Abstract
The clustering of metabolic risk factors, overweight and hypertension is of particular importance in postmenopausal women due to the negative effect of menopause on bodyweight, glucose metabolism and the development of hypertension. Menopause acts directly as a risk factor by reducing the direct beneficial effect of ovarian hormones on cardiovascular functions, and indirectly by negatively influencing traditional risk factors for coronary artery disease. All changes occurring after the menopause must be regarded under a unifying mechanism that induces unfavorable changes in cardiovascular risk factors and vascular functions, which interact with each other, amplifying the effect of ovarian hormone deficiency and aging.
The incidence of cardiovascular disease in premenopausal women is low but, after the age of 50 years, cardiovascular and cerebrovascular diseases become the leading cause of mortality and morbidity for women living in most developed countries [1]. This increased incidence is only partially explained by aging since the state of estrogen deficiency that develops after the menopause plays a key role in favoring the increased cardiovascular risk. Indeed, cessation of ovarian function and the consequent reduction of sex steroid hormone levels have important metabolic and pathological implications, which negatively influence the cardiovascular system. To this end, menopause, or more correctly ovarian hormone deficiency, has to be considered a risk factor for coronary artery disease owing to the negative impact of ovarian hormone deficiency on the development of cardiovascular disease. Menopause acts directly as a risk factor by reducing the beneficial effect of ovarian hormones on cardiovascular functions (endothelial function, salt sensitivity, renin–angiotensin–aldosterone system [RAAS] and atherosclerosis), and indirectly by negatively influencing other traditional risk factors for coronary artery disease (i.e., hyperinsulinemia, blood cholesterol, blood pressure and coagulation) (
Major effects of menopause on cardiovascular risk factors.
Data based on animal studies. HDL-C: High density lipoprotein cholesterol; LDL-C: Low density lipoprotein cholesterol; Lpa: Lipoprotein A.
The clustering of metabolic risk factors, overweight and hypertension is of particular importance in postmenopausal women due to the negative effect of menopause on cardiovascular risk factors. The association between hypertension and metabolic risk factors has long been considered only in terms of their association in determining cardiovascular risk. However, only more recently has it become clear that hypertension and metabolic risk factors are inter-related, influencing each other and often having similar underlying causes.
Although it was first described in the 1920s that some clinical conditions, such as arterial hypertension and hyperglycemia, may occur in the same individual, Avogaro and Crepaldi were the first to suggest that the association of diabetes, obesity and dyslipidemia could be associated in a syndrome, in which the main defect is an altered glucose and insulin metabolism [2]. Subsequently, in 1988 Reaven emphasized that insulin resistance (IR) and the compensatory hyperinsulinemia predisposed patients to hypertension, hyperlipidemia and diabetes, and thus was the underlying cause of most cardiovascular diseases [3]. Obesity was not included in Reaven's initial definition of the syndrome, nor in the WHO definition. In order to make the syndrome easier to diagnose and apply to the American population, the National Cholesterol Education Program (NCEP) proposed a revised definition of the metabolic syndrome in which obesity represents the key factor [4,5]. This syndrome nowadays identifies a cardiovascular risk profile that includes IR, central obesity, increased triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels and arterial hypertension [6]. Risk factors that have been found to exhibit significant mechanisms or statistical inter-relationships in the context of the metabolic syndrome include IR, impaired glucose tolerance, hyperinsulinemia, elevated triglycerides and reduced HDL cholesterol, increased visceral adiposity, arterial hypertension, elevated uric acid concentrations, increased plasminogen activator inhibitor type 1 (PAI-1) activity, impaired vasodilatory response to insulin and impaired postprandial triglyceride clearance (
Criteria for clinical diagnosis of metabolic syndrome.
Insulin sensitivity measured under hyperinsulinemic euglycemic conditions, glucose uptake below lowest quartile for background population under investigation.
Some male patients can develop multiple metabolic risk factors when their WC is only marginally increased (e.g., 94–102 cm; 37–39 inches). Such patients may have a strong genetic contribution to insulin resistance. They should benefit from changes in lifestyle habits, similar to men with categorical increases in waist circumference.
The 2001 definition identified fasting plasma glucose of Š110 mg/dl (6.1 mmol/l) as elevated. This was modified in 2004 to be >100 mg/dl (5.6 mmol/l), in accordance with the American Diabetes Association's updated definition of IFG.
ATP: Adult treatment panel; BMI: Body mass index; HDL-C: High density lipoprotein cholesterol; IDF: Internation Diabetes Federation; IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance; T2DM: Type II diabetes mellitus; TG: Triglycerides; WC: Waist circumference. From [6].
The incidence of metabolic syndrome is lower in women than in men under the age of 50 years. Indeed, premenopausal women have a lower incidence of metabolic syndrome compared with men of the same age, with the exception of those women with polycystic ovary syndrome, in whom the incidence of metabolic syndrome is twofold higher than age-matched controls and similar or even higher than their male counterparts [7,8].
In postmenopausal women, the state of ovarian hormone deficiency induces metabolic and physiological changes that lead to a greater prevalence of hypertension and metabolic syndrome compared with the premenopausal period [9]. Although hormone deficiency may have direct effects on cardiovascular risk factors, all changes occurring after the menopause must be regarded under a unifying mechanism that induces changes in bodyweight, insulin tolerance, plasma lipids, sympathetic tone and vascular function. These changes interact with each other, amplifying the effect of ovarian hormone deficiency and aging.
Menopause, obesity & body fat distribution
Menopause is associated with important changes in weight and body fat distribution. Postmenopausal women tend to gain weight within the first year after the menopause and redistribute body fat from a gynoid to an android pattern [10,11], characterized by an accumulation of body fat in the gluteo–femoral and intra-abdominal regions, respectively. Several studies have shown that visceral body fat accumulation is associated more-with both metabolic changes of metabolic syndrome and cardiovascular risk than subcutaneous fat [12–14].
The increase and change in body fat distribution occurring after the menopause are directly related to the state of ovarian hormone deficiency, as women receiving hormone replacement therapy (HRT) gain weight to a lesser extent than women not receiving HRT [15,16]. Furthermore, Gambacciani and colleagues have shown that women receiving HRT not only do not gain weight but keep the premenopausal body fat distribution, while women not receiving HRT gain weight and switch from the gynoid to the more dangerous android distribution of fat [17]. The exact mechanism through which ovarian hormone deficiency may cause weight gain and android body fat distribution is not clear, although a negative effect on the incretion of leptin and a relative increase in androgens, together with changes in thyroid function, seem to play a key role. In men and women an increase in body fat is often coupled with negative changes in IR, plasma lipids, blood pressure and increased sympathetic drive; however, these changes are enhanced in women with ovarian hormone deficiency. Increase in body mass index (BMI), waist:hip ratio and waist circumference, and an increased proportion of visceral fat, are strongly correlated with the development of arterial hypertension, a range of metabolic risk factors for cardiovascular disease and risk of cardiovascular events in women, even after controlling for BMI [18].
The relationship between obesity and hypertension is well documented; the Framingham study showed that the prevalence of hypertension as a function of age in both sexes increases substantially with increase in relative weight [19]. Furthermore, the Framingham study showed that obesity or recent weight gain accounted for 70% of new-onset hypertension. Apart from overall bodyweight, body fat distribution is an important risk factor for hypertension. An increase in abdominal circumference or waist:hip ratio, both surrogate markers for android fat distribution, are independent risk factors for the development of high blood pressure and are independently associated with other risk factors for the development of cardiovascular disease [20].
The relationship between obesity and blood pressure cannot be adequately explained by hemodynamic changes because although obese subjects have increased blood volumes and cardiac output, these variables are within the normal range when corrected for body mass. In addition, the greater intake of sodium of overweight subjects is not sufficient to explain the development of hypertension since weight loss in overweight individuals decreases blood pressure, even if the intake of sodium is not diminished. Therefore, the shift in the pressure–natriuresis curve in overweight subjects may be secondary to an increased sympathetic drive, hyperinsulinism and IR, factors that are inter-related and, in women, are worsened by menopause and body weight.
Therefore, overweight is only one of the factors among the constellation of metabolic changes associated with menopause that may lead to the development of hypertension and contribute to the metabolic syndrome.
Menopause & glucose metabolism
Menopause per se does not seem to affect fasting glucose but is associated with a progressive decline in glucose-stimulated insulin secretion [21]. This decline in insulin secretion seems to be compensated, at least in the initial stages, by a reduction in peripheral insulin elimination. Several studies have reported an increased incidence of IR and a decrease in insulin sensitivity with menopause and have related these changes to estrogen deprivation, changes in bodyweight and increased sympathetic activity accompanying the menopause [22]. The Postmenopausal Estrogens/Progestins Intervention (PEPI) study demonstrated that menopause causes a decrease in insulin sensitivity and an increase in IR [23]. IR is a multisystem disorder that induces multiple metabolic alterations and, in women, is facilitated by the state of ovarian hormone deficiency. IR is an important risk factor for the development of Type II diabetes mellitus and cardiovascular disease and occurs at multiple organ sites including the liver, skeletal muscle cells and adipocytes. IR occurs in combination with a cluster of other metabolic abnormalities and hypertension in the metabolic syndrome. Although there is a genetic basis for IR, environmental factors such as obesity, physical activity and estrogen deprivation may unmask or worsen the state of IR. Prospective studies have shown that hypertension develops more frequently in subjects with IR than in patients with normal insulin sensitivity, suggesting that IR is a key factor in the development of hypertension.
Diabetes and hypertension have a greater importance in determining the cardiovascular risk in women than in men; in fact, the association of the two risk factors has double the attributable risk for cardiovascular disease in women than in men [24].
As mentioned, the changes in glucose metabolism, bodyweight and hypertension are inter-related. Ferrannini and colleagues showed that decreased insulin sensitivity (by euglycemic clamp) is inversely associated with blood pressure [25]. The link between hyperinsulinemia, IR and hypertension is supported by the observation that the worsening of IR that occurs with weight gain is associated with a greater incidence of hypertension, and that an improvement in insulin sensitivity occurring with weight loss or drugs that improve insulin sensitivity is associated with a decrease in blood pressure values.
It becomes clear that the changes in insulin sensitivity and bodyweight that occur after the menopause are inter-related and facilitated by the state of ovarian hormone deficiency. These changes, together with the loss of the vasodilatory effect of estrogens and their effect on the autonomic nervous control of the cardiovascular system on salt sensitivity and on the activity of the RAAS, may facilitate the development of arterial hypertension. The impairment of glucose metabolism occurring in postmenopausal women has important clinical consequences since diabetes, together with hypertension, is the most important cardiovascular risk in women. Estrogen replacement therapy is associated with an improvement in insulin sensitivity and a decreased risk of diabetes. However, progestin used in HRT schemes may have different effects on glucose metabolism that depend on dose and chemical structure and may, in some cases, abolish the beneficial effect of estrogens.
Menopause & lipid profile
Menopause is associated with a more atherogenic lipid profile compared with premenopausal status. It is well known that the menopause is associated with unfavorable changes in the lipoprotein profile, such as increase in plasma triglycerides (TGs), total and low-density lipoprotein (LDL) cholesterol, lipoprotein A (Lpa) and a decline in HDL levels. As demonstrated by the Prospective Cardiovascular Münster (PROCAM) study [26], significant changes in the lipoprotein profile occur in women aged over 50 years, while in men they tend to occur much earlier in life. Several cross-sectional and prospective studies have shown that menopause is associated with an increase in the plasma levels of total cholesterol and TGs [27,28]. The increase in total cholesterol observed after the menopause is mainly attributable to an increase in LDL cholesterol, since HDL cholesterol tends to be reduced, TGs increase significantly after the menopause and their increase, coupled with the increase in Lpa, has significant adverse effect on coagulation [27–29]. However, when considering the effect of menopause on lipid metabolism, it is important to point out that, in contrast with what occurs in men, in whom total and LDL cholesterol are the two most important lipid predictors of cardiovascular events, in women high TG and Lpa levels and low HDL cholesterol are more important in the development of cardiovascular disease [26,30]. Lpa, LDL-like particle with structural homology to plasminogen, has been shown to predict cardiovascular events in women independent from LDL levels [31]. The increased Lpa levels after menopause (25–50%) may reflect the fact that Lpa levels are sensitive to ovarian hormones as they return to premenopausal levels with oral estrogen replacement [32]. The importance of lipid changes occurring after the menopause has been overemphasized in the past, and for several years it was thought that most of the beneficial cardiovascular efforts of estrogens were related to their lipid-lowering effect. The Women's Health Initiative (WHI) study showed that, in elderly women, the positive lipid changes occurring with HRT are not paralleled by a significant cardioprotective effect. Several primary prevention studies have also shown that lipid-lowering therapy in low–moderate risk women is not associated with a cardiovascular benefit.
Autonomic nervous control of the cardiovascular system
A close relationship exists between incretion of ovarian and hypothalamic hormones and autonomic control of the cardiovascular system. Cyclical variations in the secretion of cathecolamines occur during the menstrual cycle and after the menopause a clear shift of the autonomic control of the cardiovascular system towards an increased sympathetic tone occurs. This increased sympathetic tone is in part independent from the changes occurring in bodyweight and glucose metabolism but is, in the long term, heightened by these metabolic changes. Several studies have shown that after the menopause there is an increased production of cathecolamines and our study showed a clear shift of autonomic control towards increased sympathetic activity of the cardiovascular system [33]. This increased sympathetic drive is closely related to the state of estrogen deficiency as it occurs within a few days of surgical oophorectomy and is reversed by estrogens [34].
The increased sympathetic drive, together with metabolic changes occurring after the menopause, contributes to the development of the metabolic syndrome, but is also worsened by the metabolic, physiological and structural changes leading to hypertension or facilitating its development (i.e., vasoconstriction, rarefaction of skeletal muscle arterioles and an increase in angiotensin II plasma levels), and changes in insulin sensitivity leading to reduced glucose tolerance because of the effect of sympathetic stimulation to the liver, fat tissue and muscle metabolism.
Apart from the structural changes in arterioles and their rarefaction, an important mechanism through which the increased sympathetic tone affects hypertension is related to the mutual changes induced by sympathetic stimulation on insulin sensitivity and renin activity [35]. The adrenergic stimulation leads to increases in insulin and angiotensin II, which in turn act centrally and peripherally increasing sympathetic nervous system outflow and cathecolamine release.
Menopause & hypertension
Blood pressure increases with age in both sexes; however, ovarian hormone deficiency heightens the effect of aging in women. It is known that at any age, postmenopausal women have higher systolic and diastolic blood pressure values than premenopausal. This suggests a clear role of estrogen deficiency on the development of hypertension. The incidence of arterial hypertension is greater in men before the age of 50–55 years, while thereafter it becomes more prevalent in women [36]. There are several explainations for the increased incidence of hypertension in postmenopausal women. Ovarian hormone deficiency plays important direct and indirect roles on blood pressure. The decline in ovarian hormones has several unwanted effects on the female milieu that are of importance in causing an increase in blood pressure. It is known that estrogens and progesterone may induce vasodilatation, an effect that is lost after the menopause and that favors the increase in blood pressure. The increased IR and hyperinsulinemia, together with the increased sympathetic tone, may increase blood pressure directly and indirectly through the activation of the RAAS. Arterial hypertension is of greater importance to women than men, due to its role in causing cardiovascular events, as shown by the fact that at any age, for comparable levels of blood pressure, women have a significantly higher incidence of cardiovascular events than men [37,38]. Furthermore, it has been shown that in patients with the metabolic syndrome, the reduction of blood pressure from normal to optimal leads to a greater reduction of cardiovascular events in women as compared with men [39].
Menopause & metabolic syndrome
As mentioned before, the transition from pre- to postmenopause is associated with an increase in central (intra-abdominal) body fat, a shift toward a more atherogenic lipid profile, with increased LDL and TG levels, reduced HDL and small, dense LDL particles, and an increase in glucose and insulin levels, which may explain the increase in incidence of the metabolic syndrome and the apparent acceleration in cardiovascular disease after menopause [40]. Postmenopausal status is associated with a 60% increased risk of the metabolic syndrome, even after adjusting for confounding variables, such as age, BMI, household income and physical inactivity [7]. Since all changes in cardiovascular risk factors that cluster into the metabolic syndrome are worsened by the state of estrogen deficiency, it becomes clear that menopause must be considered a risk for metabolic syndrome.
Therapeutic approach to the metabolic syndrome
The frequent presence of hypertension and diabetes with metabolic syndrome has important implications for the therapeutic and preventative approach of menopausal transition and postmenopause, as some antihypertensive drugs may worsen the already altered metabolic profile while few others may have a beneficial effect.
Owing to the clustering of hypertension with other metabolic risk factors in postmenopausal women, the therapeutic approach of the metabolic syndrome must include lifestyle modifications as well as pharmacological interventions. Several studies have shown that weight reduction is an effective and well tolerated long-term treatment for hypertension in overweight patients [41]. Moderate weight loss in overweight patients has been demonstrated to decrease intravascular volume and cardiac output without affecting total peripheral resistances. Weight reduction has a beneficial effect on glucose metabolism and sympathetic nervous activity since it reduces plasma insulin levels by increasing the number and affinity of the insulin receptors and reduces sympathetic activity. Although still under debate, several studies have suggested that weight loss is associated with a reduction in plasma renin activity, plasma aldosterone levels and intracellular sodium. Despite the beneficial effect of weight loss on glucose and lipid metabolism and blood pressure, several studies suggest that drop-out rates in weight-loss programs range from 50–70% within 1–2 years. In order to enhance long-term maintenance of weight loss programs it is important to induce a gradual change in eating habits with increased intake of fruit and vegetables coupled with a gradual increase in physical activity up to 30 min/day. Tuomiletho and colleagues have shown that an integrated program of diet and exercise is able to reduce the incidence of diabetes in women with the metabolic syndrome by nearly 50% [41,42].
The therapeutic approach of patients with metabolic syndrome should be twofold, one objective being to improve glucose tolerance and thereby delay the onset of Type II diabetes, the other to allow an aggressive control of blood pressure values. The metabolic control of patients with metabolic syndrome and high insulin levels should be approached with drugs that improve insulin sensitivity. Several studies have shown that in patients with metabolic syndrome, therapy with metformin, acarbose and glitazones may delay the onset of diabetes mellitus [43,44]. However, only metformin and acarbose have been proven effective in improving survival and cardiovascular end points. Our group has shown that metformin improves endothelial function in patients with metabolic syndrome independently of the changes in glucose levels, supporting the importance of this drug in the treatment of these patients [45].
Studies evaluating the effect of the different classes of antihypertensives in patients with metabolic syndrome have always been conducted in relatively small patient populations. Therefore, at present, as suggested by the European Society of Hypertension-European Society of Cardiology (ESH/ESC) guidelines, there is no clear evidence for the superiority or inferiority of different drug classes and it appears reasonable to recommend that all effective and well-tolerated antihypertensives can be used, generally in combination [46].
Nowadays, it is possible to choose amongst several antihypertensive drug classes, all of which are effective in the control of blood pressure. However, some drugs, such as β-blockers and diuretics, may not be indicated in patients with metabolic syndrome due to their unwanted effect on glucose and lipid metabolism. Angiotensin-converting enzyme (ACE)-inhibitors and angiotensin II receptor blockers (ARBs) have been proven effective in reducing the progression of glucose intolerance in Type 2 diabetes and therefore should be the drugs of choice in the treatment of arterial hypertension in women with the metabolic syndrome. ACE-inhibitors and angotensin II (ATII) receptor blockers are effective in controlling blood pressure and have been shown to reduce the development of diabetes mellitus. However, among ACE-inhibitors it seems that the metabolic effect is more pronounced with those drugs that increase bradikinin, such as perindopril and ramipril, while the metabolic effect of most of the ATII blockers on glucose metabolism is neutral [47].
Furthermore, in the Anglo Scandinavian Cardiac Outcome Trial (ASCOT) study, the combination of amlodipine/perindopril has been recently demonstrated to be effective in reducing cardiovascular events and new-onset diabetes in hypertensive patients [48]. However, it is most likely that the metabolic effect of this association is related to the known effect of perindopril on glucose metabolism [49].
Our group has also shown that telmisartan, an ARB with peroxisome proliferative activated receptor (PPAR)γ activity, improves glucose metabolism while reducing blood pressure in hypertensive patients with metabolic syndrome [50]. Centrally acting agents and α2-blockers have been proven to effectively reduce blood pressure and improve the glycemic and lipid profile of hypertensive patients. Therefore, it seems that they should be indicated alone or in combination in the treatment of patients with metabolic syndrome. Despite the premature discontinuation of the doxazosin arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study due to an increased incidence of adverse cardiac events, most probably due to the design of the study rather than to a negative cardiovascular effect of doxazosin, there is evidence to support the use of these drugs in hypertensive patients with the metabolic syndrome [51].
Centrally acting agents may reduce blood pressure either by acting on α-receptors, such as clonidine, or by modulating the sympathetic efflux, stimulating the imidazoline receptors at the level of the rostral ventrolateral medulla, such as moxonidine. These drugs have been shown to reduce blood pressure values by a similar extent to most of the antihypertensive drugs, have an additive blood pressure-lowering effect when used in combination with any antihypertensive class, reduce sympathetic activity in hypertensive patients and improve glucose metabolism [52,53].
In symptomatic menopausal women with the metabolic syndrome, HRT improves vasomotor symptoms and may improve most of the unfavorable changes associate with the metabolic syndrome. HRT, if started within a few years from the onset of menopause, may counteract the unwanted changes in cardiovascular risk profile and, as also suggested by the estrogen-only arm of the WHI, may have positive cardiovascular effects. However, as also suggested by the WHI investigators, an early start of HRT and the choice of the progestin are of pivotal importance to maximize the benefits and minimize the risks of this therapy [54].
According to their chemical structure, progestins have different metabolic and vascular effects that may enhance or abolish those induced by estrogen therapy on cardiovascular risk factors and vascular functions. The adjunct of more androgenic progestins or progestins with gluco-and mineralcorticoid activity to estrogens negatively affects peripheral vascular resistances. However, it is possible that some of the effects observed may be dose-dependent and that lower doses of androgenic progestins may have a more neutral vascular effect [55]. Furthermore, while estrogens reduce renin activity, it is well known that oral estrogen administration increases angiotensin II plasma levels and leads to an increase in aldosterone levels. In this respect, the association of estrogens with progestins with anti-aldosterone properties, such as micronized progesterone or the more potent drospirenone, abolish the unwanted effect of the RAAS activation.
A careful selection of the dose and type of progestins to add to estrogens seems crucial in order to preserve, and possibly enhance, the beneficial vascular effects of estrogens. In addition to their effects on the vasculature, estrogen-replacement therapy may cause fluid retention and consequently increase blood pressure. Progesterone and newer progestins, especially those with an aldosterone receptor antagonistic effects, have been shown to be able to improve the cardiovascular risk profile of postmenopausal women. Amongst these progestins, drospirenone has been shown to significantly reduce blood pressure in hypertensive postmenopausal women receiving HRT, but had no blood pressure-lowering effects in normotensive women [56]. Furthermore, drosperinone blunts the increase in bodyweight associated with the menopause and may even reduce bodyweight. As mentioned above, there is currently no evidence that lipid-lowering therapy may reduce the cardiovascular risk in the primary prevention of women. Therefore, the strategy on lipids should be guided by the global cardiovascular risk of each woman.
Conclusion
In conclusion, menopause is associated with an increased cardiovascular risk and a significant increase in the risk of developing arterial hypertension. Arterial hypertension and diabetes have a greater importance as risk factors in women than in men. Therefore, in postmenopausal women, it is important to develop preventative strategies that may reduce the blood pressure increase induced by the state of ovarian hormone deficiency. In HRT schemes the cardiovascular effect of progestins may differ depending on type, dosage and route of administration. Non-androgenic progestins, such as progesterone and those with an antialdosterone activity, seem to be the progestational agents with the most favorable cardiovascular profile for hormone replacement schemes in women with and without the metabolic syndrome, because of their metabolic and blood pressure-lowering effect.
Future perspective
Owing to the unwanted effect of menopause on cardiovascular risk and the development of metabolic syndrome, and the biological plausibility that suggests that ovarian hormone replacement is associated with improvement in cardiovascular functions, it will be important in the future to assess whether personalized hormone replacement schemes initiated early after the menopause and with progestins that antagonize the activation of RAAS may reduce the progression of cardiovascular risk and protect from the development of cardiovascular diseases.
It is most probable that a careful selection of patients and estrogen–progestin associations and personalization of dosages will reduce the progression of cardiovascular risk in postmenopause and result in a sound cardioprotective effect in early postmenopausal women.
Excutive summary
The clustering of metabolic risk factors, overweight and hypertension is of particular importance in postmenopausal women due to the negative effect of menopause on the development of hypertension and on cardiovascular risk factors.
Menopause in associated with important changes in weight and body fat distribution. Postmenopausal women tend to gain weight starting within the first year following menopause and experience a redistribution of body fat from a gynoid to an android pattern.
Menopause acts directly as a risk factor by reducing the direct beneficial effect of ovarian hormones upon cardiovascular functions, and indirectly by negatively influencing other traditional risk factors for coronary artery disease.
All changes occurring after the menopause must be regarded under a unifying mechanism that induces changes in bodyweight, insulin tolerance, plasma lipids, sympathetic tone and vascular function. These changes then interact each other, amplifying the effect of ovarian hormone deficiency and aging.
Menopause is associated with a progressive decline in glucose-stimulated insulin secretion.
Insulin resistance (IR) occurs in combination with a cluster of other metabolic abnormalities and hypertension in the metabolic syndrome. Although there is a genetic basis for IR, environmental factors such as obesity, physical activity and estrogen deprivation may unmask or worsen the state of IR.
Diabetes and hypertension have a greater importance in determining the cardiovascular risk in women than in men; in fact, the association of the two risk factors has an attributable risk for cardiovascular disease double in women than in men.
Menopause is associated with unfavorable changes on lipoprotein profile such as increase in plasma triglycerides, total and low density lipoprotein (LDL) cholesterol, lipoprotein A (Lpa) and a decline in high-density lipoprotein (HDL) levels.
Conversely to what occurs in men, in whom total and LDL cholesterol are the two most important lipid predictors of cardiovascular events, in women high triglycerides and Lpa levels and low HDL cholesterol are more important in the development of cardiovascular disease.
The increase Lpa levels after menopause (25–50#x0025;) may reflect the fact that Lpa levels are sensitive to ovarian hormones as they return to premenopausal levels with oral estrogen replacement.
Cyclical variations in the secretion of cathecolamines occur during the menstrual cycle, and after the menopause a clear shift of the autonomic control of the cardiovascular system towards an increased sympathetic tone occurs.
The increased sympathetic tone is, in part, independent from the changes occurring in bodyweight and glucose metabolism but is, in the long term, heightened by these metabolic changes.
The incidence of arterial hypertension is greater in men before the ages of 50–55years, while thereafter it becomes more prevalent in women.
Ovarian hormone deficiency plays an important direct and indirect role on blood pressure.
The increased IR and hyperinsulinemia together with the increased sympathetic tone may increase blood pressure directly and indirectly through activation of the renin-angiotensin-aldosterone system.
Arterial hypertension has a greater importance in women than in men in causing cardiovascular events as demonstrated by the fact that at any age, for comparable levels of blood pressure, women have a significantly higher incidence of cardiovascular events than men.
Postmenopausal status is associated with a 60% increased risk of the metabolic syndrome.
Since all changes in cardiovascular risk factors that cluster into the metabolic syndrome are worsened by the state of estrogen deficiency it seems clear that menopause must be considered a risk factor for metabolic syndrome.
Owing to the clustering of hypertension with other metabolic risk factors in postmenopausal women the therapeutic approach to the metabolic syndrome must include lifestyle modifications as well as pharmacological interventions.
The frequent presence of hypertension in postmenopausal women with metabolic syndrome has important implications for the therapeutic and preventative approach of menopausal transition and postmenopause, as some antihypertensive drugs may worsen the already altered metabolic profile while others may have a beneficial effect.
Hormone replacement therapy, if started within a few years of the onset of menopause, may counteract the unwanted changes in cardiovascular risk profile and have positive cardiovascular effects.
However, an early start of hormone replacement therapy and the choice of the progestin are of pivotal importance to maximize the benefit and minimize the risks of this therapy.