Gender differences in the cardiovascular effects of sex hormones

Over the last decade, compelling evidence supports the idea that the different impact of cardiovascular disease (CVD) and the differences in vascular biology in men and women may be, at least in part, related to the cardiovascular and metabolic effects of sex steroid hormones. Indeed, androgens and oestrogens influence a multitude of vascular biological processes and their cardiovascular effects are multifaceted. While in women the effects of androgens mainly depend upon oestrogens’ levels and, ultimately, upon the estradiol/testosterone ratio, the effects of androgens in men mostly relate to their aromatization into oestrogens. Oestrogens exert potential beneficial effects on the cardiovascular system in both sexes. In women, the effect of oestrogens, alone or in association with progestins, has been widely investigated, but data obtained from older patient populations have lead the medical community and the general public to misleading conclusions. Growing evidence supports the ‘timing hypothesis’, which suggests that oestrogen/hormone replacement therapy may increase CVD risk if started late after menopause, but produce beneficial cardiovascular effects in younger postmenopausal women. Because in men adequate interventional studies with testosterone are lacking, specific investigations should be performed.     

Hormone therapy and phytoestrogens

As ageing progresses the levels of sex hormones decrease in the human body. In the male population, the decrease or absence of testosterone leads to decreased strength and stamina, thin bones and a low sex drive (1). In the female population, the immediate symptoms of menopause include irregular periods, painful sexual intercourse due to vaginal dryness, hot flushes and night sweats (2). Lack of oestrogen also leads to the risk of developing osteoporosis and cardiovascular diseases.
In this report, the authors will mainly discuss the effects of hormone therapy (HT) in menopausal women. Available current clinical data on the effects of calcium supplementation with and without HT, exercise, exercise plus calcium and exercise with HT on bone loss are presented. The effects of transdermal and oral oestrogen therapy (OT) on serum lipids are discussed. Commercially-available HT products, their indications, dosages, contra-indications, side-effects and drug interactions are compared. Alternative therapies for menopausal symptoms with Chinese traditional herbs, and a comparison of the molecular structures of phytoestrogens with estradiol and diethylstilbestrol are examined (3, 4). A list of medicinal herbs and foods reported to elicit an oestrogenic response in animals is compiled.     

Understanding the oestrogen action in experimental and clinical atherosclerosis

Whereas hormone replacement/menopause therapy (HRT) in postmenopausal women increases the coronary artery risk, epidemiological studies (protection in premenopaused women) suggest and experimental studies (prevention of the development of fatty streaks in animals) demonstrate a major atheroprotective action of oestradiol (E2). The understanding of the deleterious and beneficial effects of oestrogens is thus required. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas E2 favours an anti-inflammatory effect in vitro (cultured cells), it rather elicits in vivo a proinflammation at the level of several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for E2, as it potentiates endothelial NO and prostacyclin production, thus promoting the beneficial effects as vasorelaxation and inhibition of platelet aggregation. Prostacyclin, but not NO, appears to be involved in the atheroprotective effect of E2. E2 also accelerates endothelial regrowth, thus favouring vascular healing. Finally, most of these effects of E2 are mediated by oestrogen receptor alpha, and are independent of oestrogen receptor beta. In summary, a better understanding of the mechanisms of oestrogen action not only on the normal and atheromatous arteries, but also on innate and adaptive immune responses is required and should help to optimize the prevention of cardiovascular disease after menopause. These mouse models should help to screen existing and future selective oestrogen receptor modulators.     

Intrauterine growth restriction promotes vascular remodelling following carotid artery ligation in rats

Epidemiological studies revealed an association between IUGR (intrauterine growth restriction) and an increased risk of developing CVDs (cardiovascular diseases), such as atherosclerosis or hypertension, in later life. Whether or not IUGR contributes to the development of atherosclerotic lesions, however, is unclear. We tested the hypothesis that IUGR aggravates experimentally induced vascular remodelling. IUGR was induced in rats by maternal protein restriction during pregnancy (8% protein diet). To detect possible differences in the development of vascular injury, a model of carotid artery ligation to induce vascular remodelling was applied in 8-week-old intrauterine-growth-restricted and control rat offspring. Histological and immunohistochemical analyses were performed in the ligated and non-ligated carotid arteries 8 weeks after ligation. IUGR alone neither caused overt histological changes nor significant dedifferentiation of VSMCs (vascular smooth muscle cells). After carotid artery ligation, however, neointima formation, media thickness and media/lumen ratio were significantly increased in rats after IUGR compared with controls. Moreover, dedifferentiation of VSMCs and collagen deposition in the media were more prominent in ligated carotids from rats after IUGR compared with ligated carotids from control rats. We conclude that IUGR aggravates atherosclerotic vascular remodelling induced by a second injury later in life.     

Regulation of calcium-regulating hormones by exogenous sex steroids in early postmenopause

A major function of calcitonin in humans appears to be maintenance of the skeleton. There is a marked sex difference in circulating calcitonin levels: women have much lower levels. This has led to speculation that calcitonin lack may be one factor involved in the pathogenesis of postmenopausal bone loss. We have measured levels of calcitonin and the other major calcium-regulating hormones in healthy women during the early menopause, and studied the effects of reversing their oestrogen deficiency with natural and synthetic oestrogen. The major findings were that calcitonin levels were increased by oestrogen administration (P less than 0.02-less than 0.001) and that the levels of the bone-resorbing hormones, parathyroid hormone and 1,25 dihydroxyvitamin D, were not higher in postmenopausal than in premenopausal women. We suggest that loss of oestrogen at the menopause accelerates the natural age-related decline of calcitonin secretion, thus further decreasing the calcitonin levels. This leads to increased sensitivity of the skeleton to the actions of the bone-resorbing hormones. It seems likely that the well-known effect of oestrogen in preventing postmenopausal bone loss is achieved, at least in part, by enhancement of calcitonin secretion.     

Gender and the renin–angiotensin–aldosterone system

Premenopausal women are protected to some extent from cardiovascular and kidney diseases. Because this protection weakens after menopause, sex hormones are believed to play an important role in the pathogenesis of cardiovascular and kidney diseases. The cardiovascular system and the kidneys are regulated by the renin–angiotensin–aldosterone system (RAAS), which in turn, appears to be regulated by sex hormones. In general, oestrogen increases angiotensinogen levels and decreases renin levels, angiotensin‐converting enzyme (ACE) activity, AT₁ receptor density, and aldosterone production. Oestrogen also activates counterparts of the RAAS such as natriuretic peptides, AT₂ receptor density, and angiotensinogen (1‐7). Progesterone competes with aldosterone for mineralocorticoid receptor. Less is known about androgens, but testosterone seems to increase renin levels and ACE activity. These effects of sex hormones on the RAAS can explain at least some of the gender differences in cardiovascular and kidney diseases.     

Hypogonadal hypogonadism and osteoporosis in men

In recent years, osteoporosis in men has become increasingly recognized as an important clinical and public health problem. Many similarities exist in various aspects of osteoporosis in men and women, but this article focuses on the sex difference, bone biology, epidemiology, and consequences of fractures. Although maintenance of bone integrity depends on the action of sex hormones in both sexes, menopause is a much more obvious indicator of estrogen deficiency than is the subtle decrease of testosterone in aging men. This often leads to delay and neglect of diagnosis. The need to identify and screen men at a particular risk for osteoporosis, as when hypogonadism is induced for treatment of prostate cancer, has become important.     

Oestrogens and the heart.

The incidence of cardiovascular disease is lower in women before the menopause compared with men, while menopausal women have an incidence of coronary disease similar to that of men of the same age. This is mainly dependent upon oestrogen deficiency. Large-scale epidemiological studies have demonstrated that oestrogen replacement therapy leads to approximately 50 per cent reduction of cardiovascular disease in women taking hormones, compared with untreated women. Multiple mechanisms have been proposed to explain the cardiovascular risk reduction observed in women on oestrogen therapy. Oestrogens positively affect plasma lipids and exert a beneficial effect upon carbohydrate metabolism and the haemocoagulation profile. Oestrogens may also have anti-atherogenic properties. Recent in vitro studies have demonstrated that oestrogens may positively influence all the steps involved in the formation of the atherosclerotic plaque (accumulation of cholesterol in the arterial wall, arterial smooth muscle cell proliferation, platelet aggregation, collagen and elastin production). Angiographic studies conducted in humans have demonstrated that women on oestrogens have significantly less coronary disease and less severe occlusion scores compared with women not taking hormone replacement therapy. Animal and human studies have shown that oestrogens act as vasodilating substances. Endothelium-dependent mechanisms have been identified and imply that oestrogens act through the endothelial release, mainly, of nitric oxide, a potent vasodilating substance which has been identified with EDRF (endothelium derived relaxing factor). More recently, oestrogens have been shown to affect also the vascular tone in the absence of the endothelium. Therefore, endothelium-independent mechanisms could be involved in the pathogenesis of the oestrogens' vascular effects. There is evidence that oestrogens have calcium antagonistic properties; this mechanism may be responsible for the reduction of peripheral vascular resistance observed in women on hormone replacement therapy and may slow the progression of coronary artery disease. The menopausal age is characterized by an imbalance of the neurohormonal system. Sudden increases of plasma catecholamines are evident when women have hot flushes, a typical clinical sign of the menopausal period. The abnormal release of catecholamines may reduce coronary flow reserve and increase peripheral vascular resistance and, therefore, may be dangerous for the heart. It has been shown, by means of the study of heart rate variability, that oestrogens are effective in modulating the neurohormonal system. The reduction of sympathetic tone has beneficial effects on coronary flow reserve and may be important in explaining the cardioprotective effect of oestrogens. Peripheral and coronary vasodilation observed in women on hormone replacement therapy might be also due to the inhibition of the release of vasoconstrictor factors such as endothelin-1 by oestrogens. Therefore, oestrogens protect the heart against coronary artery disease and they are now regarded as being as important as aspirin and antihypertensive drugs were in the past. Hormone replacement therapy should be considered in every menopausal woman to possibly prevent the occurrence of cardiovascular disease or, if already present, to slow its progression.     

Can angiotensin-converting enzyme inhibitors reverse atherosclerosis?

Angiotensin II, a potent vasoconstrictor, is mainly present in the vascular endothelium. Multiple studies have confirmed that angiotensin-converting enzyme (ACE) inhibitors, which block the formation of angiotensin II, lower blood pressure and also improve heart failure. These agents not only have beneficial hemodynamic effects but also bestow additional benefits on vascular function and prevent clinical cardiovascular events in patients at risk for coronary artery disease. These latter benefits may represent effects of ACE inhibitors on local endocrine pathways, inflammatory processes, and atherosclerosis taking place within the arterial wall. Current evidence suggests that, although ACE inhibitors may not substantially reverse atherosclerotic plaque already present, they may slow the progression of such atherosclerotic lesions. In addition, by modulating inflammatory pathways within and adjacent to the atherosclerotic lesion, they may stabilize an unstable plaque and therefore decrease the risk of plaque rupture and its complications.     

Atherosclerosis and sex hormones: current concepts

CVD (cardiovascular disease) is the leading cause of death for women. Considerable progress has been made in both our understanding of the complexities governing menopausal hormone therapy and our understanding of the cellular and molecular mechanisms underlying hormone and hormone receptor function. Understanding the interplay of atherosclerosis and sex steroid hormones and their cognate receptors at the level of the vessel wall has important ramifications for clinical practice. In the present review, we discuss the epidemiology of CVD in men and women, the clinical impact of sex hormones on CVD, and summarize our current understanding of the pathogenesis of atherosclerosis with a focus on gender differences in CVD, its clinical presentation and course, and pathobiology. The critical animal and human data that pertain to the role of oestrogens, androgens and progestins on the vessel wall is also reviewed, with particular attention to the actions of sex hormones on each of the three key cell types involved in atherogenesis: the endothelium, smooth muscle cells and macrophages. Where relevant, the systemic (metabolic) effects of sex hormones that influence atherogenesis, such as those involving vascular reactivity, inflammation and lipoprotein metabolism, are discussed. In addition, four key current concepts in the field are explored: (i) total hormone exposure time and coronary heart disease risk; (ii) the importance of tissue specificity of sex steroid hormones, critical timing and the stage of atherosclerosis in hormone action; (iii) biomarkers for atherosclerosis with regard to hormone therapy; and (iv) the complex role of sex steroids in inflammation. Future studies in this field will contribute to guiding clinical treatment recommendations for women and help define research priorities.     

Gender differences in exercise-induced changes in sex hormone levels and lipid peroxidation in athletes participating in the Hawaii Ironman triathlon. Ginsburg-gender and exercise-induced lipid peroxidation

BACKGROUND: Exercise reduces the risk of coronary heart disease in men and women but paradoxically, may promote free-radical formation, lipid peroxidation and vascular tissue injury. In this study, we assessed whether exercise-induced oxidative stress similarly affected men and women who participated in the Hawaii Ironman triathlon. METHODS AND RESULTS: Fifty-seven athletes (38 males) who completed the triathlon (3.9 km swim, 180.2 km bike, 42.2 km run) participated in this study. Blood samples were obtained 2 days before and immediately after the triathlon for the measurement of lipids, antioxidants and sex hormones and for the assessment of the susceptibility of plasma lipids to peroxidation. Lipid changes after exercise were similar for men and women. However, the susceptibility of plasma lipids to peroxidation was reduced by 61% (P < 0.001) in men and only 14% (P = NS) in women postrace. These changes were not associated with the supplemental use or levels of antioxidants. In addition, in men there was an increase of 58% in the antioxidant sex hormone estradiol and a decrease of 58% in testosterone (P < 0.001) postrace. No significant changes were noted for these two hormones in women. CONCLUSIONS: There are significant gender-specific differences in the susceptibility of lipids to peroxidation and in changes in estradiol and testosterone levels as a result of ultra-endurance exercise. These changes may in part explain the salutary effect of exercise on the development of vascular disease.     

Lack of association between plasma lecithin: cholesterol acyltransferase concentration and plasma sex hormone concentrations in men

Plasma lecithin:cholesterol acyltransferase (LCAT) concentration has been shown to be higher in women than in men, suggesting that sex hormones may influence LCAT metabolism. In order to explore this possibility, the associations of plasma LCAT concentration with the concentrations of total, free and protein-bound testosterone, 5 alpha-dihydrotestosterone and oestradiol in plasma, and with total androstenedione concentration in plasma, were examined in 88 men aged 52-67 yr. Total cortisol in plasma was also assayed. No statistically significant correlations were observed between LCAT and androgen or oestrogen concentrations, but a weak positive association was observed between LCAT and plasma cortisol concentration (r = +0.227, p less than 0.05).     

Gender-related differences in pharmacokinetics and their clinical significance

In this review I have attempted to summarize gender differences in pharmacokinetics involving the cytochrome P450 (CYP) isozymes of young and mature adults, excluding the effects of the menstrual cycle, use of oral contraceptives and pregnancy. Sex differences in drug metabolism and elimination are mainly related to steroid hormone levels. CYP3A4, responsible for the metabolism of over 50% of therapeutic drugs, exhibits higher activity in women than in men. Nonetheless, the absence of a sex difference has been reported by some workers. The activity of several other CYP (CYP2C19, CYP2D6, CYP2E1) isozymes and the conjugation (glucuronidation) activity involved in drug metabolism may be higher in men than in women. Drug metabolism in women is affected by sex-specific factors (menopause, pregnancy and menstruation) in addition to the cigarette smoking, drug ingestion and alcohol consumption that are more commonly observed factors in men. Furthermore, they are affected by physiological factors such as drug absorption, protein binding and elimination. Thus, careful attention should be paid to the side-effects and toxicity arising from sex differences in drug metabolism in clinical situations. Although there are specific ethical considerations regarding carrying out drug trials in women, the relationship between the side-effects and toxicity that may be influenced by hormones during drug metabolism and drug treatment needs further study.     

Fractalkine/CX3CR1 and atherosclerosis

Fractalkine is a unique chemokine which has both adhesive and chemoattractant functions. With the increasing emphasis on the importance of inflammation in atherosclerosis, more attention has been focused on the role of chemokines in atherosclerosis. It has been shown that fractalkine/CX3CR1 participates in the atherosclerotic pathological process through mediating the recruitment of leukocytes and the interaction of vascular cells and leukocytes. Some signal pathways are simultaneously activated through fractalkine/CX3CR1 coupling to promote the inflammatory response in atherosclerotic vessels. Additionally, fractalkine has cytotoxic effects on endothelium as well as anti-apoptosis and proliferative effects on vascular cells which consequently changes plaque components and stability in plaque. Several studies have showed that fractalkine or CX3CR1 deficiency in atherosclerotic mice would ameliorate the severity of plaque. Population studies on CX3CR1 polymorphism have confirmed that 280M-containing haplotype is associated with reduced risk of atherosclerotic disease. Despite the apparent association with atherosclerosis, further studies on fractalkine/CX3CR1 chemokine pair are clearly warranted to more fully elucidate this relationship.     

Serum osteoprotegerin,sRANKL and carotid plaque formation and growth in a general population – the Tromsø study

Summary. Background: Intervention studies in animal models suggest that osteoprotegerin (OPG) functions as an inhibitor or marker of atherosclerosis, whereas one prospective epidemiological study in humans indicated that OPG was an independent risk factor for progression of atherosclerosis. Objective: To study the association between serum levels of OPG, soluble RANK ligand (sRANKL) and carotid artery plaque formation and plaque growth. Patients/methods: The prevalence of carotid plaque and plaque area were assessed by ultrasonographic imaging at baseline and after 7 years follow‐up in 2191 men and 2329 women who participated in a population‐based study. Results: OPG was significantly associated with atherosclerotic plaque burden and cardiovascular risk factors such as age, body mass index, blood pressure, total cholesterol, HDL cholesterol, HbA1c and fibrinogen at baseline, but not with sRANKL. In subjects without plaque at baseline, OPG predicted plaque formation in crude analysis in both women and men, but not after adjustment for age and other atherosclerotic risk factors. OPG predicted plaque growth in women (+1.8 mm², 0.6–3.0) (mean, 95% CI) per 1 SD increase in OPG (P = 0.003), whereas no associations were demonstrated in men (0.1 mm² (?1.3–1.4), P = 0.93). Soluble RANKL did not predict plaque formation or plaque growth. Conclusions: OPG was an independent predictor of plaque growth in women, but not in men, suggesting gender‐specific actions of OPG in plaque growth. OPG was not associated with novel plaque formation.     

冠状动脉旁脂肪促进冠状动脉粥样硬化的研究进展

近年来随着对全身脂肪、循环脂质水平升高与冠心病发病关系的临床证据和基础研究的深入,越来越充分的证据表明脂肪组织通过旁分泌、自分泌炎症因子加重全身血管炎症状态、介导胰岛素抵抗、促进血液高凝等途径直接导致冠心病等血管性疾病的发病率大幅增加。传统的冠状动脉粥样硬化理论认为冠状动脉粥样硬化起始于高血压、高血脂、高血糖和其他血管内危险因素导致的血管内皮损伤,继而引起内皮功能紊乱、内膜增生、炎症细胞趋化、脂质累积,最终这些"由内而外"的因素导致动脉粥样硬化斑块的形成,新近的研究渐渐把这种"由外而内"的发病机制和传统的由血管内因素(血浆脂质)异常到内皮功能损害、内膜增殖、脂质斑块形成联系起来,最近的证据表明新生滋养血管与血管壁重构是冠状动脉旁脂肪促进动脉粥样硬化斑块易损的两个重要机制。本文基于现有临床和实验方面的最新证据,阐明冠状动脉旁脂肪组织参与整个动脉粥样硬化的时间和空间过程。     

Sex differences in the association of endogenous sex hormone levels and glucose tolerance status in older men and women

OBJECTIVE: Some evidence suggests an inverse association between type 2 diabetes and androgens in men and a positive association between type 2 diabetes and androgens in women. The purpose of this community-based study was to evaluate sex differences in the association between endogenous total and bioavailable estrogen and testosterone levels and glucose tolerance status. RESEARCH DESIGN AND METHODS: We included in this study 775 men and 633 postmenopausal non-estrogen-using women, all > or =55 years of age (mean ages 72 and 75 years, respectively). A 75-g oral glucose tolerance test (OGTT) was administered to fasting subjects from 1984 to 1987, when sera were frozen for measurement of total and bioavailable hormone levels. Total testosterone and estradiol levels were measured by radioimmunoassay, and bioavailable hormone levels were determined using a modified ammonium-sulfate precipitation method. The association between steroid hormones and glucose tolerance status was tested. RESULTS: In sex-specific age- and BMI-adjusted analyses, men with impaired glucose tolerance (IGT) had significantly lower total testosterone levels. Women with IGT or type 2 diabetes had significantly higher bioavailable testosterone and total and bioavailable estradiol levels than those with normal glucose tolerance. Total testosterone and fasting plasma glucose were inversely associated in men (P = 0.0001), whereas bioavailable testosterone and estradiol were positively associated with fasting plasma glucose in women (P = 0.0001 and 0.001, respectively). CONCLUSIONS: Additional studies are needed to further develop the hormone-diabetes connection.     

Migraine and hormones: what can we be certain of?

Women suffer from migraine far more frequently than men. This sex difference during the reproductive years is considered to result from additional trigger factors, such as the fluctuating hormones of the menstrual cycle and with the reproductive milestones of women. The role of the female hormones on migraine is illustrated by the phenomenon of menstrual migraine, and the changes in the clinical course of migraine with menarche, pregnancy, menopause and the external application of hormones. In summary, epidemiological, clinical and experimental studies document a substantial influence of female sex hormones on the pathophysiology of migraine headache.     

Migräne und Hormone: Was ist gesichert?

Women suffer from migraine far more frequently than men. This sex difference during the reproductive years is considered to result from additional trigger factors, such as the fluctuating hormones of the menstrual cycle and with the reproductive milestones of women. The role of the female hormones on migraine is illustrated by the phenomenon of menstrual migraine, and the changes in the clinical course of migraine with menarche, pregnancy, menopause and the external application of hormones. In summary, epidemiological, clinical and experimental studies document a substantial influence of female sex hormones on the pathophysiology of migraine headache.