Exploring sex bias in cardiometabolic diseases

Abstract

Cardiometabolic diseases (CMDs), such as cardiovascular diseases (CVDs), obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH), represent an alarming burden on healthcare systems. Differences in the prevalence, progression and outcomes of CMD are significantly sex specific, as are differences between premenopause and postmenopause. These differences lie in the distinct body fat distributions and lipid and lipoprotein profiles associated with estrogens, particularly 17β-estradiol (E2), which play a central protective role in female cardiometabolic health. Premenopausal women generally display a more favorable lipid profile, higher HDL-C levels and enhanced fatty acid oxidation, which collectively reduce CVD risk. On the other hand, a decrease in E2 during menopause promotes visceral adiposity, dyslipidemia, impaired hepatic handling, and a proinflammatory state that accentuates cardiovascular risk. This review explores the molecular mechanisms by which estrogens, particularly E2, regulate lipid and lipoprotein metabolism, mitochondrial fatty acid oxidation and inflammatory pathways. In this review, we also highlight the knowledge gaps that limit the development of sex-specific preventative and therapeutic strategies. Understanding sex differences in CMD is essential for improving the cardiometabolic health of women, particularly during the postmenopausal period.

Introduction

Cardiometabolic diseases (CMDs), including cardiovascular disease (CVD), obesity, type 2 diabetes, metabolic dysfunction-associated steatohepatitis (MASH) and dyslipidemia represents a major public health burden worldwide. These conditions are influenced by a complex network of genetic, metabolic and hormonal factors. These conditions are interconnected through common mechanisms such as inflammation, insulin resistance and alterations in lipid metabolism. However, they do not affect all individuals equally, as there are significant biological sex differences in the incidence, manifestation and progression of CMD. Recent reviews have broadly examined sexual dimorphism in cardiometabolic diseases across developmental and lifespan contexts, including placental adaptations and therapeutic perspectives [1]. In contrast, the present review focuses specifically on the molecular and metabolic mechanisms underlying sex-specific lipid regulation and cardiometabolic risk, emphasizing hepatic lipid handling, lipoprotein metabolism, and hormonal signaling. Together, these mechanisms provide a framework for understanding the biological basis of sex differences in cardiometabolic health. Several recent reviews have addressed sex differences in cardiometabolic diseases from physiological, developmental, or clinical perspectives [2–4]. This review focuses specifically on the molecular and metabolic mechanisms underlying sex-specific lipid regulation, with emphasis on hepatic lipid handling, lipoprotein metabolism, and estrogen-dependent signaling pathways. This mechanistic positioning distinguishes the present work from the literature by prioritizing molecular integration over epidemiological or therapeutic descriptions.

Women and men differ in their body fat distribution and lipid and hormonal profiles, all of which influence cardiometabolic risk. Obesity is a well-established risk factor for CMD, particularly when it is accompanied by visceral fat accumulation, insulin resistance and dyslipidemia. According to the World Health Organization (WHO), which defines obesity in adults as a body mass index (BMI) greater than 30 kg/m², more than 1 billion people globally are living with obesity, with women being disproportionately affected: 43% of adult women worldwide are considered overweight or obese, whereas 38% of men [5] tend to store fat in a gynoid, pear-shaped pattern, which is subcutaneous and gluteofemoral, while men have a visceral and abdominal, apple-shaped pattern, which is more metabolically harmful. On the other hand, women are more likely to develop obesity, as indicated by BMI measurements, whereas men are at greater risk of visceral obesity and metabolic dysfunction-associated steatotic liver disease (masld), as indicated by waist circumference. However, visceral adiposity increases in women during their postmenopausal phase [6, 7]. Estrogens confer metabolic protection by promoting favorable lipid profiles, which protect against CMD, enhancing insulin sensitivity, and promoting subcutaneous fat storage [7, 8]. However, this protection also decreases after menopause, contributing to increased visceral adiposity and increased cardiometabolic risk [6]. This sex disparity highlights the need to examine the distinct biological and hormonal factors that may influence obesity risk and progression in women.

Obesity significantly increases the risk of CVD, which continues to be the leading cause of death worldwide. Recent estimates indicate that CVDs are responsible for nearly 20 million deaths in 2022, representing approximately one-third of all global deaths [5]. CVDs are often underrecognized in women, despite being the leading cause of mortality. Symptoms of heart disease in women can also differ from those in men, which can contribute to misdiagnosis or delayed care [9]. Furthermore, traditional risk markers such as LDL-C levels, blood pressure and waist circumference may not fully capture all cardiometabolic risk in women, especially after menopause, when the protective effects of estrogens are gone [7, 10]. Postmenopausal women often have increased visceral fat, elevated LDL-C and reduced HDL-C, which worsen their cardiometabolic profile [11]. Men develop CVD earlier in life, but women experience a rapid increase in risk after menopause [10].

A growing emphasis in cardiometabolic research is being placed on risk assessment as well as specific prevention that integrates multiple determinants of disease, including biological mechanisms and clinical indicators. Approaches that integrate genomics, metabolomics, phenotyping, and clinical risk scores provide refined differentiation of individuals according to cardiometabolic risk and support targeted interventions [12]. These precision models can combine multiomics profiling, molecular biomarkers and deep phenotyping to refine risk prediction beyond more conventional factors such as age, lipid levels and blood pressure. These tools can improve the personalization of preventive strategies. In the present review, emphasis is placed on biological sex as a critical component of cardiovascular risk assessment. However, since the detailed methodologies behind these precision-medicine models are beyond the scope of this review, readers are referred to the cited literature for comprehensive descriptions of current approaches in cardiovascular prevention.

Despite these well-known patterns, many sex-based differences remain poorly understood. Historically, biomedical research has focused predominantly on male physiology, leaving substantial gaps in our understanding of women’s metabolic health and limiting the development of effective, sex-specific interventions [7]. This review focuses on the molecular mechanisms underlying sex-specific regulation of lipid metabolism, including lipoprotein handling, hormonal modulation, particularly by estrogens, and chromosomal influences. We further discuss emerging lipid biomarkers that may improve sex driven risk in cardiometabolic disease.

In addition to hormonal and molecular mechanisms, social and environmental determinants play a critical role in CMD risk, particularly in women. Across the lifespan, women are disproportionately affected by socioeconomic inequalities, attributed to their more extensive lifetime exposure to poverty, food insecurity, the burden of being the primary caregiver, and limited access to health services, all of which contribute to higher cardiometabolic risk [13, 14]. Women are also more likely to encounter employment discrimination and financial instability, both of which contribute to chronic stress and increase cardiometabolic vulnerability [15]. Structural racism, particularly residential segregation, is associated with a 12% increased risk of incident cardiovascular disease independent of individual socioeconomic status [16]. Built-in environmental attributes such as neighborhood walkability, street connectivity, and green spaces are consistently linked to greater physical activity, a lower body mass index, and fewer coronary events [16]. Socioeconomic stressors such as unemployment increase the risk of acute myocardial infarction by approximately 35%, with longer unemployment durations further increasing the risk [15]. Food insecurity is likewise associated with poor diet quality and high incidences of obesity, diabetes, and hypertension and doubles the likelihood of cardiovascular diseases [15]. Recent evidence has shown that psychosocial and socioeconomic stress (PSES) can reshape immune cell composition, which is linked to increased monocyte frequency, altered NK cell subsets, and heightened monocyte-platelet aggregates that accelerate atherosclerotic inflammation [17]. Collectively, these findings highlight that CMD predisposition arises from the combination of biological sex, socioeconomic context, and environmental exposure. Although the present review focuses mainly on biological and molecular mechanisms, it is important to acknowledge that these social and environmental determinants are integral to understanding sex-specific cardiometabolic disparities and must be taken into account in future research. Furthermore, women are predominantly affected by these disparities.

This review first summarizes the mechanisms of estrogen activity and then outlines the core pathways of lipid and cholesterol metabolism. We next examine how sex hormones and chromosomal sex shape these pathways and phenotypes and integrate these mechanisms to explain sex-specific cardiometabolic outcomes. Finally, we discuss emerging gaps and perspectives for future research. The novelty of this review lies not in the identification of novel molecular pathways but rather in the integrative synthesis of existing mechanistic evidence to provide a sex-specific framework of lipid metabolism and cardiometabolic regulation.

Mechanism of action of estrogens

Sex steroid hormones, particularly estrogens, play a crucial role in shaping sex-specific differences in lipid metabolism and cardiometabolic health. The primary estrogens in women are 17β-estradiol (E2), estrone (E1) and estriol (E3). Among these, E2 is the most potent and biologically active form, predominating during reproductive years. E1 is weaker and becomes the dominant circulating estrogen after menopause, whereas E3, the least potent, is mostly produced during pregnancy [18]. These steroid hormones are synthesized from cholesterol via a tightly regulated pathway that involves multiple enzymatic steps. A key step is the aromatase conversion of androgens such as testosterone and androstenedione into estrogens [19].

Throughout a woman’s life, estrogen levels fluctuate significantly, rising during puberty and declining during the menopausal transition. In premenopausal women, the ovaries are the primary site for estrogen production. However, after menopause, peripheral tissues such as adipose tissue become major contributors to circulating levels of estrogens through local aromatization [19]. Aromatase, the enzyme responsible for converting testosterone to E2, is highly expressed in extragonadal tissues, particularly adipose tissue. In obesity, aromatase activity is further elevated, leading to increased peripheral estrogen production [20].

Interestingly, compared with age-matched women, obese and aging men may have higher circulating E2 levels because of the increased aromatization of androgens in adipose tissue, emphasizing the significance of fat-derived hormonal signaling in both sexes [20]. Moreover, the metabolic fate of testosterone itself is critical. While aromatizable testosterone can be converted to E2 and exert protective effects, its nonaromatizable metabolite dihydrotestosterone (DHT) binds to androgen receptors (ARs) and is associated with proatherogenic outcomes [21]. In animal studies, aromatizable testosterone improved vascular health in castrated male mice, whereas nonaromatizable androgens did not, highlighting the protective role of aromatase-mediated estrogen synthesis [22, 23].

Estrogen signaling is essential for understanding the metabolic consequences of hormonal shifts across the female lifespan. Estrogens exert their effects through binding to the intracellular estrogen receptors ERα and ERβ, which are expressed in key metabolic tissues such as the liver, adipose tissue, muscle and vasculature [24]. Upon binding E2, these receptors modulate the transcription of genes involved in de novo lipid synthesis, triglyceride (TG) storage, glucose uptake and lipoprotein metabolism [25].

In addition to classical ERs, estrogen-related receptor alpha (ERRα), a nuclear receptor that is closely related in structure to ERs, plays a critical role in energy metabolism. Unlike ERs, ERRα does not bind estrogens directly; instead, it cooperates with ERα via shared transcriptional targets and coactivators, particularly PGC-1α, which acts as a bridge between estrogen signaling and mitochondrial gene regulation [26]. E2 binding to ERα can upregulate PGC-1α expression, which enhances ERRα transcriptional activity and links estrogen signaling to mitochondrial biogenesis, fatty acid oxidation, and energy expenditure [27]. Estrogens also signal through nongenomic pathways, particularly via the G-protein-coupled estrogen receptor (GPER), which is localized at the plasma membrane. GPER activation triggers second-messenger cascades, which include cAMP/PKA signaling, which enhances fatty acid oxidation and mitochondrial activity [28]. Furthermore, the DAG/PKC pathway is also activated, influencing glucose uptake and endothelial function [29]. These pathways converge to support ERα and ERRα transcriptional activity, which creates a loop that couples estrogen signals to energy metabolism and contributes to cardiometabolic protection, particularly in premenopausal women.

Collectively, these studies demonstrate that sex hormones modulate lipid metabolism through numerous regulatory mechanisms, including transcriptional control, mitochondrial function, and posttranslational mechanisms that govern lipoprotein handling.

Lipid and cholesterol metabolism

The processes of synthesizing, storing and breaking down fat are key mechanisms involved in lipid metabolism and form the biochemical basis upon which sex-specific metabolic regulation occurs (Fig. 1). This process involves a tightly coordinated network of metabolic pathways, including lipogenesis, lipolysis, fatty acid oxidation and lipid transport, which is primarily accomplished by the liver and adipose tissue.

Fig. 1.

De novo synthesis of saturated and monounsaturated fatty acids. Acetyl-CoA generated either from mitochondria or from cytosolic acetate serves as the precursor for fatty acid synthesis. Acetyl-CoA is carboxylated by acetyl-CoA carboxylase (ACC) to form malonyl-CoA, which serves as a substrate for fatty acid synthase (FAS). FAS condenses one acetyl-CoA and seven malonyl-CoA molecules to generate palmitate (C16:0). Subsequent elongation and desaturation of palmitate occur at the cytosolic side of the endoplasmic reticulum, mediated by elongase 6 (ELOVL6) and stearoyl-CoA desaturase 1 (SCD1), producing stearate (C18:0) and oleate (C18:1), respectively

Fatty acids are synthesized from acetyl-CoA and then converted to fatty-acyl-CoA, which serves as building blocks for lipids such as TG, phospholipids, and sphingolipids, while acetyl-CoA is also the precursor for cholesterol and cholesteryl esters [30]. As shown in Fig. 1, acetyl-CoA is converted to malonyl-CoA by acetyl-CoA carboxylase (ACC1) and elongated by fatty acid synthase (FAS) to produce palmitate (C16:0). This saturated fatty acid can undergo further elongation by ELOVL6 and desaturation by stearoyl-CoA desaturase-1 (SCD1) to form monounsaturated fatty acids such as oleate (C18:1) [31, 32]. These fatty acids are then esterified into TG for storage, predominantly in adipose tissue, but can also be incorporated into cholesterol esters and phospholipids across various tissues to support membrane structure and lipid transport (Fig. 2).

Fig. 2.

Lipoprotein metabolism with emphasis on known differences in premenopausal women. Transport and metabolism of dietary lipids through intestinal (exogenous) and hepatic (endogenous) lipoprotein pathways. Dietary TG and cholesterol are absorbed by enterocytes and packaged into chylomicrons, which enter the circulation via the lymphatic system. Lipoprotein lipase (LPL) hydrolyzes chylomicron-TG to release free FA for uptake in peripheral tissues through transporters such as CD36. Chylomicron remnants are cleared by the liver via apoE receptors, including LDLr and LRP1. In hepatocytes, TG is synthesized and incorporated into apoB-containing lipoproteins through the action of MTP, resulting in the formation of VLDL particles that are secreted into circulation. Progressive lipolysis by LPL and HL (hepatic) generates IDL and LDL particles, which deliver cholesterol to tissues or are removed from the bloodstream by hepatic LDLr-mediated endocytosis. HDL particles are formed through apoA-I lipidation via ABCA1 and mature through LCAT-mediated cholesterol esterification, enabling reverse cholesterol transport to the liver and other tissues via SR-BI. PCSK9 regulates cholesterol homeostasis by promoting LDLR degradation, thus reducing LDL-C clearance. Upward pink arrows indicate pathways that are enhanced in premenopausal women vs. men because of the effect of E2, including increased LPL activity, greater HDL formation, and higher LDLr-dependent clearance of circulating LDL-C. Downward pink arrows designate pathways attenuated in premenauposal women vs. men, such as hepatic VLDL-TG secretion and PCSK9-mediated LDLr degradation

In hepatocytes, TG is synthesized primarily via the glycerol-3-phosphate (G3P) pathway with fatty acyl-CoA. This involves sequential acylation reactions catalyzed by glycerol and diacylglycerol acyltransferase [24]. Alternatively, the monoacylglycerol (MAG) pathway, mediated by monoacylglycerol acyltransferase (MGAT) and DGAT, also exists but is considerably less active in the liver and plays a more prominent role in intestinal lipid absorption.

These newly synthesized TG are packaged and stored in lipid droplets. These droplets are sources of neutral lipids for the formation of very-low-density lipoproteins (VLDLs). The assembly of VLDL particles requires microsomal triglyceride transfer protein (MTP), which facilitates the lipidation of apolipoprotein B-100 (apo B-100), a protein that is essential for lipoprotein assembly in the liver and intestinal epithelium [33]. MTP transfers TGs and other lipids, such as phospholipids and cholesterol esters, onto apo B-100 in the endoplasmic reticulum (ER), allowing proper folding and stabilization of the lipoprotein [34]. Insufficient MTP activity or ER lipid supply leads to rapid apoB-100 degradation, which reduces VLDL secretion and promotes hepatic lipid accumulation [33] (Fig. 3).

Fig. 3.

Estrogen-mediated regulation of lipid metabolism and metabolic health before and after menopause. 17β-estradiol (E2) protects against cardiometabolic diseases in premenopausal women through multiple receptors. ERα/ERβ (nuclear receptors) regulate lipogenesis, lipoprotein secretion, LPL activity, and glucose uptake, favoring subcutaneous fat storage over visceral fat storage. G-protein coupled estrogen receptor (GPER) mediates rapid, nongraomic signaling, improving insulin sensitivity, stimulating AMPK, and reducing inflammation. ERRα (estrogen-related receptor α) enhances mitochondrial function and fatty acid β-oxidation. A decrease in E2 after menopause reduces these protective effects, increasing visceral fat, dyslipidemia, inflammation, and cardiometabolic risk

Following their secretion into the bloodstream, VLDLs undergo lipolysis by lipoprotein lipase (LPL) and hepatic lipase (HL), producing intermediate-density lipoproteins (IDLs) and, subsequently, low-density lipoproteins (LDLs) [35, 36]. This lipolytic process reduces the TG content in VLDL and enriches the particles in cholesterol esters, resulting in particles typical of LDL density and size [36]. HL plays a dual enzymatic role, with its lipase and phospholipase activities that are essential for the remodeling of IDL into LDL through the hydrolysis of TG and phospholipids. LDL particles are the primary cholesterol carriers in plasma and are mainly cleared through LDLr-mediated uptake by hepatocytes [37]. This is followed by internalization in early endosomes and degradation by lysosomes, which release free cholesterol into the cell toward the regulatory compartments of the ER [37]. This regulatory system is modulated by key ER-mediators, including sterol regulatory element-binding protein 2 (SREBP-2), the cholesterol-synthesizing enzyme 3-hydroxy-3-methylglutaryl-CoA (HMGCR), SREBP cleavage-activating protein (SCAP), and insulin-induced genes (INSIGs), which collectively sense intracellular cholesterol levels and control LDL receptor expression [38]. Low intracellular cholesterol activates SREBP-2. This increases LDLr expression and cholesterol biosynthesis [38]. When cholesterol levels are insufficient, INSIG retains SREBP-2 in the ER through its interaction with SCAP, preventing the production of LDLr. Therefore, the surface expression of LDLr and the plasma levels of LDL-c are tightly regulated by this feedback loop [39]. Importantly, several of these regulatory pathways, including MTP activity, LDLr expression, and PCSK9-mediated clearance, are subject to hormonal modulation, providing a mechanistic entry point for the sex-specific differences discussed in the following sections.

Furthermore, the amount of LDLr expressed on the cell surface is a major determinant of plasma LDL-C levels. Proprotein convertase subtilisin/kexin type 9 (PSCK9) plays a central role in this process by binding to LDLr and tagging it for lysosomal degradation, which reduces LDLr-mediated clearance [40]. Importantly, PCSK9 expression is also under the control of SREBP-2, which creates a feedback mechanism. When the intracellular cholesterol level increases following sustained LDL uptake, SREBP-2 activation decreases, reducing both LDLr and PCSK9 expression [41]. This negative control is essential for maintaining cholesterol homeostasis and preventing excessive cholesterol synthesis and accumulation in cells.

In parallel, the liver synthesizes high-density lipoproteins (HDLs) through the secretion of apoA-I and apoA-II, initiating nascent HDL formation. These particles acquire free cholesterol and phospholipids from peripheral cells via ABCA1, forming the basis of reverse cholesterol transport [42]. The enzyme LCAT, which is activated by circulating apoA-I, esterifies free cholesterol to form cholesteryl esters, enabling HDL maturation and the removal of excess cholesterol from tissues [43].

Key regulatory proteins such as AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs) integrate energy and lipid homeostasis. AMPK integrates cellular energy status with lipid metabolism by suppressing lipogenesis and promoting fatty acid oxidation [44]. PPARα, expressed predominantly in the liver, stimulates genes involved in fatty acid transport and β-oxidation, particularly during fasting [44]. For a more detailed overview of these regulatory networks and their integration with mitochondrial and peroxisomal metabolism, readers are referred to Fig. 1 and the comprehensive review by Jutras-Carignan et al. (2023) [45].

While these mechanisms and pathways are conserved between sexes, current evidence supports the critical role of sex hormones, especially estrogens, in modulating these metabolic processes in a sex-specific manner [46]. These hormonal differences contribute to divergent metabolic profiles and disease risks in women and men.

Overall, the regulation of lipid and cholesterol metabolism involves tightly interconnected pathways that maintain systemic energy balance. Recognizing how these pathways are modulated by sex hormones is essential for interpreting the metabolic dimorphisms observed between men and women, as will be detailed in the next sections. While these pathways are conserved across sexes, accumulating evidence has indicated that their regulation and physiological impact are strongly modulated by sex hormones, particularly estrogens, leading to distinct metabolic outcomes in women and men.

A sex-specific perspective on obesity, fat distribution and complications

Obesity is a chronic and multifactorial disease characterized not only by an imbalance between energy intake and energy expenditure, where the calories consumed through food exceed the energy dispersed by physical activity, resting thermogenesis (metabolism) and postprandial thermogenesis [46] but also by clinical signs (e.g., knee pain) and complications. These include metabolic disturbances such as insulin resistance and dyslipidemia and vascular dysfunction such as hypertension and atherosclerosis, which collectively contribute to increased morbidity and mortality. As such, sedentary behavior and poor dietary habits cannot be considered the only factors driving obesity, as the genetic landscape (heritability) is significant for body mass index. Clinically, obesity is defined as a BMI greater than 30 kg/m², which is calculated by dividing body weight in kilograms by height in meters squared [47]. However, BMI alone cannot fully capture obesity-related health risks. BMI does not distinguish between lean and fat mass and does not account for fat distribution. In contrast, waist circumference is now widely recognized as a better predictor of obesity-related health risks, especially in regard to cardiometabolic complications [47]. Waist circumference is a simple and powerful clinical tool that reflects visceral fat accumulation and is a better predictor of CMD than BMI alone is [48].

Importantly, obesity is associated with important sex differences, as women store more subcutaneous fat, which has a more favorable metabolic profile, whereas men tend to accumulate more visceral fat, which increases their risk of CMD earlier in life [47, 49]. However, following menopause, fat distribution in women tends to shift toward a more android pattern, which is characterized by increased visceral fat accumulation, particularly in the abdominal region, significantly increasing the risk of CMD [50]. This redistribution is influenced not only by a decrease in estrogens but also by a relative increase in androgenic activity. In postmenopausal women, the ratio of testosterone to estrogens increases, driven by persistently active androgen production and reduced estrogen levels. This hormonal shift promotes an android fat distribution, with increased visceral adiposity [23]. Visceral fat is more metabolically active and proinflammatory than subcutaneous fat because of its higher rate of lipolysis [51]. Free fatty acids released from visceral fat drain directly into the portal vein and are delivered to the liver, where they promote hepatic insulin resistance, increased gluconeogenesis, and dyslipidemia [52, 53]. Furthermore, compared with subcutaneous adipose tissue, visceral adipose tissue secretes greater amounts of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) [54]. This proinflammatory and lipotoxic environment contributes to the increased risk of CMD among aging women [50].

These findings reveal that sex-specific hormonal environments shape not only fat distribution but also metabolic and inflammatory profiles that can dictate cardiometabolic risk. Understanding this link between adipose biology and hormonal status is fundamental for understanding downstream differences in cardiovascular physiology.

Role of estrogens in cardiovascular health

CVD presentation, progression and risk factors also exhibit distinct sex-specific features that are strongly influenced by estrogens. At the heart of many cardiovascular events lies atherosclerosis, a chronic inflammatory disease involving endothelial dysfunction, lipid accumulation, and immune system activation. While CVD is often perceived as a predominantly male condition, it manifests differently in women, not only in terms of biological mechanisms but also in terms of clinical presentation and outcomes. On average, women develop coronary artery disease approximately 10 years later than men do because of the protective nature of estrogens [55]. However, this delay does not mean reduced severity, as women often present with more atypical symptoms, receive delayed diagnoses, and experience higher postevent mortality [55, 56]. The presentation of symptoms differs drastically between women and women with the classical male pattern. While men frequently report chest pain, women are more likely to experience different symptoms, such as fatigue, anxiety, dyspnea, nausea and upper abdominal discomfort. For instance, the FAST-MI registry reported an average delay of 120 minbetween symptom onset and emergency call in women, compared with 84 min in men [57]. Postmenopausal women frequently present with less extensive coronary lesions but still experience severe and disabling symptoms, reduced quality of life and increased postevent mortality [57]. Even after adjusting for age and symptoms, women, particularly postmenopausal women, are 40% more likely to delay care beyond that critical first hour [57].

Additional disparities persist beyond the point of diagnosis. Following myocardial infarction, women face a 50% greater risk of mortality than men do [55]. These delays are further exacerbated by anatomical differences, such as smaller coronary arteries and different plaque characteristics, which do not protect women from thrombosis or occlusion and may even heighten vulnerability due to hormonal influences [56].

Before menopause, estrogens exert several protective effects on the cardiovascular system by modulating lipid metabolism, reducing vascular inflammation and enhancing endothelial function [24]. These protective actions decrease after menopause, contributing to a sharp increase in CVD incidence and severity among aging women.

A central player in this regulation by which estrogens protect cardiovascular health is via the regulation of proprotein convertase subtilin/kexin type 9 (PCSK9). As mentioned above, PCSK9 is a key protein that promotes the degradation of LDLr and thereby increases circulating LDL-C levels, accelerating atherosclerosis [58]. Clinical studies have shown that plasma PCSK9 concentrations are inversely correlated with endogenous estrogen levels. For instance, Ghosh et al. (2015) demonstrated that PCSK9 levels fluctuate across the menstrual cycle and are significantly lower during estrogen-dominant phases, such as the luteal phase [59]. Furthermore, Persson et al. (2019) reported that PCSK9 levels are 22% higher in postmenopausal women than in premenopausal women [58]. This increase coincides with a rise in LDL-C, which contributes to the deterioration of the lipid profile. In ovariectomized (OVX) mouse models, E2 treatment also significantly reduced hepatic PCSK9 mRNA expression and protein levels, which increased LDLr expression and decreased plasma LDL-c levels [58]. Therefore, PCKS9 emerges not only as a biological link between hormonal decline and lipoprotein dysregulation but also as a potential sex-specific therapeutic target. In addition, E2 therapy in postmenopausal women has been shown to reduce the levels of lipoprotein(a) (Lp(a)), an atherogenic lipoprotein associated with CVD risk [58, 60, 61]. Reported inconsistencies across clinical studies likely reflect differences in cohort composition, hormonal status and other parameters rather than fundamental contractions in the underlying molecular pathway. Although estrogen replacement therapy and sex-specific responses to PCSK9 inhibition remain clinically controversial, the present review focuses on the underlying molecular mechanisms rather than therapeutic efficacy. Clinical inconsistencies likely reflect heterogeneous treatments in terms of timing, formulation, population characteristics, and study design, as illustrated by large hormone therapy trials reporting mixed cardiovascular outcomes [62]. Importantly, at the molecular level, experimental evidence consistently supports a regulatory role of estrogens in PCSK9 expression and LDLr homeostasis. For instance, 17β-estradiol directly inhibits PCSK9-mediated LDLr degradation in hepatocytes through GPER-dependent signaling [43], and physiological fluctuations in endogenous estrogen levels are inversely associated with circulating PCSK9 concentrations in women [59], providing a mechanistic basis that is largely independent of clinical trial variability.

Beyond lipoprotein regulation, E2 improves endothelial function by upregulating endothelial nitric oxide synthase (eNOS) and enhancing nitric oxide bioavailability, which promotes vasodilation, reduces vascular tone, and limits platelets [19, 63]. Estrogens also modulate vascular inflammation by downregulating the expression of proinflammatory cytokines such as TNFα, IL-β and IL-6 and upregulating the expression of the anti-inflammatory mediators IL-10 and TGF-β [64]. This cytokine balance stabalizes atherosclerotic plaques and limits monocyte adhesion through reduced expression of endothelial adhesion molecules such as ICAM-1 and VCAM-1, thereby maintaining vascular homeostasis [64]. In addition, E2 promotes the release of anti-inflammatory molecules such as apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) via endothelial-derived exosomes, which contributes to vascular homeostasis [65]. In agreement, E2 supplementation in OVX mice significantly reduces atherosclerotic lesion area, macrophage infiltration in the aorta and vascular inflammation, whereas ERα-deficient mice exhibit impaired endothelial function, increased vascular stiffness, and accelerated atherosclerosis [62, 66]. E2 also increases aortic compliance and prevents vascular stiffening in OVX rats, restoring normal vascular function and reducing the expression of oxidative stress markers [24, 67]. During menopause, a decrease in estrogens disrupts these protective mechanisms. Reduced NO bioavailability, diminished endothelial repair and increased oxidative stress lead to endothelial dysfunction. The immune environment shifts toward a more proinflammatory and proatherogenic state, which is characterized by increased expression of vascular adhesion molecules, increased leukocyte infiltration, increased plaque instability, and a heightened risk of thrombosis [64, 68]. These changes accelerate the progression of atherosclerosis and contribute to elevated CVD risk in postmenopausal women.

In addition to traditional lipid markers such as LDL-C and HDL-C, other plasma lipid biomarkers, such as ceramides, sphingomyelins and phosphatidylcholines, have attracted attention because of their role in CVD risk assessment [62]. Women generally exhibit higher plasma levels of specific bioactive lipid species, including certain ceramides and phosphatidylcholine species, which may influence inflammatory pathways and are recognized as biomarkers for atherogenic risk [69]. These differences become even more pronounced after menopause, when ceramide and phosphatidylcholine concentrations increase sharply, which is associated with decreased estrogen levels [70]. Ceramides, in particular, have been implicated in the pathogenesis of atherosclerosis and CVD through their proinflammatory and pro-apoprotic effects on vascular endothelial cells and macrophages, which promote vascular dysfunction and plaque instability [69].

Lipidomic studies have also revealed that premenopausal women have higher plasma concentrations of long-chain polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and arachidonic acid (ARA), which are partly regulated by estrogens [71–73]. These fatty acids are essential for immune modulation, endothelial integrity, and membrane fluidity [74]. High DHA levels are generally associated with anti-inflammatory and vasoprotective effects, whereas excess ARA may give rise to proinflammatory pathways through the production of mediators such as prostaglandins and leukotrienes [74]. Following menopause, when estrogen levels decline, compared with age-matched men, postmenopausal women still maintain higher levels of both DHA and ARA, which is likely due to residual estrogen signaling and perhaps the aromatization of androgens [73, 74]. This duality indicates that while elevated DHA may confer cardiovascular protection, the increase in ARA could offset some of these benefits by promoting inflammation, emphasizing that the net effect on CVD outcome likely depends on the relative balance between these fatty acids.

Collectively, experimental and clinical evidence has demonstrated that estrogen maintains vascular homeostasis through the regulation of lipid metabolism, endothelial function, and inflammation. The loss of this hormonal protection after menopause accelerates cardiovascular vulnerability, linking molecular mechanisms to clinical outcomes.

Effects of estrogens on lipid metabolism and MASLD

Clear sex differences in lipid profiles are evident across the lifespan and contribute to disparities in cardiovascular and metabolic risk [6]. Human studies illustrate these differences. In a diet study by Matthan et al. (2008), healthy men, premonopausal women, and postmenopausal women consumed a Western-style diet high in saturated fat and refined carbohydrates for 4–6 weeks. Plasma lipid profiles were measured under nonfasting conditions, and compared with men, premenopausal women displayed significantly lower concentrations of total cholesterol (-23%), LDL-C (-34%), and TG (-57%). In contrast, compared with premenopausal women, postmenopausal women exhibit elevated levels of total cholesterol (+ 50%), LDL-C (+ 55%), TG-rich lipoprotein cholesterol (TRL-C; +130%) and TG (+ 232%), with no significant changes in HDL-C levels [75]. These data illustrate the central role of estrogens in preserving lipid homeostasis and mitigating diet-induced dyslipidemia in women. In premenopausal women, higher levels of HDL-C and lower levels of VLDL-C and LDL-C contribute to a cardioprotective lipid profile [63, 75]. On the other hand, a postmenopausal decline in estrogens leads to increases in total cholesterol, LDL-C and TG levels, which significantly increase cardiovascular risk [58, 75].

The underlying mechanisms are largely driven by the regulation of hepatic handling by estrogen. In the liver, estrogens play a central role in lipoprotein metabolism by regulating the production and secretion of VLDL, which is essential for the export of TG from hepatocytes into the circulation. Estrogen signaling via ERα and its partner ERRα transcriptionally upregulates apoB-100 and MTP, both of which are involved in the assembly of VLDL and its secretion [61]. E2 can also directly bind to the MTP subunit protein disulfide isomerase (PDI), which can potentially modulate the efficiency of lipoprotein assembly and act as a regulatory brake to prevent oversecretion under conditions of lipid excess [76]. This contributes to sex differences in VLDL production: premenopausal women tend to produce fewer, TG-rich VLDL particles, which are cleared more efficiently, resulting in lower plasma TG levels and improvement of the atherogenic lipid profile [77]. In contrast, a decrease in postmenopausal estrogens is associated with increased VLDL-apoB-100 and VLDL-TG secretion, contributing to hypertriglyceridemia and increased cardiovascular risk [63].

Estrogen also promotes hepatic fatty acid β-oxidation, which limits lipid accumulation [26]. Through ERRα, estrogen enhances mitochondrial function and oxidative metabolism [26]. ERRα directly regulates the expression of carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, thereby increasing lipid catabolism and protecting against hepatic steatosis [78, 79]. The interaction of estrogen with PPARα appears to be context dependent. In OVX mice, estrogen treatment attenuates PPARα activity, and females exhibit lower PPARα expression than males do, further suggesting sex-specific metabolic tuning [80]. The combined effects of enhanced VLDL export and fatty acid oxidation facilitate hepatic lipid clearance, reduce TG accumulation, and protect against mass progression.

In parallel, estrogens suppress lipogenesis and visceral fat deposition. Estrogen-AMPK signaling helps maintain lipid balance by promoting fatty acid oxidation over lipid accumulation, which reduces the risks of hepatic steatosis and cardiovascular diseases. In OVX mice, E2 treatment downregulates the expression of key lipogenic genes, including FAS, ACC1 and LPL, in adipose tissue, leading to a significant reduction in intra-abdominal adiposity [81]. However, this protection diminishes after menopause, as declining estrogen levels contribute to increased visceral adiposity and hepatic fat accumulation, thereby increasing the risk of masld and its complications [6]. Mechanistically, estrogen deficiency leads to the dysregulation of hepatic homeostasis through the impaired activation of ERα, which results in decreased fatty acid oxidation and increased lipogenesis through the upregulation of transcription factors such as SREBP-1c and carbohydrate-responsive element binding protein (ChREBP) [6, 63]. These transcription factors drive the expression of lipogenic enzymes such as FAS, ACC1 and SCD1, which promote TG synthesis and storage in hepatocytes [7, 63].

The accumulation of TG promotes insulin resistance and lipotoxicity, which in turn triggers inflammation and fibrosis, which are present in mash. The sex differences are not limited to only obesity and CVD. In mash, for example, men generally exhibit higher liver enzyme levels, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as faster fibrosis progression, whereas women may be more protected until menopause, after which their risk increases, which is likely due to hormonal shifts affecting hepatic lipid handling [6, 82]. Compared with men, postmenopausal women with masld also exhibit greater hepatic oxidative stress, mitochondrial dysfunction, and impaired autophagy, all of which are associated with more aggressive disease phenotypes [6]. These metabolic disturbances highlight the central role of estrogens in maintaining hepatic lipid balance and preventing the progression of masld and mash in women.

Taken together, these studies indicate that estrogen modulates hepatic lipid balance through effects on fatty acid oxidation, lipogenesis, and VLDL secretion. This decline in estrogen signaling after menopause therefore disrupts hepatic lipid handling and contributes to the sexual dimorphism observed in masld and mash progression.

Testosterone in female cardiometabolic health

Testosterone, while traditionally studied in the context of male physiology, also plays an important regulatory role in female metabolic health. In women, testosterone is produced by the ovaries and adrenal glands and exerts its biological effects both directly, via activation of androgen receptors (ARs), and indirectly through aromatization to E2 [25]. At the molecular level, testosterone modulates lipid metabolism in a tissue- and context-dependent manner. In hepatocytes and macrophages, testosterone upregulates scavenger receptor class B type I (SR-BI), which increases cholesterol uptake from HDL particles and contributes to reverse cholesterol transport [20]. This mechanism may contribute to improved lipid clearance and reduced atherosclerotic burden in tissues with active AR signaling. While a direct effect of testosterone on SCD1 appears minimal, it does reduce hepatic ELOV6 expression, an effect opposite to that of E2, which upregulates both SCD1 and elongase 6 [83]. Reduced ELOVL6 expression may lead to shorter-chain saturated fatty acids and less efficient TG synthesis, limiting hepatic lipid accumulation and protecting against liver steatosis, particularly in women with balanced androgen/estrogen signaling [83].

Even at lower concentrations than in men, fluctuations in testosterone levels in women, especially during menopause, have been linked to significant changes in body composition, insulin sensitivity, and CVD. Clinical studies have shown that elevated androgen levels, as seen in polycystic ovary syndrome (PCOS), are associated with increased visceral adiposity, hepatic steatosis, insulin resistance, and a pro-atherogenic lipid profile [23, 84]. In postmenopausal women, decreased testosterone is associated with increased fat mass and metabolic dysfunction, particularly when coupled with reduced estrogen levels [85]. This is particularly relevant in aging women, where adipose tissue becomes a predominant site for sex hormone conversion because of increased aromatase activity, which alters the local balance between androgens and estrogens [86].

Despite these findings, the role of testosterone in female metabolism remains understudied. Much of the current knowledge is extrapolated from male-based models, which highlights the need for research directly examining androgen effects in women.

Despite these findings, the role of testosterone in female metabolism remains understudied since much of the current knowledge is based on male-based models. Taken together, these findings suggest that androgens play dual roles in female metabolism, such as by supporting lipid handling and reversing cholesterol transport under balanced conditions but promoting metabolic dysfunction when dysregulated. This duality highlights the need to investigate in depth how estrogen and androgen interact in women’s cardiometabolic health.

Role of sex chromosomes

Sex differences in metabolism arise from complex interactions between sex chromosomesomes and hormone regulation. Clinical syndromes highlight the metabolic influence of sex chromosome dosage. An example of this phenomenon is Klinefelter syndrome (XXY), characterized by the presence of an extra X chromosome in males, which is associated with a fivefold increase in the risk of developing metabolic syndrome, insulin resistance and increased visceral adiposity and dyslipidemia [87]. Conversely, Turner syndrome (X0) is characterized by either complete or partial loss of one X chromosome and leads to E2 deficiency in females. This alters lipid and glucose metabolism, increasing insulin resistance and mortality rates, which are attributed mainly to CVD [88]. A cohort study involving 102 women with Turner syndrome revealed that 30% of them had hyperlipidemia compared with the general population [88]. Women affected by Turner syndrome who were given hormone replacement therapy were found to have improved blood pressure and lean mass, while glucose intolerance often worsened [88, 89].

Experimental evidence supports the independent and combined effects of sex chromosomes and gonodal hormones on metabolism. This has been demonstrated using the four-core-genotype (FCG) mouse model. This model is an experimental tool that allows investigators to distinguish the effects of gonadal sex (testes or ovaries) from those of chromosomal sex (XX, XY). This is achieved by relocating the Sry gene, which determines testis development, from the Y chromosome to an autosome. This results in a model with four combinations, XX mice with either ovaries or testes or XY mice with either ovaries or testes [90]. Studies using the FCG model have consistently shown that XX mice, regardless of whether they have ovaries or testes, exhibit greater total subcutaneous fat accumulation, increased adiposity, and altered feeding behaviors compared with their XY counterparts [91–93]. Evidence also suggests that mice with XX chromosomes display elevated levels of leptin and insulin and show heightened susceptibility to diet-induced obesity and hepatic steatosis [91, 93]. Furthermore, when fed an obesogenic diet, XX mice demonstrate greater diurnal feeding behavior, which leads to increased caloric intake and accelerated weight gain [93]. These effects suggest that the presence of two X chromosomes, independent of gonodal hormones, may inherently predispose individuals to metabolic dysfunctions.

At the molecular level, chromosomal dosage further contributes to these differences. Approximately 15–24% of X-linked genes escape X inactivation in females, which leads to increased expression of genes such as G6PD, XIAP and other antiapoptotic or antioxidant factors [1]. These effects confer enhanced oxidative-stress defenses and improved cardiac cell survival in females. Furthermore, X chromosomes have numerous immune-related genes, including IL-2Rγ, IL-3Rα, IL-9R, IL-13Rα, TLR7/8, and IL-1RAK1, whose higher dosage in females shapes sex-specific inflammatory responses [1]. These differences within the genome may contribute to a greater incidence of autoimmune-associated cardiovascular diseases observed in women.

In addition to metabolic effects, chromosomal sex also influences cardiovascular outcomes. For instance, compared with XY mice, XX mice experience larger infarct sizes and worse cardiac recovery following ischemia, regardless of gonadal sex [87, 90].

Taken together, these findings emphasize that sex chromosomes are critical determinants of metabolic and cardiovascular health and act through both hormone-independent mechanisms and interactions with gonadal signals. Recognizing these chromosomal contributions expands the understanding of sex bias beyond hormonal explanations and integrates genetic and molecular perspectives in cardiometabolic diseases.

Conclusion and future perspectives

Sex differences in lipid metabolism are shaped by a multifactorial interplay of hormonal, chromosomal and physiological factors that influence the risk, presentation and progression of CMD, such as obesity, dyslipidemia, and CVD. Among these factors, estrogens, particularly E2, play a central protective role in premenopausal women, as detailed in this review. E2 promotes favorable lipid profiles, enhances fatty acid oxidation, supports vascular integrity and reduces systemic inflammation.

The transition to menopause, which is marked by a sharp decline in E2 levels, disrupts these protective mechanisms and triggers increased visceral adiposity, hepatic lipid accumulation, endothelial dysfunction and a more atherogenic lipid and lipoprotein profile. Chromosomal sex also exerts an independent influence on lipid metabolism, highlighting that CMD risk is not solely driven by hormones.

Despite the strong evidence that there are significant sex differences in CMD, women remain underdiagnosed and undertreated, in part because research has been historically centered around male models. While E2 clearly confers cardiometabolic protection, the precise molecular mechanisms through which E2 regulates hepatic lipid handling, VLDL assembly and secretion and mitochondrial fatty acid oxidation remain incompletely understood. Additionally, how estrogen signaling interacts with inflammatory pathways, lipoprotein remodeling, and vascular lipid deposition in women is still poorly defined. The independent contribution of sex chromosomes to lipid metabolism and their interaction with hormones in shaping postmenopausal vulnerability to CMD is also not fully understood, despite evidence from clinical syndromes and detailed models. Addressing these gaps is critical for understanding why the loss of E2 alters female cardiometabolic health and for guiding the development of more precise, sex-specific interventions. Finally, while we focused on the biological and molecular pathways contributing to sex-specific cardiometabolic risk, it is essential to address that the clinical translation of these insights will require practical risk assessment and personalized tools. From a therapeutic perspective, increasing evidence suggests that sex influences pharmacological responses in cardiometabolic disease, including lipid-lowering strategies and anti-inflammatory interventions. These differences likely reflect underlying molecular differences in hormone signaling, lipid handling, and receptor regulation, which reinforces the need for sex-driven therapies.

In summary, this review integrates molecular, hormonal, and chromosomal determinants of lipid metabolism to explain sex-specific susceptibility to cardiometabolic diseases. Mechanistic insights into clinical outcomes highlight how the loss of estrogen signaling, chromosomal composition, and metabolic remodeling converge to shape disease trajectories. Future research should aim to translate these mechanisms into precision strategies that account for sex as a biological variable.

Abbreviations

ACC1

Acetyl-CoA carboxylase 1

ARA

Arachidonic acid

ApoA-I

Apolipoprotein A-I

ApoA-II

Apolipoprotein A-II

ApoB-100

Apolipoprotein B-100

AR

Androgen receptor

BMI

Body mass index

CVD

Cardiovascular diseases

CMD

Cardiometabolic diseases

ChREBP

Carbohydrate-responsive element-binding protein

CPT1

Carnitine palmitoyltransferase 1

DAG

Diacylglycerol

DHT

Dihydrotestosterone

E2

17β-estradiol

E1

Estrone

E3

Estriol

ERRα

Estrogen-related receptor

ERα

Estrogen receptor alpha

Erβ

Estrogen receptor beta

ER

Endoplasmic reticulum

eNOS

Endothelial nitric oxide synthase

FAO

Fatty acid oxidation

FAS

Fatty acid synthase

FCG

Four core genotypes

G3P

Glycerol-3-phosphate

GPAT

Glycerol-3-phosphate acyltransferase

GPER

G-protein-coupled estrogen receptor

HDL-C

High-density lipoprotein cholesterol

HL

Hepatic lipase

HMGCR

3-hydroxy-3-methylglutaryl-CoA reductase

HSL

Hormone-sensitive lipase

IL

Interleukin

INSIG

Insulin-induced gene

LCAT

Lecithin: cholesterol acyltransferase

LDL

Low-density lipoprotein

LDL-C

Low-density lipoprotein cholesterol

LKO

Liver-specific knockout

LPL

Lipoprotein lipase

Lp(a)

Lipoprotein(a)

MAG

Monoacylglycerol

MASLD

Metabolic dysfunction-associated atypical liver disease

MGAT

Monoacylglycerol acyltransferase

MGL

Monoglyceride lipase

MTP

Microsomal triglyceride transfer protein

NO

Nitric oxide

OVX

Ovariectomized

PAP

Phosphatidic acid phosphatase

PCOS

Polycystic ovary syndrome

PCSK9

Proprotein convertase subtilisin/kexin type 9

PDI

Protein disulfide isomerase

PGC-1α

Peroxisome proliferator-activated receptor gamma coactivator-1alpha

PKC

Protein kinase C

PKA

Protein kinase A

PPARα

Peroxisome proliferator-activated receptor alpha

PUFA

Polyunsaturated fatty acid

SCAP

SREBP cleavage-activating protein

SCD1

Stearoyl-CoA desaturase 1

SREBP

Sterol regulatory element-binding protein

SR-BI

Scavenger receptor class B type I

TG

Triglyceride

TNF-α

Tumor necrosis factor-alpha

TRL-C

Triglyceride-rich lipoprotein cholesterol

VLDL

Very-low-density lipoprotein

WHO

World Health Organization

XCI

X chromosome inactivation

Authors’ contributions

Tania Guillemette conceptualized the review, conducted the literature review, wrote the manuscript, and prepared the figures. All authors critically revised the manuscript and approved the final manuscript.

Funding

Not applicable.

Data availability

Not applicable. This is a review article; no new data were generated or analyzed during the preparation of this manuscript.

Declarations

Ethics approval and consent to participate

Not applicable. This article is a review and does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.