Vascular Effects of Synthetic or Natural Progestagen Combined With Conjugated Equine Estrogen in Healthy Postmenopausal Women

Koh, Kwang Kon; Jin, Dong Kyu; Yang, Seong Hee; Lee, Seon Kyu; Kang, Moon Ho; Kim, Wan; Kim, Dae Sung; Choi, In Suck; Shin, Eak Kyun

doi:10.1161/01.cir.103.15.1961

Cited by 131 publications

(91 citation statements)

References 56 publications

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“…77 However, 2 other well-conducted studies did not find any attenuation of CEE-induced dilatation by MPA or micronized progesterone. 78,79 Whether progestins attenuate the anti-atherosclerotic effects of estrogen is also unclear. In cynomolgus monkeys, chronic estradiol or estradiol plus progesterone had similar anti-atherosclerotic effects.…”

Section: Progestin In the Hrt Regimenmentioning

confidence: 99%

Hormone Replacement Therapy and Cardiovascular Disease

et al. 2004

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Abstract-Observational studies in humans and experimental studies in animals and isolated cells supported the widely held belief that hormone replacement therapy protects the cardiovascular system from disease. To nearly everyone's astonishment, the Women's Health Initiative Study and the Heart and Estrogen/Progestin Replacement Study overturned the conclusion that hormone replacement therapy protects the cardiovascular system and, in fact, supported the opposite view that such therapy may actually increase the risk of cardiovascular disease. Observational Studies Suggest HRT Has Beneficial Cardiovascular EffectsIn modern societies, cardiovascular disease is the main cause of morbidity and mortality in men and women. Women, however, are comparatively spared. For example, in people younger than age 65 years, the prevalence of coronary heart disease (CHD) is several-fold higher in men. 3,4 Although CHD prevalence increases with age in both genders, before the age of 65 years the relationship between age and CHD prevalence is shifted rightward by 5 years in women; 5,6 compared with postmenopausal women, CHD deaths are rare in premenopausal women. 7 Autopsy studies demonstrated increased CHD in oophorectomized young women, 8 and several studies demonstrated an increased risk of cardiovascular disease in women with bilateral oophorectomy without HRT compared with those receiving HRT. 9,10 Women with natural early-onset menopause who did not use HRT had a greater likelihood for CHD compared with age-matched premenopausal women. 9,11 Also, studies reported an inverse relationship between age at natural menopause and mortality from CHD 12,13 and carotid atherosclerosis. 14 Bush et al demonstrated that HRT was associated with reduced all-cause mortality in postmenopausal women, 15 primarily because of favorable effects on high-density lipoprotein. 16 Barrett-Connor and Bush 8 reported that many, but not all, cross-sectional and prospective studies demonstrated a statistically significant reduction in CHD in women taking HRT, and Grady et al 17 presented a meta-analysis of published observational studies and reported that HRT was associated with one-third less fatal CHD. An up-to-date meta-analysis of 25 observational studies conducted between 1976 and 1996 showed that the relative risk for CHD in women who ever used HRT compared with never users was 0.70. 18 The Nurses' Health Study was a comprehensive investigation conducted in 121 700 female nurses aged 30 to 55 years. In the latest report, compiled with data from 70 533 postmenopausal women followed-up for 20 years, the overall risk of CHD in current users of HRT was reduced, with a relative risk of 0.61 after adjustment for age and cardiovascular risk factors. 19

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Section: Progestin In the Hrt Regimenmentioning

confidence: 99%

Hormone Replacement Therapy and Cardiovascular Disease

et al. 2004

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“…Assays for lipids, plasma nitrate (using the Griess reaction), malondialdehyde (MDA), monocyte chemoattractant protein (MCP)-1, and PAI-1 antigen were performed in duplicate by enzyme-linked immunosorbent assay (R&D Systems, Bioxytech LPO-586, OxisResearch, or Biopool for PAI-1 antigen) as previously described. 4,7,21,22 C-reactive protein (CRP) levels were determined with an immunonephelometry system according to methods described by the manufacturer (rate nephelometry; Immage, Beckman Coulter) as previously described. 23,24 …”

Section: Laboratory Assaysmentioning

confidence: 99%

Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

et al. 2004

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Abstract-Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Thus, we studied vascular responses to combination therapy in hypercholesterolemic patients. A randomized, double-blind, placebo-controlled, crossover trial was conducted with 50 hypercholesterolemic patients with simvastatin and either placebo or ramipril (study I) and in 45 hypercholesterolemic diabetic patients with simvastatin or ramipril with placebo or simvastatin combined with ramipril (study II) for 2 months with 2 months washout. In study I simvastatin combined with ramipril significantly reduced blood pressure after 2 months. Simvastatin alone or combined with ramipril significantly changed lipoproteins, improved percent flow-mediated dilator response to hyperemia by 30Ϯ5% and 53Ϯ6%, respectively (PϽ0.001), and reduced plasma levels of malondialdehyde by 4Ϯ7% (Pϭ0.026) and 25Ϯ4% (PϽ0.001), respectively. Monocyte chemoattractant protein-1 levels decreased by 3Ϯ3% and 12Ϯ2%, respectively (Pϭ0.049 and Pϭ0.001, respectively), C-reactive protein levels changed by 0% and 18%, respectively (Pϭ0.036 and PϽ0.001, respectively), and plasminogen activator inhibitor-1 antigen levels changed by Ϫ7Ϯ7% and 17Ϯ5%, respectively (Pϭ0.828 and PϽ0.001, respectively). In study II ramipril alone did not significantly change lipoproteins and C-reactive protein levels, however, simvastatin combined with ramipril significantly changed lipoproteins and C-reactive protein levels more than ramipril alone (PϽ0.001 and Pϭ0.048 by ANOVA, respectively). Ramipril alone or simvastatin combined with ramipril significantly improved the percent flow-mediated dilator response to hyperemia (both PϽ0.001), however, simvastatin combined with ramipril showed significantly more improvement than ramipril alone (PϽ0.001 by ANOVA). Simvastatin combined with ramipril significantly improved endotheliumdependent vasodilation and fibrinolysis potential and reduced plasma levels of oxidant stress and inflammation markers in hypercholesterolemic patients. Key Words: angiotensin-converting enzyme Ⅲ atherosclerosis Ⅲ endothelial growth factors Ⅲ hypercholesterolemia Ⅲ blood pressure L arge-scale clinical studies demonstrate that statins and angiotensin-converting enzyme (ACE) inhibitor prevent or retard the progression of coronary heart disease. 1,2 The mechanisms of this apparent benefit of these therapies may include vascular effects. Statins reduce LDL cholesterol and improve endothelial function, consistent with enhanced NO bioactivity. 3-5 ACE inhibition also improves endothelial function. 6,7 A potential mechanism of this effect is augmented NO bioactivity via diminished bradykinin degradation by ACE with activation of endothelial B 2 kinin receptors and stimulation of NO synthase activity. 8 Alternatively, ACE inhibition may diminish intracellular production of superoxide anions via reduced activity of angiotensin II-dependent oxidases in the endothelium and vascular smooth muscle, 9,10 thus protecting NO from oxidant degradatio...

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“…Four smaller studies confirm the inhibitory effect of a variety of menopausal hormone regimens on sE-selectin levels ( Figure 3A). [35][36][37][38] sVCAM-1 and sICAM-1…”

Section: Soluble E-selectinmentioning

confidence: 99%

“…These reductions were statistically significant in all of the trials, which tested a variety of menopausal hormone preparations ( Figure 3B). 33,[35][36][37][38][39] …”

Section: Soluble E-selectinmentioning

confidence: 99%

Hormone Replacement Therapy and Inflammation

et al. 2003

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Abstract-Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Atherogenesis begins with endothelial damage, and the damaged endothelium expresses adhesion molecules, chemokines, and proinflammatory cytokines that direct atherosclerotic plaque formation and spill into the circulation as biomarkers of atherosclerotic disease risk. Menopausal hormone therapy, including a variety of estrogen preparations with or without a progestin, has negative modulatory effects on most of these soluble inflammatory markers, including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-␣, inconsistent effects on interleukin-6, and stimulatory effects on transforming growth factor-␤, a vasoprotective cytokine. In contrast, C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen. Although C-reactive protein is clearly linked to increased cardiovascular disease risk in women, the hormone-induced rise in this biomarker is not associated with increased risk and may be related to a first-pass effect of C-reactive protein production in the liver after oral estrogen absorption. Many important questions about the effects of ovarian hormones on vascular inflammation and the pathogenesis of vascular disease cannot be answered in human subjects. Insights from fundamental mechanistic studies in animal models are needed to delineate the cellular/molecular events that determine whether these hormones protect or injure blood vessels.

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Vascular Effects of Synthetic or Natural Progestagen Combined With Conjugated Equine Estrogen in Healthy Postmenopausal Women

Cited by 131 publications

References 56 publications

Hormone Replacement Therapy and Cardiovascular Disease

Hormone Replacement Therapy and Cardiovascular Disease

Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

Hormone Replacement Therapy and Inflammation

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