MON-208 The Metabolic Syndrome of Menopause: The Role of Estrogen in an Interconnected Disease State

Abstract Disclosure: K.C. Haver: None. J.N. Griffin: None. Background: Menopause is a universal and inevitable transition characterized by a sharp decline in estrogen levels. The concept of the Metabolic Syndrome of Menopause (MSM) is introduced to encapsulate the cluster of metabolic dysfunctions—including visceral adiposity, insulin resistance, dyslipidemia, hypertension, and non-alcoholic fatty liver disease (NAFLD)—that arise due to estrogen decline rather than solely age or lifestyle factors. While Metabolic Syndrome (MetS) has been extensively studied, the role of menopause-specific hormonal shifts in metabolic dysregulation remains underappreciated in both research and clinical practice. Objective: This study aims to synthesize emerging evidence on the role of estrogen in regulating metabolic function and to propose a shift in understanding menopause as an independent risk factor for metabolic syndrome. Methods: A comprehensive review of current literature was conducted, integrating molecular, clinical, and epidemiological studies on menopause, metabolic syndrome, and estrogen's regulatory role in metabolic pathways. Key aspects examined include estrogen receptor (ER) signaling, fat distribution, glucose homeostasis, lipid metabolism, and inflammatory responses in postmenopausal women. Results: Estrogen plays a critical role in metabolic homeostasis via its actions on ERα and ERβ, which regulate adipogenesis, insulin sensitivity, and inflammatory pathways. Postmenopausal estrogen decline mirrors the profile of MetS. This includes increased central obesity and shifts in adipose storage from subcutaneous to visceral deposits, increasing cardiometabolic risk as a consequence of estrogen loss. Estrogen deficiency alters glucose transporter 4 expression, leading to impaired glucose uptake, reduced insulin sensitivity, heightened diabetes risk, and increased inflammation leading to insulin resistance. A rise in LDL cholesterol, triglycerides, and total cholesterol, and a decline in HDL, increases atherogenic potential in postmenopausal women, increasing dyslipidemia. Estrogen’s vasodilatory and renin-angiotensin system effects are lost, leading to increased vascular stiffness and hypertension. Estrogen loss is linked to hepatic steatosis and fibrosis, further exacerbating metabolic risk of NAFLD. Conclusion: Menopause should be recognized as an independent contributor to metabolic syndrome, necessitating a shift in clinical practice towards sex-specific risk assessment and management strategies. Given estrogen's role in metabolic regulation, targeted interventions—including hormone therapy, lifestyle modifications, and emerging pharmacotherapies—are essential for mitigating long-term health consequences of MSM. Future research should prioritize development of comprehensive treatment guidelines addressing metabolic dysfunctions specific to menopausal women. Presentation: Monday, July 14, 2025