Current Vascular Pharmacology - Volume 17, Issue 6, 2019

There is increasing evidence that menopause is associated with the progression and severity of non-alcoholic fatty liver disease (NAFLD). Estrogen deficiency worsens non-alcoholic steatohepatitis (NASH) in mice models with fatty liver. The prevalence of NAFLD seems to be higher in postmenopausal compared with premenopausal women. Although more data are needed, lower serum estradiol levels are associated with NASH in postmenopausal women. Apart from estrogen deficiency, relative androgen excess and decrease in sex hormone-binding protein are observed in postmenopausal women. These hormonal changes seem to interplay with an increase in abdominal adipose mass, also observed in postmenopausal women, and aging, which are both closely related to the severity and progressive forms of NAFLD. NAFLD adds extra morbidity to postmenopausal women, possibly increasing the risk of type 2 diabetes mellitus and cardiovascular disease. Improving parameters of the metabolic syndrome via modifications in diet and physical exercise may reduce the risk of NAFLD and its related morbidity. Limited studies have shown a beneficial effect of hormone replacement therapy (HRT) on NAFLD, although adverse hepatic effects have been attributed to progesterone in one study. Phytoestrogens may be alternatives to HRT, but their long-term efficacy and safety remain to be shown. The aim of this review was to summarize evidence linking menopause with NAFLD with a special focus on potential therapeutic perspectives.

The aim of this review is to present, critically appraise and qualitatively synthesize current evidence on the risk of type 2 diabetes mellitus (T2DM) development during menopause, the management of climacteric symptoms in women with T2DM and the management of T2DM in postmenopausal women. Menopause represents the end of reproductive life in women, as a result of ovarian aging. It is characterized by substantial decrease in the endogenous oestrogen concentrations and it is accompanied by alterations in body weight, adipose tissue distribution and energy expenditure, as well as insulin secretion, insulin sensitivity and activity that can predispose to the development of T2DM, independently of, and additively to, aging. Many women in midlife experience climacteric symptoms, including hot flushes and night sweats, resulting in an indication to receive Hormone Replacement Treatment (HRT). HRT has a favourable effect on glucose homeostasis both in women without and with T2DM. The latter was considered in the past as a cardiovascular disease (CVD) equivalent, which would suggest that women with the disease should not receive HRT. However, nowadays evidence exists to support an individualized approach of women based on their CVD risk, as some women with T2DM may be excellent candidates for HRT. Regarding T2DM management for women in menopause, lifestyle intervention, including diet and exercise, constitutes its cornerstone. However, most of these women will eventually require pharmacologic therapy. The most suitable agents should be selected according to their metabolic, cardiovascular and bone effects, taking into consideration the specific characteristics and comorbidities of each postmenopausal woman.

Transition to menopause is associated with an increase in cardiovascular disease (CVD) risk, mainly attributed to lipid and glucose metabolism dysregulation, as well as to body fat redistribution, leading to abdominal obesity. Indeed, epidemiological evidence suggests that both early menopause (EM, defined as age at menopause <45 years) and premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with 1.5-2-fold increase in CVD risk. Menopausal hormone therapy (MHT) exerts a favorable effect on CVD risk factors (with subtle differences regarding oestrogen dose, route of administration, monotherapy or combination with progestogen and type of progestogen). Concerning CVD morbidity and mortality, most studies have shown a beneficial effect of MHT in women at early menopausal age (<10 years since the final menstrual period) or younger than 60 years. MHT is strongly recommended in women with EM and POI, as these women, if left untreated, are at risk of CVD, osteoporosis, dementia, depression and premature death. MHT has also a favorable benefit/ risk profile in perimenopausal and early postmenopausal women, provided that the patient is not at a high CVD risk (as assessed by 10-year calculation tools). Transdermal oestrogens have a lower risk of thrombosis compared with oral regimens. Concerning progestogens, natural progesterone and dydrogesterone have a neutral effect on CVD risk factors. In any case, the decision for MHT should be individualized, tailored according to the symptoms, patient preference and the risk of CVD, thrombotic episodes and breast cancer.

Introduction: Menopause is associated with adverse effects on quality of life of perimenopausal and post-menopausal women. It also has an impact on the development of cardiovascular disease (CVD). Hormonal treatments are the most effective medications for menopausal symptoms relief. Given the fact that hormonal treatments are contraindicated for many women, non-hormonal treatment, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), gabapentin, pregabalin, clonidine and phytoestrogens, constitute alternative treatments. Nevertheless, little is known about their effects on CVD risk. Methods: PubMed, EMBASE and Cochrane Library were searched for the effects of non-hormonal treatment on CVD risk, blood pressure, heart rate, lipids and glucose concentrations, weight gain, cardiovascular events, stroke, mortality and morbidity. Results: Phytoestrogens, pregabalin and gabapentin seem to have no adverse effects on the cardiovascular system. Phytoestrogens, in particular, seem to reduce CVD risk through many pathways. On the other hand, SSRIs and SNRIs, although effective in reducing menopausal vasomotor symptoms, should be cautiously administered to women with known CVD (e.g. with cardiac arrhythmias, atherosclerotic disease or stroke). As clonidine has been associated with cardiovascular adverse effects, it should be administered only in cases where blood pressure regulation is mandatory. Conclusion: Further research is needed to produce definite conclusions regarding the cardiovascular safety of non-hormonal medications for menopausal symptoms relief.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age. The hormonal alterations of PCOS have been linked with a higher risk of metabolic disturbances in young, reproductively active women. However, it remains to be clarified whether the presence of PCOS increases the risk of cardiovascular disease (CVD) later in life. Aging ameliorates the clinical manifestations of PCOS; hyperandrogenaemia and metabolic abnormalities, however, persist beyond the menopause. On the other hand, aging and menopause increase CVD risk in the general female population. The results of the limited available studies in aging women with a previous diagnosis of PCOS demonstrate early atherosclerosis. However, studies addressing clinical CVD outcomes in women with PCOS report inconsistent findings. A possible explanation for this heterogeneity is the difficulty in diagnosing PCOS after the menopausal transition, due to the absence of validated diagnostic criteria for this population. Larger prospective studies of women diagnosed during their reproductive years will shed more light on the longer-term CVD implications of PCOS.

Cardiovascular disease, and particularly coronary heart disease (CHD), has a low incidence in premenopausal women. Loss of ovarian hormones during the perimenopause and menopause leads to a sharp increase in incidence. Although most CHD risk factors are common to both men and women, the menopause is a unique additional risk factor for women. Sex steroids have profound effects on many CHD risk factors. Their loss leads to adverse changes in lipids and lipoproteins, with increases being seen in low density lipoprotein (LDL) cholesterol and triglycerides, and decreases in high density lipoprotein (HDL) cholesterol. There is a reduction in insulin secretion and elimination, but increases in insulin resistance eventually result in increasing circulating insulin levels. There are changes in body fat distribution with accumulation in central and visceral fat which links to the other adverse metabolic changes. There is an increase in the incidence of hypertension and of type 2 diabetes mellitus, both major risk factors for CHD. Oestrogens have potent effects on blood vessels and their loss leads to dysfunction of the vascular endothelium. All of these changes result from loss of ovarian function contributing to the increased development of CHD. Risk factor assessment in perimenopausal women is recommended, thereby permitting the timely introduction of lifestyle, hormonal and therapeutic interventions to modify or reverse these adverse changes.

The metabolic syndrome (MetS) comprises individual components including central obesity, insulin resistance, dyslipidaemia and hypertension and it is associated with an increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The menopause per se increases the incidence of MetS in aging women. The effect(s) of menopause on individual components of MetS include: i) increasing central obesity with changes in the fat tissue distribution, ii) potential increase in insulin resistance, iii) changes in serum lipid concentrations, which seem to be associated with increasing weight rather than menopause itself, and, iv) an association between menopause and hypertension, although available data are inconclusive. With regard to the consequences of MetS during menopause, there is no consistent data supporting a causal relationship between menopause and CVD. However, concomitant MetS during menopause appears to increase the risk of CVD. Furthermore, despite the data supporting the association between early menopause and increased risk of T2DM, the association between natural menopause itself and risk of T2DM is not evident. However, the presence and the severity of MetS appears to be associated with an increased risk of T2DM. Although the mechanism is not clear, surgical menopause is strongly linked with a higher incidence of MetS. Interestingly, women with polycystic ovary syndrome (PCOS) have an increased risk of MetS during their reproductive years; however, with menopausal transition, the risk of MetS becomes similar to that of non-PCOS women.

Premature ovarian insufficiency (POI) is defined as the cessation of ovarian function before the age of 40 years. The trio of amenorrhea, elevated gonadotropins and oestrogen deficiency is associated with long-term health consequences including increased cardiovascular disease (CVD), decreased bone mineral density (BMD), significantly reduced fertility, psychological distress, vulvovaginal atrophy, neurological effects and overall reduced life expectancy. There are deficits in our understanding of this condition and subsequently the long-term health consequences. The underlying aetiology of POI and the optimal management strategies are also poorly understood. Our knowledge of long-term cardiovascular consequences specifically relating to women with POI is limited as most data on the subject are derived from studies involving women who experienced menopause at the natural age (after 40 years with an average age of 51).

Vitamin D and calcium are considered crucial for the treatment of bone diseases. Both vitamin D and calcium contribute to bone homeostasis but also preserve muscle health by reducing the risk of falls and fractures. Low vitamin D concentrations result in secondary hyperparathyroidism and contribute to bone loss, although the development of secondary hyperparathyroidism varies, even in patients with severe vitamin D deficiency. Findings from observational studies have shown controversial results regarding the association between bone mineral density and vitamin D/calcium status, thus sparking a debate regarding optimum concentrations of 25-hydroxyvitamin D and calcium for the best possible skeletal health. Although most of the intervention studies reported a positive effect of supplementation with calcium and vitamin D on bone in patients with osteoporosis, this therapeutic approach has been a matter of debate regarding potential side effects on the cardiovascular (CV) system. Thus, the aim of this review is to consider the current evidence on the physiological role of vitamin D and calcium on bone and muscle health. Moreover, we provide an overview on observational and interventional studies that investigate the effect of vitamin D and calcium supplementation on bone health, also taking into account the possible CV side-effects. We also provide molecular insights on the effect of calcium plus vitamin D on the CV system.

Cancer treatment is an area of continuous improvement. Therapy is becoming more targeted and the use of anti-angiogenic agents in multiple cancers, specifically tyrosine kinase inhibitors (TKIs), has demonstrated prolonged survival outcomes compared with previous drugs. Therefore, they have become a well-established part of the treatment. Despite good results, there is a broad range of moderate to severe adverse effects associated with treatment. Hypertension (HTN) is one of the most frequent adverse effects and has been associated with favourable outcomes (in terms of cancer treatment) of TKI treatment. High blood pressure is considered a class effect of TKI treatment, although the mechanisms have not been fully described. Three current hypotheses of TKI-associated HTN are highlighted in this narrative review. These include nitric oxide decrease, a change in endothelin-1 levels and capillary rarefaction. Several studies have investigated HTN as a potential biomarker of TKI efficacy. HTN is easy to measure and adding this factor to prognostic models has been shown to improve specificity. HTN may become a potential biomarker in clinical practice involving treating advanced cancers. However, data are currently limited by the number of studies and knowledge of the mechanism of action.

Background: Triflusal has demonstrated an efficacy similar to aspirin in the prevention of vascular events in patients with acute myocardial infarction () and ischaemic stroke but with less bleeding events. Objective: We performed a randomised, multicentre, phase 4 clinical trial to compare the clinical efficacy and safety of triflusal versus aspirin, administered for 12 months in patients eligible to receive a cyclooxygenase-1 (COX-1) inhibitor. Methods: Patients with stable coronary artery disease or with a history of non-cardioembolic ischaemic stroke were randomly assigned to receive either triflusal 300 mg twice or 600 mg once daily or aspirin 100 mg once daily for 12 months. The primary efficacy endpoint was the composite of: (a) , (b) stroke (ischaemic or haemorrhagic), or, (c) death from vascular causes for the entire follow-up period. The primary safety endpoints were the rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria. Results: At 12-month follow-up, an equivalent result was revealed between the triflusal (n=559) and aspirin (n=560) in primary efficacy endpoint. Specifically, the combined efficacy outcome rate (i.e. MI, stroke or death from vascular causes) difference was equal to -1.3% (95% confidence interval -1.1 to 3.5) and lied within the a-priori defined equivalence interval (p<0.001). Regarding the primary safety endpoints, patients on triflusal treatment were 50% less likely to develop bleeding events according to the BARC criteria, and especially any clinically overt sign of haemorrhage that requires diagnostic studies, hospitalisation or special treatment (BARC type 2). Conclusion: The efficacy of triflusal in the secondary prevention of vascular events is similar to aspirin when administered for 12 months. Importantly, triflusal significantly reduced the incidence of and showed a better safety profile compared with aspirin. (ASpirin versus Triflusal for Event Reduction In Atherothrombosis Secondary prevention, ASTERIAS trial; Clinical Trials.gov Identifier: NCT02616497).