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Sex hormones exert significant effects on the cardiovascular system. Ovarian hormone deficiency associated with menopause plays an important role in the development of cardiovascular disease in women. The reduced risk of cardiovascular diseases associated with hormone replacement therapy (HRT), reported in observational studies, has not been subsequently confirmed in randomized clinical trials. Therefore, at the present time, HRT is not recommended for postmenopausal women for the prevention of cardiovascular diseases. However, the possible role and safety of HRT in women who experience menopausal symptoms that significantly affect their quality of life is still under debate. The increased risk of cardiovascular disease in the larger randomized trial was found in the oldest women and in those who started HRT late after menopause began. Further basic and clinical studies are necessary to evaluate the mechanisms underlying the possible detrimental or protective effects of HRT and to assess benefits and risks of different dosages, route of administration, and duration of HRT. In the absence of clear evidence on the safest hormone regimen, the prescription of HRT in order to reduce menopausal symptoms should be limited to younger postmenopausal women at low risk for cardiovascular diseases, starting in the period close to the beginning of menopause. The benefit of HRT in relieving menopausal symptoms and reducing the occurrence of hip fractures should be weighted against the increased risk of cardiovascular disease and breast cancer. For this purpose, it is crucial to identify the presence of cardiovascular risk factors in perimenopausal and postmenopausal women. The cardiovascular effects of sex hormones, the increased risk of cardiovascular disease after menopause, and the effects of HRT on cardiovascular risk are critically reviewed, as well as their impact on the recommendations for clinical practice.