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Obstetrics & Gynecology 2000;96:250-255
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Low-Dose Contraceptive Estrogen-Progestin and Coronary Artery Atherosclerosis of Monkeys

MICHAEL R. ADAMS, DVM, MARY S. ANTHONY, MS, JAMES M. MANNING, PhD, DEBORAH L. GOLDEN and JOHN S. PARKS, PhD

From the Department of Pathology (Comparative Medicine), Wake Forest University School of Medicine, Winston-Salem, North Carolina; and the Department of Exercise and Movement Sciences, William Paterson University, Wayne, New Jersey.

Address reprint requests to: Michael R. Adams, DVM Department of Pathology Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem, NC 27157 E-mail: madams{at}wfubmc.edu


   Abstract
Top
Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To determine the separate and combined effects of the estrogen and progestin components of a modern triphasic oral contraceptive (OC) formulation on extent of coronary artery atherosclerosis.

Methods: Female cynomolgus monkeys (n = 81) were fed atherogenic diets for 32 months. After the first 7 months, they were randomized to four groups and treated triphasically for 21 of each 28 days with ethinyl estradiol (E2) (monkey equivalent of 30–40 µg), levonorgestrel (monkey equivalent of 50–125 µg), a combination of the two steroids, or placebo.

Results: Treatment with estrogen alone reduced coronary artery atherosclerosis extent 67% compared with untreated controls (P < .05). Treatment with progestin alone had no effect (P > .20). While atherosclerosis extent in monkeys treated with the combined OC was reduced 28%, this did not differ statistically from the other groups (P > .20).

Conclusion: In doses used for oral contraception, E2, like all other estrogens studied to date, has a marked inhibitory effect on atherosclerosis progression. Levonorgestrel, at doses used in modern OC formulations, antagonizes this effect. When considered with other experimental evidence, these findings support the concept that progestins used in OCs and hormone replacement therapy can antagonize estrogen’s atheroinhibitory effects. Whether this occurs seems to depend on a relative balance between estrogen and progestin with respect to dose, potency, route, and pattern of administration. However, when considered with evidence from previous studies, the findings also indicate a modest atheroinhibitory influence of combination (estrogenprogestin) OCs.

Since their introduction some 50 years ago, there has been controversy regarding possible adverse effects of oral contraceptives (OCs) on risk of coronary heart disease. This is true, in part, because the older formulations caused decreases in plasma high-density lipoprotein (HDL) cholesterol concentrations. Although interpretation of the epidemiologic data is made difficult by the changes in formulation of OCs that have occurred over the years, there is no compelling evidence for an adverse effect of OC use on coronary risk1 except in users who are also cigarette smokers.1 In fact, in the Nurses’ Health Study,2 a prospective observational study with more than 920,000 person-years of follow-up, there was a statistically significant 20% reduction in coronary risk in past users of OCs and a trend toward an inverse relationship between duration of use and risk. Those findings are in agreement with data from a large case-control study3 in which past users were found to have a 46% reduction in risk, and support the possibility of a modest cardioprotective effect mediated by an inhibition of atherosclerosis progression. Further supporting this possibility are findings from a study of a series of premenopausal women undergoing angiography for the diagnosis of myocardial infarction.4 In that study, the prevalence of angiographically evident atherosclerosis was 50% lower in OC users than nonusers.4

Consistent with these clinical and epidemiologic findings are results of previous studies by our group that indicate modest inhibitory effects of combination OCs on extent of coronary artery atherosclerosis in monkeys.5,6 However, those studies were done using older formulations that contained much higher doses of estrogen and progestin than those used currently.

This study was designed to determine the effect of a modern, second-generation triphasic OC and the independent effects of its estrogen and progestin components on the progression of diet-induced atherosclerosis in monkeys. Because it was found in previous studies that antiatherosclerotic effects of OCs were most pronounced in monkeys at high risk owing to hyperlipoproteinemia, we also addressed the relationship between atherosclerosis extent and plasma lipoproteins.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
Sample size was determined by estimating variability in plaque size based on data from a previous study of the effects of OCs on atherosclerosis.5 The distribution of plaque size in that study was skewed to the right; therefore, the sample size calculation was based on differences between groups after logarithmic transformation. The standard deviation (SD) for the logarithm of plaque size was 1.54 and the difference between control and treatment groups was a 60.1% decrease in the treatment group. Therefore, the sample size in the current study was based on the objective of being able to detect a 60% decrease in plaque size in OC-treated monkeys compared with controls. A sample size of 88 monkeys is required to have 80% power at the 5% two-sided level of significance.

Accordingly, 88 adult (4–10 years of age as estimated from dentition) female cynomolgus monkeys were imported from Indonesia (Institut Pertanian, Bogor). Monkeys lived in social groups consisting of four or five individuals. All procedures involving animals were conducted in compliance with institutional animal care and use committee policies.

For a total of 32 months, all animals were fed a moderately atherogenic diet (40% of calories as fat, 0.28 mg cholesterol per kilocalorie). During a 7-month pre-experimental period, determinations were made of plasma total and HDL cholesterol concentration. Using a stratified randomization scheme, monkeys were then assigned to four groups balanced for these measurements and age. Multivariate matching was used to form clusters of four subjects each based on subjects’ pairwise mahalanobis distances. Within each cluster of four, simple randomization was used to assign the subjects to four treatment groups. One group served as placebo-treated controls (n = 20). A second group received ethinyl estradiol (E2) (Wyeth-Ayerst Research, Princeton, NJ) and levonorgestrel (Wyeth-Ayerst Research) (n = 20). A third group received ethinyl E2 only (n = 21). A fourth group received levonorgestrel only (n = 20). The hormones were mixed in the diet. We have shown that the dose of contraceptive steroid for a monkey should be scaled from the human dose based on species differences in average caloric consumption.5,6 Accordingly, if it is assumed that the average woman consumes 1800 calories per day, the average monkey in groups two, three, and four was treated on a 28-day triphasic schedule. The schedule was days 1 to 6, 8.2 µg levonorgestrel and/or 5 µg ethinyl E2; days 7 to 11, 12.5 µg levonorgestrel and/or 6.7 µg ethinyl E2; days 12 to 21, 21 µg levonorgestrel and/or 5 µg ethinyl E2; and days 22 to 28, inert placebo. As in previous experiments,5,6 menstrual cyclicity ceased in contraceptive steroid-treated monkeys.

Total plasma cholesterol,7 triglyceride,8 and HDL cholesterol9 concentrations were determined at the end of a 7-month pre-experimental period and at 3-month intervals throughout the experimental period.

At the end of the pre-experimental period and at month 12 of the experimental period, assessments were made of plasma lipoprotein distribution. Lipoprotein fractions were separated by ultracentrifugation and high-performance liquid chromatography,10 and the cholesterol content of each fraction was quantified.11 In macaques, four major fractions were obtained: very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), HDL, and intermediate-density lipoprotein (IDL), which is intermediate in molecular weight to LDL and VLDL. In addition, average LDL molecular weight was determined for each sample by including a trace amount of iodinated LDL of known molecular weight.12 At these same times, plasma concentrations of apolipoprotein B,13 apolipoprotein A-1,14 and lipoprotein(a)13 were also determined.

At month 12, the subfractional heterogeneity and chemical composition of plasma LDL and HDL were assessed in a subset of 32 animals (eight from each treatment group) using density-gradient centrifugation, gradient gel electrophoresis, and traditional biochemical techniques.10,15,16

Fasting plasma glucose17 and insulin18 were determined at the end of the pre-experimental period and at month 12 of the experimental period.

At the end of the experimental period, animals were anesthetized deeply with pentobarbital (30 mg/kg, intravenously) and the cardiovascular system was flushed with normal saline. After ligation of the vena cava and pulmonary arteries, the heart was excised and perfusion-fixed through the aorta with 10% neutral buffered formalin at a pressure of 100 mmHg. The heart was then immersed in 10% neutral buffered formalin. After fixation, five serial tissue blocks were cut from each of the left circumflex, left anterior descending, and right coronary arteries. Sections from each block were stained with Verhoeff–van Gieson stain and the cross-sectional area occupied by intimal lesion (plaque area) was determined using a projecting microscope and a digitizer. Plaque size for each animal was expressed as the mean intimal area of the 15 sections of coronary artery.

To reduce skewness and equalize group variances, atherosclerosis data underwent square root transformation before analysis. One-way analysis of variance, repeated-measures analysis of variance, and analysis of covariance were used for detecting effects of treatment on the various end points. Duncan’s new multiple range test was used for post hoc comparisons. Multiple linear regression was used to assess the relationship between effects of treatment on risk variables and effects on atherosclerosis. Analyses were done using BMDP statistical software (University of California, Berkeley, CA).


   Results
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Abstract
 Materials and Methods
 Results
Discussion
 References
 
During the treatment period, seven animals, equally distributed among groups, either died or were eliminated from the study owing to poor health. Thus, the analyses reported here represent data obtained from the remaining 81 animals.

There was a main effect of treatment on coronary artery atherosclerosis extent (F3,77 = 3.04; P < .04) (Figure 1Go). Post hoc comparisons revealed that atherosclerosis extent was reduced 67% in animals receiving estrogen alone compared with untreated controls (P < .05). Treatment with progestin alone had no effect (P > .20). Atherosclerosis in animals treated with the combination OC was intermediate in extent and did not differ statistically from the other three groups (P > .20).



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  		Figure 1. Extent of diet-induced atherosclerotic plaque in coronary arteries of female cynomolgus monkeys that were treated with placebo (control), ethinyl estradiol (EE), levonorgestrel (LNG), or a combination (EE + LNG). For main effect of treatment F3,77 = 3.04, P < .04. Bars with different letters differ from each other (P < .05) (Duncan new multiple range test).

 
Total plasma cholesterol, HDL cholesterol, and triglyceride concentrations (Table 1Go) represent means of all values for each animal during the 25-month treatment period. Treatment did not affect total plasma cholesterol concentration (P > .10). Plasma HDL cholesterol concentration was reduced in animals receiving estrogen alone or the combination OC compared with untreated controls (P < .01) (Table 1Go). Plasma triglyceride concentrations were increased in animals receiving estrogen alone (P < .05) and reduced in animals receiving progestin alone (P < .05) (Table 1Go).


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  		Table 1. Plasma Lipids and Apoproteins
 
Plasma lipoprotein(a) and apolipoprotein B concentrations were unaffected by treatment (Table 1Go). Plasma apolipoprotein A-1 was reduced in animals treated with progestin alone (P < .05) (Table 1Go).

Although there was no effect of treatment on LDL cholesterol (Table 2Go), average LDL molecular weight was decreased in animals treated with estrogen alone or the combination OC (P < .05) (Table 2Go). Changes in plasma HDL cholesterol, as assessed by high-performance liquid chromotography (Table 2Go), were similar to those shown in Table 1Go. Plasma VLDL plus IDL was increased in animals treated with progestin alone (Table 2Go).


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  		Table 2. Cholesterol Content of Lipoprotein Fractions and Average Low-Density Lipoprotein Molecular Weight
 
Effects of treatment on plasma LDL heterogeneity and composition are published elsewhere.10 In brief, in the groups treated with estrogen either alone or combined with progestin, LDL particles were smaller and contained less free and esterified cholesterol than in the other two groups (P < .05); there was less cholesterol and apolipoprotein B in the density (d) = 1.015–1.025 g/mL subfraction (P < .05); there was correspondingly more cholesterol in the d = 1.025–1.035 g/mL subfraction (P < .05); and there was less apolipoprotein E in all subfractions (P < .05). There were no effects of treatment on plasma HDL heterogeneity or composition.

There were effects of treatment on fasting plasma insulin concentrations. Plasma insulin was increased 92% in animals receiving estrogen alone and 60% in animals receiving the combination OC compared with untreated controls (P < .05).

Multiple regression was used to determine the best risk variable predictors of atherosclerosis extent. Because LDL and HDL heterogeneity was studied in a subset of animals only, these variables were not included in this analysis. In the control group, the regression equation identified higher plasma LDL cholesterol, LDL molecular weight, and fasting plasma insulin as predictive of more extensive atherosclerosis. The relationship between these predictors and atherosclerosis extent in the control group was used to estimate the expected atherosclerosis extent in the treatment groups, assuming the only effect of treatment on atherosclerosis was due to effects on these risk variables. Table 3Go compares the predicted and actual (observed) extent of atherosclerosis in the treatment groups and the control group. In the estrogen-only group, effects on risk variables predicted no change in atherosclerosis extent, whereas a 67% reduction was observed. In the combined OC group, a 68% increase in atherosclerosis was predicted and a 28% reduction was observed. In the progestin group, a 57% decrease was predicted, whereas a 24% increase was observed.


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  		Table 3. Difference in Observed and Predicted Atherosclerosis Extent Between Study and Control Groups
 

   Discussion
Top
Abstract
 Materials and Methods
 Results
 Discussion
References
 
The principal findings of this study were that the potent contraceptive estrogen ethinyl E2 markedly inhibited atherosclerosis progression and that this effect was antagonized by the addition of the contraceptive progestin levonorgestrel when administered in a triphasic regimen commonly prescribed for birth control. This latter finding was unexpected because previous studies using this model had revealed inhibitory effects of combination OCs on atherosclerosis progression.5,6 The most likely explanation for the differences in outcomes relates to the differences in OC formulations among studies. Previous studies addressed the effects of an older, monophasic (continuously administered) formulation containing higher doses of both estrogen and progestin than in the study described here. In the more modern triphasic formulations, the doses of both estrogen and progestin are lower and the reduction in dose is greater for the progestin component. This suggests that the relative estrogen–progestin balance would be shifted in the estrogenic direction and result in a greater atheroinhibitory effect. However, the difference in dose and pattern of administration may mitigate against that outcome; ie, the fact that the estrogen is administered only 21 of each 28 days and at a lower dose probably reduces its atheroinhibitory influence.

Taken together, the results of these studies indicate that there is no evidence for an atherogenic effect and some evidence for a modest antiatherogenic effect (20–40% reduction) of OCs. An atheroinhibitory effect is further supported by the finding that these OC formulations result in reduced arterial degradation of plasma LDL.19 Although there is no evidence for an atherogenic effect of OCs, concern persists regarding potential adverse effects of OCs on thrombosis-mediated arterial cardiovascular events, eg, coronary thrombosis and stroke. However, although there appears to be an increased risk of venous thrombosis in OC users,1,20 there is no compelling evidence for an increase in arterial thrombosis or risk of coronary heart disease events in OC users, except in those who are cigarette smokers.1 In fact, a recent study using this same primate model of atherosclerosis showed that administration of the OC formulation used in the current study reduced the incidence of arterial thrombosis induced experimentally by an injury/stenosis procedure.21 Furthermore, whereas most epidemiologic studies have found no relationship between OC use and coronary risk except among smokers, two large observational studies2,3 detected statistically significant reductions in risk in past users of OCs and one found an inverse relationship between duration of use and risk.2 This seems to support the notion of a modest cardioprotective effect of OCs mediated by the atheroinhibitory properties of estrogen.

The mechanism(s) by which ethinyl E2 inhibits atherosclerosis is not clear. However, it appears that effects on lipoproteins or carbohydrate metabolism are not involved. Results of multiple regression analysis identified plasma LDL cholesterol concentration, plasma LDL molecular weight, and fasting plasma insulin as predictors of atherosclerosis extent in the control group. These findings are consistent with the results of previous studies5,6 and the fact that the atherogenicity of the diet used in this study is explained primarily by its effects on plasma LDL cholesterol and LDL molecular weight. However, treatment-induced changes in these variables did not account for the observed effects of treatment on atherosclerosis. This is shown by the fact that the regression analysis predicted no change or an increase in atherosclerosis extent in the two groups receiving estrogen whereas decreases were observed in both (Table 3Go). This outcome indicates that risk variables not assessed in this study or direct antiatherosclerotic effects of estrogen are involved. It is well known that estrogen has direct influences on the artery. Several types of estrogen inhibit the arterial uptake and metabolism of plasma LDL independently of plasma LDL concentration.19,22 Estrogen modulates immune and inflammatory processes, localized variations of which have been implicated in atherosclerosis.23,24 For example, there is compelling in vivo and in vitro evidence that estrogen inhibits expression of molecules involved in monocyte chemoattraction (monocyte chemoattractant protein-1)25,26 and adhesion (vascular cell adhesion molecule-1),27 and implicated in atherosclerosis. Furthermore, evidence from studies of cultured cells indicates the possibility of inhibitory effects of estrogen on other cytokines/inflammatory mediators (eg, interleukin-6,28,29 E-selectin,30,31 and intercellular adhesion molecule-130,31). Taken together, these findings suggest that estrogen acts directly on the artery to interfere with the LDL uptake–oxidation–inflammation pathway and impede atherosclerosis progression. Effects of progestins on these processes remain uncertain. However, the findings reported here and elsewhere5,6 suggest that progestins may act directly as antiestrogens at the level of the intima to antagonize these antiatherosclerotic effects. This possibility is biologically plausible, and perhaps, predictable because of the well-known effects of progestins in sex steroid target tissues, most notably the uterus. The role of progesterone in the regulation of the reproductive cycle depends on its direct antiestrogenic effects on cellular processes involved in endometrial proliferation.

Estrogen may also inhibit atherosclerosis progression by modulating arterial vasomotor responsiveness. Estrogen reverses the atherosclerosis-related impairment of coronary artery vasodilator function in monkeys32–34 and women.35,36 Progestins of some types and doses are capable of antagonizing these effects. In atherosclerotic monkeys, we have found that medroxyprogesterone acetate antagonizes the estrogen-induced augmentation of coronary vasodilator responsiveness and coronary flow reserve.34 Furthermore, Miyagawa et al37 showed that medroxyprogesterone acetate but not progesterone antagonizes the estrogen-induced reduction in the incidence of experimentally induced vasospasm in monkeys. Because atherosclerosis-related vasospasm can lead to accelerated progression of atherosclerosis, plaque instability or rupture, thrombosis, and myocardial infarction,38–40 this evidence adds further weight to the concept that medroxyprogesterone acetate and levonorgestrel (and perhaps other progestins) but not progesterone have estrogen-antagonistic effects on the progression of atherosclerosis and pathophysiologic consequences of atherosclerosis.


   Footnotes
 
This study was supported by National Heart, Lung, and Blood Institute grant RO1 HL46409 and the Center for Research, College of Science and Health, William Paterson University.

The authors thank Wyeth-Ayerst Research (Princeton, NJ) for providing ethinyl estradiol and levonorgestrel.

PII S0029-7844(00)00891-7

Received November 29, 1999. Received in revised form February 8, 2000. Accepted February 17, 2000.


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 Materials and Methods
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8. Fossati P, Principe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982;28:2077–80.[Abstract/Free Full Text]

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