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Obesity is a major public health concern that affects women disproportionately more than men ((1)). In the United States, the prevalence of obesity in women was 39.7% among those aged 20 to 39 years, 43.3% among those aged 40 to 59 years, and 43.3% among those aged 60 years and over (2). During the menopause transition, women experience dramatic decreases in circulating estrogens—particularly estradiol (E2)—and increases in the gonadotropin follicle-stimulating hormone (FSH) ((3)). These hormonal changes are associated with changes in energy expenditure and energy intake that promote a positive energy balance, leading to weight gain ((3-5)). This weight gain is due to increased fat mass and, in particular, increased abdominal fat deposition ((3-5)), which contribute to increased cardiometabolic risk. Despite these known detrimental consequences of the menopause transition, many researchers avoid combining premenopausal, perimenopausal, and postmenopausal women in their studies or avoid enrolling perimenopause-aged women. Yet the menopause transition itself has much to teach us about how these adverse cardiometabolic profiles arise. Because all women will experience menopause and have the potential of spending much of their lives in the postmenopausal phase, understanding how the menopause transition affects body composition and cardiometabolic health is critically important to understanding the evolution of women’s health across the life-span.
This narrative review details how the menopause transition imposes a significant health burden on women and affects total body weight, body composition, and body fat distribution, as well as how these changes impact cardiometabolic health. We also briefly review lifestyle interventions to improve cardiometabolic health in women. Finally, we call for further research during the menopause transition to identify the inflection points of risk accrual, as they are likely to be the time points at which interventions have the best chance of being effective.
DEFINING THE MENOPAUSE TRANSITION: STAGING AND STUDY DESIGN CONSIDERATIONS The menopause transition—a brief overviewThe menopause transition (i.e., perimenopause) is characterized by an increased rate of attrition of ovarian follicles. The initial result of this decrease in follicle number is reduced inhibin-B release from the ovaries. This reduction in inhibin-B signals the anterior pituitary to upregulate secretion of FSH which, in turn, stimulates ovarian E2 production, with FSH continuing to increase as ovarian function declines. As women transition through perimenopause, the ovarian follicle supply becomes critically low, and the ovary can no longer respond to the increased FSH signaling with consistent output of E2. Eventually, all functioning follicles are lost, and E2 production by the ovary ceases, accompanied by a steady state of high FSH output. Natural menopause is typically defined after amenorrhea of 12 months in a woman aged 45 or older ((6)). Median age of natural menopause is 51.4 years ((7)), with an approximate 95% CI of 45 to 55 years, and it has been reported to be slightly higher at 52.5 years among longitudinally studied women ((8)). Although the length of the menopause transition typically encompasses 4 to 5 years, the length of the transition is highly variable and it can last from <1 to 10 years or longer ((9)). While 12% of women report sudden amenorrhea, the remainder of women experience changes in cycle length and variability in cycles during the transition ((9)). Approximately 5% of women experience early menopause, defined as having a final menstrual cycle between ages 40 and 45 years. A minority of women (~1%) experience primary ovarian insufficiency (POI), defined as hypergonadotropic amenorrhea before 40 years of age. A woman can also undergo iatrogenic premature menopause after having bilateral oophorectomy surgery or iatrogenic ablation of ovarian function (e.g., chemotherapy, pelvic radiation) prior to natural menopause ((10)).
When classifying menopause stages, it is important to know that the menopause transition can be divided into early or late perimenopause stages ((11)). Early perimenopause is marked by increases in menstrual cycle length of 7 days or more, and some women report small but noticeable increases in common menopausal symptoms, such as vasomotor symptoms (e.g., hot flashes, night sweats). Late perimenopause is characterized by intervals of amenorrhea for at least 60 days and an elevated FSH >25 mIU/mL with a more sharply increased prevalence of menopausal symptoms. The Stages of Reproductive Aging Workshop (STRAW)+10 guidelines provide a comprehensive and easy to understand staging system for determining where a woman is in her menopause transition (Table 1) ((11)).
TABLE 1. The Stages of Reproductive Aging Workshop +10 staging system for reproductive aging in women
This table was adapted with permission from the previously published STRAW+10 staging guidelines ((11)).
Abbreviations: AMH, anti-Mϋllerian hormone; FMP, final menstrual period; FSH, follicle-stimulating hormone.
↑ = elevated.
Considerations when studying the stages of the menopause transition
The menopause transition is difficult to study because of the inherent variability in the process of ovarian failure (initiation and duration), the confounding effects of chronological aging, and the variability of hormones (ovarian and gonadotropins) both between cycles and between women. These highly variable characteristics might explain why many studies exclude women in the perimenopausal age range. However, classification systems such as STRAW+10 criteria assist in identifying stages of the transition without relying on spot-check levels of hormones, which can lead to misclassification. It is helpful, in longitudinal studies, to organize changes around the final menstrual period (FMP) to better elucidate how and when changes in the parameters of interest relate to menopause. This approach does not, however, adequately account for variability in transition duration, which can be meaningful.
Even though the STRAW+10 criteria has simplified classification of women as they progress through the menopause transition, early perimenopause remains more difficult to identify than late perimenopause. Entry into the menopause transition is defined by the STRAW+10 criteria as increased variability in cycle length (i.e., a difference of ±7 days within 10 cycles). This change can be challenging to accurately measure as it requires a well-documented cycle history. Most women notice more obvious changes, such as a missed menstrual cycle. With the evolution of new menstrual period tracking apps, it may become easier for women to observe and report changes in menstrual cycle length and regularity (e.g., tracking of deviation in more than 7 days from “usual” menstrual cycle length) ((12)). Researchers often rely on self-reported cycle lengths, elevated early follicular phase FSH (cycle days 1 to 5), or serum E2 to help define early perimenopause ((11)). Because of cycle-to-cycle variability in FSH and E2, single measurements of these hormones are of limited value for classifying women in the early stage of the menopause transition. Anti-Mϋllerian hormone (AMH), which is secreted by small antral follicles (granulosa cells), is also a reliable marker of ovarian follicle reserve, with lower AMH indicative of being closer to the FMP. Although AMH can be predictive of age at FMP, there are several caveats. First, AMH is most predictive in women in their late 40s or early 50s. It is possible for women aged 35 to 39 years to have an undetectable concentration of AMH but still have regular menstrual cycles ((13)). Additionally, the lack of an international standard for AMH means that measurement techniques can vary ((13)). Nonetheless, AMH is one of the best predictors of FMP ((13-15)). With greater population data, AMH could be a useful qualitative measure of the early menopause transition.
Late perimenopause is easier to characterize than early perimenopause, given that it is defined by the presence of at least 60 days of amenorrhea ((11)). An FSH concentration greater than 25 IU/L is now also considered to be characteristic of the late perimenopausal period ((11)). Although listed in the STRAW+10 criteria, using the presence of vasomotor symptoms to define the late perimenopausal period is not recommended because their appearance does not strictly follow changes in the menstrual cycle or hormones across the menopause transition ((16)). Additionally, not all women will experience vasomotor symptoms ((16)).
CHANGES IN WEIGHT AND BODY COMPOSITIONOn average, women gain approximately 5 to 7 pounds (or 2 to 3 kg) over the course of the menopause transition ((17, 18)), yet there is substantial interindividual variability. Increased weight and particularly abdominal fat are associated with more severe vasomotor symptoms (i.e., hot flashes and night sweats) and insomnia ((19, 20)), as well as increased fatigue and decreased quality of life ((21, 22)). Some women may not experience weight gain even though changes in body composition occur (i.e., increased fat mass, decreased fat-free mass, and decreased bone mineral density). The following section details the changes in body composition and fat distribution that have been reported in both animal and human (observational and clinical) studies focused on the loss of ovarian function. A summary of the known changes in body composition and cardiometabolic risk that occur during the menopause transition and into the postmenopausal years is included (Figure 1).
Changes in cardiometabolic risk factors occur during the menopause transition, which is separated into two subcategories (early perimenopause and late perimenopause) and into the postmenopausal years. Horizontal arrows (↔) indicate stability, and smaller or larger/thicker directional arrows (↑ or ↓) indicate smaller or larger changes that occur. *Although E2 concentrations are lower at menopause onset compared with premenopausal concentrations, the patterns of E2 decline and FSH rise during perimenopause are heterogenous across women. AMH, anti-Mϋllerian hormone; C-IMT, carotid intima-media thickness; E2, estradiol; EE, energy expenditure; FSH, follicle-stimulating hormone; FMP, final menstrual period; PWV, pulse wave velocity
Findings from animal studiesOvariectomy (OVX) is used as a model of menopause in laboratory animals to study how the loss of ovarian function causes fat mass accumulation. OVX eliminates ovarian estrogens and raises FSH due to the loss of negative feedback from E2. OVX is associated with increased body weight and abdominal adiposity when compared with animals that undergo sham surgery ((23-25)). Although increased body weight and abdominal adiposity is caused by a combination of increased energy intake and/or decreased energy expenditure, the regulation of energy intake by E2 appears to differ in mice and rats, such that OVX increased energy intake in rats but not mice. The increase in energy intake (+20%) in rats can last for several weeks ((26-29)), but in one study, returned to the level of energy intake of that in sham-operated controls ((29)). OVX also caused marked decreases in spontaneous physical activity (locomotor activity), metabolic rate, and energy expenditure in both mice ((26-28, 30)) and rats ((26, 29, 31)). Another study reported that energy expenditure is lower in OVX mice than OVX+E2 mice when activity is similar ((28)). Evidence also supports a strong, protective effect of E2 against weight gain in OVX rodents, as weight gain was prevented in OVX rats treated with E2 add-back or estrogen receptor (ER)-α agonist ((25, 32)).
The metabolic actions of estrogens that cause alterations in body weight and adiposity are mediated through the ER. As a member of the nuclear receptor superfamily, ER regulates gene expression by binding to the estrogen response element (ERE) located on the promotor sequence of target genes. ER has two main subtypes, ERα and ERβ, which are widely expressed through the body (e.g., brain, blood vessels, and adipose tissue). Much of our understanding on the molecular pathways that ER action regulates cardiovascular health and metabolism has been derived exclusively from rodent models ((33)). Evidence suggests that ERα is the primary mediator of the estrogen suppression of adiposity, as ERβ knockout (ERβKO) mice have stable body weight and percent fat ((34)). In contrast, ERα knockout (ERαKO) mice have increased fat mass, as well as adipocyte number and size ((35)). Brain-specific ERαKO mice have abdominal obesity mediated through hyperphagia and hypometabolism, produced by decreased heat production and decreased physical activity ((36)). There is a third known estrogen receptor that binds E2 at the cell surface. This G-protein coupled estrogen receptor (GPER, formerly GPCR30) induces rapid, nongenomic signaling and, like the classical ERs, is expressed widely through the body ((37)). Mice lacking GPER are reported to have increased body weight and visceral adiposity ((38)), although this is not a consistent observation in female mice ((39, 40)).
Although most differences in body composition between males and females have been attributed to E2 and testosterone, more recently, FSH has been implicated as a mediator of abdominal adiposity. Liu and colleagues demonstrated that animals treated with an FSH beta-subunit-blocking antibody had a marked reduction in adiposity ((41)). The anti-obesity response to blocking FSH activity occurred in both sham and OVX animals, suggesting an effect of FSH even when FSH is in the normal range. Indeed, the anti-obesity effect of the FSH antibody was most pronounced in the abdominal visceral region (~70% difference in visceral fat volume vs. the comparator group), but differences were also apparent in abdominal subcutaneous fat volume (~30%) and total fat mass (~30%) ((41)).
Findings from human studies Observational studiesObservational studies have shown that body weight and adiposity increase across the menopause transition. The Study of Women’s Health Across the Nation (SWAN) provided very compelling evidence that an accelerated gain in fat mass and loss of fat-free (lean) mass were related to the menopause transition ((42)) rather than aging ((43, 44)). Although an increase in fat mass and a decline in fat-free mass were observed during pre-menopause (prior to the menopause transition), these changes accelerated during perimenopause before stabilizing in the postmenopausal years ((42)). Other observational studies confirmed the increase in fat mass, particularly attributed to increased abdominal fat (subcutaneous and visceral), during the menopause transition ((3-5, 18)). Changes in body composition may also vary depending on race or initial level of adiposity on entering perimenopause ((18)). These observed changes in body composition are partially the result of reductions in energy expenditure and fat oxidation ((3)), with the reduction in energy expenditure possibly explained by a reduction in regular physical activity during the perimenopausal years ((45)). The Healthy Transitions longitudinal study comprehensively phenotyped women across menopause and was the first study to demonstrate that women who completed the menopause transition had a greater reduction in 24-hour energy expenditure and sleep energy expenditure compared with women who did not complete the transition ((3)). Although resting energy expenditure (REE) was not measured in Healthy Transitions, average REE remained stable through menopause in the Montreal-Ottawa New Emerging Team (MONET) study ((46)). Data from SWAN also indicated that bone mineral density declines at the greatest rate beginning 1 year before the FMP and decelerates (but does not cease) 2 years after the FMP at both the lumbar spine (7.38% loss) and femoral neck (5.8% loss) sites ((47)). Another study demonstrated that bone loss begins 2 to 3 years before the FMP and ends 3 to 4 years after the FMP, with spine, total body bone mineral, and femoral neck declining by 10.5%, 7.7%, and 5.3%, respectively ((48)). Supportive evidence suggests that the loss of estrogens is associated with or triggers the decreases in energy expenditure and physical activity ((49, 50)), as well as bone mineral density ((51)). Because low rates of energy expenditure and fat oxidation at rest predict future fat gain ((52-54)), understanding the impact of menopause on human bioenergetics is critical. Although increased energy intake can also contribute to weight gain, longitudinal studies that assessed changes in energy intake across the menopause transition are limited (both by the lack of research examining energy intake across menopause, as well as the pitfalls surrounding self-reported energy intake ((55))), but suggested energy intake decreased over the 3 to 4 years leading up to menopause onset ((3)).
An increase in fat mass (predominantly in the abdominal region) and decrease in fat-free mass during the menopause transition may result in little or no change in body weight yet will subsequently lead to increased cardiometabolic risk. The Women’s Health Initiative demonstrated that central obesity (defined by a waist circumference >88 cm ((56))) was detrimental regardless of weight status, as normal-weight central obesity (defined by BMI 18.5 to 24.9 kg/m2 and waist circumference >88 cm) was associated with excess risk of mortality that was similar to women with BMI-defined obesity and central obesity ((57)). Thus, body fat distribution, rather than weight status alone, is a good determinant of cardiometabolic risk during the menopause transition.
Intervention studiesSeveral interventional studies indicated that hormone therapy initiated in the perimenopausal or early postmenopausal years attenuated weight gain (adiposity). In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, a randomized, placebo-controlled trial, women who received oral conjugated equine estrogens (CEE) gained less body weight and had smaller increases in waist girth than women randomized to placebo ((58)). The Danish Osteoporosis Prevention Study was a partially randomized study in which women who received sequential oral estrogen and progestogen gained less body weight, fat mass, and trunk fat than untreated women ((59)). In the Kronos Early Estrogen Prevention Study (KEEPS), increases in weight and waist circumference were attenuated in women randomized to either transdermal E2 or CEE for 4 years ((60)).
The administration of gonadotropin-releasing hormone agonist (GnRHAG) or GnRH antagonist (GnRHANT) in combination with E2 versus placebo therapy is useful for isolating specific effects of the loss of ovarian E2 in premenopausal women. Both GnRHAG and GnRHANT reversibly suppresses ovarian function via the suppression of the hypothalamic-pituitary-ovarian axis, essentially creating a “medical menopause.” Studies have shown that both acute and chronic ovarian hormone suppression with GnRHAG and GnRHANT alters REE and total energy expenditure. In a small group of premenopausal women, REE was measured during the mid-luteal phase of the menstrual cycle (when E2 was elevated), during the early follicular phase (when E2 was low), and after 6 days of GnRHANT treatment (when E2 was even lower) ((49)). REE across these 3 conditions paralleled the changes in E2, with higher REE when E2 was higher. In another study, REE decreased in premenopausal women randomized to 5 months of GnRHAG therapy, but this decrease in REE was attenuated in women who received transdermal E2 add-back ((50)). Conversely, total energy expenditure measured by whole-room indirect calorimetry decreased in response to GnRHAG (−128 kcal/d) but was not prevented by E2 add-back ((50)).
GnRHAG and GnRHANT therapy also alters body composition. In brief, 4 months of GnRHAG therapy in premenopausal women resulted in no change in total body weight, but increased total body fat and trunk fat mass ((61-63)). Administering GnRHAG for shorter durations also resulted in no change in total body weight; however, visceral fat mass was increased in as little as 4 weeks, with estrogen add-back attenuating this effect ((64)). Althought body weight, fat mass, and trunk mass were all increased after 6 months of GnRHAG suppression in one study ((65)), some studies do not observe changes in overall fat mass after 3 to 5 months of suppression ((51, 66)). Despite no change in total fat mass, one of these studies found that 5 months of GnRHAG resulted in an increase in visceral fat area measured by computerized tomography (CT) ((51)). Collectively, these studies suggest that the loss of ovarian E2 promotes abdominal fat accumulation and a decline in energy expenditure.
CHANGES IN CARDIOMETABOLIC HEALTHChanges in reproductive hormones and body composition across the menopause transition are associated with increased overall metabolic and cardiovascular disease (CVD) risk. These changes in cardiometabolic risk have led some researchers to suggest that obesity in women may be more appropriately diagnosed by a BMI ≥25 kg/m2 (rather than 30 kg/m2) later in life ((67, 68)). Furthermore, the presence of central obesity is likely more detrimental to overall health and cardiometabolic risk than BMI-defined weight status alone ((57)). The following section details the changes in metabolic and cardiovascular health observed during the menopause transition and into the postmenopausal years and highlights how menopausal hormone therapy modifies cardiometabolic risk.
Metabolic health Insulin sensitivity and glucose toleranceAlthough the physiological effects of ovarian hormones on insulin metabolism are not clear, a role for estrogens (particularly E2) in maintaining glucose homeostasis through effects on insulin secretion and clearance has been suggested ((69)). It is well-established that E2 promotes peripheral (vs. central) fat distribution and improves insulin sensitivity in women ((70)).
In cross-sectional studies, evidence linking menopausal status and abdominal adiposity with insulin resistance and prevalent diabetes is mixed. Several of these studies found no associations between menopausal status and metabolic factors, including fasting glucose and insulin, insulin secretion rate, insulin sensitivity, and diabetes risk ((71-74)). Longitudinal studies, including the 6-year Pizarra Study ((75)), the 8-year Australian Longitudinal Study on Women’s Health ((76)), and the 3-year Diabetes Prevention Program ((77)), also found no association between natural postmenopausal status and diabetes risk. Conversely, data from SWAN indicated a progressive increase in the risk of metabolic syndrome development with menopause; this increased risk was primarily driven by worsening lipid profile rather than deleterious changes in glucose ((78)). In postmenopausal women without obesity, increase in abdominal fat during menopause was associated with decreased tissue insulin sensitivity and glucose tolerance ((79)). In a longitudinal study across the menopause transition, no changes in fasting glucose, fasting insulin, lipids, or insulin sensitivity were observed ((3)). However, a secondary analysis found that insulin sensitivity was reduced in women who gained the most abdominal adiposity ((18)). Although it was hypothesized that menopause status is associated with reduced insulin secretion and clearance ((80)), these associations are complicated by numerous factors that may be different between premenopausal and postmenopausal women. Increased BMI and abdominal adiposity, however, has always been strongly linked to insulin resistance and consequently, is associated with an increased risk for type 2 diabetes and CVD ((81)). Therefore, the increase in abdominal adiposity observed during the menopause transition is likely to be associated with insulin resistance and reduced glucose homeostasis.
Clinical studies involving exogenous E2 administration provide insight into the mechanistic effects of menopause on insulin sensitivity and glucose tolerance. E2 administration to postmenopausal women suggests a role for estrogens in maintaining glucose homeostasis through effects on insulin secretion and clearance ((82)). The risk of developing type 2 diabetes was significantly reduced in postmenopausal women who used hormone therapy in several randomized clinical trials, including the Women’s Health Initiative and Heart and Estrogen/Progestin Replacement Study (HERS) ((83-85)). Compared with transdermal estrogens, the effects of oral estrogens are difficult to interpret because of the influences of first-pass metabolism in the liver (discussed in greater detail in this publication ((83))). One recent study found that a short, 8-week treatment of orally administered CEE and the selective estrogen receptor modulator (SERM), bazedoxifene, did not alter insulin sensitivity or ectopic fat in postmenopausal women with obesity ((86)). Still, the effects of transdermal E2 on glucose metabolism in postmenopausal women are conflicting. Although some studies of daily transdermal E2 reported reduction in insulin concentrations during oral glucose tolerance testing (OGTT) ((87, 88)), others did not ((89-91)). C-peptide concentrations during an OGTT have also been shown to be increased ((89, 91)) or decreased ((90)) in response to transdermal E2 therapy. One study found that acute administration (2.5-mg intravenous bolus) of conjugated estrogens increased insulin clearance and action in postmenopausal women during a constant rate of insulin infusion ((92)). However, a follow-up study revealed that 24-hour transdermal E2 administration did not alter insulin secretion or clearance in postmenopausal women, yet longer time since menopause did reveal a reduced effect of transdermal E2 to increase glucose uptake ((93)). It is likely that estrogen therapy has a beneficial effect on β-cell function and insulin secretion in postmenopausal women ((83)). Specifically, increased glucose-stimulated insulin secretion, as assessed by secretion of C-peptide and HOMA-β, and enhanced hepatic insulin clearance have been reported ((94-96)).
Although study findings do not currently support that menopausal hormone therapy consistently improves insulin sensitivity or glucose tolerance, the full extent of its potential risks and benefits needs further investigation. Importantly, the variability in treatments (estrogen only, estrogen plus progestins or SERM, etc.), treatment duration (weeks, months, or years), method of administration (oral vs. transdermal), and differences in metabolic status on administration (normal vs. obesity weight status, insulin resistant vs. type 2 diabetic, etc.) is important to consider when evaluating the effect of such therapies on metabolic health.
DyslipidemiaPostmenopausal abdominal fat gain is associated with an adverse lipid profile ((97)). Dyslipidemia develops 10 to 15 years later in women than in men ((98)), presumably due to the protective effect of ovarian hormones (particularly E2). In SWAN, women had sharp increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (Apo)B concentrations within a 1-year interval surrounding the FMP ((99)). Furthermore, the menopause-related increase in LDL-C was associated with greater risk of carotid plaque later in life in follow-up analysis ((99)). Postmenopausal women also experience elevated concentrations of LDL-C and triglycerides, which contribute to the atherosclerotic process ((99)). In contrast to epidemiological studies supporting that high-density lipoprotein cholesterol (HDL-C) is cardioprotective, a number of studies have reported higher HDL-C as a CVD risk factor after menopause ((100)). Future longitudinal studies are needed to further evaluate the effect of HDL-C on CVD across menopause. Studies have shown that oral estrogen therapy resulted in decreased LDL-C and increased HDL-C ((101-103)); however, this was at the expense of an increase in triglycerides ((102)).
Sleep disruptionDisruptions in sleep health also become more prevalent in women as they age and particularly around the menopause transition with the decline of E2 and progesterone. Sleep health is characterized by a number of sleep parameters that are affected by menopause, including changes in sleep duration, sleep times, awakenings, sleepiness, and sleep disorders ((104)). In SWAN, the prevalence of sleep disturbances ranged from 16% to 42% in premenopausal women and increased to 39% to 47% and 35% to 60% in perimenopausal and postmenopausal women, respectively ((104)). Vasomotor symptoms are associated with reduced sleep quality and increased waking, yet late perimenopausal and postmenopausal women still report more sleep difficulties compared with premenopausal women regardless of vasomotor symptom presence ((99)). Importantly, sleep disruption promotes increased energy intake ((105)) likely due to a combination of altered appetite hormones (i.e., decreased leptin and increased ghrelin, hunger, and appetite) ((106)), as well as altered sensitivity to food reward and disinhibited eating ((105)). Although sleep disruption is a well-recognized risk factor for metabolic abnormalities, including insulin resistance and glucose tolerance ((107, 108)), the regulatory mechanisms linking sleep disruption and the changes in metabolic homeostasis that coincide with menopause have yet to be fully elucidated. Given the current breadth of literature, it is likely that women who experience sleep disruption during menopause may experience even greater weight and abdominal fat gain compared with women who do not.
Cardiovascular healthPostmenopausal women experience an increase in CVD risk that is primarily thought to be due to ovarian failure and the loss of E2 that occurs across the menopause transition. CVD is the leading cause of mortality in postmenopausal women. The CVD risk factors that become more prevalent after menopause include vascular dysfunction, hypertension, and cardiac dysfunction.
Vascular dysfunction and hypertensionAging is associated with vascular dysfunction, featuring endothelial dysfunction and large elastic arterial stiffening. The vascular endothelium is a single-cell layer that lines arterial walls and becomes dysfunctional during the aging process due, in part, to reduced nitric oxide (NO) availability, secondary to increased oxidative stress and inflammation. Oxidative stress is characterized by an excessive production of reactive oxygen species that scavenge NO and subsequently impairs endothelial function and increases large elastic arterial stiffness ((109)). Vascular inflammation and increased reactive oxygen species can also impair endothelial nitric oxide synthase (eNOS), further reducing NO bioavailability and worsening endothelial function and arterial stiffening.
In women, vascular function appears to be preserved up until the menopause transition, after which vascular function progressively deteriorates, possibly due to a shift in redox balance and inflammatory status. In postmenopausal women, the loss of the antioxidant and anti-inflammatory effects of E2 are linked with a pro-oxidant and low-grade pro-inflammatory condition ((110, 111)). Early observations noted that endothelial function, measured via brachial artery flow-mediated dilation (FMD), was preserved in women ≤40 years of age, decreased by 0.21% per year after age 40 years, and lowest in women ages 50+ years (by 0.49% per year) ((112)). A subsequent study f
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