus, obesity's associated gut dysbiosis, systemic inflammation, and suspected alteration of the EC microbiome support further investigations of microbial contributions to EC pathogenesis and treatment.

In summary, this review sheds light on the critical clinical implications of obesity in EC. The growing concern for EC is the rising incidence and mortality rates, making it the most common gynecologic malignancy and the fourth most common cancer in women ( 135 ). Obesity is a well-established risk factor for EC, contributing significantly to its development, and nearly 75% of EC cases can be attributed to obesity and physical inactivity ( 4 ). There are strong associations between obesity and EC in key risk factors such as diabetes, hormonal imbalances, and insulin resistance. Furthermore, the mechanisms of obesity contribute to EC pathogenesis, including endogenous hormone metabolism and the pro-inflammatory state induced by excess adiposity. The emerging field of microbiome research shows apparent relevance in EC, as the gut microbiome plays a crucial role in modulating systemic estrogen levels and inflammation linked to EC development ( 112 , 113 ). Exploring the microbial composition within the endometrial tumor microenvironment adds a new dimension to our understanding of EC etiology and potential treatment strategies. As weight loss interventions are associated with reducing and preventing the risk of EC and improving overall health outcomes, novel pharmacotherapies, like incretin receptor agonists, are potentially improved strategies to overcome poor adherence to diet and exercise interventions or feared, stigmatized gastric surgical procedures ( 123 , 125 ). This review underscores the multifaceted relationship between obesity and EC, providing valuable insights into the mechanisms driving carcinogenesis and potential avenues for prevention and treatment. There is an urgent need for continued research and clinical interventions aimed at addressing obesity as a significant risk factor for EC and improving the outcomes of those affected by this prevalent disease. By addressing the critical intersection of obesity, inflammation, and microbiome alterations, this review expands on the intricate metabolic disruptions caused by obesity, such as increased estrogen levels, hyperinsulinemia, and inflammation that directly and indirectly affect the endometrium, thus leading to carcinogenesis. In addition, in evaluating the less explored but vital aspect of gut dysbiosis in obesity, data reveals that gut dysbiosis exacerbates metabolic derangements and predisposes individuals to EC while possibly influencing treatment outcomes. Furthermore, data highlights that significant and sustained weight loss, achievable through interventions like bariatric surgery and pharmacological treatments, can substantially reduce EC risk by reversing these altered metabolic processes and gut dysbiosis caused by obesity. Therefore, maintainable weight loss strategies with supportive teams and obesity education must be encouraged within the endometrial cancer community.

In 1983, Bokhman dichotomized EC into two subtypes, termed type I and type II, based on pathogenicity ( 10 ). Type I ECs are characterized as being more common (approximately 80% of ECs), low grade, endometrioid histology, having a favorable prognosis, and driven by unopposed estrogen as typically found in patients with obesity, hyperlipidemia, anovulation, and diabetes ( 10 – 12 ). Type II ECs differ from type I in being less common, high-grade, non-endometrioid (e.g., serous) histology, have a poor prognosis, and do not seem to be estrogen driven ( 11 , 12 ). However, dichotomizing ECs into type I and II disease is falling out of favor for molecular subtyping as there is significant clinical overlap between type I and II disease, demonstrating our incomplete understanding of the biological mechanisms driving EC carcinogenesis. For example, obesity and diabetes are risk factors contributing to excess unopposed estrogen; however, high rates of obesity and diabetes are seen in women with estrogen-driven type I ECs and non-estrogen-driven type II disease ( 13 ). Data from The Cancer Genome Atlas (TCGA) has reclassified ECs into four subtypes based on their molecular profiles: POLE ultra-mutated, microsatellite instability (MSI) hyper-mutated, copy-number low (CNL), and copy-number high (CNH) ( 14 ). Endometrioid histology makes up the majority of tumors classified as POLE , MSI, and CNL. In contrast, serous histology comprises most CNH subtypes, although 25% of CNH tumors are of endometrioid histology ( 14 ). POLE tumors have the best prognosis, while CNH tumors have the worst ( 14 ). Interestingly, an association between obesity and EC molecular subtype has been described, with POLE tumors having the lowest BMI and CNL having the highest ( 15 ). Further investigation into obesity's contribution to the differing molecular alterations in EC and their prognosis is needed as our understanding of its involvement has yet to be completely elucidated. The current understanding of obesity's role in the carcinogenesis of EC is partially explained by its influence on levels of endogenous hormones. Adipose tissue essentially works as an endocrine organ. Excess adiposity results in dysregulation of its endocrine function, contributing to carcinogenesis through excess estrogen, insulin resistance, and inflammation ( 16 ). The leading theory of EC carcinogenesis occurs when the hyper-estrogenic state of obesity is unopposed by progesterone, resulting in stimulation of the endometrium to continue unabated proliferation, as summarized in Fig. 2 ( 17 ). Excess bioavailability of endogenous estrogen occurs through three primary mechanisms, two resulting from insulin resistance—decreased levels of sex hormone binding globulin (SHBG) and enhanced androgen synthesis. Hyperinsulinemia contributes to hepatic inhibition of sex hormone binding globulin synthesis and increased androgen production ( 18 , 19 ). This process helps partly explain why insulin resistance and polycystic ovarian syndrome have been demonstrated to be risk factors associated with EC, independent of obesity [17, 20]. The third mechanism in which obesity contributes to a hyper-estrogenic state is the peripheral aromatization of androgens to estrogen in adipose tissue. The presence of progesterone to counterbalance this excess estrogen is naturally absent in post-menopausal women. However, pre-menopausal progesterone deficiency can occur through anovulation due to ovarian hyperandrogenism from insulin resistance ( 17 ). Increasing circulating insulin from obesity may also contribute to increased endometrial cell proliferation and decreased apoptosis by activating the oncogenic PI3K/AKT/mTOR pathway which is frequently altered in EC ( 20 – 24 ). High levels of estrogen from excess visceral adipose tissue, in addition to hyperinsulinemia, promote gene expression of cellular receptors, such as insulin-like growth factor 1 (IGF1), with subsequent activation in phosphorylation of substrate proteins PI3K and AKT, causing a cascading effect in cellular proliferation, survival, and metastasis ( 20 , 25 , 26 ). In addition, the tumor-suppressor gene phosphatase and tensin homolog (PTEN), responsible for the inactivation of the prolific PI3K/AKT/mTOR pathway, and p53, responsible for cellular apoptosis, are commonly mutated or silenced, promoting endometrial carcinogenesis ( 27 – 29 ). Unsurprisingly, increased IGF1R (IGF1 receptor) and oncogenic gene expression have been demonstrated in endometrial intraepithelial neoplasia (EIN), a precursor to EC ( 28 , 29 ). The pro-inflammatory state of obesity contributes to carcinogenesis through local alterations in the endometrium contributing to an inflammatory milieu ( 30 – 32 ). Excess adipose tissue results in its infiltration of macrophages and other immune cells that produce inflammatory cytokines, resulting in systemic inflammatory effects including insulin resistance ( 33 , 34 ). Increased systemic levels of inflammatory cytokines including leptin, C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) have all been seen in obesity and EC ( 35 – 38 ). Leptin and IL-6 have been shown to contribute to EC by promoting cell proliferation, cell invasion, prevention of apoptosis, and cell cycle modulation ( 32 , 39 ). One mechanism linked to carcinogenesis through obesity-mediated inflammation is activation and dysregulation of nuclear factor- κ B (NF- κ B). TNF-α and other inflammatory cytokines activate NF- κ B, which has been shown to promote proliferation and metastasis by inhibiting apoptosis and angiogenesis ( 20 , 40 , 41 ). In addition to the local effect of obesity-induced inflammation on the endometrium, IL-6 and TNF-α act on aromatase, resulting in increased estrogen production, further contributing to the carcinogenesis of EC [38]. In contrast to this inflammatory activation of the endometrium, progesterone works to establish an anti-inflammatory endometrial milieu through inhibition of several inflammatory-mediated pathways, including inhibition of the proliferative and antiapoptotic effects of NF- κ B ( 40 , 42 – 44 ). Thus, obesity's contributions to establishing an inflammatory state of the endometrium, systemic inflammation, hyperinsulinemia, and excess endogenous bioavailable estrogen work in concert with promoting endometrial carcinogenesis.