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Original Studies |
Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157
Address all correspondence and requests for reprints to: Thomas B. Clarkson, D.V.M., Department of Comparative Medicine, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1040. E-mail: tclarkson{at}cpm.bgsm.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Partially offsetting these health benefits of postmenopausal estrogen therapy are increases in breast (5, 6) and endometrial cancer (7). Synthetic progestins prevent the estrogen-induced increases in endometrial cancer, but either have no effect or tend to increase the risk of breast cancer (6, 8) and may diminish estrogen’s beneficial effects of inhibiting the progression of atherosclerosis (9).
Despite these major benefits of estrogen replacement therapy, compliance is poor, generally about 10% or less among postmenopausal women 55 yr of age or older (10, 11, 12, 13). Poor compliance relates primarily to fear of breast cancer and the adverse side-effects of progestins coadministered to prevent endometrial cancer.
There is currently a major research effort to identify gonadal hormone substitutes with estradiol’s beneficial effects on brain, bones, and arteries, without its adverse effects on the mammary gland and endometrium. The term selective estrogen receptor modulator has been applied to compounds such as raloxifene that have tissue-specific estrogen agonist/antagonist properties. Raloxifene, previously called keoxifene, is a benzothiophene derivative that binds to the estrogen receptor with high affinity (14). Raloxifene has tissue specificity, with estrogen antagonistic effects on breast and uterus, but with estrogen agonistic effects on bone and plasma cholesterol concentrations (15, 16). Recently, Sato and co-workers (17) compared the long term effects of treating ovariectomized (OVX) rats with raloxifene or estrogen. They concluded that compared to estrogen, raloxifene had a broader range of desirable effects on bone, uteri, and plasma cholesterol concentrations.
Whether selective estrogen receptor modulators such as raloxifene have the estrogen agonistic effect of inhibiting coronary artery atherogenesis has not been tested previously. In this communication, we report on the lack of an estrogen agonistic effect in the diminution of diet-induced coronary artery atherosclerosis of surgically postmenopausal cynomolgus monkeys.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The subjects of this study were 117 female cynomolgus monkeys (Macaca fascicularis) at least 10 yr old on the basis of radiographic evidence. The animals were obtained through our collaborative arrangement with the Indonesian Primate Center (Bogor, Indonesia). They were transported to Winston-Salem, NC, by air and quarantined for 30 days, and their ages were reestimated radiologically. During the remainder of the pretrial phase, they were fed the experimental diet, and measurements were made of their plasma lipid and lipoprotein responses to the diet.
There were 103 animals that remained in the study for the duration of the experimental period. Of the 14 animals that were lost between randomization and the end of the study, 2 were removed for poor dose acceptance, 1 was killed due to poor health, and 11 died due primarily to gastrointestinal disease or trauma resulting from social group organization. There were 3 deaths in the sham-OVX group, 2 in the OVX placebo-treated group, 1 in the conjugated equine estrogens group, 1 in the low dose raloxifene group, and 4 in the high dose raloxifene group.
Study design
The animals were randomized into 5 groups of 22–25 animals/group on the basis of their baseline ratio of total plasma cholesterol (TPC) to high density lipoprotein cholesterol (HDLC) and bone density measurements. One group was sham OVX and received a placebo (intact; n = 19). As this group was not of interest for comparison of the efficacy of postmenopausal replacement therapies, it was not included in this report. Four groups were OVX and were administered a placebo, raloxifene at 1 mg/kg (low dose raloxifene), raloxifene at 5 mg/kg (high dose raloxifene), or conjugated equine estrogens (CEE) at 0.04 mg/kg. The experimental period was 2 yr. The groups sizes available for atherosclerosis evaluations were: OVX, n = 20; low dose raloxifene, n = 21; high dose raloxifene, n = 20; and CEE, n = 23. The low dose of raloxifene (1 mg/kg) was chosen to approximate a dose of 60 mg/day for women, and the high dose (5 mg/kg) was selected to represent a 5-fold higher dose for safety evaluations. The dose of CEE (0.04 mg/kg) was selected to be the monkey equivalent of a woman’s dose of 0.625 mg/day.
Monkeys were kept in social groups of five to six monkeys each and were trained to enter an observation cage once daily to ingest either a placebo solution (Crystal Lite, Kraft Foods, White Plains, NY; plus vehicle) or that solution containing the drug to be administered. Compliance was assessed by watching the animals drink their dose and was followed up with periodic blood concentrations.
At 3-month intervals, the monkeys were sedated with ketamine hydrochloride (15 mg/kg, im) and weighed, and blood samples were obtained for measurements of plasma lipid concentrations. All procedures involving animals were performed in compliance with state and federal regulations and were approved by the institutional animal care and use committee.
Diet
During the pretrial period and during the trial period, the
animals were fed a moderately atherogenic diet. The diet composition is
shown in Table 1
. The moderately
atherogenic diet contained 17% of calories from protein, 41% from
carbohydrates, and 42% from fat. The cholesterol concentration of the
diet was 0.42 mg/Cal. The diet provided daily 88 mg/kg calcium and 84
mg/kg phosphorus. The diets were prepared in our diet laboratory in
10-kg batches and were stored frozen. One day’s worth of diet was
thawed overnight at 4 C before feeding. Diet was given to the animals
at the rate of 120 Cal/kg·day.
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Plasma lipids and lipoproteins. Blood for lipid and lipoprotein analyses was collected from the animals into evacuated tubes containing ethylenediamine tetraacetate (final concentration, 1 g/L) after food was withheld for 18 h. TPC was measured by enzymatic techniques based on the methods of Allain et al. (18). HDLC concentrations were measured using the heparin-manganese precipitation procedure described in the Manual of Laboratory Operations of the Lipid Research Clinics Program (19). Low density lipoprotein cholesterol (LDLC) plus very low density lipoprotein cholesterol (VLDLC) was calculated as the difference between TPC and HDLC. All analyses were performed on a COBAS FARA II autoanalyzer (Roche Diagnostic Systems, Montclair, NJ). The laboratory subscribes to the Centers for Disease Control (Atlanta, GA) Lipid Standardization Program. The data used for analyses are the means of the experimental period, obtained from six samples collected at approximately 4-month intervals.
Estradiol concentrations. Estradiol concentrations were measured just before administration of the daily dose of CEE. Assays were performed at the Comparative Endocrinology Laboratory of the Yerkes Regional Primate Center (Atlanta, GA; Dr. Mark Wilson). Concentrations of estradiol were determined using a modification of a commercially available RIA kit employing a double antibody technique (Diagnostic Products Corp., Los Angeles, CA) (20). The data used for analyses are means of samples collected at 3-month intervals.
Coronary artery atherosclerosis evaluations
Necropsies were performed after 24 months of treatment. The animals were sedated with ketamine hydrochloride (15 mg/kg BW, im), and sodium pentobarbital (13 mg/kg, iv) was administered to attain surgical anesthesia. An infusion of Ringer’s solution was initiated via an 18-gauge needle inserted into the left ventricle. A 1-cm longitudinal incision was made in the abdominal vena cava for drainage of blood from the cardiovascular system, and the Ringer’s solution infusion was continued until the vena caval drainage was colorless. The heart was removed, and the coronary arteries were perfused for 1 h at 100 mm Hg pressure using 10% buffered formalin.
The prevalence, extent, and severity of coronary artery atherosclerosis were evaluated blind to treatment, as described previously (21). We took 15 blocks (each 3 mm in length) cut perpendicular to the long axis of the arteries. Five of these were serial blocks from the left circumflex (LCX), five were from the left anterior descending (LAD), and five were from the right coronary artery (RCA).
The tissue blocks were dehydrated through increasing concentrations of ethanol and embedded in paraffin. Two 5-µm sections were cut from each block and stained with either hematoxylin and eosin or Verhoeff-van Gieson’s stain. Sections of arteries stained with Verhoeff-van Gieson’s stain were projected, using a projection microscope, onto a digitizer plate. Using a hand-held stylus and a computer-assisted digitizer, the component parts of the artery were traced. The coronary artery morphometric measurements included intimal area, intimal area per unit length of internal elastic lamina, area within the internal elastic lamina, and luminal area. Descriptions of each measurement are given below.
Intimal area. Intimal areas were determined by digitizing the area between the internal elastic lamina and the luminal surface of each coronary artery section. The integration method was used for calculations of intimal areas. The area of the intima describes plaque size.
Prevalence. Prevalence was based on the occurrence of atherosclerotic lesions in the proximal portions of the LAD and/or the LCX (blocks 1 and 2). Intimal lesions larger than 0.101 mm2 in cross-sectional area were considered affected. A case was counted as affected if it had an atherosclerotic lesion in the LAD or LCX.
Area within the internal elastic lamina. We calculated the area within the internal elastic lamina by considering the length of the internal elastic lamina as the circumference of that area. We use this measurement as an indicator of artery size. The area within the external elastic lamina could be measured also; however, the interpretation of its precise location is sometimes less clear than with the internal elastic lamina. The two indicators are so highly correlated that we conclude that it is justified to use internal elastic lamina area as an indicator of artery size.
Lumen area. This area is calculated as the difference between the artery area (area within the internal elastic lamina) and the atherosclerotic lesion area (intimal area). This describes the area for blood flow.
Statistical analyses
All analyses were performed using BMDP Statistical Software (version 7.0, BMDP, Los Angeles, CA). Analyses were concentrated on the intimal area (measure of atherosclerotic plaque) and the lumen area (area of blood flow).
The means of intimal and lumen areas for each of the three arteries and
the coronary artery mean were first evaluated for their distribution
(i.e. normality of the distribution using Pearson’s
2 test of normality, skewness, and kurtosis). Levene’s
test was used to assess the equality of variances between groups. Lumen
area met the assumption of equality of variances for each of the
coronary arteries (LAD, LCX, and RCA) and the coronary mean
(P > 0.20). Intimal area data violated the assumption
of equality of variances for the RCA and the coronary mean. For all
arteries, these data were very skewed, with heavy tails; thus, a
transformation of the data log(IA+0.01) was performed. This
transformation improved the distribution so that for all arteries the
assumption of equality of variances was met (P >
0.20). The data in this report are retransformed into original
units.
The data for lumen area and transformed intimal area were stratified by
artery (LAD, LCX, and RCA). The five measurements of lumen area and
intimal area for each coronary artery (one measurement per block) were
analyzed using repeated measures ANOVA to determine whether there were
important group x block interactions and, thus, whether the
different treatments were affecting atherosclerosis progression
differently in the distal or proximal portions of the artery. As there
were no significant group x block interactions in any artery
(P > 0.60), the mean of the five blocks for each
artery for each animal was generated. The means for intimal area and
lumen area for each artery were then analyzed using repeated measures
ANOVA to test for group x artery interactions, i.e.
whether the different treatments affected atherogenesis differently in
the three coronary arteries. As there were no significant group x
artery interactions (P > 0.80), an overall mean of the
three coronary artery means for intimal area and lumen area was then
calculated for each animal (mean coronary artery intimal area and lumen
area). Treatment group comparisons were performed using ANOVA to derive
the unadjusted means and overall P values. Comparisons were
also made by analysis of covariance, using the baseline measurements of
LDLC plus VLDLC and HDLC as covariates to generate the adjusted group
means and P values. Between-group comparisons were
performed, adjusting for multiple comparisons. For the unadjusted mean
comparisons, the Student-Newman-Keuls multiple range test was used. For
the adjusted mean comparisons, a Bonferroni adjustment was made, using
an 
level of 0.01 to determine statistical significance, as there
were five comparisons of interest to us. These were OVX vs.
CEE, OVX vs. low dose raloxifene, OVX vs. high
dose raloxifene, CEE vs. low dose raloxifene, and CEE
vs. high dose raloxifene.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Treatment with CEE resulted in lower TPC concentrations relative to those in the OVX group (500 vs. 373 mg/dL; P = 0.0002). Low dose, but not high dose, raloxifene significantly lowered TPC concentrations (403 and 450 mg/dL, respectively) relative to those in the OVX group (OVX vs. low dose, P = 0.005; OVX vs. high dose, P = 0.14).
The effects of treatments on plasma concentrations of LDL plus VLDL and
HDL cholesterol, expressed as the percent difference from the OVX
group, are shown in Fig. 1. The CEE and
low dose raloxifene groups had significantly lower LDL plus VLDL
cholesterol concentrations than the OVX group (CEE vs. OVX,
P = 0.0003; low dose raloxifene vs. OVX,
P = 0.01). High dose raloxifene did not significantly
lower LDL plus VLDL cholesterol concentrations relative to those in the
OVX group (P = 0.17). For HDL cholesterol, none of the
treated groups was significantly different from the OVX group
(P > 0.16), nor were there significant differences
between the treated groups, although the higher HDLC value in the CEE
group relative to that in the low dose raloxifene group was of
borderline statistical significance (P = 0.052).
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The dose of CEE used in this experiment was chosen to be comparable to a dose of 0.625 mg CEE for an average woman. The dose was based on our previous experience in which we added 0.625 mg CEE to 1800 Cal of diet (22). We have used measurements of plasma estradiol concentration as a means of estimating the appropriateness of the monkey dose. In our previous studies in which CEE was added to the diet, we found the mean plasma estradiol concentration (±SEM) to be about 167 ± 10 pg/mL (22). In the current study, CEE was administered orally once daily in a vehicle. On the average, plasma estradiol concentrations in this study (mean ± SEM, 174 ± 16 pg/mL) were comparable to our former study. In the present study, there were considerable individual differences in the plasma concentrations of estradiol. When we divided the animals into tertiles based on plasma estradiol concentrations, the lowest third of the animals (n = 8) had a mean concentration of 99 ± 7 pg/mL, the middle third (n = 7) had a mean concentration of 169 ± 7 pg/mL, and the highest third (n = 8) had a mean concentration of 260 ± 17 pg/mL.
The variability in average estradiol concentrations among the monkeys
in the CEE-treated group provided us with an opportunity to relate the
progression of coronary artery atherosclerosis to the individual
differences in plasma estradiol concentrations. We divided the
CEE-treated group into tertiles based on plasma estradiol
concentrations and compared them to the OVX group (Fig. 2). As would be expected, the lowest
plasma estradiol concentrations and the largest coronary artery
atherosclerotic plaques were seen in the OVX group. Among the
CEE-treated group, plaques were increasingly smaller as the plasma
estradiol concentrations were increasingly greater. However, because of
the small sample size in these subsets (n = 7–8 animals/tertile),
the variances are quite large. Within the CEE-treated group, the
beneficial effects on inhibiting atherosclerosis progression appeared
to be highly associated with its beneficial effects on plasma
lipoprotein concentrations. If one looks at the plasma lipoprotein data
for the animals grouped by the tertiles of estradiol concentrations,
then there is a progression for LDL plus VLDLC concentrations from
402 ± 83 to 376 ± 52 to 205 ± 36 mg/dL with
increasing estradiol levels. The HDLC concentrations are positively
associated with plasma estradiol concentrations, although when
stratified by estradiol tertiles, the relationship is not as linear. In
the lowest tertile of estradiol concentrations, the average HDLC
concentration was 41 ± 8 mg/dL; it was 30 ± 3 mg/dL in the
middle tertile and 54 ± 8 mg/dL in the highest tertile.
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The prevalence of atherosclerosis in the LAD and/or the LCX
arteries is shown in Fig. 3. Among the
monkeys of the OVX group, 80% were affected. Treatment of
postmenopausal monkeys with CEE resulted in a lower prevalence of
coronary artery atherosclerosis. Raloxifene-treated monkeys, on the
other hand, had a prevalence of coronary artery atherosclerosis
indistinguishable from that of the OVX group (low dose group, 71%
affected; high dose group, 80% affected).
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. The OVX
group had relatively large atherosclerotic plaques in all three of the
main branch coronary arteries. Treatment with CEE resulted in smaller
coronary artery atherosclerotic plaques than those in the OVX group.
Treatment with raloxifene at either dose provided no protection from
coronary artery atherosclerosis. All of the treatment groups had
comparably sized lumen areas.
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, we have depicted the extent of
coronary artery atherosclerosis, expressed as the percent difference in
mean coronary artery atherosclerosis from the OVX group. Low dose
raloxifene treatment did not affect atherosclerosis progression
relative to that in the OVX group (P = 0.87). The high
dose of raloxifene also did not have a significant effect on
atherosclerosis progression (high dose raloxifene vs. OVX,
P = 0.72). CEE treatment resulted in about a 70%
reduction in plaque extent (intimal area) relative to that in the OVX
group (P = 0.007). Both raloxifene treatment groups had
significantly more atherosclerosis than the CEE group
(P 
0.01 for both comparisons). The low dose
raloxifene group had about 2 times more atherosclerosis, and the high
dose group about 3 times more atherosclerosis than the CEE group.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effects of raloxifene on plasma lipid concentrations in this study are comparable to those observed by Draper et al. (23) when raloxifene was given to postmenopausal women. In their studies, postmenopausal women received either 200 or 600 mg raloxifene/day. On a body weight basis, our low dose of raloxifene was comparable to 60 mg/day for an average woman, and our high dose was equivalent to 300 mg/day for an average 60-kg woman. For both monkeys and women, there were no significant effects on HDLC. In women, LDL concentrations were reduced by about 10% by raloxifene treatment. In monkeys, raloxifene treatment resulted in reductions of about 15% in LDLC concentrations relative to those in the OVX group.
The coronary artery atherosclerosis-protective effect of CEE treatment observed in the current study is somewhat more robust than that we observed with the physiological replacement of estradiol via SILASTIC brand implants (Dow Corning, Midland, MI) in OVX monkeys (25). In that earlier study, we observed about a 50% reduction in coronary artery atherosclerosis, whereas the reductions noted in the present study were about 70%. This finding is very comparable to that reported in a study by Adams et al. (9), in which CEE was administered in a moderately atherogenic diet at a dose comparable to a dose of 0.625 mg/day in women and resulted in a 72% decrease in coronary artery atherosclerosis. It is unclear whether the more robust effect of the CEE compared with estradiol administered via SILASTIC implants relates to the possible interactions among the estrogens contained in CEE or to the route of administration (oral for CEE vs. transdermal for estradiol). It is likely that estrogens have multiple mechanisms of action, including antioxidant effects on lipoproteins and direct effects on the artery wall. The design of this experiment did not permit us to assess other coronary artery vascular effects, such as possible changes in proteoglycan composition and their affinity for LDL particles or accumulation of lipid oxidation products.
The plasma estradiol concentrations observed in this study are somewhat higher than those observed in women after CEE treatment. Englund and Johansson (26) reported estradiol concentrations of about 100 pg/mL 24 h after a CEE dose of 1.25 mg among women, who were more responsive to estrogen administration. On the average, however, the observations reported here are well below follicular phase estradiol concentrations in nonstressed premenopausal female cynomolgus monkeys, which we have found to be about 240 pg/mL (27). The variation in estradiol concentrations of the CEE-treated group has provided us with some indication of their relationship to the primary progression of coronary artery atherosclerosis. It appears that there is increasing protection against atherogenesis with increasingly higher plasma estradiol concentrations. The coronary artery atherosclerosis lesion size in the subset of the CEE group with the lowest average estradiol concentrations (76–131 pg/mL) was, on the average, 39% smaller than that in the OVX group, the middle tertile was 52% smaller, and the subset with the highest plasma estradiol concentrations was 95% smaller. However, because of the small sample size in these subsets, the variances were quite large. The beneficial effects of CEE on inhibiting atherosclerosis progression appeared to be highly associated with its beneficial effects on plasma lipoprotein concentrations. Within the CEE group, there was a positive association between plasma estradiol concentrations and HDLC concentrations and an inverse association with LDL plus VLDLC concentrations.
The results of the study reported herein provide no evidence that raloxifene has an estrogen agonistic effect on coronary arteries in this animal model despite a moderately beneficial effect on plasma lipid concentrations. It may be that the estrogen receptors of the coronary arteries lack the ability to facilitate two pathways, and thus activate the raloxifene response element.
Whereas the data on bone loss in OVX monkeys (28) and the data on bone biomarkers from postmenopausal women (23) suggest that raloxifene has benefits comparable to those of mammalian estrogens in preventing bone loss associated with estrogen deficiency, the data reported herein suggest that it would be at the expense of any protection against coronary artery atherosclerosis.
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Acknowledgments |
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Footnotes |
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Received July 9, 1997.
Revised November 11, 1997.
Accepted November 24, 1997.
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References |
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N. F. Col, S. G. Pauker, R. J. Goldberg, M. H. Eckman, R. K. Orr, E. M. Ross, and J. B. Wong Individualizing Therapy to Prevent Long-term Consequences of Estrogen Deficiency in Postmenopausal Women Arch Intern Med, July 12, 1999; 159(13): 1458 - 1466. [Abstract] [Full Text] [PDF]
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 A. L. Franks and K. K. Steinberg Encouraging News From the SERM Frontier JAMA, June 16, 1999; 281(23): 2243 - 2244. [Full Text] [PDF]
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M. E. Mendelsohn and R. H. Karas The Protective Effects of Estrogen on the Cardiovascular System N. Engl. J. Med., June 10, 1999; 340(23): 1801 - 1811. [Full Text] [PDF]
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 V. C. Jordan and M. Morrow Tamoxifen, Raloxifene, and the Prevention of Breast Cancer Endocr. Rev., June 1, 1999; 20(3): 253 - 278. [Abstract] [Full Text]
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J. V. Pinkerton and R. Santen Alternatives to the Use of Estrogen in Postmenopausal Women Endocr. Rev., June 1, 1999; 20(3): 308 - 320. [Abstract] [Full Text]
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 W. Khovidhunkit and D. M. Shoback Clinical Effects of Raloxifene Hydrochloride in Women Ann Intern Med, March 2, 1999; 130(5): 431 - 439. [Abstract] [Full Text] [PDF]
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T. B. Clarkson and M. S. Anthony Lack of Effect of Raloxifene on Coronary Atherosclerosis of Postmenopausal Monkeys--Authors' Response J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 3002 - 3004. [Full Text]
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H. U. Bryant, R. F. Kauffman, P. Iversen, D. A. Cox, B. H. Mitlak, and H. Heath III Comment on Lack of Effect of Raloxifene on Coronary Artery Atherosclerosis of Postmenopausal Monkeys J. Clin. Endocrinol. Metab., August 1, 1998; 83(8): 3001a - 3002. [Full Text]
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B. M. Rifkind and J. E. Rossouw Of Designer Drugs, Magic Bullets, and Gold Standards JAMA, May 13, 1998; 279(18): 1483 - 1485. [Full Text] [PDF]
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L. A. Fitzpatrick and M. D. Editorial: Coronary Artery Disease in Women--an Equal Opportunity Killer J. Clin. Endocrinol. Metab., March 1, 1998; 83(3): 719 - 720. [Full Text]
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