Hormone Replacement Therapy and Endothelial Function
2001; Lippincott Williams & Wilkins; Volume: 21; Issue: 12 Linguagem: Inglês
10.1161/atvb.21.12.1867
ISSN1524-4636
AutoresJoseph A. Vita, John F. Keaney,
Tópico(s)Cardiovascular Health and Disease Prevention
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 21, No. 12Hormone Replacement Therapy and Endothelial Function Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHormone Replacement Therapy and Endothelial FunctionThe Exception That Proves the Rule? Joseph A. Vita and John F. KeaneyJr Joseph A. VitaJoseph A. Vita From the Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass. and John F. KeaneyJrJohn F. KeaneyJr From the Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass. Originally published15 Mar 2018https://doi.org/10.1161/atvb.21.12.1867Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1867–1869The endothelium plays a central role in the regulation of vascular homeostasis by releasing paracrine factors that influence vascular tone, thrombosis, and inflammation in the arterial wall.1 A principal endothelial product responsible for homeostasis is nitric oxide (NO), which is synthesized by the endothelial isoform of NO synthase2 in response to a number of stimuli, including increased shear stress that accompanies increased arterial flow.3 Atherosclerosis and its risk factors are characterized by an impairment of endothelial NO-dependent vasodilation,1 and the magnitude of this defect in the coronary circulation predicts cardiovascular disease events, raising the possibility of a pathogenic relationship.4,5See page 1955This notion of a causal relation between endothelial dysfunction and cardiovascular events is also supported by intervention data. For example, lipid-lowering therapy, angiotensin-converting enzyme inhibition, smoking cessation, and exercise all reverse endothelial dysfunction and have proven benefitial against cardiovascular disease events.1 This concordance between improved endothelial function and reduced cardiovascular events has prompted speculation that changes in endothelial function are partially responsible for the benefits.6–8 Thus, endothelial dysfunction could potentially be used as a surrogate marker for cardiovascular disease risk in study of risk reduction therapies.3Hormone replacement therapy has received considerable attention as a means for primary and secondary prevention of cardiovascular disease. This interest was initially based on population-based studies linking a reduced incidence of cardiovascular disease to hormone replacement therapy.9–11 Estrogen has many potential benefits, including favorable influence on serum lipids and thrombotic factors, and there is substantial evidence that chronic estrogen treatment also improves endothelial function in postmenopausal women (Table). Despite these apparent benefits, a relatively large-scale randomized clinical trial of hormone replacement therapy (conjugated equine estrogen plus medroxyprogesterone acetate) for secondary prevention of cardiovascular disease (HERS) failed to demonstrate a benefit from estrogen.24 Furthermore, in a separate study, neither the combination of estrogen and progesterone nor estrogen alone had any effect on angiographic extent of coronary artery disease.25 As a consequence of these findings, a consensus panel concluded that hormone replacement therapy has no role in either the primary or secondary prevention of cardiovascular disease, pending the results of ongoing clinical trials.11 These data highlight an apparent lack of concordance between the effects of estrogen treatment on endothelial function and clinical outcome, fueling speculation against the clinical relevance of endothelial function.26Table 1. Studies of Chronic Hormone Replacement Therapy and Endothelial Function in Postmenopausal WomenFirst AuthorNAge (years)Medical ConditionsRxEndpointEffectN indicates number of women receiving treatment; CVD, cardiovascular disease; FMD, brachial artery flow-mediated dilation; NO2/NO3, total nitrite and nitrate; meds, cardiac medications; HRT, hormone replacement therapy.Lieberman121355±7Healthy women with no CVD or risk factorsOral estrogenFMD+Herrington134PostmenopausalCoronary artery disease and anginaOral or topical estrogenIntracoronary acetylcholine+Rosselli1413>45Healthy womenTopical estrogenPlasma NO2/NO3+Topical estrogen+oral norethisteronePlasma NO2/NO3−McCrohon155558±3Healthy womenEstrogen aloneFMD+Estrogen+progesteroneFMD+Gerhard161760 (48–70)Healthy women with no CVD or risk factorsTopical estrogenFMD+Topical estrogen+vaginal progestinFMD+Sorensen174653±3Healthy women with no CVD or risk factorsOral estrogen+oral norethisteroneFMD−Bush181756±9No CVDEstrogen and estrogen/progesteroneFMD+Arora191153 (43–58)Healthy womenEstrogenSkin microvessel acetylcholine+Koh202857±6LDL cholesterol>130 mg/dLEstrogenFMD+Koh212055±8Healthy womenEstrogen+progesteroneFMD+Wakatsuki221453 (45–65)Healthy womenOral estrogenFMD+31Oral estrogen+oral medroxyprogesteroneFMD−Herrington2329170–80+Elderly womenHRT (76% unopposed oral estrogen)FMD−32Women with no risk factors, CVD, or medsFMD+Hulley24276367±7Coronary artery diseaseOral estrogen+medroxy-progesteroneCardiovascular events−In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Herrington and colleagues23 report the effect of hormone replacement therapy on endothelium-dependent vasodilation in 1662 women participating in the Cardiovascular Health Study, a longitudinal study of cardiovascular risk factors in the elderly. The authors used vascular ultrasound to measure flow-mediated dilation of the brachial artery, a response that has been shown to be NO-dependent27 and to correlate with responses in the coronary circulation.28 As with the coronary circulation, endothelial dysfunction in the brachial artery improves with many risk reduction therapies,1,3 and a preliminary study suggests that brachial artery endothelial dysfunction is an independent predictor of short-term cardiovascular disease events in high risk patients.29Overall, Herrington and colleagues23 found no significant difference in endothelium-dependent vasodilation in the 291 women with current or previous hormone replacement therapy (largely unopposed estrogen) compared with the women who had never received replacement therapy. When the subjects' data were stratified according to current versus previous therapy, or to unopposed estrogen versus estrogen-progesterone combination therapy, the results were unchanged. Interestingly, when the patients were stratified according to age, the presence of cardiovascular disease, cardiovascular medication use, and risk factors, there was a benefit of hormone replacement therapy that was restricted to younger, lower-risk women. The authors concluded that the beneficial effects of estrogen might be limited to women without established cardiovascular disease. The strengths of the study include the large, well-characterized patient cohort, the careful and well-validated methodology for assessment of brachial vasodilation, and the rigorous statistical approach.How do these findings relate to the HERS results? The women in the study by Herrington et al23 were substantially older than women in other studies of hormone replacement therapy and endothelial function. In contrast to all previous studies except one that involved only 4 subjects, this study is the only one that included patients with known cardiovascular disease (Table). Thus, the subjects were much more comparable to the HERS patient population, and the results are parallel. When women without cardiovascular disease or cardiovascular disease risks were considered, the results from Herrington and colleagues23 are similar to previous studies of chronic unopposed estrogen and endothelial function. It remains unclear why older women with established cardiovascular disease would have a reduced response to estrogen treatment, but as pointed out by the authors, there currently is evidence for reduced expression of the estrogen receptor in women with advancing age30 and with cardiovascular disease.31 Although the current study showed no effect of progesterone therapy on endothelial function, many of the previous studies suggest that inclusion of medroxyprogesterone reduces or eliminates the benefits of estrogen, and these findings also are concordant with HERS.The study by Herrington and colleagues23 has several limitations. First, it was observational in nature and not a randomized trial. Thus, the hormone combination and duration of treatment varied, and many women were no longer receiving therapy at the time of the ultrasound study. Second, given the overall negative result, the subgroup analysis showing a benefit in younger, healthier subjects must be considered exploratory in nature. Third, the small number of subjects in certain subgroups limits the findings. For example, only 32 women had no cardiovascular disease, risk factors, or cardiovascular medication use, and a relatively small number of patients were receiving estrogen and progesterone in combination. Fourth, the study did not include an examination of nitroglycerin-mediated dilation, so the apparent effect of hormone replacement therapy in low-risk subjects must be interpreted as an effect on vascular function, rather than on endothelial function. Finally, the degree of brachial artery dilation was rather low compared with previous studies. As the authors acknowledge, this discrepancy is likely related to the older subject age, the lower arm cuff position, and the use of a 4-minute, rather than 5-minute period of cuff occlusion to induce hyperemia. Despite these limitations, this study represents a relatively large-scale and careful study of the effects of hormone replacement therapy on endothelial function in older, higher risk women.Thus, when a more comparable population is studied, the effects of hormone replacement therapy on endothelial function do seem to parallel the HERS results, supporting the utility of endothelial function as a surrogate endpoint. The available endothelial function studies would predict a beneficial effect of unopposed estrogen for the primary prevention of cardiovascular disease in healthy women that are closer to menopause. This question will be addressed in ongoing clinical trials, including the Women's Health Initiative. If it turns out that unopposed estrogen has benefit, any clinical recommendations will have to be considered carefully, because of the potential for pro-carcinogenic effects of unopposed estrogen. It remains quite conceivable that these and other adverse effects will outweigh any beneficial effects on the vasculature. Use of newer selective estrogen receptor modulations (SERMs) may be another way to take advantage of the benefits of estrogen without inducing its adverse effects. These agents have already been shown to have beneficial effects on endothelial function,32 and thus would be predicted to have benefit against cardiovascular disease.Drs. Vita and Keaney are supported by NIH grants HL55993, HL60886, HL 52936, and DK55656. Dr. Keaney is an Established Investigator of the American Heart Association.FootnotesAddress correspondence to Joseph A. Vita, MD, Section of Cardiology, Boston Medical Center, 88 East Newton St C-818, Boston, MA 02118. E-mail [email protected] References 1 Gokce N, Keaney JFJ, Vita JA. Endotheliopathies: clinical manifestations of endothelial dysfunction.In: Loscalzo J, Shafer AI, eds. Thrombosis and Hemorrhage. Baltimore, Md: Williams and Wilkins; 1998:901–924.Google Scholar2 Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987; 84: 9265–9269.CrossrefMedlineGoogle Scholar3 Corretti M, Anderson TJ, Benjamin EJ, Celermajer DS, Charbonneau F, Creager M, Daley WL, Deanfield JE, Drexler H, Gerhard M, Herrington DM, Vallance P, Vita JA, Vogel RA. Guidelines for the ultrasound assessment of endothelium-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 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December 2001Vol 21, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/atvb.21.12.1867PMID: 11742856 Originally publishedMarch 15, 2018 PDF download Advertisement
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