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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 5 2135-2140
Copyright © 2003 by The Endocrine Society

Endothelial Function and Menopause: Effects of Raloxifene Administration

Nicola Colacurci, Daniela Manzella, Felice Fornaro, Marco Carbonella and Giuseppe Paolisso

Departments of Gynecology and Obstetrics (N.C., F.F.), Geriatric Medicine, and Metabolic Diseases (D.M., M.C., G.P.), Second University of Naples, I-80138 Naples, Italy

Address all correspondence and requests for reprints to: Giuseppe Paolisso, M.D., Department of Geriatric Medicine and Metabolic Diseases, IV Internal Medicine, Piazza Miraglia 2, I-80138 Napoli, Italy. E-mail: giuseppe.paolisso{at}unina2.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Postmenopausal women have more severe endothelial dysfunction than premenopausal women. In the present study, we evaluated the possible beneficial effect of raloxifene administration, a selective estrogen receptor modulator, on endothelial regulation in postmenopausal women. In a double-blind, randomized vs. placebo trial, 60 healthy postmenopausal women were treated with raloxifene (60 mg/d) or placebo for 4 months to evaluate the effect of raloxifene treatment on endothelial function. Furthermore, in raloxifene-treated subjects (n = 30), the effect of raloxifene was also assessed during the intraarterial infusion of NG-monomethyl-L-arginine (4 µmol/min). Raloxifene administration vs. placebo was associated with a decrease in plasma low-density lipoprotein cholesterol (P < 0.01), triglyceride (P < 0.05), thiobarbituric acid-reactive substance (P < 0.01), vascular cell adhesion molecule-1 (P < 0.05), intercellular adhesion molecule-1 (P < 0.001), and E-selectin (P < 0.001) levels and with an increase in plasma Trolox equivalent antioxidant capacity (P < 0.001) levels. Indeed, raloxifene treatment was also associated with a significant improvement in endothelial-dependent vasodilatation assessed by brachial reactivity technique. Raloxifene administration had no impact on endothelial-independent vasodilatation. Furthermore, intraarterial infusion of NG-monomethyl-L-arginine inhibited the significant effect of raloxifene on endothelium-mediated brachial arterial diameter and flow. In conclusion, our results demonstrate that raloxifene administration is associated with a positive modulation of endothelial-dependent vasodilatation likely due to a reduction of risk factors for endothelial damage.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SELECTIVE ESTROGEN RECEPTOR modulators are new compounds exerting estrogenic agonistic or antagonistic actions on different tissues (1). Such compounds have been recently introduced as new hormone replacement agents, targeting selective tissues and avoiding the side effects of the estroprogestinic treatments (2). Nevertheless, their actions on the cardiovascular system have still not been defined. Raloxifene, one of these selective estrogen receptor modulators (2), decreases the expression of endothelial-leukocyte adhesion molecules on the cell surface of human endothelial cells (3), inhibits arterial cholesterol accumulation in animal model (4), and improves lipid profile and homeostatic parameters in postmenopausal women (5, 6, 7, 8). Thus, it is conceivable that raloxifene, as for natural estrogens, may target the vascular wall and exert an antiarteriosclerosis role in postmenopausal women.

It is well known that nitric oxide (NO) regulates blood pressure and blood flow (9) and that those estrogens induce endothelial NO production (10). In vitro, it has also been shown that raloxifene induces endothelium-dependent vasodilatation (11); thus, one can hypothesize that raloxifene may directly activate NO release from endothelial cells. Unfortunately, data from humans are lacking. Thus, our aim was investigating the possible modulator effect of raloxifene administration on endothelial function in postmenopausal women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Experimental subjects

Sixty healthy postmenopausal women (months since last menstrual period: mean, 35; range, 12–73; FSH levels, >50 IU/liter; 17ß-estradiol levels, <100 pmol/liter) volunteered for the study. None of them had ever received any hormonal treatment before the study and/or antioxidant vitamin or other drugs that might have influenced endothelial function. Exclusion criteria were arterial hypertension, diabetes mellitus, smoking, hepatic and renal disorders, venous thrombosis, coronary heart disease, and a history of hot flashes.

Study design

The study was designed as double-blind, randomized vs. placebo trial. At baseline, after an overnight fast (at least 12 h) in a quiet comfortable room with a temperature range between 22 and 24 C, all patients underwent the following tests: 1) anthropometrics and metabolic determinations; 2) brachial reactivity test to evaluate the endothelial-dependent and independent function through the study of arterial diameter and flow changes; 3) blood sampling for assessment of oxidative stress indexes and plasma adhesion molecules levels. In addition, brachial reactivity test was performed in 30 healthy young women in the premenopausal state for evaluating the possible difference in endothelial function between premenopausal and postmenopausal women. Only postmenopausal women were randomly assigned to receive raloxifene (60 mg/d; Evista, Eli Lilly Italia, Rome, Italy; n = 30) or placebo (n = 30). Each treatment lasted 4 months. No dropouts were reported throughout the study, and no woman had any side effect throughout raloxifene administration. At the end of this treatment period, a complete reevaluation of patients was made. In the raloxifene-treated subjects (n = 30), the brachial reactivity test was repeated along with intraarterial infusion of NG- monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase (4 µmol/min, CLINALFA, Läufelfingen, Switzerland).

After clear explanation of potential risks of participation, each volunteer gave a written informed consent to participate in the study, approved by the Ethical Committee of our institution.

Anthropometric determinations

Weight and height were measured using a standard technique. Body mass index (BMI) was calculated as body weight (kilograms)/height (square meters). Waist circumference was measured at the midpoint between the lower rib margin and the iliac crest (normally umbilical level), and hip circumference was measured at the level of the trochanter. Both circumferences were measured to the nearest 0.5 cm with a plastic tape, and the waist to hip ratio (WHR) was calculated.

Endothelial function

Endothelial function was evaluated by brachial reactivity study as previously reported (12, 13). Briefly, brachial reactivity was detected using a high-frequency ultrasound technique. Differences between endothelial-dependent and endothelial-independent vasodilatation were assessed by evaluating brachial reactivity parameters after reactive hyperemia and after nitroglycerin (0.4 mg sublingual), respectively. All patients were kept at rest in the supine position in a temperature-controlled room (~22 C). The left arm was immobilized in the extended position to allow consistent brachial artery access for imaging. Brachial artery diameter and flow velocity were imaged using a 10-MHz linear array transducer ultrasound system (ATL5000HDI, ATL Ultrasound Inc., Bothell, WA). Brachial arterial diameter and blood flow velocity were recorded at 1-min intervals. After that, a blood pressure cuff was placed over the ipsilateral upper arm just above the transducer, inflated for 5 min at 200 mm Hg, and then suddenly deflated. The postischemic scan was performed 60 sec after cuff deflation, whereas brachial artery diameter and flow were measured at 1-min intervals for 5 min. After an additional 10-min rest period (to allow arterial diameter to return to prereactive hyperemia size), two-dimensional images were again obtained at baseline and 3 min after sublingual nitroglycerin. All images were recorded on videotape for subsequent off-line analysis on the same instrument by the single observer blinded to the conditions under which the ultrasonic images were obtained.

Intraobserver variability for measuring brachial artery diameter and flow was assessed by comparing a minimum of three separate baseline measurements in each patient. The coefficient of variation was 2.1% for baseline arterial and 9% for percentage change of arterial diameter. Baseline arterial flow and percentage change in arterial flow were 9.7% and 9.2%, respectively. These values were not dissimilar from those reported by other authors (14).

Analytical techniques

Plasma glucose concentration was determined by the glucose oxidative methods (glucose autoanalyzer, Beckman Coulter, Inc., Fullerton, CA). Plasma fasting high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, and triglyceride levels were determined by routine laboratory methods. C-reactive protein (CRP) was measured in serum using an ELISA based on purified protein and polyclonal anti-CRP antibodies (Calbiochem, San Diego, CA). The degree of serum oxidative stress was measured as the reaction product of malondialdehyde with thiobarbituric acid-reactive substance (TBARS; Refs. 17, 18, 19), the inter- and intraassay coefficients of variation were 3.4 and 2.3%, respectively. The plasma total antioxidant capacity, assessed as Trolox equivalent antioxidant capacity (TEAC), was estimated by the 2,2-azinobis-3-ethylbenzothiazoline-6-sulfonic acid radical cation decolorization assay, using Trolox as a standard, according to the method of Miller et al. (21), the inter- and intraassay coefficients of variation were 5.2% and 3.8%, respectively. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin were determined by an ELISA (R\|[amp ]\|D Systems, Abingdon, UK). The procedures were performed according to the manufacturer’s instructions. For ICAM-1, VCAM-1, and E-selectin, the intraassay coefficients of variation were 4.1%, 3.1%, and 3.1%, respectively.

Calculation and statistical analyses

All results are mean ± SD. Mean arterial blood pressure was calculated as diastolic blood pressure plus one third-pulse pressure. Nonnormally distributed variables were log-transformed (for all calculations) and then back-transformed (for result presentation). The percentage change was calculated with baseline values equal to 100%. The nQuery test was used to predict the adequacy of sample size. This test demonstrated that 14 subjects in each group were sufficient to obtain a significant difference in brachial reactivity parameters (P < 0.001). Because we were interested in examining the effect of a risk factor cluster, we converted all risk factors associated with endothelial damage (plasma oxidative stress indices and plasma adhesion molecules levels) into the same unit, as z-score. Successively, the sum of z-scores of all five factors (TEAC, TBARS, VCAM1, ICAM1, and E-selectin) for each individual was calculated as a summary measure of endothelial damage score. This z-score sum gives equal weights to all factors. The z-score sum was shown to yield a measure of the endothelial damage similar to one derived by a principal components analysis. ANOVA was used to calculate the difference between the two study groups. Pearson’s simple correlation was used to study the association between two variables. Partial correlation was used to investigate the relationship between two variables independently of covariates. All calculations were made on an IBM PC computer by SPSS 9.0 (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline condition in premenopausal and postmenopausal women

Premenopausal and postmenopausal women had similar anthropometrics and metabolic parameters, as well as arterial blood pressure (Table 1Go). In contrast, plasma CRP level, oxidative stress indexes, and plasma adhesion molecule levels were significantly different between pre- and postmenopausal women. With regard to brachial artery parameters (Table 2Go), endothelial-dependent changes in brachial artery diameter and flow were significantly higher in premenopausal women than in postmenopausal women. In contrast, no differences in diameter and flow of nitroglycerin-mediated changes were found between the two groups.


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  		Table 1. Clinical characteristics in premenopausal and postmenopausal women at baseline condition

 

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  		Table 2. Endothelial parameters in premenopausal and postmenopausal women at baseline

 
Placebo and raloxifene treatments in postmenopausal women

At the end of the treatment period, no changes in anthropometric parameters, plasma glucose levels, and arterial blood pressure between placebo and raloxifene groups were found; in contrast, raloxifene treatment was associated with a significant decline in plasma LDL cholesterol and triglyceride levels, whereas plasma HDL cholesterol and CRP levels remained unchanged. With regard to oxidative stress indexes and plasma adhesion molecule levels, raloxifene treatment significantly increased plasma TEAC whereas it reduced TBARS, VCAM-1, ICAM-1, and E-selectin levels (Table 3Go). Changes in endothelial-dependent parameters are reported in Table 4Go. Raloxifene, but not placebo, treatment was associated with a significant increase in brachial artery diameter and flow; in contrast, no significant changes in endothelial-independent arterial diameter and flow, after placebo and raloxifene treatment, were found (Table 4Go).


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  		Table 3. Clinical characteristics after placebo and raloxifene treatments

 

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  		Table 4. Endothelial parameters after placebo and raloxifene treatments

 
Intraarterial infusion of L-NMMA smoothed the beneficial effect of raloxifene on endothelium-dependent brachial arterial diameter and flow (Fig. 1Go).



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  		Figure 1. Percentage changes in brachial diameter and flow after raloxifene (60 mg/d) and raloxifene plus L-NMMA (4 µmol/min) treatments. Statistically significant differences were: *, P < 0.01; **, P < 0.02 for raloxifene vs. raloxifene plus L-NMMA.

 
Raloxifene treatment was associated with a significant improvement in TEAC z-score, TBARS z-score, VCAM-1 z-score, ICAM-1 z-score, and E-selectin z-score (Table 5Go). Thus, raloxifene treatment, but not placebo, was associated with a significant reduction of endothelial damage score (P < 0.03).


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  		Table 5. Mean values of z-scores representing the endothelial damage

 
In the raloxifene group (n = 30), no correlations between percentage change in brachial arterial diameter and in plasma LDL cholesterol (r = 0.42; P = NS) or triglyceride (r = 0.40; P = NS) levels were found, whereas percentage changes in brachial arterial diameter and flow correlated negatively with endothelial damage score (r = -0.45, P < 0.01; and r = -0.49, P < 0.01, respectively). Such correlations were still significant after adjusting for confounders, such as age, BMI, plasma triglyceride, and cholesterol levels (r = -0.37; P < 0.05 for all).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study demonstrates that raloxifene treatment improves the endothelium-dependent brachial reactivity and reduces plasma oxidative stress indices as well as adhesion molecule levels in postmenopausal women. Indeed, we now provide evidence for: 1) an antioxidant effect of raloxifene independent of changes in lipid levels in nondiabetic subjects; and 2) an action of raloxifene on endothelial function through NO production.

It is well known that premenopausal women have a low incidence of risk of coronary artery disease compared with men, and that such risk rises markedly after menopause. At the present time, the role of hormone replacement therapy is very controversial. In fact, numerous studies seem to show that hormone replacement therapy lowers the risk of coronary artery disease to premenopausal levels in postmenopausal women (22, 23, 24, 25, 26). In addition, acute estrogen administration restores the endothelium-dependent dilatation of atherosclerotic arteries in primate models (27), a phenomenon partially related to the ability of estrogen to enhance the bioavailability of NO. On the other hand, NO exerts antiinflammatory and antiaterogenic activities (28). In fact, the loss of endothelium-derived NO activity leads to enhanced platelet aggregation, and it increases vascular smooth muscle cell proliferation and endothelial-leukocyte interactions (29). Natural estrogens exert most of their cardioprotective effects by directly enhancing endothelial NO production (30). Despite such evidence, several data (31, 32, 33, 34) seemed to demonstrate that although estrogen has an acute vasodilatation effect, its long-term effect does not show any cardioprotection, but it shows instead a harmful effect in menopausal women. Thus, whether the raloxifene effect has long-term impact on prevention of arteriosclerosis in postmenopausal women needs to be investigated. In fact, less is known about possible actions of selective estrogen receptor modulators such as raloxifene on the cardiovascular wall. Recent studies have shown that droloxifene, a new selective estrogen receptor modulator, reduces plasma levels of LDL in postmenopausal women (35). Indeed, LY117018, a raloxifene analog, acts directly on the vessel wall, regulating endothelial-leukocyte adhesion molecule expression (3), and has an antiatherosclerotic action on cholesterol-fed rabbits (4). Thus, it has been hypothesized that raloxifene may act through NO-mediated mechanisms. This hypothesis is supported by recent investigations describing an endothelium-dependent vascular relaxing activity for raloxifene and suggesting that NO release may be involved. In fact, Saitta et al. (36) have demonstrated that raloxifene administration is associated with brachial reactivity improvement and with an increase in plasma NO levels in postmenopausal women. Indeed, Simoncini et al. (11) demonstrated that raloxifene acutely stimulates NO production from human endothelial cells, describing a potential novel mechanism that could explain the vasodilatatory effects of raloxifene and its antiaterogenic role. Indeed, such authors (11) demonstrated that: 1) raloxifene acutely (<30 min) increases endothelial NO synthase (eNOS) enzymatic activity, and this effect is dependent on a functional interaction with an estrogen receptor; and 2) eNOS activation by this molecule may be mediated by a nongenomic mechanism as for natural estrogen (11). Such results may also indicate that eNOS activation in endothelial cells can be triggered by different estrogen receptor conformational changes (11). According to these results, our study provides evidence that raloxifene administration, in postmenopausal women, has an antiatherosclerotic effect due to a significant improvement in endothelial-dependent brachial reactivity and to a lowering of plasma oxidative stress and plasma adhesion molecule levels. An unexpected and additional finding of our study is that the effect of raloxifene treatment on plasma LDL cholesterol and triglyceride levels is not correlated to the improvement of endothelial function. This latter result prompts us to hypothesize that change in plasma lipid levels do not contribute significantly to the raloxifene-mediated improvement in endothelial function. This event is particularly important in light of the hypothesis that, in postmenopausal women, raloxifene acts directly on endothelial cells releasing NO, as already shown in vitro and in animal models. The direct impact of raloxifene on endothelial function is also strengthened by our data showing that raloxifene treatment is associated with an improvement in endothelial-dependent. This last effect is inhibited by the contemporary presence of L-NMMA. In fact, the intraarterial administration of L-NMMA, after raloxifene treatment, neutralized the positive effect of raloxifene per se on endothelial function. Thus, in light of such results, it is possible to assert that the effect of raloxifene is NO mediated. Furthermore, we also hypothesize that the impact of raloxifene on endothelial function might be due to a decline in the risk factors (oxidative stress indices and plasma cell adhesion molecules levels) for endothelial damage, such as demonstrated by the cluster analysis.

Indeed, most previous evidence has addressed the hypothesis that a risk factor per se may negatively affect endothelial function. The evidence that the relationship between endothelial-dependent vasodilatation parameters and clustering of risk factors for endothelial damage persists, even after adjusting for age, BMI, and major plasma lipid levels, supports, even if it does not demonstrate, the hypothesis that raloxifene administration can control the whole negative impact of high plasma levels of oxidative stress indices and cell adhesion molecules on endothelial function. It is important to point out that our study does not show a raloxifene-related decline in CRP. Indeed such data need to be confirmed because contradictory results (37, 38, 39) have been provided.

In conclusion, our study provides evidence that raloxifene treatment is associated with a protective effect on endothelial function, as evidenced by a significant positive modulation of endothelial-dependent vasodilatation. Such effect seems also to be related to a reduction in risk factors for endothelial damage. This finding opens new potential therapeutic insight into the prevention of vascular atherosclerotic events for such molecules.


   Footnotes
 
This work was supported by grants from Second University of Naples.

Abbreviations: BMI, Body mass index; CRP, C-reactive protein; eNOS, endothelial NO synthase; HDL, high-density lipoprotein; ICAM-1, intercellular adhesion molecule-1; LDL, low-density lipoprotein; L-NMMA, NG- monomethyl-L-arginine; NO, nitric oxide; TBARS, thiobarbituric acid-reactive substance; TEAC, Trolox equivalent antioxidant capacity; VCAM-1, vascular cell adhesion molecule-1; WHR, waist to hip ratio.

Received October 7, 2002.

Accepted February 18, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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 J. Pharmacol. Exp. Ther.Home page
E. J. Jeong, H. Lin, and M. Hu
Disposition Mechanisms of Raloxifene in the Human Intestinal Caco-2 Model
J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 376 - 385.
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