Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen

Abstract

Premenopausal women have a lower risk for cardiovascular events, and mortality due to coronary vascular disease (CVD) in premenopausal women is rare. These facts suggest that endogenous estrogens, such as estradiol, protect the cardiovascular system, and several observational studies and a few small clinical studies conducted in healthy and younger postmenopausal women support this hypothesis. In contrast, two large randomized clinical trials (RCTs), using conjugated equine estrogens and conducted in older women with established CVD or without overt CVD, failed to demonstrate protection against CVD by exogenous estrogens. These divergent findings have resulted in confusion with regard to the association between estrogen deficiency and CVD in postmenopausal women. In order to reconcile these contradictory findings, it is necessary to examine the pathophysiology associated with age-dependent changes within the vessel wall and to compare the pharmacology of different types of estrogens. Understanding age-dependent changes in vascular pathology and the pharmacology of different estrogens may facilitate the development of therapeutic strategies for hormone replacement therapy (HRT) that would be effective in delaying vascular remodeling leading to CVD following menopause. In this review we provide an overview of the impact of menopause and estrogen deficiency on vascular remodeling and emphasize the importance of timing and type of estrogen to achieve maximum benefits with regard to reducing the risk of CVD.

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

“…Since 17␤-estradiol administered during hormone replacement therapy will rapidly increase estrone sulfate after conversion in adipose tissue, hormone replacement therapy can have proinflammatory effects by providing estrone sulfate to the inflamed synovial tissue. This is particularly true when a crude mixture of estrogenic compounds is used with various estrone-derived estrogens (32). The preponderance of 16␣OH-estrone relative to other estrogens was not observed in the presence of 17␤-estradiol.…”

Endogenous sex hormones and risk factors for atherosclerosis in healthy Greek postmenopausal women

“…Finally, some investigators have found no significant association between estrogen and lipid levels (17)(18)(19). Moreover, although menopausal transition increases insulin resistance (20) and arterial pressure (21), no data exist as to whether fluctuations in circulating estradiol within the menopausal range have any impact on these parameters. The same discrepancy holds for homocysteine metabolism.…”

“…The matter is further complicated when studying the effect of exogenous estrogens on CVD risk factors and incidence in postmenopausal women. Although ample evidence exists that exogenous estrogens improve lipid-lipoprotein profile, insulin resistance, homocysteine metabolism, and vasodilation and that estrogens have anti-inflammatory properties at the vascular wall (21), the results of recent randomized controlled studies have revealed an increased risk of ischemic cardiac events in postmenopausal women treated with estrogen-progestin therapy (23).…”

17β-Estradiol Increases Basal but Not Bradykinin-Stimulated Release of Active t-PA in Young Postmenopausal Women

“…11 For example, the Heart and Estrogen/progestin Replacement Study (HERS) 8 and the Women's Health Initiative (WHI) 6,7 study assessed the effect of treatment with conjugated equine estrogens, a mixture of estrogens extracted from horse urine that also contains progestins and androgens, whereas estradiol is the major endogenous estrogen. 12 Differences in the outcomes of epidemiological studies and clinical trials are best interpreted in the context of an understanding of the biological effects of estrogen. On the one hand, oral HRT increases circulating fibrin split products (FSP), concentrations of inflammatory cytokines, and C-reactive protein.…”