Long-term effects of combined hormone replacement therapy on markers of endothelial function and inflammatory activity in healthy postmenopausal women

Baal, W.M. van; Kenemans, P.; Emeis, J.J.; Schalkwijk, Casper G.; Mijatovic, Velja; Mooren, M.J. van der; Vischer, Ulrich M.; Stehouwer, Coen D.A.

doi:10.1016/s0015-0282(98)00513-5

Cited by 92 publications

(59 citation statements)

References 51 publications

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“…10 -12 Treatment of postmenopausal women with estrogens reduces plasma levels of adhesion molecules and other markers of endothelial activation. 13,14 In hypercholesterolemic rabbits, estradiol both inhibits monocyte adhesion and decreases vascular cell adhesion molecule (VCAM)-1 expression. 15 Estradiol also inhibits VCAM-1 expression in cultured endothelial cells through interference of NF-B activity.…”

mentioning

confidence: 99%

Reciprocal Antagonism Between Estrogen Receptor and NF-κB Activity In Vivo

Evans

Eckert

Lai

et al. 2001

Circulation Research

148

100

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Abstract-The functional interaction, or "cross-talk," between estrogen receptor (ER) and the proinflammatory transcription factor nuclear factor (NF)-B demonstrated in vitro has been suggested to play a role in estrogen prevention of cardiovascular disease. Here, we demonstrate that this reciprocal cross-talk occurs in vivo. Ovariectomized C57BL/6 mice fed an atherogenic diet had increased hepatic levels of active NF-B and numerous inflammatory genes, including MHC invariant chain (Ii), vascular cell adhesion molecule-1, tumor necrosis factor-␣, and RANTES. Treatment with 17␣-ethinylestradiol (EE) strongly blocked induction of these genes but had no effect on their basal expression levels. ER was required for this activity, because the antagonist ICI 182,780 completely blocked the inhibitory activity of EE. Gene activation by EE was not required for inhibition of inflammatory gene expression, because both the phytoestrogen genistein and low doses of EE were effective in blocking inflammatory gene induction without inducing marker genes such as intestinal trefoil factor (ITF) or myo-inositol-1-phosphate synthase (IPS). The in vivo transcriptional interference was reciprocal, with EE induction of ITF and IPS greatly reduced in animals fed the atherogenic diet versus chow-fed controls. This interference was specific to the liver, because diet had no effect on uterine weight increases produced by EE. Transfection experiments confirmed that the extent of inhibition of ER-mediated transcription by inflammatory stimuli correlated with the extent of NF-B activation. These results suggest that the cross-talk between ER and NF-B does occur in vivo and may indeed contribute significantly to the cardioprotective effects of estrogen.

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mentioning

confidence: 99%

Reciprocal Antagonism Between Estrogen Receptor and NF-κB Activity In Vivo

Evans

Eckert

Lai

et al. 2001

Circulation Research

148

100

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“…Recently, it was shown that MCP-1, a particularly important mediator and amplifier of atherogenic signals, was downregulated after introduction and upregulated after discontinuation of 17b-estradiol; this observation was reproduced by others with conjugated equine estrogens [41,42]. Downregulation of inflammatory and vasoactive markers by different types, dosages and routes of HRT application has been demonstrated for cell adhesion molecules -such as ICAM-1, VCAM-1 and E-selectin [43 -54] -TNF-a [55 -57], vascular endothelial growth factor [58] and endothelin-1 [59][60][61][62][63][64][65][66][67]. As an endotheliumderived relaxing factor with anti-atherosclerotic and antiinflammatory properties, nitric oxide (NO) has received particular attention.…”

mentioning

confidence: 74%

“…The effect appeared to be strongest with unopposed conjugated equine estrogen [75] and was possibly ameliorated by the addition of a gestagen [76]. Conversely, six randomized trials with 17b-estradiol (three with oral [43,64,77], two with transdermal administration [78,79], and one comparing both [80]) and four non-randomized studies [53,81 -83] found reduced or unaffected CRP levels with either transdermal or oral combined regimens. Apparently, unopposed 17b-estradiol also raised CRP in a dose-dependent manner [77,80,82].…”

mentioning

confidence: 99%

Estrogen, inflammation and cardiovascular risk in women: a critical appraisal

Störk

Schouw

Grobbee

et al. 2004

Trends in Endocrinology & Metabolism

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“…Basal release of NO is higher in females than in males, and oophorectomy diminishes both circulating-estradiol concentration and basal release of NO to levels seen in males (Hayashi et al, 1992), thus offering an explanation for the protective effect of estradiol against the development of atherosclerosis. In agreement with experimental evidence, estrogen replacement therapy in postmenopausal women improves the impaired endothelial-dependent relaxation (Gerhard et al, 1998), but this evidence has been recently questioned (Van Baal et al, 1999). However, estrogens also have adverse effects on the reproductive system of females (Grady et al, 1995) and males (Robinson et al, 1963) that limits their therapeutic use.…”

mentioning

confidence: 88%

The Phytoestrogen α-Zearalenol Reverses Endothelial Dysfunction Induced by Oophorectomy in Rats

Altavilla

Saitta

Galeano

et al. 2001

Laboratory Investigation

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SUMMARY:It has been shown recently that ␣-zearalenol, a resorcyclic acid lactone, prevents bone loss in a rat model of postmenopausal bone loss. We have therefore investigated the effects of this phytoestrogen on endothelial dysfunction induced by estrogen deficiency in rats. Female mature Sprague-Dawley rats underwent a bilateral oophorectomy (OVX rats). Shamoperated animals (sham OVX rats) were used as controls. Three weeks after surgery, animals were randomized to the following treatments: ␣-zearalenol (1 mg/kg/day, im, for 4 weeks), 17␤-estradiol (20 g/kg/day, im, for 4 weeks), or their vehicle (100 l, im, of cottonseed oil). Two other groups of rats were treated with ␣-zearalenol or 17␤-estradiol plus the pure estrogen receptor antagonist ICI 182780 (2.5 mg/kg/day, im, for 4 weeks). Mean arterial blood pressure (MAP), heart rate (HR), total plasma cholesterol, plasma estradiol, and plasma ␣-zearalenol were studied. We also investigated endothelial-dependent (acetylcholine, 10 nM to 10 M) and endothelial-independent (sodium nitroprusside, 15 nM to 30 nM) relaxation of aortic rings, as well as N(G)-methyl-L-arginine (L-NMA: 10 to 100 M)-induced vasoconstriction and calcium-dependent nitric oxide synthase (cNOS) activity in homogenates of lungs taken from both sham OVX rats and OVX rats. Untreated OVX rats had, compared with sham OVX animals, unchanged body weight, MAP, HR, and plasma cholesterol. In contrast oophorectomy reduced plasma estradiol levels (OVX, 2 Ϯ 0.5 pg/ml; sham OVX, 35 Ϯ 6 pg/ml), impaired endothelial-dependent relaxation and blunted L-NMA-induced contraction (L-NMA 100 M: sham OVX, 2.7 Ϯ 0.3 g/mg tissue; OVX, 1.3 Ϯ 0.1 g/mg tissue). Moreover OVX rats showed a reduced calcium-dependent NO synthase (cNOS) activity. Treatment with ␣-zearalenol or with 17␤-estradiol reverted the endothelial dysfunction and increased cNOS activity in lung homogenates. These effects were abolished by the pure estrogen receptor antagonist ICI 182780. Our data suggest that ␣-zearalenol improves endothelial-dependent relaxation in OVX rats through an estrogen receptor-mediated effect. (Lab Invest 2001, 81:125-132).

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Long-term effects of combined hormone replacement therapy on markers of endothelial function and inflammatory activity in healthy postmenopausal women

Cited by 92 publications

References 51 publications

Reciprocal Antagonism Between Estrogen Receptor and NF-κB Activity In Vivo

Reciprocal Antagonism Between Estrogen Receptor and NF-κB Activity In Vivo

Estrogen, inflammation and cardiovascular risk in women: a critical appraisal

The Phytoestrogen α-Zearalenol Reverses Endothelial Dysfunction Induced by Oophorectomy in Rats

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