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Postmenopausal Hormone Therapy and Risk of Stroke : The Heart and Estrogen-progestin Replacement Study (HERS)
Abstract
Observational studies have shown that postmenopausal hormone therapy may increase, decrease, or have no effect on the risk of stroke. To date, no clinical trial has examined this question. To investigate the relation between estrogen plus progestin therapy and risk of stroke among postmenopausal women, we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial.
Postmenopausal women (n=2763) were randomly assigned to take conjugated estrogen plus progestin or placebo. Primary outcomes for these analyses were stroke incidence and stroke death during a mean follow-up of 4.1 years. The number of women with strokes was compared with the number of women without strokes. A total of 149 women (5%) had 1 or more strokes, 85% of which were ischemic, resulting in 26 deaths. Hormone therapy was not significantly associated with risk of nonfatal stroke (relative hazard [RH] 1.18; 95% CI 0.83 to 1.66), fatal stroke (RH 1.61; 95% CI 0.73 to 3.55), or transient ischemic attack (RH 0.90; 95% CI 0.57 to 1.42). Independent predictors of stroke events included increasing age, hypertension, diabetes, current cigarette smoking, and atrial fibrillation. Black women were at increased risk compared with white women, and unexpectedly, body mass index was inversely associated with stroke risk.
Hormone therapy with conjugated equine estrogen and progestin had no significant effect on the risk for stroke among postmenopausal women with coronary disease.
... Postmenopausal hormone therapy (HT) is recognized as the most effective treatment currently available for menopausal symptoms [1,2]. Nevertheless, findings of a number of observational studies and randomized controlled trials (RCTs) of the influence of HT on stroke risk have been inconsistent [3][4][5][6][7][8][9]. A systematic review based on 10 RCTs concluded that oral HT in postmenopausal women increases the risk of stroke [10]. ...
... Our finding that HT users had a similar stroke risk compared to never users is in agreement with the results from some observational studies [18], as well as from 2 RCTs: the Heart and Estrogen/Progestin Replacement Study (HERS) [3] and the Women's Estrogen for Stroke Trial (WEST) [4]. By contrast, the Nurses' Health Study (NHS) [20] and the Women's Health Initiative (WHI) [21,35] reported an increased risk of stroke, although neither timing of HT initiation nor regimens other than oral CEE therapy were considered. ...
... The majority of studies on HT and stroke risk have considered only oral administration [3,4,14,18,21]. However, among the different routes of administration, transdermal HT has been postulated as safer compared to oral HT with regard to stroke risk [38][39][40][41]. ...
Background
Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.
Methods and findings
Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987–2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI −0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0–5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, −4.41 years; 95% CI −7.14 to −1.68) and haemorrhagic stroke-free (first PD, −9.51 years; 95% CI −12.77 to −6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, −1.97 years; 95% CI −3.81 to −0.13), but not with a shorter stroke-free period (fifth PD, −1.21 years; 95% CI −3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.
Conclusions
When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0–5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.
... Early menopause (before 45 years of age) increases the risk of stroke [8]. In as much as E2 appears to be protective in premenopausal females, it can also increase the risk of stroke when given to females many years after postmenopausal [9][10][11][12][13]. While the neuroprotective effects of E2 is less clear in humans [9,10,[14][15][16][17][18][19], E2 treatment in female and male rodent models of stroke reduces infarct volumes or improves neurological deficits [20][21][22][23][24][25]. ...
... In as much as E2 appears to be protective in premenopausal females, it can also increase the risk of stroke when given to females many years after postmenopausal [9][10][11][12][13]. While the neuroprotective effects of E2 is less clear in humans [9,10,[14][15][16][17][18][19], E2 treatment in female and male rodent models of stroke reduces infarct volumes or improves neurological deficits [20][21][22][23][24][25]. This highlights the need to understand how sex and E2 mechanistically mediate this protection. ...
Estrogens, such as the biologically active 17-β estradiol (E2), regulate not only reproductive behaviors in adults, but also influence neurodevelopment and neuroprotection in both females and males. E2, contingent upon the timing and concentration of the therapy, is neuroprotective in female and male rodent models of stroke. In Vivo studies suggest that E2 may partially mediate this neuroprotection, particularly in the cortex, via ERα. In Vitro studies, utilizing a chemically induced ischemic injury in cortical explants from both sexes, suggest that ERα or ERβ signaling is needed to mediate the E2 protection. Since we know that the timing and concentration of E2 therapy may be sex-specific, we examined if E2 (1 nM) mediates neuroprotection when female and male cortical explants are separately isolated from postnatal day (PND) 3–4 rat. Changes in basal levels ERα, ERβ, and AR mRNA expression are compared across early post-natal development in the intact cortex and the corresponding days in vitro (DIV) for cortical explants. Following ischemic injury at 7 DIV, cell death and ERα, ERβ and AR mRNA expression was compared in female and male cortical explants. We provide evidence that E2-mediated protection is maintained in isolated cortical explants from females, but not male rats. In female cortical explants, the E2-mediated protection at 24 h occurs secondarily to a blunted transient increase in ERα mRNA at 12 h. These results suggest that cortical E2-mediated protection is influenced by sex and supports data to differentially treat females and males following ischemic injury.
... 82 Results may have differed as this was a smaller placebo-controlled, randomized, double-blind study of 969 women that assessed the effect of conjugated estrogen (0.625 g d -1 ) plus medroxy-progesterone acetate (2.5 mg d -1 ) in a single daily tablet rather than just estrogen alone on postmenopausal women with documented coronary disease. 83 At the 4-year follow-up visit, 24% of the treated group compared with 26% of the placebo control had frequent knee symptoms (95% CI: -7.4% to 3.5%) and had almost identical Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score and disability score. Results per protocol did not change materially from that of intent-to-treat. ...
Osteoarthritis (OA) is a leading cause of chronic pain and disability, not only in the United States but also worldwide. The burden of OA is higher in women than in men. Estrogen as a possible explanation for observed sex differences in OA has not been definitively established. The purpose of this review was to summarize the results from studies of estrogen, estrogen depletion and treatment, and their impact on knee, hip, hand, and spine OA. We conducted a targeted review of the literature using PubMed. Although several studies show that hormone replacement therapy has the potential to be protective of OA for some joints, there are studies that showed no protective effect or even adverse effect. Taken together, the evidence for the protective effect of estrogen therapy depends on OA joint, OA outcome, and study design. Although this area has been studied for decades, more exclusively since the 1990s, there is a lack of high-quality experimental research in this topic. The lack of definitive conclusion on whether estrogen can play a role in the development in OA of either the knee, hip, spine, or hand is often in part due to the noncomparability of studies existing within the literature. Differences in diagnostic criteria, imaging modalities, populations studied, study designs, and outcome measures, as well as random error, have all contributed to inconclusive evidence. Future research on the role of estrogen in OA is needed, particularly as global demographic shifts in increasing overweight/obesity prevalence and ageing populations may contribute to widening OA-related health inequalities.
... Women's Health Initiative, Heart and Estrogen-Progestin Replacement Study 2 (HERS2), and HERS studies do not support the beneficial vascular effects of hormone replacement therapy in postmenopausal women. [8,9] Receptors for estrogen, progesterone, and testosterone are expressed in endothelium and vascular smooth muscle of multiple vascular systems. [10,11] It is one of the proposed mechanism responsible for gender difference in vascular tone. ...
Objectives: Higher testosterone and lower Estrogen levels are associated with cardiovascular disease in women. However, studies on endogenous sex hormones and acute coronary syndrome (ACS) in pre-menopausal women are sparse. Material and Methods: We studied 50 pre-menopausal women presenting with ACS and age-matched controls who consented to the study with Testosterone, Estradiol, and Sex hormone-binding globulin (SHBG) levels at baseline. They were clinically followed up for 6 months duration. Results: The mean age was 37.42 ± 5.7 years. 48% patients were obese. The mean body mass index was 27.53 ± 5.41 kg/m 2. Hypertension followed by Diabetes was the most common risk factor. 14% had family history of coronary artery disease (CAD). 24% had atypical chest pain at presentation. Anterior wall ST elevation myocardial infarction was the most common presentation. Single-vessel disease was seen in 38%; 24% had Non-Obstructive CAD. Ratios of Bioavailable Testosterone: Estradiol, Estradiol: Low-density Lipoprotein (LDL), Estradiol: High-density Lipoprotein, SHBG: LDL, and SHBG: HbA1c were analyzed in cases and controls and were not found to be significantly associated. Conclusion: Endogenous sex hormones were not found to be significantly associated with ACS in premenopausal women.
... Women's Health Initiative, Heart and Estrogen-Progestin Replacement Study 2 (HERS2), and HERS studies do not support the beneficial vascular effects of hormone replacement therapy in postmenopausal women. [8,9] Receptors for estrogen, progesterone, and testosterone are expressed in endothelium and vascular smooth muscle of multiple vascular systems. [10,11] It is one of the proposed mechanism responsible for gender difference in vascular tone. ...
Objectives
Higher testosterone and lower Estrogen levels are associated with cardiovascular disease in women. However, studies on endogenous sex hormones and acute coronary syndrome (ACS) in pre-menopausal women are sparse.
Material and Methods
We studied 50 pre-menopausal women presenting with ACS and age-matched controls who consented to the study with Testosterone, Estradiol, and Sex hormone-binding globulin (SHBG) levels at baseline. They were clinically followed up for 6 months duration.
Results
The mean age was 37.42 ± 5.7 years. 48% patients were obese. The mean body mass index was 27.53 ± 5.41 kg/m ² . Hypertension followed by Diabetes was the most common risk factor. 14% had family history of coronary artery disease (CAD). 24% had atypical chest pain at presentation. Anterior wall ST elevation myocardial infarction was the most common presentation. Single-vessel disease was seen in 38%; 24% had Non-Obstructive CAD. Ratios of Bioavailable Testosterone: Estradiol, Estradiol: Low-density Lipoprotein (LDL), Estradiol: High-density Lipoprotein, SHBG: LDL, and SHBG: HbA1c were analyzed in cases and controls and were not found to be significantly associated.
Conclusion
Endogenous sex hormones were not found to be significantly associated with ACS in premenopausal women.
... There is limited evidence that estrogens combined with oral micronized progesterone applied for more than 5 years are associated with an increased breast cancer risk [97]. Despite its favourable effect on lipids and the belief that it may be beneficial in preventing cardiovascular disease [98,99], HT (especially with oral estrogen) may increase coagulability and has not been shown to protect against cardiovascular disease or stroke [73,[100][101][102]. Ultimately, the benefits of HT in symptomatic women appear to outweigh the risks and it is therefore recommended as first-line medical treatment for vasomotor and urogenital symptoms in menopause [84,87]. ...
Perimenopause marks the transition from a woman’s reproductive stage to menopause. Usually occurring between 42 and 52 years of age, it is determined clinically by the onset of irregular menstrual cycles or variable cycle lengths. Women are at an increased risk of depression and anxiety during perimenopause and the menopausal transition. Depressive symptoms experienced in perimenopause are often more severe compared to pre- and post-menopause. During menopausal transition, the impact of fluctuating estrogen in the central nervous system (CNS) can have negative psychological effects for some women. Traditional first-line management of menopausal depression involves antidepressants, with modest outcomes. The positive effects of estrogen treatment in the CNS are becoming increasingly recognised, and hormonal therapy (HT) with estrogen may have a role in the treatment of menopausal depression. In this review we will outline the prevalence, impact and neurochemical basis of menopausal-associated depression, as well as hormone-based approaches that have increasing promise as effective treatments.
... However, the use of hormone replacement therapy (HRT) in postmenopausal women has yielded disappointing results. The Women's Estrogen for Stroke Trial and Heart and Estrogen-Progestin Replacement Study failed to show any stroke reduction benefit from HRT [126,127]. Furthermore, the Women's Health Initiative (WHI) study showed that exogenous estrogen actually increased the risk of stroke among postmenopausal women [128]. The link between estrogen and ischemic stroke may be complex and depend on age, timing, dose, and other factors [129]. ...
Purpose of Review
The menstrual cycle involves recurrent fluctuations in hormone levels and temperature via neuroendocrine feedback loops. This paper reviews the impact of the menstrual cycle on several common neurological conditions, including migraine, seizures, multiple sclerosis, stroke, and Parkinson’s disease.
Recent Findings
The ovarian steroid hormones, estrogen and progesterone, have protean effects on central nervous system functioning that can impact the likelihood, severity, and presentation of many neurological diseases. Hormonal therapies have been explored as a potential treatment for many neurological diseases with varying degrees of evidence and success. Neurological conditions also impact women’s reproductive health, and the cessation of ovarian function with menopause may also alter the course of neurological diseases.
Summary
Medication selection must consider hormonal effects on metabolism and the potential for adverse drug reactions related to menstruation, fertility, and pregnancy outcomes. Novel medications with selective affinity for hormonal receptors are desirable. Neurologists and gynecologists must collaborate to provide optimal care for women with neurological disorders.
... 12 El estudio HERS evidencia que existe un aumento de la enfermedad vesicular en las pacientes con terapia hormonal de reemplazo, y los eventos venosos tromboembólicos fueron 3 veces más comunes que en el grupo placebo, aunque la mortalidad total fue igual en ambos grupos 24 , pero no hubo efecto signifi cativo en el riesgo de enfermedad cerebrovascular de las postmenopáusicas con enfermedad coronaria. 56 Idénticos riesgos fueron confi rmados por el seguimiento de la investigación anterior de 6.8 años (HERS II). 46 El estudio WHI refi ere que el peligro de cáncer de seno estuvo directamente relacionado con la duración de la terapia. ...
El uso de la terapia de reemplazo hormonal oral ha sido una controversia en los últimos años, como consecuencia de una serie de estudios aleatorios que contradicen los lineamientos anteriores. Algunos autores refi eren sus observaciones respecto a estas investigaciones, así como las limitaciones. Sin embargo, se demuestra que las únicas indicaciones que persisten para su uso son el tratamiento del síndrome menopáusico, al menor tiempo y la menor dosis posible, y como segunda elección, la osteoporosis. El objetivo de esta revisión es ofrecer un apoyo a los profesionales en medicina que prescriben terapia de reemplazo hormonal en mujeres menopáusicas mayores de 50 años.
... Studies have shown that transdermal oestrogen is associated with a lower risk while progesterone only HRT is not associated with an increased risk of VTE [88,89]. There is a wealth of literature showing the increased incidence of stroke in women on either oestrogen only or oestrogen-progestin HRT [90][91][92]. The current users of transdermal or oral HRT have a higher risk of stroke than non-users [93]. ...
BACKGROUND: Throughout history, menopause has been regarded as a transition in a woman's life. With the increase in life expectancy, women now spend more than a third of their lives in menopause. During these years, women may experience intolerable symptoms both physically and mentally, leading them to seek clinical advice. It is imperative for healthcare providers to improve the quality of life by reducing bothersome menopausal symptoms and preventing disorders such as osteoporosis and atherosclerosis. The current treatment in the form of hormone replacement therapy (HRT) is sometimes inadequate with several limitations and adverse effects. Objective and rationale: The current review aims to discuss the need, efficacy, and limitations of current HRT; the role of other ovarian hormones, and where we stand in comparison with ovary-in situ; and finally, explore towards the preparation of an HRT model by regeneration of ovaries tissues through stem cells which can replicate a functional ovary.
... The Heart and Estrogen/Progesterone Replacement Study (HERS) Trial did not demonstrate any benefit of hormone therapy among postmenopausal women who had a MI. 406,407 The Women's Health Initiative (WHI), which examined the role of hormonal therapy for the primary prevention of cardiovascular disease and stroke among postmenopausal women, was stopped early because of an increase in vascular events. 408 An increased stroke risk among women with a previous hysterectomy who were randomized to hormonal therapy was also observed in a separate parallel trial. ...
The aim of this new statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches for atherosclerotic disease, antithrombotic treatments for cardioembolism, and the use of antiplatelet agents for noncardioembolic stroke. Further recommendations are provided for the prevention of recurrent stroke in a variety of other specific circumstances, including arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly with regard to pregnancy and the use of postmenopausal hormones; the use of anticoagulation after cerebral hemorrhage; and special approaches for the implementation of guidelines and their use in high-risk populations.
... Several randomized clinical trials were designed to examine whether HRT could reduce the incidence or severity of ischemic stroke in postmenopausal women. Unfortunately, two of these trials found no benefit of HRT after menopause on ischemic stroke rates (72,73). Two additional trials found that postmenopausal women receiving HRT were at increased risk for ischemic stroke and experienced more severe strokes compared with women in the placebo arm (74,75). ...
Ischemic stroke is a devastating brain injury, resulting in high mortality and significant loss-of-function. Understanding the pathophysiology of ischemic stroke risk, mortality and functional loss is critical to novel therapeutic development. Age and sex have a complex and interactive effect on ischemic stroke risk and pathophysiology. Aging is the strongest non-modifiable risk factor for ischemic stroke, and aged stroke patients have higher mortality, morbidity and poorer functional recovery than their young counterparts. Importantly, patient age modifies the influence of patient sex in ischemic stroke. Early in life, the burden of ischemic stroke is higher in males, but becomes more common and debilitating for women in elderly populations. The profound effects of sex and age on clinical ischemic stroke are mirrored in the results of experimental in vivo and in vitro studies. Here, we will review current knowledge on the influence of age and sex in ischemic stroke incidence, mortality and functional outcome in clinical populations. We will also discuss the experimental evidence for sex- and age- differences in stroke pathophysiology, and how a better understanding of these biological variables can improve clinical care and enhance novel therapeutic development.
... 39 Similar results have been found in secondary cardiovascu- lar prevention. Both the HERS (Heart and Estrogen/Progestin Replacement Study) in women with prior coronary heart dis- ease 43 and the WEST (Women's Estrogen for Stroke Trial) in women with recent mild ischemic stroke or transient ischemic attack 44 found no significant effect of treatment with oral estrogen or combined oral estrogen and progestin on risk of stroke, with a trend toward harm. ...
... 26,27 Also, TE has beneficial effects in the vascular system in premenopausal women, whereas in postmenopausal women, large clinical trials have reported use of exogenous estradiol, which increases circulating estrogen levels, to increase risk of stroke. 28,29 Women's Health Initiative clinical trials reported harmful effect of HT on ischemic stroke risk in women >50 years of age. 30,31 Observational data from the Nurses' Health Study confirmed those findings. ...
Rationale:
Sex steroids may play a role in plaque composition and in stroke incidence.
Objectives:
To study the associations of endogenous estradiol and testosterone with carotid plaque composition in elderly men and postmenopausal women with carotid atherosclerosis, as well as with risk of stroke in this population.
Methods and results:
Data of 1023 postmenopausal women and 1124 men (≥45 years) with carotid atherosclerosis, from prospective population-based RS (Rotterdam Study), were available. At baseline, total estradiol (TE) and total testosterone (TT) were measured. Carotid atherosclerosis was assessed by ultrasound, whereas plaque composition (presence of calcification, lipid core, and intraplaque hemorrhage) was assessed by magnetic resonance imaging. TE and TT were not associated with calcified carotid plaques in either sex. TE was associated with presence of lipid core in both sexes (in women odds ratio, 1.48 [95% confidence interval [CI], 1.02-2.15]; in men odds ratio, 1.23 [95% CI, 1.03-1.46]), whereas no association was found between TT and lipid core in either sex. Higher TE (odds ratio, 1.58 [95% CI, 1.03-2.40]) and lower TT (odds ratio, 0.82 [95% CI, 0.68-0.98]) were associated with intraplaque hemorrhage in women but not in men. In women, TE was associated with increased risk of stroke (hazard ratio, 1.98 [95% CI, 1.01-3.88]), whereas no association was found in men. TT was not associated with risk of stroke in either sex.
Conclusions:
TE was associated with presence of vulnerable carotid plaque as well as increased risk of stroke in women, whereas no consistent associations were found for TT in either sex.
... However, multiple lines of evidence support an increased risk of breast cancer with estrogen use, including cell culture studies, [38], animal models, [39] and epidemiological studies [40][41][42]. In the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative studies, the risk of breast cancer in postmenopausal women was increased about 25% in those taking estrogen plus progestin [43][44][45]. Co-administration of celecoxib may reduce the risk of breast cancer incidence in postmenopausal women based on the following speculations: 1) E1-sulfate is the major component in Premarin, and it is metabolized to E1 and 17β-E2 [46]. It is well accepted that 17β-E2 is one of the most important factors in the growth and evolution of hormonedependent breast tumors. ...
Celecoxib is known to alter the preferred position of SULT2A1-catalyzed sulfonation of 17β-estradiol (17β-E2) and other estrogens from the 3- to the 17-position. Understanding the effects of celecoxib on estrogen sulfonation is of interest in the context of the investigational use of celecoxib to treat breast cancer. This study examined the effects on celecoxib on cytosolic sulfotransferases in human and rat liver and on SULT enzymes known to be expressed in liver. Celecoxib’s effects on the sulfonation of several steroids catalyzed by human liver cytosol were similar but not identical to those observed previously for SULT2A1. Celecoxib was shown to inhibit recombinant SULT1A1-catalyzed sulfonation of 10 nM estrone and 4 μM p-nitrophenol with IC50 values of 2.6 and 2.1 μM, respectively, but did not inhibit SULT1E1-catalyzed estrone sulfonation. In human liver cytosol, the combined effect of celecoxib and known SULT1A1 and 1E1 inhibitors, quercetin and triclosan, resulted in inhibition of 17β-E2-3-sulfonation such that the 17-sulfate became the major metabolite: this is of interest because the 17-sulfate is not readily hydrolyzed by steroid sulfatase to 17β-E2. Investigation of hepatic cytosolic steroid sulfonation in rat revealed that celecoxib did not stimulate 17β-E2 17-sulfonation in male or female rat liver as it does with human SULT2A1 and human liver cytosol, demonstrating that rat is not a useful model of this effect. In silico studies suggested that the presence of the bulky tryptophan residue in the substrate-binding site of the rat SULT2A homolog instead of glycine as in human SULT2A1 may explain this species difference.
... Проблема менопаузального периода состоит не только в его природе [1], противоречивыми до настоящего времени являются взгляды на терапию климактерических расстройств, что связано с неоднозначностью полученных данных. До 1996 г. существовала позиция о кардиопротективном эффекте ЗГТ [2][3][4], однако дальнейшие крупные многоцентровые исследования такие как Heart and Estrogen/Progestin replacement Study (HERS) и Women's Health Initiative (WHI) выявили увеличение относительного риска венозных тромбозов и сердечно-сосудистых осложнений [5,6]. В настоящее время Американская кардиологическая ассоциация не рекомендует ЗГТ женщинам в постменопаузе в качестве профилактики сердечно-сосудистых заболеваний. ...
he paper gives the data available in the literature on abnormal menopause, clinical manifestations of climacteric syndrome, and possible complications of menopausal hormone therapy. It describes experience in using magnesium preparations in complex nonhormonal treatment of climacteric syndrome. Co-administration of phytoestrogens with magnesium organic salts preparations (Magne B6) is most effective.
Several strategies have been proposed to prevent or reduce the rate of physiological decline in organ functions among aging postmenopausal women. These include increasing physical activity, improving nutrition, managing stress, and enhancing sleep quality. Although hormone replacement therapy (HRT) has been recommended, it remains a controversial topic, eliciting debate both in scientific circles and the public sphere. This book chapter aims to provide a comprehensive review of the current literature on the accelerated aging phenotype observed in postmenopausal women due to sex hormone deficiency. It will assess the efficacy and safety of HRT, offering a critical analysis of its benefits and risks. Moreover, the chapter will present a clinical perspective, suggesting practical advice for women approaching menopause. This guidance is intended for everyday clinical practice, aiming to support healthcare providers in offering informed, holistic care to this population.
This chapter focuses on acute ischemic stroke: initial evaluation and management, treatment, epidemiology, outcomes, pathophysiology, risk factors, and stroke syndromes. Endovascular treatment of stroke and the clinical evidence behind thrombectomy for large vessel occlusions are discussed in Chap. 8. Ischemic stroke in pediatric patients is discussed separately in an appendix.
This systematic review assesses the effect of menopausal hormone therapy (MHT) on cardiovascular outcomes and risk factors in postmenopausal women with cardiovascular disease (CVD). The Medline, Embase and Cochrane databases were searched from inception to December 2022 for randomized controlled trials (RCTs) and observational studies using methodology from a previous Cochrane review. Quality assessment used the Cochrane risk of bias tool and Newcastle-Ottawa scale, respectively. From 5647 studies identified, 29 (23 RCTs and six observational studies) were included. Most studies were conducted in North America or Europe and investigated oral estrogens. Participants were older with varying frequency of cardiac risk factors and underlying CVD. No significant difference was observed between MHT users and controls regarding primary outcomes of non-fatal myocardial infarction, cardiovascular death or stroke. No difference in frequency of angina, heart failure and transient ischemic attacks was observed. Inconsistent effects of MHT on angiographic progression were seen and varied with glycemic status. Estradiol had a positive effect on flow-mediated dilatation. Limited studies identified differing effects of MHT on cardiac risk factors, varying with estrogen preparation. This study confirms no benefit of MHT for secondary CVD prevention, highlighting evidence limitations and the importance of shared decision-making when managing menopausal symptoms in women with CVD.
Background:
The main drawback of oral contraceptives (OC) and hormone replacement therapy (HRT) is an increased risk of venous and, to a lesser extent, arterial thrombosis.
Materials and methods:
This narrative, case-based review describes the effect of available estrogens and progestogens on the hemostatic system and their potential impact on the risk of thrombosis. Clinical cases are used to illustrate different options for prescribing OC and HRT in the real-word. The aim is to offer discussion topics that could be helpful to guide the choice of different hormonal treatments over a woman's lifetime and in the presence of risk factors.
Results:
We describe physio-pathological changes occurring during the administration of hormonal therapies. Furthermore, we analyze the risk of venous and arterial thrombosis associated with different products, routes of administration and additional risk factors. New hormonal preparations, such as estradiol combined with dienogest, as well as non-oral hormonal therapies, are suggested to decrease thrombotic risk significantly.
Discussion:
The availability of many products and different routes of administration allow most women to use safely contraception, as well as HRT. We encourage careful counselling instead of inflexible or fearful behavior, as expanding options and choices will allow women to make the best decisions for their health.
Objective
To identify sex-related differences in the outcome of hospitalized patients with spontaneous intracerebral hemorrhage (SICH), and to identify potential causal pathways between sex and SICH outcome.
Methods
A total of 111,112 medical records of in-hospital patients with SICH were collected. Data- and expert-driven techniques were applied, such as a multivariate logistic regression model and causal mediation analysis. These analyses were used to determine the confounders and mediators, estimate the true effect of sex on the SICH outcome, and estimate the average causal mediation effect for each mediator.
Results
(1) Failure (disability or death) rates in women with SICH were significantly lower than in men with SICH. On the day of discharge, the odds ratio (OR) of failure between women and men was 0.9137 [95% confidence interval (CI), 0.8879–0.9402], while the odds ratio at 90 days post-discharge was 0.9353 (95% confidence interval, 0.9121–0.9591). (2) The sex-related difference in SICH outcome decreased with increasing age and disappeared after 75 years. (3) Deep coma, brainstem hemorrhage, and an infratentorial hemorrhage volume of >10 ml accounted for 62.76% (p < 0.001), 33.46% (p < 0.001), and 11.56% (p < 0.001) of the overall effect on the day of discharge, and for 52.28% (p < 0.001), 27.65% (p < 0.001), and 10.86% (p < 0.001) of the overall effect at the 90-day post-discharge.
Conclusion
Men have a higher failure risk than women, which may be partially mediated by a higher risk for deep coma, brainstem hemorrhage, and an infratentorial hemorrhage volume of >10 ml. Future work should explore the biological mechanisms underlying this difference.
BACKGROUND: Hormonal contraceptive therapy is considered the easiest and most convenient contraceptive method. Commercially, available contraceptive combination differs in their composition and concentration of combined constituents. These variations make some of these products preferred over others by consumers based on their side effects profile. AIM: The objective of the current research was to ascertain the proinflammatory influences of commercially available products. METHODS: To do so, five groups of rats (ten rats in each group) were exposed to Microgynon, Depo-Provera, marvel on, and Yasmin compared to the control non-treated group. We measured proinflammatory markers including d-dimer, TNF-α (tumor necrosis factor-alpha), IL (interleukin)-6, IL (interleukin)-1B, and c-reactive protein. RESULTS: The results confirmed that Yasmin has induced the most deleterious effects on proinflammatory markers indicated by significant elevation of IL1B. CONCLUSION: Hormone replacement therapy should be critically indicated and precautions raised inpatient with subclinical diseases, especially cardiovascular ones.
Stroke risk and prevalence increase with advanced age and women tend to be older than men at the time of their first stroke. Advanced age in women confers unique stroke risks that are beyond reproductive factors. Previous reviews and guidelines have largely focused on risk factors specific to women, with a predominant focus on reproductive factors and, therefore, younger to middle-aged women. This review aims to specifically describe stroke risk factors in elderly women, the population of women where the majority of strokes occur, with a focus on atrial fibrillation, hormone therapy, psychosocial risk factors, and cognitive impairment. Our review suggests that prevention and management of stroke risks that are unique or more prevalent in elderly women needs a coordinated system of care from general physicians, general neurologists, vascular and cognitive neurologists, psychologists, cardiologists, patients, and their caretakers. Early identification and management of the elderly woman–specific and traditional stroke risk factors is key for decreasing stroke burden in elderly women. Increased education among elderly women regarding stroke risk factors and their identification should be considered, and an update to the guidelines for prevention of stroke in women is strongly encouraged.
Pregnancy, postpartum and menopause are regarded as periods women are more vulnerable to ischaemic events. There are conflicting results regarding stroke risk and hormone replacement therapy (HRT) during menopause. Stroke in pregnancy is generally increasing with serious consequences for mother and child; therefore, recommendations for acute treatment with intravenous thrombolysis (IVT) and/or mechanical thrombectomy (MT) are needed. The aim of this guideline is to support and guide clinicians in treatment decisions in stroke in women. Following the "Grading of Recommendations and Assessment, Development and Evaluation (GRADE)" approach, the guidelines were developed according to the European Stroke Organisation (ESO) Standard Operating Procedure. Systematic reviews and metanalyses were performed. Based on available evidence, recommendations were provided. Where there was a lack of evidence, an expert consensus statement was given. Low quality of evidence was found to suggest against the use of HRT to reduce the risk of stroke (ischaemic and haemorrhagic) in postmenopausal women. No data was available on the outcome of women with stroke when treated with HRT. No sufficient evidence was found to provide recommendations for treatment with IVT or MT during pregnancy, postpartum and menstruation. The majority of members suggested that pregnant women can be treated with IVT after assessing the benefit/risk profile on an individual basis, all members suggested treatment with IVT during postpartum and menstruation. All members suggested treatment with MT during pregnancy. The guidelines highlight the need to identify evidence for stroke prevention and acute treatment in women in more vulnerable periods of their lifetime to generate reliable data for future guidelines.
Menopause is defined as the cessation of menstrual periods occurring from the genetically programmed loss of ovarian follicles. The transition between the woman’s fertile period and menopause begins with variations in the duration of menstrual cycle and an increase in serum concentrations of follicle-stimulating hormone (FSH) and ends with the final menstrual cycle, unrecognized until 12 months of amenorrhea is completed.This chapter reviews the epidemiological aspects, clinical manifestations, diagnosis, differential diagnosis, current treatment, and new perspectives in the treatment of the menopause.KeywordsMenopauseHormone therapyCardiovascular effectOsteoporosisBreast cancerTreatment
Despite the well-known sex dimorphism in cardiovascular disease traits, the exact genetic, molecular, and cellular underpinnings of these differences are not well understood. A growing body of evidence currently points at the links between cardiovascular disease traits and the genome, epigenome, transcriptome, and metabolome. However, the sex-specific differences in these links remain largely unstudied due to challenges in bioinformatic methods, inadequate statistical power, analytic costs, and paucity of valid experimental models. This review article provides an overview of the literature on sex differences in genetic architecture, heritability, epigenetic changes, transcriptomic signatures, and metabolomic profiles in relation to cardiovascular disease traits. We also review the literature on the associations between sex hormones and cardiovascular disease traits and discuss the potential mechanisms underlying these associations, focusing on human studies.
Stroke is a leading cause of death and disability worldwide. Women are disproportionately affected by stroke, exhibiting higher mortality and disability rates post-stroke than men. Clinical stroke research has historically included mostly men and studies were not properly designed to perform sex- and gender-based analyses, leading to under-appreciation of differences between men and women in stroke presentation, outcomes, and response to treatment. Reasons for these differences are likely multifactorial; some are due to gender-related factors (i.e. decreased social support, lack of stroke awareness), yet others result from biological differences between sexes. Unlike men, women often present with ‘atypical’ stroke symptoms. Lack of awareness of ‘atypical’ presentation has led to delays in hospital arrival, diagnosis, and treatment of women. Differences also extend to carotid atherosclerotic disease, a cause of stroke, where plaques isolated from women are undeniably different in morphology/composition compared to men. As a result, women may require different treatment than men, as evidenced by the fact that they derive less benefit from carotid revascularization than men but more benefit from medical management. Despite this, women are less likely than men to receive medical therapy for cardiovascular risk factor management. This review focuses on the importance of sex and gender in ischaemic stroke and carotid atherosclerotic disease, summarizing the current evidence with respect to (i) stroke incidence, mortality, awareness, and outcomes, (ii) carotid plaque prevalence, morphology and composition, and gene connectivity, (iii) the role of sex hormones and sex chromosomes in atherosclerosis and ischaemic stroke risk, and (iv) carotid disease management.
BACKGROUND
The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).
METHODS
The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year’s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year’s edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease.
RESULTS
Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.
CONCLUSIONS
The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
It is well known that stroke incidence and outcome is sex-dependent and influenced by age and gonadal hormones. In post-menopausal and/or aged females, declining estrogen levels increases stroke risk. However, women who experience early menopause also have an increase in stroke risk. This suggests that, regardless of age, gonadal hormones regulate stroke risk and severity. This review discusses prolonged gonadal hormone dysfunction in a common female endocrine disorder known as polycystic ovarian syndrome, PCOS, and the associated increased risk of stroke due to resulting hyperandrogenism and metabolic comorbidities.
Introduction
Asymptomatic intracranial atherosclerotic stenosis (AICAS) is a common cause of stroke. Elderly women were more likely than men to develop AICAS, although it indicated that a lifelong exposure to estrogen could lower the risks of cardiovascular disease (CVDs).
Objective
The present study aims to ascertain whether postmenopausal time is a risk factor of AICAS. Fostering a correct perception of menopause is of great significance for the overall well-being of the elderly women.
Methods
All participants received a questionnaire, physical examination, laboratory testing and transcranial Doppler. The menopausal population (n = 701) was divided into three groups by tertiles of postmenopausal time. Two-tailed testing and trend test were used to reveal the relationship between postmenopausal time and newly discovered AICAS. Other potential risk factors were also analyzed to ascertain whether there was a relation between postmenopausal time and the newly discovered ICAS.
Results
Both mean age and mean postmenopausal time were gradually increased from G0 to G2. The same trend occurred in hypertension, diabetes mellitus, total cholesterol, triglyceride, C-reactive protein and serum homocysteine. Adjusting for various confounding factors, postmenopausal time was not a risk factor for newly discovered AICAS. Multifactor analysis and stratifying analysis showed no correlation between newly discovered AICAS and postmenopausal time.
Conclusions
Postmenopausal time is not an independent risk factor of AICAS. No relationship was detected between postmenopausal time and newly discovered AICAS, while vigorous control of body weight, blood pressure/glucose/lipids and smoke cessation are vital for preventing the occurrence of AICAS.
Epidemiological studies demonstrate that there are sex differences in the incidence, prevalence, and outcomes of cerebrovascular disease (CVD). The present study compared the structure and composition of the middle cerebral artery (MCA), neurovascular coupling, and cerebrovascular function and cognition in young SD rats. Wall thickness and the inner diameter of the MCA were smaller in females than males. Female MCA exhibited less vascular smooth muscle cells (VSMCs), diminished contractile capability, and more collagen in the media, and a thicker internal elastic lamina with fewer fenestrae compared to males. Female MCA had elevated myogenic tone, lower distensibility, and higher wall stress. The stress/strain curves shifted to the left in female vessels compared to males. The MCA of females failed to constrict compared to a decrease of 15.5 ± 1.9% in males when perfusion pressure was increased from 40 to 180 mmHg. Cerebral blood flow (CBF) rose by 57.4 ± 4.4% and 30.1 ± 3.1% in females and males, respectively, when perfusion pressure increased from 100-180 mmHg. The removal of endothelia did not alter the myogenic response in both sexes. Functional hyperemia responses to whisker-barrel stimulation and cognition examined with an eight-arm water maze were similar in both sexes. These results demonstrate that there are intrinsic structural differences in the MCA between sexes, which are associated with diminished myogenic response and CBF autoregulation in females. The structural differences do not alter neurovascular coupling and cognition at a young age; however, they might play a role in the development of CVD after menopause.
BACKGROUND
The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).
METHODS
The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year’s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year’s edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association’s 2020 Impact Goals.
RESULTS
Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.
CONCLUSIONS
The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
Stroke remains the second leading cause of death in the world, and its prevalence is projected to rise in the United States and globally. The main driver for increased stroke prevalence is aging of the population; however, best evidenced-based strategies for stroke treatment and prevention are not always followed for older patients. Furthermore, considerable gaps in knowledge exist for stroke prevention and treatment in elderly and very elderly patients. In this chapter, we discuss various aspects of stroke care in the elderly, including the evidence that guides stroke prevention and treatment. We focus on the challenges in managing stroke in the very elderly including the paucity of data to guide management. The sections span the continuum of stroke care, from primary prevention to management of stroke complications. Finally, we highlight the most significant unanswered questions regarding stroke care in the elderly.
Premenopausal women are relatively protected from developing hypertension compared to men. Perivascular adipose tissue (PVAT) has been shown to mediate vasoactive effects; however, a sex-dependent difference in PVAT function in the setting of hypertension has not yet been explored. We investigated the effect of PVAT on resistance vessel biology in male and female 16 week old stroke prone spontaneously hypertensive rats (SHRSP). This preclinical model of hypertension exhibits a sex-dependent difference in the development of hypertension similar to humans. Wire myography was used to assess vascular function in third-order mesenteric arteries. KATP channel-mediated vasorelaxation by cromakalim was significantly impaired in vessels from SHRSP males + PVAT relative to females (maximum relaxation: male + PVAT 46.9 ± 3.9% vs. female + PVAT 97.3 ± 2.7%). A cross-over study assessing the function of male PVAT on female vessels confirmed the reduced vasorelaxation response to cromakalim associated with male PVAT (maximum relaxation: female + PVATfemale 90.6 ± 1.4% vs. female + PVATmale 65.8 ± 3.5%). In order to explore the sex-dependent differences in PVAT at a molecular level, an adipokine array and subsequent western blot validation identified resistin expression to be increased approximately 2-fold in PVAT from male SHRSP vessels. Further wire myography experiments showed that pre-incubation with resistin (40 ng/ml) significantly impaired the ability of female + PVAT vessels to relax in response to cromakalim (maximum relaxation: female + PVAT 97.3 ± 0.9% vs. female + PVAT + resistin[40ng/ml] 36.8 ± 2.3%). These findings indicate a novel role for resistin in mediating sex-dependent vascular function in hypertension through a KATP channel-mediated mechanism.
Every year, stroke affects more than 15 million people around the world. Stroke is currently the second leading cause of death worldwide, and the leading cause of disability in the United States. The cost of caring for stroke patients is projected to reach $183 million dollars by 2030, driven largely by improving life expectancy and a concomitant increase in the aged population. Ischemic stroke, caused by loss of blood flow to the brain due to an embolus or vessel thrombosis, is responsible for 87% of all strokes. Profound sex differences exist in ischemic stroke epidemiology and pathophysiology, impacting almost all facets of future stroke research and therapeutic development. In this chapter, we will focus on ischemic stroke and discuss sex differences in cerebral ischemia, including the role of sex in clinical stroke, stroke risk factors and basic stroke pathophysiology.
Menopausal hormone therapy (MHT) was widely used to improve quality of life by controlling menopausal symptoms, including vasomotor symptoms and urogenital atrophy. Furthermore, observational studies consistently reported beneficial effects of MHT on late problems of menopause, such as osteoporosis, coronary heart disease (CHD), and possibly dementia. However, circumstances changed abruptly after the 2002 publication of the first findings from the Women's Health Initiative (WHI) study, which was conducted in postmenopausal women (average age, 63 years) using conventional doses of conjugated equine estrogen (CEE) and medroxyprogesterone acetate. CEE with medroxyprogesterone acetate increased the risk of breast cancer and did not prevent CHD. However, CEE alone showed a tendency to decrease the risk of both breast cancer and CHD, with significant differences between the two therapies. A subgroup analysis by age and years since menopause led to a timing hypothesis regarding the effects of MHT on CHD. Indeed, CEE alone in women aged 50 to 59 significantly reduced CHD risk by 35% after 13 years of follow-up. In 2015, a Cochrane meta-analysis of MHT trials reported a 48% reduction in CHD, no change in stroke, and most importantly, a 30% decrease in total mortality in women with less than 10 years since menopause. Long-term follow-up of WHI participants confirmed beneficial impacts of CEE on breast cancer incidence and mortality. Further, fracture reduction in women with osteopenia was observed during the intervention phase of the WHI study. If initiated early after menopause, MHT could again be considered to improve menopause-related quality of life and decrease all-cause mortality.
Abstract
Context: Hormonereplacement therapy (HRT) is widely used to control postmenopausal symptoms. This therapy is also used to prevent
diseases such as osteoporosis and dementia. However, clinical trials suggest some negative effects regarding postmenopausal
HRT. This study evaluates the effects of HRT on postmenopausal cardiovascular events.
Evidence Acquisition: We collected data from 32 articles by using valid keywords and searching databases of PubMed, Medlib,
ScienceDirect, EmBase, Scopus, Index Copernicus, SID, and Iranmedex. Analysis was performed by comparing three groups of postmenopausal
women: combined hormone therapy (estrogen + progesterone), estrogen alone treated group, and placebo-receiving
group (control group). Data were analyzed using the random effect model meta-analysis by using R software and Stata software
Version 11.2.
Results: Of the collected 32 studies between 1998 and 2016, there were 1277686 subjects with an average age of 60.6 years. The prevalence
of myocardial infarction were (2.64%), coronary heart disease (1.7%), stroke (254%), cardiovascular death (1.54%), revascularization
(3.26 %), and cerebrovascular disease (CVD) (2.78%) in the combined hormone therapy group. Also, in the estrogen-treated group
were 2.95%, 3.41%, 2.49%, 2.8%, - , 3.14%, respectively. In the placebo-receiving group these events were 2.09%, 2.73%, 2.9%, 2.25%, 4.96%,
and 11.92, respectively. The results showed that estrogen therapy could increase the incidence of stroke. Moreover, HRT could have
positive effects on the serum lipid profile in postmenopausal women.
Conclusion: Postmenopausal HRT appears to be non-effective on coronary artery disease, revascularization, myocardial infarction,
and cardiac-related deaths; however, it could play a role in increasing the stroke rate.
Keywords: Cardiovascular, Hormone Therapy, Meta-Analysis, Postmenopausal
Ischemic Stroke in a Transgender Woman Receiving Estrogen Therapy - Volume 46 Issue 1 - Priscilla Kwan, Aleksandra Pikula
Cardiovascular diseases are a worldwide health problem and are the leading cause of mortality in developed countries. Together with experimental data, the lower incidence of cardiovascular diseases in women than in men of reproductive age points to the influence of sex hormones at the cardiovascular level and suggests that estrogens play a protective role against cardiovascular disease and that this role is also modified by ageing. Estrogens affect cardiovascular function via their specific estrogen receptors to trigger gene expression changes at the transcriptional level. In addition, emerging studies have proposed a role for microRNAs in the vascular effects mediated by estrogens. miRNAs regulate gene expression by repressing translational processes and have been estimated to be involved in the regulation of approximately 30% of all protein-coding genes in mammals. In this review, we highlight the current knowledge of the role of estrogen-sensitive miRNAs, and their influence in regulating vascular ageing.
Tratamiento hormonal y no hormonal en el climatérico
This chapter focuses on acute ischemic stroke: mechanisms, risk factors, clinical presentation, diagnostic evaluation, and treatment other than intravenous thrombolysis and mechanical thrombectomy, which are discussed in Chap. 8. The topics are arranged alphabetically. Ischemic stroke in pediatric patients is discussed separately in the Appendix.
The beneficial effects of estrogen on the cardiovascular system have been reported extensively. In fact, the incidence of cardiovascular diseases in women is lower than in age-matched men during their fertile stage of life, a benefit that disappears after menopause. These sex-related differences point to sexual hormones, mainly estrogen, as possible cardiovascular protective factors. The regulation of vascular function by estrogen is mainly related to the maintenance of normal endothelial function and is mediated by both direct and indirect gene transcription through the activity of specific estrogen receptors. Some of these mechanisms are known, but many remain to be elucidated. In recent years, microRNAs have been established as non-coding RNAs that regulate the expression of a high percentage of protein-coding genes in mammals and are related to the correct function of human physiology. Moreover, within the cardiovascular system, miRNAs have been related to physiological and pathological conditions. In this review, we address what is known about the role of estrogen-regulated miRNAs and their emerging involvement in vascular biology.
Ischemic stroke is one of the leading causes of morbidity and mortality worldwide. Females are protected against stroke before the onset of menopause. Menopause results in increased incidence of stroke when compared to men. The mechanisms of these differences remain to be elucidated. Considering that there is a postmenopausal phenomenon and females in general, are living longer sex hormone-dependent mechanisms have been postulated to be the primary factors responsible for the premenopausal protection from stroke and later to be responsible for the higher incidence and increased the severity of stroke after menopause. Animal studies suggest that administration of estrogen and progesterone is neuroprotective and decreases the incidence of stroke. However, the real-world outcomes of hormone replacement therapy have failed to decrease the stroke risk. Despite the multifactorial nature of sex differences in stroke, here, we briefly discuss the pathophysiology of sex steroid hormones, the molecular mechanisms of estrogen receptor-dependent signaling pathways in stroke, and the potential factors that determine the discrepant effects of hormone replacement therapy in stroke.
Objective:
Because age affects hormonal production differently in women compared with men, we sought to define sex and age interactions across a multiracial/ethnic population after intracerebral hemorrhage (ICH) to uncover evidence that loss of gonadal hormone production would result in loss of the known neuroprotective effects of gonadal hormones.
Methods:
Clinical and radiographic data from participants in the Ethnic/Racial Variations of Intracerebral Hemorrhage study and the Genetic and Environmental Risk Factors for Hemorrhagic Stroke study prior to December 2013 were used. Relationships among sex, age, and outcome after ICH in 616 non-Hispanic black, 590 Hispanic, and 868 non-Hispanic white participants were evaluated using multivariable logistic regression analysis. Poor outcome was defined as modified Rankin Scale score ≥3 at 90 days after ICH.
Results:
Sex differences were found in multiple variables among the racial/ethnic groups, including age at onset, premorbid neurologic status, and neurologic outcome after ICH. Overall, no sex-age interaction effect was found for mortality (p = 0.183) or modified Rankin Scale score (p = 0.378) at 90 days after ICH. In racial/ethnic subgroups, only the non-Hispanic black cohort provided possible evidence of a sex-age interaction on 90-day modified Rankin Scale score (p = 0.003).
Conclusion:
Unlike in ischemic stroke, there was no evidence that patient sex modified the effect of age on 90-day outcomes after ICH in a large multiracial/ethnic population. Future studies should evaluate biological reasons for these differences between stroke subtypes.
Clinicaltrialsgov identifier:
NCT01202864.
Stroke has been emerged as one of major health problems for women worldwide. Increasing of knowledge in this field provided new data in this area which contribute to finding of new risk factors and could improve stroke treatment. A large number studies indicated a variety of risk factors including sex, age, race, smoking, diabetes, and physical inactivity could be involved in stroke in women. The understanding of various aspects involved in women stroke including risk factors, outcomes, stroke recovery, and prevention could provide new therapeutic platforms which could likely lead to better treatment in women stroke. Diagnosis is one of important steps in stroke therapy. It has been showed that a variety of biomarkers such as microRNAs (miRNAs), tPA and von willebrand factor could be used as therapeutic and diagnostic biomarkers in stroke therapy. Here, we summarized various aspects of stroke in women which could help to recognition risk factors, outcomes, care, treatment, and novel biomarkers involve in treatment of stroke. This article is protected by copyright. All rights reserved.
Context.—
Observational studies have found lower rates of coronary heart disease
(CHD) in postmenopausal women who take estrogen than in women who do not,
but this potential benefit has not been confirmed in clinical trials.Objective.—
To determine if estrogen plus progestin therapy alters the risk for
CHD events in postmenopausal women with established coronary disease.Design.—
Randomized, blinded, placebo-controlled secondary prevention trial.Setting.—
Outpatient and community settings at 20 US clinical centers.Participants.—
A total of 2763 women with coronary disease, younger than 80 years,
and postmenopausal with an intact uterus. Mean age was 66.7 years.Intervention.—
Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone
acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383).
Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were
taking it at the end of 1 year, and 75% at the end of 3 years.Main Outcome Measures.—
The primary outcome was the occurrence of nonfatal myocardial infarction
(MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization,
unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke
or transient ischemic attack, and peripheral arterial disease. All-cause mortality
was also considered.Results.—
Overall, there were no significant differences between groups in the
primary outcome or in any of the secondary cardiovascular outcomes: 172 women
in the hormone group and 176 women in the placebo group had MI or CHD death
(relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The
lack of an overall effect occurred despite a net 11% lower low-density lipoprotein
cholesterol level and 10% higher high-density lipoprotein cholesterol level
in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically
significant time trend, with more CHD events in the hormone group than in
the placebo group in year 1 and fewer in years 4 and 5. More women in the
hormone group than in the placebo group experienced venous thromboembolic
events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84
vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences
in several other end points for which power was limited, including fracture,
cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).Conclusions.—
During an average follow-up of 4.1 years, treatment with oral conjugated
equine estrogen plus medroxyprogesterone acetate did not reduce the overall
rate of CHD events in postmenopausal women with established coronary disease.
The treatment did increase the rate of thromboembolic events and gallbladder
disease. Based on the finding of no overall cardiovascular benefit and a pattern
of early increase in risk of CHD events, we do not recommend starting this
treatment for the purpose of secondary prevention of CHD. However, given the
favorable pattern of CHD events after several years of therapy, it could be
appropriate for women already receiving this treatment to continue.
Figures in this Article
MANY OBSERVATIONAL studies have found lower rates of coronary heart
disease (CHD) in women who take postmenopausal estrogen than in women not
receiving this therapy.1- 5
This association has been reported to be especially strong for secondary prevention
in women with CHD, with hormone users having 35% to 80% fewer recurrent events
than nonusers.6- 12
If this association is causal, estrogen therapy could be an important method
for preventing CHD in postmenopausal women. However, the observed association
between estrogen therapy and reduced CHD risk might be attributable to selection
bias if women who choose to take hormones are healthier and have a more favorable
CHD profile than those who do not.13- 15
Observational studies cannot resolve this uncertainty.
Only a randomized trial can establish the efficacy and safety of postmenopausal
hormone therapy for preventing CHD. The Heart and Estrogen/progestin Replacement
Study (HERS) was a randomized, double-blind, placebo-controlled trial of daily
use of conjugated equine estrogens plus medroxyprogesterone acetate (progestin)
on the combined rate of nonfatal myocardial infarction (MI) and CHD death
among postmenopausal women with coronary disease. We enrolled women with established
coronary disease because their high risk for CHD events and the strong reported
association between hormone use and risk of these events make this an important
and efficient study population in which to evaluate the effect of hormone
therapy.
We assessed the association of hormonal replacement therapy with mortality and incidence of multiple diseases in over 40,000 postmenopausal women followed for 6 years as part of the Iowa Women's Health Study. Compared with women who never used hormone replacement therapy, current users had multivariate adjusted relative risks (RR) as follows: total mortality (RR = 0.78; 95% confidence interval [CI] = 0.65, 0.94), coronary heart disease mortality (RR = 0.74; 95% CI = 0.48, 1.12), endometrial cancer incidence (RR = 4.3; 95% CI = 2.7, 6.9), breast cancer incidence (RR = 1.23; 95% CI = 0.99, 1.55), colon cancer incidence (RR = 0.72; 95% CI = 0.46, 1.12), and hip fracture incidence (RR = 0.53; 95% CI = 0.31, 0.91).
To quantify the effect of selection of relatively healthy women in studies reporting reduced relative risk for cardiovascular disease in postmenopausal women taking hormone replacement therapy.
Review of the follow up studies reported in three recent meta-analyses to determine the effect of oestrogen therapy on both total cancer and cardiovascular disease. The same standard statistical methods as in the original analyses were used.
Relative risks of total cancer and cardiovascular disease.
In most of the follow up studies the relative risk for total cancer was below 1. The studies that showed the largest reduction in cardiovascular disease also showed the largest reduction in cancer, indicating a healthy cohort effect. Although heterogeneity within the studies prevented pooling, the best estimate for the protective effect on total cancer was a relative risk of 0.83 among women taking oestrogen (95% confidence interval 0.71 to 0.96), while in the same studies the relative risk for cardiovascular disease was 0.57 (0.50 to 0.64).
Unintended selection of relatively healthy women for oestrogen therapy may have influenced the reported beneficial effect of oestrogen therapy on cardiovascular disease. It is unclear how much of the cardioprotection is due to this selection. Universal preventive hormonal replacement therapy for postmenopausal women is unwarranted at present.
Postmenopausal hormone therapy has both benefits and hazards, including decreased risks of osteoporosis and cardiovascular disease and an increased risk of breast cancer.
We examined the relation between the use of postmenopausal hormones and mortality among participants in the Nurses' Health Study, who were 30 to 55 years of age at base line in 1976. Data were collected by biennial questionnaires beginning in 1976 and continuing through 1992. We documented 3637 deaths from 1976 to 1994. Each participant who died was matched with 10 controls alive at the time of her death. For each death, we defined the subject's hormone status according to the last biennial questionnaire before her death or before the diagnosis of the fatal disease; this reduced bias caused by the discontinuation of hormone use between the time of diagnosis of a potentially fatal disease and death.
After adjustment for confounding variables, current hormone users had a lower risk of death (relative risk, 0.63; 95 percent confidence interval, 0.56 to 0.70) than subjects who had never taken hormones; however, the apparent benefit decreased with long-term use (relative risk, 0.80; 0.67 to 0.96, after 10 or more years) because of an increase in mortality from breast cancer among long-term hormone users. Current hormone users with coronary risk factors (69 percent of the women) had the largest reduction in mortality (relative risk, 0.51; 95 percent confidence interval, 0.45 to 0.57), with substantially less benefit for those at low risk (13 percent of the women; relative risk, 0.89; 95 percent confidence interval, 0.62 to 1.28).
On average, mortality among women who use postmenopausal hormones is lower than among nonusers; however, the survival benefit diminishes with longer duration of use and is lower for women at low risk for coronary disease.
In a prospective study of 8881 postmenopausal female residents of a retirement community in southern California, we evaluated in detail the relationship between estrogen use and overall mortality. After 71/2 years of follow-up, there had been 1447 deaths. Women with a history of estrogen use had 20% lower age-adjusted, all-cause mortality than lifetime nonusers (95% confidence interval, 0.70 to 0.87). Mortality decreased with increasing duration of use and was lower among current users than among women who used estrogens only in the distant past. Current users with more than 15 years of estrogen use had a 40% reduction in their overall mortality. Among oral estrogen users, relative risks of death could not be distinguished by specific dosages of the oral estrogen taken for the longest time. Women who had used estrogen replacement therapy had a reduced mortality from all categories of acute and chronic arteriosclerotic disease and cerebrovascular disease. This group of women had a reduced mortality from cancer, although this reduction was not statistically significant. The mortality from all remaining causes combined was the same in estrogen users and lifetime nonusers.(Arch Intern Med. 1991;151:75-78)
Background: The protective effect of postmenopausal estrogen replacement therapy on coronary heart disease has been shown in several studies. However, the effect on stroke is more controversial, and data on estrogen-progestin combinations are sparse.
Methods: A total of 23 088 women living in the Uppsala (Sweden) Health Care Region were identified from pharmacy records as having been prescribed noncontraceptive estrogens during 1977 through 1980. They were followed up from 1977 to 1983 for admissions to the hospital because of a first stroke (International Classification of Diseases, Eighth Revision, codes 430 through 438 and 344). The mean observation time was 5.8 years. The expected number was based on person-years in the cohort and incidence rates in the population of the region.
Results: Overall, 361 cases of first stroke were observed in the cohort, as compared with 403.2 expected (relative risk [RR], 0.90; 95% confidence limits, 0.81, 0.99). The RR for acute stroke (International Classification of Diseases, Eighth Revision, codes 431 through 436) was 0.85 (0.75, 0.97). In women younger than 60 years at entry who were prescribed estradiol compounds (1 to 2 mg) or conjugated equine estrogens (0.625 to 1.25 mg), the risk of any stroke was reduced by almost 30% (RR, 0.72; 0.58, 0.88) and the risk of acute stroke was reduced by 40% (RR, 0.61; 0.46, 0.79). Women prescribed a combined estradiol-levonorgestrel brand also had a lowered risk of stroke (RR, 0.61; 0.40, 0.88). Weak compounds (mainly estriol) showed no stroke-protective effect, nor was there any relationship between hormone replacement and risk of subarachnoid hemorrhage.
Conclusion: Hormone replacement therapy with potent estrogens alone or cyclically combined with progestins can, particularly when started shortly after menopause, reduce the risk of stroke.(Arch Intern Med. 1993;153:1201-1209)
Objective - To assess the effectiveness of health checks by nurses in reducing risk factors for cardiovascular disease in patients from general practice. Design - Randomised controlled trial. Setting - Five urban general practices in Bedfordshire. Subjects - 2136 patients receiving an initial health check in 1989-91 and scheduled to be re-examined one year later in 1990-2 (intervention group); 3988 patients receiving an initial health check in 1990-2 (control group). All patients were aged 35-64 years at recruitment in 1989. Main outcome measures - Serum total cholesterol concentration, blood pressure, body mass index, confirmed smoking cessation. Results - Mean serum total cholesterol was 2.3% lower in the intervention group than in the controls (difference 0.14 mmol/l (95% confidence interval 0.08 to 0.20)); the difference was greater in women (3.2%, P < 0.0001) than men (1.0%, P = 0.18). There was no significant difference in smoking prevalence, quit rates, or body mass index. Systolic and diastolic blood pressure were 2.5% and 2.4% lower respectively in the intervention group. The proportion of patients with diastolic blood pressure ≥ 100 mm Hg was 2.6% (55/2131) in the intervention group and 3.4% (137/3987) in the controls (difference 0.9% (0.0 to 1.7)); the proportion with total cholesterol concentration ≥ 8 mmol/l 4.8% (100/2068) and 7.6% (295/3905) (difference 2.7% (1.5 to 4.0)); and that with body mass index ≥ 30 12.4% (264/2125) and 14.0% (559/3984) (difference 1.6% (-0.2 to 3.4)). Conclusion - General health checks by nurses are ineffective in helping smokers to stop smoking, but they help patients to modify their diet and total cholesterol concentration. The public health importance of this dietary change depends on whether it is sustained.
The effect of postmenopausal estrogen therapy on the risk of cardiovascular disease remains controversial. Our 1985 report in the Journal, based on four years of follow-up, suggested that estrogen therapy reduced the risk of coronary heart disease, but a report published simultaneously from the Framingham Study suggested that the risk was increased. In addition, studies of the effect of estrogens on stroke have yielded conflicting results.
We followed 48,470 postmenopausal women, 30 to 63 years old, who were participants in the Nurses' Health Study, and who did not have a history of cancer or cardiovascular disease at base line. During up to 10 years of follow-up (337,854 person-years), we documented 224 strokes, 405 cases of major coronary disease (nonfatal myocardial infarctions or deaths from coronary causes), and 1263 deaths from all causes.
After adjustment for age and other risk factors, the overall relative risk of major coronary disease in women currently taking estrogen was 0.56 (95 percent confidence interval, 0.40 to 0.80); the risk was significantly reduced among women with either natural or surgical menopause. We observed no effect of the duration of estrogen use independent of age. The findings were similar in analyses limited to women who had recently visited their physicians (relative risk, 0.45; 95 percent confidence interval, 0.31 to 0.66) and in a low-risk group that excluded women reporting current cigarette smoking, diabetes, hypertension, hypercholesterolemia, or a Quetelet index above the 90th percentile (relative risk, 0.53; 95 percent confidence interval, 0.31 to 0.91). The relative risk for current and former users of estrogen as compared with those who had never used it was 0.89 (95 percent confidence interval, 0.78 to 1.00) for total mortality and 0.72 (95 percent confidence interval, 0.55 to 0.95) for mortality from cardiovascular disease. The relative risk of stroke when current users were compared with those who had never used estrogen was 0.97 (95 percent confidence interval, 0.65 to 1.45), with no marked differences according to type of stroke.
Current estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease, but it is not associated with any change in the risk of stroke.
In a prospective study of 8881 postmenopausal female residents of a retirement community in southern California, we evaluated in detail the relationship between estrogen use and overall mortality. After 7 1/2 years of follow-up, there had been 1447 deaths. Women with a history of estrogen use had 20% lower age-adjusted, all-cause mortality than lifetime nonusers (95% confidence interval, 0.70 to 0.87). Mortality decreased with increasing duration of use and was lower among current users than among women who used estrogens only in the distant past. Current users with more than 15 years of estrogen use had a 40% reduction in their overall mortality. Among oral estrogen users, relative risks of death could not be distinguished by specific dosages of the oral estrogen taken for the longest time. Women who had used estrogen replacement therapy had a reduced mortality from all categories of acute and chronic arteriosclerotic disease and cerebrovascular disease. This group of women had a reduced mortality from cancer, although this reduction was not statistically significant. The mortality from all remaining causes combined was the same in estrogen users and lifetime nonusers.
To reexamine the mortality experience of a cohort of long-term users of hormone replacement therapy (HRT) in comparison with that reported previously for the same cohort of women, paying particular attention to cardiovascular mortality, deaths from breast and endometrial cancer, and deaths attributed to suicide or suspected suicide.
Longitudinal cohort of 4544 long-term users of HRT amongst whom mortality is being monitored prospectively in comparison with expected rates in the female population of England and Wales (taking account of age and calendar period).
4544 women, all of whom were recruited from specialist menopause clinics around Britain and had taken at least one year's continuous HRT at the time of recruitment to the study.
All cause mortality, cardiovascular mortality, deaths from female cancers, deaths attributed to suicide or suspected suicide.
Overall mortality (based on 236 deaths over the entire study period from recruitment to December 1988) remained significantly lower than expected on the basis of national rates (relative risk (RR) 0.56, 95% confidence limits (CL) 0.47-0.66). When specific causes were considered, the only mortality ratios greater than unity were for injury, poisoning and violence (1.54, 95% CL 1.02-2.06), and for suicide and suspected suicide ('suicide') (2.40, 95% CL 1.68-3.11). Comparison of the ratios for the 112 additional deaths with those obtained in our previous analysis revealed that one of the few ratios to show any increase was that for breast cancer mortality. This rose from a significant deficit of 0.55 (95% CL 0.28-0.96) in the earlier period to 1.00 (95% CL 0.55-1.45) in the later period. There was also a suggestion of an increase in breast cancer risk with increasing duration since first use of HRT. Most of the other cause-specific ratios were very similar over the two periods. The ratio of death from all circulatory diseases was notably lower in the later analysis (RR 0.37, 95% CL 0.15-0.58) than in the earlier analysis (0.51, 95% CL 0.36-0.69), as were all of the subcategories of cardiovascular death. The mortality ratio for cancer of the ovary and uterine adnexa fell from 1.12 in the previous analysis to 0.63 (95% CL 0-1.41). The mortality ratio for 'suicide' also decreased, but was only slightly lower in the later period. As before, however, there was evidence of a relatively high prevalence of prior psychiatric problems amongst the recent 'suicide' deaths, suggesting that the excess of deaths from 'suicide' may be a manifestation of selection.
These data are consistent with a beneficial effect of HRT on cardiovascular diseases, although updated information comparing progestogen-opposed and -unopposed treatment is not available. The increase in breast cancer mortality contrasts with the pattern for all other specific causes examined; taken together with the suggestion of an increase in breast cancer mortality with increasing interval since first exposure to HRT, this finding is somewhat worrying.
There is a lack of consensus among studies on the possible risks of stroke from cigarette smoking; because of this a meta-analysis was conducted. All published data on the association were sought and the relative risk for each study obtained whenever possible. The pooled relative risks were calculated by using estimates of the precision of the individual relative risks to weight their contribution to the meta-analysis. Thirty two separate studies were analysed. The overall relative risk of stroke associated with cigarette smoking was 1.5 (95% confidence interval 1.4 to 1.6). Considerable differences were seen in relative risks among the subtypes: cerebral infarction 1.9, cerebral haemorrhage 0.7, and subarachnoid haemorrhage 2.9. An effect of age on the relative risk was also noted; less than 55 years 2.9, 55-74 years 1.8, and greater than or equal to 75 years 1.1. A dose response between the number of cigarettes smoked and relative risk was noted, and there was a small increased risk in women compared with men. Ex-smokers under the age of 75 seemed to retain an appreciably increased risk of stroke (1.5); for all ages the relative risk in ex-smokers was 1.2. The meta-analysis provides strong evidence of an excess risk of stroke among cigarette smokers. Stroke should therefore be added to the list of diseases related to smoking.
We studied the effect of estrogen use on morbidity from cardiovascular disease in 1234 postmenopausal women, aged 50 to 83 years, participating in the Framingham Heart Study's 12th biennial examination (index examination). The medication history recorded at biennial examinations 8 through 12 was used to classify the degree of estrogen exposure before eight years of observation for cardiovascular morbidity and mortality. Despite a favorable cardiovascular risk profile and control for the major known risk factors for heart disease, women reporting postmenopausal estrogen use at one or more examinations had over a 50 per cent elevated risk of cardiovascular morbidity (P less than 0.01) and more than a twofold risk for cerebrovascular disease (P less than 0.01) after the index examination. Increased rates for myocardial infarction (P less than 0.05) were observed particularly among the estrogen users who smoked cigarettes. Conversely, among nonsmokers estrogen use was associated only with an increased incidence of stroke (P less than 0.05). No benefits from estrogen use were observed in the study group; in particular, mortality from all causes and from cardiovascular disease did not differ for estrogen users and nonusers.
There have been few prospective studies of the epidemiology of cardiovascular disease in women, especially black women. The authors report the 20-year mortality experience of 391 black and 549 white women aged 40-64 years recruited in 1960-1961 into the Evans County Cardiovascular Study. The vital status of 98.9% of the white women and 96.2% of the black women had been determined as of May 1, 1980. Using Cox' proportional hazards model, the authors estimated that black women had a 70% excess risk of cardiovascular disease mortality compared with white women, unadjusted for any risk factors. At entry, black women had higher systolic blood pressure, higher Quetelet index, lower serum cholesterol, lower social status, and similar age distribution and prevalence of cigarette smoking compared with white women. Cardiovascular disease mortality was significantly associated with systolic pressure in all women, serum cholesterol in white women, and Quetelet index in low social status white women. Adjustment for cardiovascular disease risk factors and social status explained most of the difference in cardiovascular disease mortality between blacks and whites.
The relationship between the degree of obesity and the incidence of cardiovascular disease (CVD) was reexamined in the 5209 men and women of the original Framingham cohort. Recent observations of disease occurrence over 26 years indicate that obesity, measured by Metropolitan Relative Weight, was a significant independent predictor of CVD, particularly among women. Multiple logistic regression analyses showed that Metropolitan Relative Weight, or percentage of desirable weight, on initial examination predicted 26-year incidence of coronary disease (both angina and coronary disease other than angina), coronary death and congestive heart failure in men independent of age, cholesterol, systolic blood pressure, cigarettes, left ventricular hypertrophy and glucose intolerance. Relative weight in women was also positively and independently associated with coronary disease, stroke, congestive failure, and coronary and CVD death. These data further show that weight gain after the young adult years conveyed an increased risk of CVD in both sexes that could not be attributed either to the initial weight or the levels of the risk factors that may have resulted from weight gain. Intervention in obesity, in addition to the well established risk factors, appears to be an advisable goal in the primary prevention of CVD.
We examined the relation between menopausal estrogen use and all-cause and cause-specific mortality in a cohort of over 49,000 women followed between 1979 and 1989 in the Breast Cancer Detection Demonstration Project (BCDDP) Follow-Up Study. We found a lower all-cause mortality rate among women who took estrogens [rate ratio (RR) = 0.7; 95% confidence interval (CI) = 0.7-0.8], particularly current users (RR = 0.3; 95% CI = 0.2-0.4), than among women who never took them. Additional analyses, however, revealed that women who had recently stopped taking estrogens had a higher all-cause mortality rate than women who had never taken them (RR = 1.4; 95% CI = 1.2-1.7). Women who had recently stopped taking estrogens also had higher mortality rates from circulatory disease (RR = 1.3; 95% CI = 1.0-1.8) and cancer (RR = 1.6; 95% CI = 1.2-2.2) than women who never took them. The most likely explanation for these results is that women stop taking estrogens when they develop symptoms of serious illness. As a consequence of this "healthy estrogen user survivor effect," nonexperimental studies are susceptible to overestimating the benefits of menopausal estrogen use, particularly current use, on mortality.
African-Americans have an unexplained increased incidence and mortality from stroke compared with whites, and little is known about stroke in Hispanics. To investigate cross-sectional differences in sociodemographic and stroke risk factors, we prospectively evaluated 430 patients hospitalized for acute ischemic stroke (black 35%. Hispanic 46%, white 19%) over the age of 39 from Northern Manhattan. Blacks and Hispanics were younger than whites (mean ages, blacks 70, Hispanics 67, whites 80; p < 0.001) and were more likely to have less than 12 years of education than whites. Hypertension was more prevalent in blacks and Hispanics with stroke than whites (blacks 76%, Hispanics 79%, whites 63%; p < 0.05) and was often untreated in blacks. Left ventricular hypertrophy by ECG was more frequent in blacks (blacks 20%, whites 9%; p = 0.02). History of cardiac disease (atrial fibrillation, myocardial infarction, angina, and congestive heart failure) was less prevalent in both blacks and Hispanics. Black women were significantly more obese than white women (mean Quetelet Index percent, blacks 3.9%, whites 3.6%; p < 0.05). Heavy alcohol use was more often reported by blacks and Hispanics; cigarette smoking was increased only in blacks. Moreover, blacks were less likely to have visited a physician 1 year after their stroke (blacks 85%, whites 98%; p < 0.05), and Hispanics less often lived alone compared with whites. These cross-sectional differences suggest that the burden of stroke risk factors is increased in both blacks and Hispanics with stroke. Further studies controlling for stroke risk factors are needed to establish whether race-ethnicity is an independent determinant of stroke risk.
Stroke continues to have a great impact on public health in the United States. Stroke is frequent, recurring, and is more often disabling than fatal. The annual incidence of new strokes in the United States is nearly one half million, with over 3 million stroke survivors alive today. Identifying risk factors for initial ischemic stroke, as well as characterizing the determinants of outcome (stroke recurrence and mortality) after ischemic stroke, is the basis for stroke prevention strategies. Modifiable and nonmodifiable risk factors for ischemic stroke have been identified and include age; gender; race/ethnicity; heredity; hypertension; cardiac disease, particularly atrial fibrillation; diabetes mellitus; hypercholesterolemia; cigarette smoking; and alcohol abuse. New risk factors, such as hypercoagulable states and patient foramen ovale, are currently being investigated. Follow-up studies have quantified case-fatality rates, early recurrence risk, and long-term mortality and recurrence risks. Despite advances in stroke prevention strategies and treatments, stroke recurrence is still the major threat to any stroke survivor. A major goal set by the Public Health Service in its National Health Promotion and Disease Prevention Objectives for the year 2000 is "to reduce stroke deaths to no more than 20 per 100,000." Part of this can be achieved if the risk of stroke recurrence is reduced. However, the frequency and determinants of stroke recurrence are poorly understood. Data from epidemiologic studies can help identify risk factors and outcomes after ischemic stroke, as well as the selection of high-risk individuals for focused risk-factor modification. Current information on these topics is discussed.
The purpose of this study was to test the hypothesis that overall and truncal adiposity increase the risk of stroke independent of their association with cardiovascular disease risk factors and other preexisting illnesses.
Analyses were conducted of longitudinal data from a poor, biracial cohort of noninstitutionalized adults 65 to 74 years of age who participated in the Chicago Stroke Study from 1965 to 1970.
Ponderal index (cm/kg1/3) and chest skinfold were significantly associated with systolic and diastolic blood pressure, serum cholesterol and triglycerides, plasma glucose, and smoking. Ponderal index was also associated with diabetes and risk of stroke. After potential confounders were controlled, the following variables showed significant independent associations with risk of stroke: Black race, female gender, and age 70+; hypertensive heart disease; and diabetes. Neither adiposity variable was associated with risk of stroke in the presence of these powerful predictors.
Control of hypertension and diabetes continues to be important among older adults. Since excess adiposity seems to influence risk of stroke through its association with these disorders and other cardiovascular disease risk factors, control of weight and fat remains an important concern as well.
A cohort of 2181 men and women, aged 40 to 79 years, without evidence of coronary heart disease or cancer at entry to the Tecumseh Study was evaluated.
Subjects were defined as lean if their Metropolitan Life Insurance table relative weight was < 110 (n = 584) and as obese if their relative weight was > or = 120 (n = 1024). There were 688 subjects with hypertension at study entry (systolic blood pressure > or = 160, diastolic blood pressure > or = 95, or treated). The 29-year relative risk (RR) of mortality from ischemic heart disease (IHD) or cardiovascular disease (CVD) associated with systolic blood pressure level was significant for both lean and obese subjects. Among hypertensive subjects, the RR of fatal IHD for lean versus obese hypertensive subjects was 1.87 (95% confidence interval, 1.21 to 2.88) and the RR of fatal CVD was 1.56 (95% confidence interval, 1.10 to 2.20) using a Cox proportional-hazards model to adjust for the independent effects of age and traditional CVD risk factors. The findings are consistent with other studies in men showing lean hypertensive subjects to be at greater risk of IHD or CVD mortality than obese hypertensive subjects. A similar finding is now observed in women.
Associations do not prove causality or dictate management. Nevertheless, the unexplained higher mortality in lean versus obese hypertensive subjects has now been reported with sufficient frequency to suggest that the association is real (if unexplained). Determining the reasons for this association may improve targeted prevention and treatment strategies.
The purpose of the present analysis was to determine how lifestyle influences the risk of cerebrovascular disease in women participating in the Copenhagen City Heart Study.
A random sample of a white, lower and middle-class, urban population selected in 1976 was invited to two cardiovascular examinations at 5-year intervals. The present analysis was based on 7060 women invited to an initial examination from 1976 through 1978, aged 35 years or more, and without previous stroke or transient ischemic attack. At the initial examination, potential risk factors were recorded. The 265 first cases of stroke and transient ischemic attack were ascertained at a second examination 5 years later and through hospital records and death certificates through 1988. The Cox regression model was used to estimate the influence of the factors recorded on the risk of cerebrovascular disease.
The relative risks of cigarette smoking and lack of physical activity were 1.4 and 1.45; 95% confidence limits, 1.02 to 1.94 and 1.01 to 2.08, respectively). The relative risk of daily consumption of tranquilizers was 1.25 (95% confidence limits, 0.96 to 1.62). No significant influence was found for number of cigarettes, body mass index, or alcohol intake. In postmenopausal women, there was a statistically significant interaction (P < .041) between smoking and hormone replacement therapy. Smokers receiving this therapy had a 28% lower risk of cerebrovascular disease than smokers not receiving it.
The statistically significant and equally potent effects on the risk of cerebrovascular disease were found for cigarette smoking and lack of physical activity. The risk associated with smoking seemed to be influenced by hormonal replacement therapy.
The protective effect of postmenopausal estrogen replacement therapy on coronary heart disease has been shown in several studies. However, the effect on stroke is more controversial, and data on estrogen-progestin combinations are sparse.
A total of 23,088 women living in the Uppsala (Sweden) Health Care Region were identified from pharmacy records as having been prescribed noncontraceptive estrogens during 1977 through 1980. They were followed up from 1977 to 1983 for admissions to the hospital because of a first stroke (International Classification of Diseases, Eighth Revision, codes 430 through 438 and 344). The mean observation time was 5.8 years. The expected number was based on person-years in the cohort and incidence rates in the population of the region.
Overall, 361 cases of first stroke were observed in the cohort, as compared with 403.2 expected (relative risk [RR], 0.90; 95% confidence limits, 0.81, 0.99). The RR for acute stroke (International Classification of Diseases, Eighth Revision, codes 431 through 436) was 0.85 (0.75, 0.97). In women younger than 60 years at entry who were prescribed estradiol compounds (1 to 2 mg) or conjugated equine estrogens (0.625 to 1.25 mg), the risk of any stroke was reduced by almost 30% (RR, 0.72; 0.58, 0.88) and the risk of acute stroke was reduced by 40% (RR, 0.61; 0.46, 0.79). Women prescribed a combined estradiol-levonorgestrel brand also had a lowered risk of stroke (RR, 0.61; 0.40, 0.88). Weak compounds (mainly estriol) showed no stroke-protective effect, nor was there any relationship between hormone replacement and risk of subarachnoid hemorrhage.
Hormone replacement therapy with potent estrogens alone or cyclically combined with progestins can, particularly when started shortly after menopause, reduce the risk of stroke.
Diabetes is a major risk factor for development of ischemic cerebrovascular disease. Patients with diabetes are at least two times more likely to have a stroke than nondiabetics. In addition, they are more likely to suffer increased morbidity and mortality after stroke. The mechanism of production of stroke secondary to diabetes may be due to cerebrovascular atherosclerosis, cardiac embolism, or rheologic abnormalities. The evaluation of cerebrovascular disease in diabetic patients is similar to the nondiabetic patient, with particular attention paid to adequate hydration prior to the administration of contrast agents. Treatment options for stroke in diabetics requires individualization but should include risk factor modification, and may include platelet antiaggregants, anticoagulation, or, in a well-defined subgroup, carotid endarterectomy.
To assess the impact of postmenopausal hormone use on the risk of stroke incidence and stroke mortality.
Longitudinal study consisting of three data collection waves. The average follow up for cohort members was 11.9 years (maximum, 16.3 years). Cox proportional hazards regression models were used to estimate the relative risk of stroke for postmenopausal hormone ever-users compared with never-users.
A national sample of 1910 (of 2371 eligible) white postmenopausal women who were 55 to 74 years old when examined in 1971 through 1975 as part of the first National Health and Nutrition Examination Survey and who did not report a history of stroke at that time.
The main outcome measure was incident stroke (fatal and nonfatal). Events were determined from discharge diagnosis information coded from hospital and nursing home records and cause of death information coded from death certificates collected during the follow-up period (1971 through 1987).
There were 250 incident cases of stroke identified, including 64 deaths with stroke listed as the underlying cause. The age-adjusted incidence rate of stroke among postmenopausal hormone ever-users was 82 per 10,000 woman-years of follow-up compared with 124 per 10,000 among never-users. Postmenopausal hormone use remained a protective factor against stroke incidence (relative risk, 0.69; 95% confidence interval, 0.47 to 1.00) and stroke mortality (relative risk, 0.37; 95% confidence interval, 0.14 to 0.92) after adjusting for the baseline risk factors of age, systolic blood pressure, diabetes, body mass index, smoking, history of hypertension and heart attack, and socioeconomic status.
The results suggest that postmenopausal hormone use is associated with a decrease in risk of stroke incidence and mortality in white postmenopausal women.
Estrogen therapy in postmenopausal women has been associated with a decreased risk of heart disease. There is little information, however, about the effect of combined estrogen and progestin therapy on the risk of cardiovascular disease.
We examined the relation between cardiovascular disease and postmenopausal hormone therapy during up to 16 years of follow-up in 59,337 women from the Nurses' Health Study, who were 30 to 55 years of age at base line. Information on hormone use was ascertained with biennial questionnaires. From 1976 to 1992, we documented 770 cases of myocardial infarction or death from coronary disease in this group and 572 strokes. Proportional-hazards models were used to calculate relative risks and 95 percent confidence intervals, adjusted for confounding variables.
We observed a marked decrease in the risk of major coronary heart disease among women who took estrogen with progestin (multivariate adjusted relative risk, 0.39; 95 percent confidence interval, 0.19 to 0.78) or estrogen alone (relative risk, 0.60; 95 percent confidence interval, 0.43 to 0.83), as compared with women who did not use hormones [corrected]. However, there was no significant association between stroke and use of combined hormones (multivariate adjusted relative risk, 1.09; 95 percent confidence interval, 0.66 to 1.80) or estrogen alone (relative risk, 1.27; 95 percent confidence interval, 0.95 to 1.69).
The addition of progestin does not appear to attenuate the cardioprotective effects of postmenopausal estrogen therapy.
Geographical differences in stroke mortality are not fully explained by population variations in blood pressure and antihypertensive treatment. Some studies have suggested that factors connected with health and nutrition in early life may be related to stroke morbidity and mortality. Body height is a sensitive marker for socioeconomic conditions, but results are conflicting as to whether height is associated with stroke.
In a population-based study, we investigated stroke incidence in relation to height and classic cardiovascular risk factors. A total of 13,266 men and women 35 to 52 years of age were followed for 14 years, and 241 first events of stroke were registered. Stroke incidence was 36% higher in men. Height was inversely related to stroke in a dose-response manner. Per 5-cm increase in height, the age-adjusted risk of stroke was 25% lower in women (P < .0001) and 18% lower in men (P = .0007). Systolic blood pressure and daily smoking were positively associated with stroke in both sexes, while serum triglyceride level was a significant risk factor in women only (relative risk per 1 mmol/L, 1.3; 95% CI, 1.1 to 1.5). The associations remained after adjustment for possible confounders and were also observed in certain subtypes of stroke.
The results are consistent with the theory that factors influencing early growth as well as adult lifestyle factors contribute to cerebrovascular disease in adult age.
We linked data from the National Longitudinal Mortality Study to census tract information on 239,187 persons to assess 11-year mortality risk among black and white men and women associated with median census tract income, adjusted for individual family income from the Current Population Survey. We stratified Cox proportional hazards models by ages 25-64 years and 65 years and older. We used a robust covariance matrix to obtain standard errors for the model coefficients that account for correlation among individuals in the same census tract. Both income indicators were independently related to all-cause mortality. Among persons age 25-64 years, the rate ratios (RR) for individual family income and the median census tract income, respectively, for low income relative to high income were RR = 2.10 vs 1.49 for black men, RR = 2.03 vs 1.26 for white men; and RR = 1.92 vs 1.30 for black women and RR = 1.61 vs 1.16 for white women. Among persons age 65 years or greater, only individual family income was associated with mortality, and only for white men. Although family income has a stronger association with mortality than census tract, our results indicate that, more broadly, area socioeconomic status makes a unique and substantial contribution to mortality and should be explored in health policy and disease prevention research.
The effect of postmenopausal hormone replacement therapy (HRT) on the risk of subtypes of stroke is as yet unclear. To investigate the effect of oestrogen and combined oestrogen-progestagen therapy on the risk of non-fatal haemorrhagic and thromboembolic stroke, we carried out a case-control study.
From the Danish National Patient Register we identified all Danish women aged 45-64 years who had a non-fatal, first-ever cerebrovascular attack during 1990-92. Two age-matched controls were randomly selected for each case from the Danish National Person Register. Important correlates of hormone use and stroke, on which information was obtained from postal questionnaires, were controlled for by multivariate analyses based on log-linear graphical models. The analyses included data on 1422 cases classified in four subtypes of stroke (160 subarachnoid haemorrhage, 95 intracerebral haemorrhage, 846 thromboembolic infarction, 321 transient ischaemic attack) and 3171 controls.
After adjustment for confounding variables and correction for the trend in sales of HRT preparations, no significant associations were detected between current use of unopposed oestrogen replacement therapy and non-fatal subarachnoid haemorrhage (odds ratio 0.52 [95% CI 0.23-1.22]), intracerebral haemorrhage (0.15 [0.02-1.09]), or thromboembolic infarction (1.16 [0.86-1.58]), respectively, compared with never use. Current use of combined oestrogen-progestagen replacement therapy had no significant influence on the risk of subarachnoid haemorrhage (1.22 [0.79-1.89]), intracerebral haemorrhage (1.17 [0.64-2.13]), or thromboembolic infarction (1.17 [0.92-1.47]). A significantly increased incidence of transient ischaemic attacks among former users of HRT and among current users of unopposed oestrogen may to some extent be explained by selection--HRT users being more aware of symptoms than non-users.
Unopposed oestrogen and combined oestrogen-progestagen replacement therapy have no influence on the risk of non-fatal thromboembolic or haemorrhagic stroke in women aged 45-64 years.
Information about the risk of stroke in current postmenopausal hormone users is limited.
In this case-control study, women aged 45 to 74 years hospitalized with a fatal or nonfatal stroke in any of 10 Northern California Kaiser Permanente facilities during the period November 1991 to November 1994 were identified as cases. Controls were selected at random from female Health Plan members. Data regarding use of estrogen plus progestogen or estrogen alone were obtained in interviews.
The analysis was based on nonproxy responses from 349 cases of ischemic stroke and 349 matched control subjects. After adjustment for confounders, the odds ratio for ischemic stroke in current hormone users was 1.03 (95% confidence interval, 0.65 to 1.65). The odds ratios for ischemic stroke in current hormone users showed no clear trend of increasing or decreasing risk in relation to duration of hormone use. The odds ratio for ischemic stroke in past hormone users was 0.84 (95% confidence interval, 0.54 to 1.32).
In this study postmenopausal hormone use was not associated with an increase or decrease in the risk of ischemic stroke, a finding that is consistent with the body of literature on this topic.
Studies of the effect of hormone replacement therapy (HRT) on the risk of stroke in postmenopausal women have yielded divergent results. Many of the studies had small numbers of estrogen-using women and relatively young women. All were confounded because women who use estrogen are healthier than the general population. Case-control studies, which included a larger number of cases, usually were limited to stroke survivors and had problems of recall bias regarding exposure. We describe the independent risk of fatal and nonfatal stroke in a socioeconomically homogeneous cohort of older, postmenopausal, community-dwelling women in Rancho Bernardo, California, who had a high rate of past or current HRT use. During 1984-1987, estrogen use and stroke risk factors were ascertained for 1031 women over age 60 without a history of stroke in the Rancho Bernardo cohort. Stroke deaths were monitored by obtaining 100% of death certificates, and nonfatal strokes were determined through questionnaires. At baseline, the average age was 73.1 years, 27% were current estrogen users, and 45% were past estrogen users. Over 8.8 follow-up years, 263 deaths occurred, and 37 of the death certificates listed stroke as an underlying or contributing cause of death. Only 7 of current HRT users had a stroke compared with 16 former users and 14 never users. The age-adjusted odds ratio (OR) was 0.92 (95% CI = 0.56-1.50) in HRT users versus never users. Results were not materially changed in multiply adjusted analyses. Similar analyses of nonfatal strokes and transient ischemic attacks (n = 20) showed an increased risk (OR = 3.02, 95% CI = 0.70-13.08). This study provides no evidence that HRT prevents stroke in older women, but the confidence intervals are wide, suggesting that more studies are needed.
Nonvalvular atrial fibrillation (AF) is a strong, independent risk factor for stroke, but the absolute rate of stroke varies widely among AF patients, importantly influencing the potential benefit of antithrombotic prophylaxis. We explore factors associated with ischemic stroke in AF patients taking aspirin.
We performed multivariate logistic regression analysis of 2012 participants given aspirin alone or in combination with low, inefficacious doses of warfarin in the Stroke Prevention in Atrial Fibrillation I-III trials followed for a mean of 2.0 years, during which 130 ischemic strokes were observed.
Age (relative risk [RR]=1.8 per decade, P<0.001), female sex (RR=1.6, P=0.01), history of hypertension (RR=2.0, P<0.001), systolic blood pressure >160 mm Hg (RR=2.3, P<0.001), and prior stroke or transient ischemic attack (RR=2.9, P<0.001) were independently associated with increased stroke risk. Regular consumption of >/=14 alcohol-containing drinks per week was associated with reduced stroke risk (adjusted RR=0.4, P=0.04). Among SPAF III participants, estrogen hormone replacement therapy was associated with a higher risk of ischemic stroke (adjusted RR=3.2, P=0.007). With the use of these variables, a risk stratification scheme for primary prevention separated participants into those with high (7.1%/y, 22% of the cohort), moderate (2.6%/y, 37% of the cohort), and low (0.9%/y, 41% of the cohort) rates of stroke. Ischemic strokes in low-risk participants were less often disabling (P<0.001).
Patients with AF who have high and low rates of stroke during treatment with aspirin can be identified. However, validation of our risk stratification scheme is necessary before it can be applied with confidence to clinical management. Postmenopausal estrogen replacement therapy and moderate alcohol consumption may additionally modify the risk of stroke in AF, but these findings require confirmation.
Postmenopausal estrogen use is associated with a reduced risk of heart disease and hip fracture; in observational studies, different behaviors among hormone users and nonusers may partially explain these results. We examined risk of cardiovascular disease and hip fracture with medium-potency compared with low-potency or short-term estrogen use, and the effect of added progestin, among 9,236 women in Uppsala, Sweden, who responded to a mailed questionnaire in 1987-1988. Using population registries, we identified 213 cases of myocardial infarction, 289 strokes, and 114 hip fractures from 1987-1995. We found a reduced risk of myocardial infarction for medium-potency compared with low-potency or short-term estrogen use (relative risk = 0.75, 95% confidence interval (CI) = 0.56-0.99), with a similar decrease in the subgroup that took estrogens with progestin (RR = 0.69, 95% CI = 0.45-0.90). There was no relation of medium-potency estrogen to stroke (RR = 0.91, 95% CI = 0.71-1.17, and RR = 0.81, 95% CI = 0.61-1.10 for the subgroup taking progestin), and no effect of duration on either heart disease or stroke. We observed a reduction in hip fractures for medium-potency use (RR = 0.65, 95% CI = 0.45-0.95), and for use of combined estrogen-progestin therapy (RR = 0.64, 95% CI = 0.41-1.00). These data support a decreased risk of heart disease and hip fracture for medium-potency estrogen use alone or with progestin; self-selection to hormone use cannot explain these reductions.