Postmenopausal hormone therapy and cardiovascular disease: an overview of main findings

Cardiovascular disease has emerged as a leading cause of death in women. In recent years, significant attention has been paid to the potential benefits of hormone therapy on chronic diseases such as cardiovascular disease. Large prevention trials failed to confirm the cardioprotective effect of estrogen. The divergent findings from observational and randomized clinical studies are summarized and reasons for the different results are postulated. Use of estrogen alone or estrogen opposed with progestins is not indicated for the prevention of cardiovascular disease and may even increase the risk of stroke. Oral estrogen increases venous thromboembolism events. Recent data suggest that transdermal estrogens are safe with respect to venous thromboembolism. Current data have limited ability to investigate the wide variety of hormone treatments available. Clinical research should be continued to assist patients and clinicians in making treatment decisions on the basis of an individual's benefits and risks.     

Female specific risk factors for the development of Alzheimer’s disease neuropathology and cognitive impairment: Call for a precision medicine approach

Alzheimer's disease (AD) includes a long asymptomatic stage, which precedes the formal diagnosis of dementia. AD biomarker models provide a framework for precision medicine approaches during this stage. However, such approaches have ignored the possible influence of sex on cognition and brain health, despite female sex noted as a major risk factor. Since AD-related changes may emerge in midlife, intervention efforts are being redirected around this period. Midlife coincides with several endocrinological changes, such as the menopausal transition experienced by women. In this narrative review, we discuss evidence for sex-differences in AD neuropathological burden and outline key endocrinological mechanisms for both sexes, focussing on hormonal events throughout the lifespan that may influence female susceptibility to AD neuropathology and dementia onset. We further consider common non-modifiable (genetic) and modifiable (lifestyle and health) risk factors, highlighting possible sex-dependent differential effects for the AD disease course. Finally, we evaluate the studies selected for this review demonstrating sex-differences in cognitive, pathological and health factors, summarising the state of sex differences in AD risk factors. We further provide recommendations for targeted research on female-specific risk factors, to inform personalised strategies for AD-prevention and the promotion of female brain health.     

Tissue specificity: the clinical importance of steroid metabolites in hormone replacement therapy

Metabolic activations or inactivations of estrogens, progesterone and androgens are important steps towards the understanding of the physiological and the pathological effects of these hormones in the female organism. Analysis of the tissue specific metabolic pathways of sex steroids will result in a better understanding of successful hormone replacement therapy on the one hand and of the occurrence of steroid hormone related side effects on the other hand. In this contribution we analyse the different mechanisms involved in the synthesis of tissue specific metabolites and discuss the therapeutical importance of these metabolites in hormone replacement therapy.     

Do women using hormone replacement treatment have less pre-existing cardiovascular risk

Background: Several studies have suggested that women who choose to use hormone replacement therapy (HRT) already, before starting this therapy, have a better cardiovascular risk profile than those who do not use it. Some of these studies contain factors of confusion and biases, such as HRT users’ greater educational achievement or physical activity, which could have led to wrong conclusions. Aim: To study a cohort, without confounding factors in order to analyse whether the cardiovascular risk profile is different in women who choose to use HRT. Material and methods: Coronary risk factors of 387 women between 45 and 64 were studied. This study was carried out at the Unit for the Preventive Medical Examination of the South Metropolitan Health Service in Santiago (Chile) during the annual check-up. The first evaluation was in 1991–1992; with a second evaluation 5 years later. Of all the women, 174 (45%) never received hormones (Group A), 124 (32%) were HRT users at the time (Group B), and 89 (23%) were former-users (Group C). Results: No differences were found between the three groups for age, body mass index (BMI), educational background, alcohol consumption, smoking or physical activity. Blood pressure was similar in the three groups. No significant differences were found in total cholesterol (A, 221.7±42.2; B, 228.2±47.0; and C, 227.3±44.9 mg/dl); high density lipoprotein (HDL, A, 53.5±13.2; B, 51.8±12.8; and C, 54.0±12.4 mg/dl); low density lipoprotein (LDL, A, 141.7±38.9; B, 148.5±43.1 and C, 148.3±43.8 mg/dl); triglycerides (A, 134.5±67.9; B, 141.0±66.1; and C, 127.3±68.5 mg/dl) and glucose plasma levels (A, 90.5±32.2; B, 87.7±15.3; and C, 85.0±8.8 mg/dl). Conclusions: Our results suggest that women who choose to use HRT have a cardiovascular risk profile, before starting the therapy, similar to those who do not use it.     

Estrogens,hormone therapy,and hippocampal volume in postmenopausal women

The brain atrophies in late life. However, there are many factors that either magnify or mitigate the rate of atrophy. Loss of estrogens during menopause and administration of hormone therapy have both been hypothesized as sources of individual variation in the prevalence of cortical and subcortical atrophy and loss of cognitive function in late adulthood. In this review we critically summarize and assess the extant rodent and human neuroimaging studies that examine the link between estrogens and hippocampal morphology and function and focus predominantly on human studies of the hippocampus in postmenopausal women. Several cross-sectional studies report that the size of the hippocampus is larger in women receiving hormone therapy while several other cross-sectional studies report either negligible effects or smaller volumes in women receiving hormone therapy. We suggest that these differences might be caused by the variation between studies in the age of the samples studied, the duration of therapy, and the age at which hormone therapy is initiated. Unfortunately, all of the human studies reviewed here are cross-sectional in nature. With the lack of well-controlled randomized trials with neuroimaging measures on postmenopausal women both before and after some exposure interval, the effect of hormone therapy on hippocampal atrophy will remain equivocal and poorly understood.     

Hormone replacement therapy and hemostasis: principles of a complex interaction

Postmenopausal women on hormone replacement therapy (HRT) have been shown to be at reduced risk of arterial thrombotic disease. The risk of venous thrombosis appears not to be increased in HRT users in the absence of specific risk factors. However, while these data refer predominantly to women using conjugated equine estrogens, it is less clear whether the favourable impact on cardiovascular diseases may also be achieved by other preparations. Dose, as well as route of application and, particularly, the combination of steroids have been shown to affect both the clinical and the metabolic profile. With regard to cardiovascular diseases, differential effects on the hemostatic system are of particular interest. The principles of the interaction of steroids with the hemostatic system are reviewed. Also, the principal limitations of the assessment of the hemostatic system, as well as its interpretation, with regard to cardiovascular diseases are discussed. It is proposed to view the hemostatic system predominantly as a monitor of endothelial function rather than as a mediator of potential harmful effects on the cardiovascular system.     

The role of premorbid personality and cognitive factors in awareness of illness,memory, and behavioural functioning in Alzheimer's disease

Introduction. Research has suggested an association between personality factors and awareness in patients with dementia, yet valid measurement of premorbid personality is problematic. The present study aimed to better reveal the relationship between premorbid personality and awareness by using improved methodology. Moreover, the study aims to contrast the strength of the relationship of premorbid personality and awareness with that of cognitive factors.

Methods. Awareness of illness, symptoms, mnemonic and behavioural impairments, and treatment compliance were measured in 27 patients with mild-to-moderate Alzheimer's disease (AD) diagnosed by standard criteria for probable AD. Participant premorbid personality was measured using average retrospective Neuroticism-Extroversion-Openness Inventory (NEO-FFI) scores from two informants. Correlations were performed to investigate the relationship between awareness and personality dimensions, as well as measures of cognitive style, neuropsychological function, mood, carer burden, and sociodemographic factors.

Results. There was little relationship between awareness and personality scores, but modest associations between awareness and mood, age, and age of onset of first symptoms. Awareness of memory was related to memory functioning. Increased carer burden was associated with lack of awareness of cognitive-behavioural deficits but there were only few and weak associations between awareness and measures of cognitive functioning.

Conclusions. There was little support for an association between previous personality and awareness in dementia. However, increased carer burden was associated specifically with lack of awareness of cognitive-behavioural deficits not deficits in ADL, whereas lower awareness of ADL and not cognitive-behavioural deficits was associated with age. Awareness of memory appeared to be a metamemory capacity. Mood and age rather than personality and cognition are stronger predictors of awareness in early Alzheimer's disease.     

Menopausal hormone therapy and risk of lung cancer—Systematic review and meta-analysis

Objectives

Lung cancer rates increase among women in many regions of the world. To explore whether menopausal hormone therapy (MHT) plays a role.

Methods

We conducted a systematic search of the literature and performed meta-analyses of cohort studies (C), case–control studies (CC), randomized controlled trials (RCTs), and cancer registry studies (CR) to analyse the impact of estrogen therapy (ET), estrogen/progestin therapy (EPT) and any hormone therapy (HT) on lung cancer risks. We explored associations between ever-use of therapies and risks, analysed annual changes of risk, and the impact of therapies on histological subtypes. We calculated summary odds ratios, relative risks, 95% confidence intervals (CI; fixed-effects model), and assessed heterogeneity across studies. Eighteen studies were eligible (9 CC, 4 C, 3 RCT, 2 CR).

Results

We found a significant increase of risk – 76.2% – in non-smoking women with adenocarcinoma (CI 1.072–2.898) reporting ever-use of HT. Estrogen plus progestin therapy does not change the risk; however, the pooled analysis of 2 RCTs points at an increased risk (RR 1.359; CI 1.031–1.791). Our further results should be interpreted with caution as significances were found in analyses only when smoking and non-smoking women, various hormone regimens, or histological subtypes, respectively, were pooled.

Conclusions

Dedicated studies designed to more adequately delineate the role of MHT are necessary to substantiate whether use of MHT is a risk factor for this or other types of lung cancer.     

HRT and heart disease: problems and prospects

The divergent findings of hormone replacement therapy (HRT) from observational and randomized clinical studies are summarized and reasons for the different results are postulated. Chronic use of HRT since menopause has no harmful effects on CHD event rate, while the initiation of therapy after a recent cardiovascular event causes an early increase in recurrent CHD events. Once endothelial dysfunction and atherosclerotic disease has developed, the starting of HRT promotes plaque instability, vascular inflammation and prothrombotic effects. The timing of HRT use since menopause is therefore crucial in the effectiveness and safety of HRT on the vascular system.     

Cardiovascular risk factors and lifetime risk estimation in HIV-infected patients under antiretroviral treatment in Spain

Background and objectives:

Cardiovascular disease is a major concern in HIV-infected patients. Lifetime risk estimations use the risk of developing it over the course of remaining lifetime, and are useful in communicating this risk to young patients. We aim to describe the prevalence of cardiovascular risk factors among a representative sample of HIV-infected subjects under antiretroviral therapy in Spain, and to estimate their lifetime risk of cardiovascular disease.

Methods:

Cross-sectional survey about cardiovascular risk factors in 10 HIV units across Spain. Lifetime risk assessed according to Barry was classified in two major categories: low and high lifetime risk.

Results:

We included 895 subjects, 72% men, median age 45.7?years; median CD4 lymphocyte count 598?cells/μl, median time since HIV diagnosis 11?years, median time on antiretroviral treatment 6.3?years, 87% had undetectable HIV viral load. Tobacco smoking was the most frequent risk factor (54%), followed by dyslipidemia (48.6%) and hypertension (38.6%). Estimated 10-year coronary risk (Framingham/Regicor Risk Score) risk was low (?Conclusions:

Modifiable cardiovascular risk factors in this population are very common. There are significant disparities between the low 10-year risk estimated with the Framingham/Regicor score and the higher lifetime risk in HIV patients on antiretroviral therapy. A more aggressive management of modifiable cardiovascular risk factors in these patients seems advisable.     

Characteristics of familial aggregation in early-onset Alzheimer's disease: Evidence of subgroups

Characteristics of familial aggregation of Alzheimer's Disease were studied in 92 families ascertained through a clinically diagnosed proband with an onset below age 60 years. In each family data were systematically collected on the sibships of the proband, of his father, and of his mother. A total of 926 relatives were included and 81% of the living relatives (i.e., 251 individuals) were directly examined. The estimated cumulative risk among first degree relatives was equal to 35% by age 89 years (95% confidence interval 22 to 47%). This result does not support the hypothesis that an autosomal dominant gene, fully penetrant by age 90 years, is segregating within all these pedigrees. Despite the fact that all probands were selected for an onset before age 60 years it was shown that two types of families could be delineated with respect to age at onset among affected relatives: all secondary cases with an onset below age 60 years were contributed by a particular group of families (type 1 families), whereas all secondary cases with an onset after age 60 years were contributed by another group of families (type 2 families). Although genetic interpretation of these findings is not straightforward, they support the hypothesis of etiologic heterogeneity in the determinism of early-onset Alzheimer's disease. © 1995 Wiley-Liss, Inc.     

The benefits of androgens combined with hormone replacement therapy regarding to patients with postmenopausal sexual symptoms

OBJECTIVE: To evaluate the benefits and risks of hormone replacement therapy (HRT) combined with methyltestosterone (MT) in postmenopausal women with sexual dysfunction. DESIGN: This study was a randomized, double-blind, placebo-controlled and crossover trial. Eighty-five women using HRT were divided into four treatment groups: GI-HRT plus placebo for 4 months; GII-HRT plus MT 2.5mg/day for 4 months; GIII-HRT plus placebo for 2 months and then replaced with HRT plus MT 2.5mg/day for 2 months; GIV-HRT plus MT 2.5mg/day and then replaced with HRT plus placebo for 2 months. Blood was collected at baseline, after 2 months (T1) and 4 months (T2) of treatment for hormone determinations of estradiol, FSH, total and free testosterone, GOT, GPT, glucose, total and fractions of cholesterol and triglycerides. All participants answered clinical questions and a validated questionnaire of modified McCoy's sex scale. RESULTS: The association of HRT with MT 2.5mg/day did not significantly change liver enzymes or increase cardiovascular risk factors. The patients of GII, GIIII and GIV when using MT presented amelioration of sex symptoms, mainly satisfaction and desire (p<0.01); however, GIII at T1 (1.3+/-0.3) presented similar problem score results as compared to GIII at T2 (1.5+/-0.6). CONCLUSION: All data suggest that combined HRT-androgen therapy may be beneficial for postmenopausal women receiving HRT who continue to complain of sexual difficulties or for postmenopausal women with sexual complaints who are not undergoing estrogen therapy.     

The health benefits of berry flavonoids for menopausal women: Cardiovascular disease, cancer and cognition

There is an increasing amount of research into the health benefits of berry flavonoids. Moreover, the consumption of flavonoid-rich food is on the increase; with women in particular showing a interest in eating a diet which may benefit their long-term health. The aim of this review was to examine the evidence for the benefits of berry flavonoids for cardiovascular health, cancer and cognition in the menopausal woman. Due to the limited amount of clinical data on this subject both in vitro and animal as well as human studies have been included.These data appear to support epidemiological studies that suggest cardiovascular benefits, cancer prevention and cognitive improvement from berry flavonoid consumption. However to date, it is not possible to be definitive about the specific berry type, preparation or regime which confers maximum benefits, or to give specific advice to menopausal women. Limited data from a combination of pre-clinical and clinical studies suggest that the addition of berry flavonoids to the diet has moderate effects on cardiovascular function in subjects at risk and potential preventative effects in oesophageal cancer. Evidence for cognitive benefits is limited to animal data but shows promise.     

Oral contraceptives, menopause hormone replacement therapy, and risk of stroke

Objectives: To review available evidence from observational and intervention studies on oral contraceptives (OC), menopause hormone replacement therapy (HRT) and stroke. Methods: Qualitative literature review. Results: High dose OC were associated to elevated risk of stroke. However, the use of low oestrogen OC preparations by non-hypertensive women not at high baseline risk is not related to an appreciable risk of stroke. With reference to HRT, randomised clinical trials showed an excess risk of stroke among users of combined therapy. Conclusions: In non-hypertensive women below age 35 stroke is not materially related to the use of low dose OC. HRT is associated to a moderate excess risk in randomised studies, and should therefore not be used for the prevention of stroke.     

Cardiovascular risk markers during treatment with estradiol and trimegestone or dydrogesterone

Objective

To study cardiovascular risk markers in women taking estradiol/trimegestone or estradiol/dydrogesterone.

Design

Multicenter, randomized, prospective, double-blind study of 184 healthy post-menopausal women randomized to 6 cycles of either estradiol (2 mg) + trimegestone (0.5 mg) (T-group) or estradiol (2 mg) + dydrogesterone (10 mg) (DYDR group). Cardiovascular risk markers were measured before, after cycle 1, 3 and 6 and at 4 weeks post-treatment.

Results

Fibrinogen was reduced in both groups but more markedly in the DYDR group. Factor VIIc activity levels decreased in both groups with a greater change in the T-group. Factor VII antigen was increased in both groups with a greater increase in the DYDR group. Factor VIIa was increased in the DYDR group only. Plasminogen levels were also increased in both groups with a greater increase in the T-group. There were no statistically significant changes in lipid variables between the different regimens. Changes in total cholesterol and LDL cholesterol were correlated positively with changes in factor VIIc in the DYDR group and negatively with changes in factor VIIc in the T-group.Trigemestone was associated with a better bleeding pattern.

Conclusions

Trimegestone was associated with less procoagulant changes in factor VIIa and factor VIIc activity and larger decrease in PAI-1 activity compared with the dydrogesterone preparation. These results reflect less androgenic properties of the trimegestone preparation. The fibrinogen level and Lp(a) were more decreased during dydrogesterone treatment. Further investigation is required to clarify the relative importance of beneficial effects with respect to cardiovascular risk.     

Use of hormone replacement therapy: women's representations of menopause and beauty care practices

Objectives: Hormone replacement therapy (HRT) during menopause has been shown to have beneficial effects on women’s health, including preventing osteoporosis and probably reducing cardiovascular mortality and morbidity. However, these effects appear only after long use. Knowledge of factors influencing HRT use is a prerequisite for developing and assessing preventive actions. Most studies of user characteristics have focused on medical knowledge and socioeconomic characteristics, although social and cultural models of menopause may also play a role. Therefore, our study of the determinants of HRT use focused on representations of menopause and on beauty care. Methods: Two scores, one concerning the level of beauty care and the other the representations of menopause, were calculated. In our population of 561 postmenopausal women from the GAZEL cohort in France, 409 (72.9%) had been using HRT for more than one year, and 152 (27.1%) had used it for less than three months, if ever. Associations between the study variables and HRT use were then analysed. Results: No association was found between representations of menopause and HRT use. Beauty care and some beliefs about HRT (i.e. that it is useful for osteoporosis prevention, causes resumption of menstruation, and has anti-aging effects) were independently associated with HRT use. Moreover, the proportion of HRT users increased with socioeconomic status, with vasomotor symptoms in early menopause, and among hysterectomised women. Conclusions: The results suggest that the amount of attention women pay to beauty care plays a role, in determining HRT use.