Precision Nutrition for Management of Cardiovascular Disease Risk during Menopause Open Access

In the USA, cardiovascular disease (CVD) affects women disproportionately more than men [1]. It is estimated over 14 million women are living with ischemic heart disease (>8 million), heart failure (>3 million), pulmonary hypertension (>3 million), and congenital heart disease (0.3–0.6 million) [1]. There is a notable increase in CVD risk during a woman’s midlife, a period that coincides with the menopause transition, suggesting the loss of estrogen during menopause increases CVD risk [2]. Due to the severity and prevalence of CVD, the American Heart Association recommends dietary patterns (e.g., plant-based, Mediterranean, Dietary Approaches to Stop Hypertension [DASH]) that encourage increased fruit, nut, vegetable, legume, and lean vegetable or animal protein (preferably fish) consumption [3]. While these dietary pattern guidelines demonstrate improvements in mortality and disease progression, they only offer single recommendations. Such one-size-fits-all approaches neglect individual characteristics that contribute to CVD morphology and the additive effects of menopause on cardiometabolic health. As women spend up to 40% of their lives in menopause [4], developing precision nutritional strategies that address CVD progression, and the unique physiological changes that occur during menopause, is critically important for preventing and managing CVD as women age.

This review details how the menopause transition impacts cardiovascular health and examines the current dietary recommendations for managing CVD. We review how precision nutrition can address cardiometabolic health during menopause. Finally, we call for further research examining precision nutrition as a method of CVD management during menopause to identify mechanistic and applied techniques for clinical care.

In this review, the words “woman/women” are used extensively. These terms are defined in reference to individuals assigned female at birth who are >18 years of age. These interpretations are used due to the available research literature and are based on self-identified gender identity.

Estrogens secreted by the ovaries protect vascular endothelial function and metabolism [5]. In females, the cyclical fluctuations of estrogen and follicle-stimulating hormone (FSH) levels remain consistent from puberty into adulthood (e.g., premenopause) [4, 6]. In the years preceding menopause, known as perimenopause (average age 45 years), the ovarian follicle supply diminishes, leading to decreased estrogen despite rising FSH levels, resulting in longer intervals between menstrual periods and physical and psychological menopause symptoms. Eventually, ovarian follicles are depleted, ceasing estrogen production and despite high FSH levels, which triggers natural menopause (over 12 months of amenorrhea; average age 51 years) [4, 6].

The length of the menopause transition is highly variable between women, typically lasting 4–5 years but ranging from 1 to 10 years or longer [7]. During this time, women gain approximately 2–3 kg of fat mass, which is redistributed toward central or abdominal obesity [8‒10]. Additionally, women experience accelerated losses in lean mass and bone mineral content adversely affecting fat-free mass [10‒12]. These body composition changes are concurrently tied to a 60% increased risk for developing metabolic syndrome (e.g., increased visceral fat, elevated total cholesterol, reduced high-density lipoprotein, and elevated low-density lipoprotein), insulin insensitivity, and dysglycemia [2] (as shown in Fig. 1). Data from the Study of Women’s Health Across the Nation (SWAN) indicated that about 14% of women transitioning through menopause will develop metabolic syndrome with an odds per year of 1.45 (95% confidence interval, 1.35–1.56), particularly due to worsening lipid profiles [13].

Furthermore, physiological symptoms that occur during the menopause transition, such as sleep and cognitive disturbances, depression and anxiety, and vasomotor symptoms (e.g., hot flashes), have been linked to increases in blood pressure, dyslipidemia, and obesity [2, 6, 14]. One cross-sectional study examining body composition changes and menopausal symptoms demonstrated that percent body fat predicted nearly half of the variance in perimenopausal symptoms [15]. Experiences with menopause symptoms may vary by race with black women consistently self-reporting more severe vasomotor symptoms, and with Hispanic/Latina women being more likely to self-report both vasomotor symptoms and genitourinary symptoms, compared to non-Hispanic/Latinx white women [16]. Racial differences in body composition changes during the menopause transition my also contribute to increased cardiometabolic risk with non-Hispanic/Latinx white women gaining more abdominal adiposity than black women [9]. These data demonstrate the importance of understanding the potential racial disparity in CVD risk factors across the menopause transition.

Social determinants of health are related to the health of women throughout the menopause transition. Cultural factors, family support, education level, economic status, marital status, employment, and lifestyles (nutrition, exercise, tobacco use, etc.) are the key mediators for cardiometabolic health [17]. Specifically, unhealthy diet is a major modifiable risk factor for CVD and modifications can be used as a method for mediating adverse changes in body composition and metabolomics, thus improving cardiometabolic health in peri- and postmenopausal women.

Dietary intervention is considered one of the most important lifestyle modifications to prevent CVD risk. Higher intake of individual foods and nutrients (i.e., low-fat skimmed milk) has been associated with later menopause onset [18] and improvement in menopause symptoms (i.e., fiber) [19, 20], as well as improved CVD risk factors (i.e., blueberries) [21]. It is imperative to promote a diverse and healthy dietary pattern for CVD prevention due to the synergistic effects and interactions of nutrients, phytochemicals, and the food matrix. For example, blueberries improved vascular endothelial function in adults with at least one CVD risk factor when eaten alone or with water. However, these benefits were not observed when blueberries were consumed with an energy-dense meal or semi-skimmed milk [21]. Thus, well-balanced diets with all necessary nutrients are crucial for preventing or managing CVD in postmenopausal women.

Hypertension is the leading CVD risk factor and is estimated to be present in ∼75% of women postmenopause [22‒24]. A dietary intervention that was low sodium consumption (60–70 mmol/day), low-acid, fruit- and vegetable-rich diet reduced systolic and diastolic blood pressure in postmenopausal women with HNT, emphasizing the importance of diverse dietary strategies for disease prevention [25]. The DASH diet is a well-known dietary pattern consistently shown to reduce blood pressure in diverse populations. The DASH diet plan includes increasing intake of fruits, vegetables, and whole grains, fat-free and/or low-fat dairy products, beans, nuts, fish and poultry, and vegetable oils, while limiting intake of foods high in saturated fat and sugar-sweetened beverages and staying under 2,300 mg of sodium per day [26]. While the literature is limited regarding the beneficial effects of a DASH diet in postmenopausal women, a systematic review and meta-analysis revealed that the DASH diet improved CVD risk biomarkers of total cholesterol and low-density lipoprotein cholesterol in adults with and without co-morbidities [27]. Furthermore, concomitant changes in cholesterol and blood pressure lead to ∼13% reduction in 10-year risk for CVD using the Framingham risk score [27]. Utilizing the DASH diet approach in women transitioning through menopause may be an acceptable and feasible approach to mitigate cardiovascular changes that contribute to HTN and CVD (as shown in Fig. 2).

Postmenopausal women incur an increased risk of endothelial dysfunction due at least in part to oxidative stress [24, 29‒31], as well as elevated levels of proinflammatory cytokines [30]. Oxidative stress and systemic inflammation contribute to the development of endothelial dysfunction, which is the initial step in atherosclerosis development [21, 23, 32]. The Mediterranean diet (MED) tends to be rich in olive oil, nuts, and fruits, and adherence has shown to lower oxidative stress and inflammation and improve endothelial function [33, 34], as well as reduce CVD events by ∼76% [35] and reduce endothelial damage in healthy male and female elderly adults >65 years [36]. In a cross-sectional evaluation of 176 menopausal women (most with overweight or obesity), a higher MED adherence lowered android/gynoid fat ratio and visceral adipose tissue [37]. Additionally, adherence to MED improved blood lipid profiles and blood pressure in postmenopausal women with metabolic syndrome [20] (as shown in Fig. 2).

The menopause transition is often accompanied by changes in dietary patterns, particularly increases in saturated fat and dietary cholesterol [8]. Several randomized controlled trials have been conducted to assess the impact of fat-modified (30 fat with 10% saturated fat), low-fat plant-based diet (10 fat, 75 carbohydrate, and 15% protein) and very low carbohydrate diet (5–10% carbohydrate) [20]. Compared to high-fat diets, low-fat diets seem to collectively improve total blood lipid profiles in postmenopausal women with overweight after 3–8 weeks suggesting decreasing dietary fat may mediate dyslipidemia that often occurs during the menopause transition [20, 38]. Following a low-fat, plant-based diet for 14–18 weeks decreased insulin, fasting blood sugar, and increased insulin sensitivity in postmenopausal women [20, 39, 40], which is particularly important for women who experience dysglycemia. Taken together, a low-fat diet appears to be a promising dietary strategy for reducing CVD risk factors and metabolic syndrome in postmenopausal women. On the other hand, in postmenopausal women living with overweight and obesity, following a very-low carbohydrate diet for 4 weeks significantly decreased total cholesterol, low-density cholesterol, triglycerides, insulin, and fasting blood sugar levels [20, 41], highlighting the interindividual responses to the low-fat versus low-carbohydrate dietary intervention debate. Indeed, energy-restricted diets (up to 4.2 MJ/day) have shown to improve CVD risk factors similar to the low-fat and low-carbohydrate diets but also reduced systolic blood pressure and improved the ratio of high-density lipoprotein to low-density lipoprotein [20] indicating energy-restrictive diets may provide similar, if not more, beneficial effects on CVD risk factors as low-fat and low-carbohydrate diets (as shown in Fig. 2).

A systematic review and other narrative reviews identified that in addition to diets discussed thus far, other dietary interventions such as a “healthy diet” (defined as ≥5 servings of fruits and vegetables, whole grains, high-fiber foods, and fish), plant-based (MED vegetarian), energy reduction, low-fat, and low-fat + energy intake reduction, have beneficial effects on CVD risk factors in healthy postmenopausal women [20, 42, 43] while aforementioned dietary interventions show mixed results in improving CVD risk factors in healthy individuals but more robust benefits in postmenopausal women with existing CVD risk factors [20]. Regardless, there is no “one-size-fits-all” diet for postmenopausal women. Similar to other subgroups of people, it is likely that individual differences in physiological characteristics as well as environmental differences contribute to the response heterogeneity among women. For example (as shown in Fig. 3), in age-matched premenopausal and postmenopausal women, sugar intake, sleep quality, and postprandial glucose peak (0–2 h) were significantly different on average, yet there was a large individual variation among the measures [44]. Thus, research is needed to examine the effects of how foods, diets, and dietary patterns impact CVD risk in menopausal women individually. By understanding the contributions of factors within domains such as health status, environment, metabolism, genetics, and microbiome, both individually as well as their interactions, future diets can be better tailored for this population.

The concept of precision nutrition has gained popularity over the last decade with the penultimate goal of tailoring nutritional recommendations to treat or prevent metabolic disorders [28]. Within this concept, individual differences in genetics, metabolomics, demographics, environments, and internal and external lifestyle factors are considered for nutrition recommendations. Across the lifespan, women have diverse hormonal landscapes with eumenorrheic menstrual cycles, hormonal contraception use, pregnancy, and menopause. There is a need for women’s health research to quantify the impact of female sex hormones to adequately address female-specific needs, particularly as estrogen and progesterone may impact metabolic and functional outcomes [45]. By evaluating a women’s menopausal status in addition to risk factors for CVD, and bone health, precision nutrition can directly target disease prevention. A practical first step is to comprehensively assess the nutritional needs of menopausal women. Accessible tools include self-reported instruments such as dietary recalls, food behavior questionnaires, and physical activity questionnaires. A more targeted approach is to use laboratory tests to assess metabolic profiles, metabolomics, and nutritional status. Such assessments can be a strong foundation for personalized diet prescription, but the precise way to use this deep phenotyping to benefit given individuals is still not known.

To date, research studies have explored genetic-directed nutrition based on the presence (or not) of genetic variants with high penetrance to particular foods. The “Personalized Responses to Dietary Composition Trial-1” (PREDICT-1) was the first in a series of large-scale, robust nutritional science studies designed to quantify and predict individual metabolic responses to different foods [44]. When they compared PREDICT-1 cohort data collected from pre-, peri-, and postmenopausal women, postprandial glycemic responses and other metabolic health indicators (e.g., visceral fat) were worsened in the postmenopause group, not because of increasing age but because of altered hormonal status [44]. These effects were partially mediated by changes to dietary habits and the gut microbiome composition as estrogen decreased. Thus, nutritional strategies that address postprandial glycemic responses and the gut microbiome may attenuate some of the unfavorable effects of menopause on CVD risk factors. Administration of isoflavone-rich soy foods can elevate levels of gut microbial derived estrogen-like metabolites and in turn reduce markers of systemic inflammation [46]. Other dietary approaches that can target improvements to postprandial glycemic responses include reducing dietary sugar, adhering to the MED or DASH diet and increasing fiber consumption. While in the early stages, the current state of precision nutrition is rapidly progressing with personalized nutrition programs like PREDICT that aid in the exploration of best practices and inform future designs for population use.

Another dietary strategy that may target glycemic responses and other metabolic health indicators in menopausal women are diets tailored to an individual’s ability to optimally oxidize fat or carbohydrates. Several studies have reported that baseline insulin dynamics can explain differential weight loss success observed with a low-fat diet compared to a low-carbohydrate diet [47‒49]. Women with an overweight BMI in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) study were matched or mismatched to a low-fat or low-carbohydrate diet intervention based on their individual multilocus genotype patterns relevant to fat and carbohydrate metabolism (single-nucleotide polymorphisms [SNPs] from 3 genes [PPARG, ADRB2, and FABP2]) [49]. Women matched (based on genotype) to the dietary intervention demonstrated a 3-fold greater weight loss over 12 months (mean weight loss of 6 kg) compared to those who were mismatched (mean weight loss of 2 kg) to a dietary intervention [49]. This was an exciting advance that suggested characterization of individual genotypes may be beneficial, particularly as insulin regulation can mediate CVD risk factors and metabolic syndrome. However, when the DIETFITS multilocus genotype pattern methodology was expanded to healthy male and female adults with overweight and obesity, there was no difference in 12-month weight loss between the low-fat and low-carbohydrate diets, and neither genotype pattern nor baseline insulin secretion was associated with the dietary effects on weight loss [50]. As the later study did not provide sex-based analysis and included women 18–50 years old, it is difficult to parse out the impact of the menopause transition and role of estrogen in genetic phenotyping. However, previous research may allude to the potential benefit of deep genotyping in women specifically.

Following DIETFITS, genotype-directed nutrition gained momentum particularly as variation in inter-individuality has been determined to be a strong predictor of weight loss success. To address the need for a more comprehensive genotype assessment composed of a greater number of SNPs and with SNPs having demonstrated validity for high-fat/high-carbohydrate diets, the Personalized Nutrition Study (POINTS) determined fat- or carbohydrate-responsive genotypes based on an algorithm involving 10 SNPs in 122 participants (84% female) [51]. Similar to DIETFITS, there was a lack of significant and clinically meaningful differences in weight loss (∼0.6 kg) between genotype-matched and genotype-mismatched diets. Interestingly, 70% of the sample was identified as fat responders, highlighting the impact diet quality and dietary intake habits can have on weight regulation [51]. As such, future research should explore the inter-individuality in postmenopausal women regarding how weight loss with dietary interventions impacts CVD risk factors (as shown in Fig. 2).

In addition to genotype-directed nutrition and individualized nutrition, stratified nutrition is a level of precision nutrition that can be applicable to menopausal women [28]. This approach can be beneficial for including various populations and settings to have a well-rounded, more globally minded understanding of precision nutrition, particularly regarding social determinants of health and interindividual responses. Specifically, defining phenotypes through behavioral and physical components can further increase the application of nutritional strategies for successful disease prevention and management. The leading work in phenotyping is related to obesity medicine, which suggests obesity presents in four overlapping ways: hungry brain (defined by abnormal satiation), emotional hunger (defined by hedonic eating), hungry gut (defined by abnormal satiety), and slow burn (decreased metabolic rate) [52]. Clinical tests (e.g., visual analog scales, Hospital Anxiety and Depression Score, Three Factor Eating Questionnaire) are used to identify these pathophysiologies and many of the tests can be impactful for creating dietary prescriptions. Indeed, this stratified nutrition approach was used in a 12-month pragmatic weight management trial with 450 adults demonstrating 32% of patients presented with hungry brain, 32% with hungry gut, 21% with emotional hunger, and 21% with slow burn [52]. These phenotypes have also been explored in the context of obesity medications such as glucagon-like peptide-1 receptor (GLP-1) agonists [52]. For example, individuals with a hungry brain phenotype may be more responsive to phentermine-topiramate (oral pill) while those with hungry gut may respond best to liraglutide, a GLP-1 agonist. Importantly, Acosta et al. [52] work suggests that the majority of participants had overlapping phenotypes highlighting the role of individual level factors in predicting phenotypes for precision nutrition. Current research shows that GLP-1s are an effective method for encouraging weight loss of at least 5% in most individuals, yet understanding individually the underlying pathophysiology for each patient’s obesity may allow for a more personalized approach to care and may be useful in addressing barriers to obesity medication use such as side effects and lack of weight loss (<10%). These categories may be useful in menopausal women particularly as body weight, body composition, and eating behaviors are known to change during the menopause transition (as shown in Fig. 1).

The menopause transition is defined by a dramatic decrease in estrogen, which is accompanied by distinct changes in body composition, dietary habits, energy expenditure, and other CVD risk factors. Identifying nutritional strategies that address adverse effects that occur during the menopause transition is vital for supporting women’s health as they age. Randomized control trials demonstrate promising findings for the DASH and MED dietary strategies for the prevention and management of CVD risk factors in postmenopausal women [25]. While low-fat and low-carbohydrate diets also demonstrate beneficial effects, the outcomes with these approaches are more mixed. Deep genotyping studies exploring SNPs that can better predict the variation in responses to low-fat and low-carbohydrate diets suggest that while differential oxidation preferences occur, they may not be the leading contributor to weight loss success [51]. Precision nutrition is a new frontier that has demonstrated potential for creating personalized diet prescriptions linked to genetic phenotypes as well as behavioral and environmental factors. Future research considerations beyond genotyping include combining other individual phenotypes including microbiome diversity, proteome, medication use, and family history and using advanced statistical techniques such as machine learning and artificial intelligence to understand the contributors of intra-individual variation to foods, diets, and eating patterns. There is an important need for research examining beneficial dietary strategies to improve CVD risk factors in menopausal women.

The authors declare no conflicts of interest.

Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award No. T32DK064584 and Eunice Kennedy Shriver National Institute of Child Health and Human Development under Award No. 5UG1HD107696-03. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in the design, data collection, data analysis, and reporting of this review.

H.E.C., E.K.W., and L.M.R. conceptualized the manuscript, participated in manuscript preparation, and approved the final manuscript.