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      Combined effect of physical exercise and hormone replacement therapy on cardiovascular and metabolic health in postmenopausal women: A systematic review and meta-analysis

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          Abstract

          The cardioprotective effect of postmenopausal hormone replacement therapy (HRT) has been demonstrated in several studies. Similarly, physical exercise has yielded positive results. However, the effects of their combination remain inconclusive. This review describes the combined effects of physical exercise and hormone therapy on cardiovascular and metabolic health in postmenopausal women. We searched the Scopus, Web of Science, PubMed, and Embase databases and included randomized controlled trials published up to December 2021 on the combined effects of physical exercise and hormone therapy on cardiovascular and metabolic health in postmenopausal women. We identified 148 articles, of which only seven met the inclusion criteria (386 participants; 91 [23%] HRT + exercise; 104 [27%] HRT; 103 [27%] exercise; 88 [23%] placebo). The combined treatment further decreased systolic blood pressure (SBP) compared to the isolated effect of aerobic training (AT) (mean difference [MD]=-1.69; 95% confidence interval [CI]=-2.65 to -0.72, n=73). Nevertheless, it attenuated the decrease in diastolic blood pressure (DBP) (MD=0.78; 95%CI: 0.22-1.35, n=73), and the increase in peak oxygen consumption (VO 2 peak) promoted by exercise (AT + HRT=2.8±1.4 vs AT + placebo=5.8±3.4, P=0.02). The combination of AT and oral HRT improved SBP. However, AT alone seemed to have a better effect on physical fitness and DBP in postmenopausal women.

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          The emergence of the metabolic syndrome with menopause.

          Women with the metabolic syndrome (central obesity, insulin resistance, and dyslipidemia) are known to be at especially high risk for cardiovascular disease (CVD). The prevalence of the metabolic syndrome increases with menopause and may partially explain the apparent acceleration in CVD after menopause. The transition from pre- to postmenopause is associated with the emergence of many features of the metabolic syndrome, including 1) increased central (intraabdominal) body fat; 2) a shift toward a more atherogenic lipid profile, with increased low density lipoprotein and triglycerides levels, reduced high density lipoprotein, and small, dense low density lipoprotein particles; 3) and increased glucose and insulin levels. The emergence of these risk factors may be a direct result of ovarian failure or, alternatively, an indirect result of the metabolic consequences of central fat redistribution with estrogen deficiency. It is unclear whether the transition to menopause increases CVD risk in all women or only those who develop features of the metabolic syndrome. This article will review the features of the metabolic syndrome that emerge with estrogen deficiency. A better understanding of these metabolic changes with menopause will aid in the recognition and treatment of women at risk for future CVD, leading to appropriate interventions.
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            The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

            Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.
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              Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.

              Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. clinicaltrials.gov Identifier: NCT00000611.
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                Author and article information

                Journal
                Braz J Med Biol Res
                Braz J Med Biol Res
                bjmbr
                Brazilian Journal of Medical and Biological Research
                Associação Brasileira de Divulgação Científica
                0100-879X
                1414-431X
                15 May 2023
                2023
                : 56
                : e12241
                Affiliations
                [1 ]Laboratório de Cardiologia, Fisiologia e Fisioterapia, Departamento de Ciências da Saúde, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
                [2 ]Universidad de Santander, Facultad de Ciencias Médicas y de la Salud, Bucaramanga, Colombia
                Author notes
                Correspondence: H.C.D. Souza: < hugocds@ 123456fmrp.usp.br >
                Author information
                http://orcid.org/0000-0001-7198-6258
                http://orcid.org/0000-0002-4833-3707
                http://orcid.org/0000-0003-3174-0557
                http://orcid.org/0000-0002-8276-1035
                http://orcid.org/0000-0002-7443-4974
                http://orcid.org/0000-0002-8093-1897
                http://orcid.org/0000-0002-0009-0005
                Article
                00351
                10.1590/1414-431X2023e12241
                10241482
                37194832
                f8bc90f1-be35-4320-99a5-3b2b2efab120

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 August 2022
                : 31 March 2023
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 74
                Categories
                Systematic Review

                exercise training,secondary prevention,metabolic diseases,review,menopause,estrogens

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