Endometrial Cancer and Metabolic Syndrome: Interplay of Hormonal and Inflammatory Pathways

Abstract

Endometrial cancer is the most common gynecological malignancy in developed countries, with rising incidence globally, largely paralleling the epidemic of obesity and metabolic syndrome. Metabolic syndrome, characterized by central obesity, insulin resistance, dyslipidemia, and hypertension, contributes to an altered hormonal and inflammatory milieu that promotes endometrial carcinogenesis. The interplay of these factors underscores the complex biological pathways linking metabolic dysregulation to tumor initiation and progression. Hyperinsulinemia and insulin resistance increase circulating insulin and insulin-like growth factor-1 (IGF-1), both of which activate proliferative signaling cascades, such as the PI3K/Akt and MAPK pathways, leading to enhanced cellular proliferation and resistance to apoptosis in endometrial tissue. Concurrently, obesity-associated chronic low-grade inflammation is marked by elevated pro-inflammatory cytokines, such as TNF-α, IL-6, and CRP, which contribute to oxidative stress, DNA damage, and dysregulated immune surveillance. Adipose tissue dysfunction further amplifies these risks through increased aromatase activity, leading to higher peripheral estrogen production unopposed by progesterone, particularly in postmenopausal women. This unopposed estrogenic stimulation remains a central driver of endometrial hyperplasia and malignant transformation. Moreover, adipokines such as leptin and adiponectin exert opposing influences: leptin promotes angiogenesis and cell proliferation, while reduced adiponectin levels diminish insulin sensitivity and tumor-suppressive signaling. Together, these hormonal and inflammatory alterations create a pro-tumorigenic microenvironment. Understanding the interconnected roles of hormonal imbalance and chronic inflammation provides opportunities for targeted preventive and therapeutic strategies. Lifestyle interventions addressing obesity and insulin resistance, pharmacologic agents such as metformin and selective estrogen receptor modulators, and anti-inflammatory therapies may help mitigate risk and improve outcomes in endometrial cancer patients with metabolic syndrome. This review highlights the mechanistic insights into the relationship between metabolic syndrome and endometrial cancer, emphasizing the importance of integrated approaches that address both metabolic health and oncologic risk.