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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2599
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 6 2097-2103
Copyright © 2008 by The Endocrine Society

Effect of Low-Dose Oral Contraceptives on Metabolic Risk Factors in African-American Women

Barbara A. Frempong, Madia Ricks, Sabyasachi Sen and Anne E. Sumner

Clinical Endocrinology Branch, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1612

Address all correspondence and requests for reprints to: Anne E. Sumner, M.D., National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Building 10-CRC, Room 6-5940, MSC 1612, Bethesda, Maryland 20892. E-mail: annes{at}intra.niddk.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The effect of oral contraceptive pill (OCP) use on cardiovascular risk in African-American women is unknown.

Objective: Our objective was to examine in African-American women the effect of OCP use on insulin resistance, glucose intolerance, and triglycerides (TGs).

Design: This was a cross-sectional study.

Setting: The study was conducted at the National Institutes of Health Clinical Research Center.

Participants: A total of 104 healthy nondiabetic African-American women [21 OCP users, 83 controls, age mean ± SD, 34.7 ± 7.6 yr, body mass index (BMI) 31 ± 8.4 kg/m2] was included in the study.

Interventions: Subjects had oral glucose tolerance tests, insulin-modified frequently sampled iv glucose tolerance tests, and fasting lipid profiles. Insulin resistance was determined by the insulin sensitivity index (SI).

Main Outcome Measures: Insulin resistance, glucose tolerance status, and TG levels were determined.

Results: Fasting glucose did not differ between OCP users and controls (P = 0.27). In contrast, compared with controls, 2-h glucose (135 ± 23 vs.120 ± 25 mg/dl; P = 0.01) and fasting TGs (73 ± 31 vs.57 ± 27 mg/dl; P = 0.02) were higher in OCP users. OCP users tended to be more insulin resistant than controls (SI: 2.51 ± 2.01 vs. 3.46 ± 2.09; P = 0.09). Multiple regression analysis revealed that BMI, age, and OCP use were significant determinants of 2-h glucose (adjusted R2 = 0.37; P < 0.001) and TG levels (adjusted R2 = 0.21; P < 0.001). As BMI was a determinant of both 2-h glucose and TGs, participants were divided into nonobese and obese groups, and the analyses repeated. Among the nonobese women, the OCP users were more insulin resistant (SI: 2.91 ± 1.58 vs. 4.35 ± 1.88; P = 0.03) and had a higher prevalence of glucose intolerance than controls (odds ratio 5.7; 95% confidence interval 1.4–24; P = 0.01).

Conclusion: In African-American women, OCP use is associated with an increase in markers of cardiovascular risk manifested by increased insulin resistance, glucose intolerance, and elevated TGs.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
In the United States, the oral contraceptive pill (OCP) is the leading form of contraception (1). Since its introduction in 1960, efforts have been directed to balance its risks and benefits. First-generation OCP preparations combined high-dose ethinyl estradiol (≥50 µg) and androgenic progestins, and were associated with several adverse effects, the most acute being strokes and thromboembolic events (2, 3) In addition, OCP use was found to be associated with cardiovascular risk factors that promote myocardial infarctions in older populations. Therefore, it was assumed that OCP use would increase cardiovascular risk in women who use this form of contraception (3) In an attempt to minimize these adverse occurrences, oral contraceptives with lower doses of estrogen (≤50 µg ethinyl estradiol) and less androgenic progestins were developed (3, 4, 5). In the United States, most low-dose OCPs have estrogens in the range of 20–35 µg (2). Although low-dose oral contraceptives are associated with a better metabolic profile than higher doses, cardiovascular and embolic risks have not been eliminated (6, 7).

Just as premenopausal women may elect to use the OCP, postmenopausal women may choose hormone replacement therapy (HRT). In postmenopausal women with an intact uterus, HRT usually consists of a combination of estrogen and progesterone. Many formulations of HRT are available. From HRT, important lessons have been learned about the effect of exogenous hormones on cardiovascular risk. Among the first studies to report that HRT decreased cardiovascular risk was the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial (8). The PEPI investigators found that women on HRT had lower low-density lipoprotein (LDL), higher high-density lipoprotein (HDL), and lower fibrinogen. Subsequent to the PEPI trial, two large randomized placebo-controlled trials, the Heart and Estrogen/Progestin Replacement Study (HERS) (9) and the Women’s Health Initiative (WHI) (10), challenged the benefits and safety of HRT. In the HERS, postmenopausal women with established coronary disease were enrolled. In the first year of the HERS, increased coronary heart disease events, including myocardial infarction, sudden death, and congestive heart failure, were found (9).

The WHI studied healthy postmenopausal women without coronary artery disease. Results of the WHI provided insight into both the benefits and risks of HRT. In fact, the risks were determined to be so great that the WHI was terminated early because the women on HRT had an increased incidence of not only breast cancer but also of acute myocardial infarction, silent myocardial infarction, and deaths attributed to coronary heart disease (10). Yet, in the WHI younger women (50–59 yr) who were taking HRT for 7 yr had less coronary artery calcified plaque than control women (11). Therefore, the cardiovascular risk of exogenous estrogen and progesterone remains unresolved.

There is relatively little information available about the effect of exogenous hormones in African-American women. Postmenopausal African-American women are less likely than whites to use HRT and are often underrepresented in studies with HRT (12, 13, 14). Similarly, studies of OCP use have either not enrolled African-American women or enrolled too few African-American women to allow for the assessment of metabolic consequences of the OCP in African-Americans (14, 15, 16). In fact, it has been assumed that because African-American women have a high prevalence of glucose intolerance, the OCP would not pose a risk for African-American women (15).

In white women, OCP use has been documented to increase cardiovascular risk by promoting insulin resistance, glucose intolerance, and hypertriglyceridemia (15, 16, 17). However, compared with white women, African-American women are more insulin resistant, have a higher prevalence of glucose intolerance, and paradoxically lower triglyceride (TG) levels (18, 19, 20). Therefore, the metabolic effects of OCP observed in white women cannot be extrapolated to African-American women. Our goal was to study the effect of OCP use on insulin resistance, glucose tolerance status, and TG levels in African-American women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The participants were 104 healthy premenopausal African-American women [age 34.7 ± 7.6 yr (mean ± SD), range 22–50, and body mass index (BMI) 31 ± 8.4 kg/m2, range 18.9- 54.5]) enrolled in the Triglyceride and Cardiovascular Risk in African-Americans study at the National Institutes of Health, in Bethesda, MD (21, 22). Of the women, 21 were OCP users, and 83 were not. OCP use was for contraceptive purposes only. The OCP formulations taken by the participants are provided Table 1Go. Women not using the OCP were considered controls. Of the control women, 63 participated in previous investigations (21, 22). All participants were born in the United States and reported that both parents were African-American. Women 40 yr or older had gonadotropin levels to confirm premenopausal status. All subjects had normal hemograms, and liver, kidney, and thyroid function. Diabetics were excluded. Subjects took no other medications known to affect insulin resistance. Study participants were recruited by advertisements in local newsletters, flyers, and the National Institutes of Health web site. The study was approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases. All subjects gave informed consent before participation.


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  		TABLE 1. List of oral contraceptives used by participants

 
The study consisted of three study visits conducted over 3 months. At the first visit, each subject had a history, physical examination, and screening blood work. Visits 2 and 3 were scheduled during the follicular phase of the menstrual cycle and occurred in the morning after a 12-h fast. At the second visit, all participants had a 75-g oral glucose tolerance test (Trutol 75; Custom Laboratories, Baltimore, MD) with glucose and insulin measured at 0 and 2 h. Fasting blood samples were taken for lipid profile and sex steroid measurements. Dual x-ray absorptiometry was performed to assess percent body fat. At 0800 h on the third visit, insulin modified-frequently sampled iv glucose tolerance tests were performed. Intravenous catheters were placed in each antecubital vein. At time zero, glucose (0.3 g/kg) was injected over 1 min. Insulin (4 mU/kg–1·min–1) was infused from 20–25 min. Blood samples for glucose and insulin were obtained at –10, –1, 0, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, and 180 min.

Assessment of social factors and family history

Alcohol use was defined as intake of more than one drink per week. Subjects were divided into three categories of tobacco use: 1) current smokers (women smoking at enrollment), 2) ex-smokers (women who had smoked in the past but not during the 12 months before enrollment), and (3) never smokers. Regular physical activity was defined as participating in recreational/fitness activities such as jogging, swimming, or cycling at least three times per week for 30–60 min each time. A positive family history of diabetes was defined as the presence of type 2 diabetes in a first-degree relative.

Analytical methods

Glucose was assayed using the glucose oxidase method (Glucostat; Yellow Springs Instrument Inc., Yellow Springs, OH). Insulin assays were performed using the double-antibody chemiluminescent sandwich assay (Diagnostic Products Corp., Los Angeles, CA). TGs were analyzed by enzymatic methods using an automated analyzer (Hitachi 917; Roche Molecular Biochemicals, Indianapolis, IN). HDL-cholesterol was measured by homogenous assay using synchron SX-20 analyzer (Beckman Coulter, Inc., Fullerton, CA). The glucose, insulin, TGs, and HDL-cholesterol were run in duplicate, and the coefficients of variation were 2, 4.9, 1.8, and 1.8%, respectively. Estradiol levels were obtained by competitive chemiluminescence immunoassay, and SHBG was measured with immunometric assay with chemiluminescence detection (Diagnostic Products). The interassay coefficient of variation for estradiol and SHBG levels were 8.6 and 5.4%, respectively.

Determination of insulin resistance

Insulin resistance was determined by the insulin sensitivity index (SI) using minimal model analyses and data from the insulin-modified frequently sampled iv glucose tolerance test (23) (Min Mod Millennium V6.02; MinMod. Inc., Los Angeles, CA).

Insulin secretion

Acute insulin response to glucose (AIRg) during the insulin-modified frequently sampled iv glucose tolerance test was calculated as the area under the insulin curve for insulin concentration above basal from 0–10 min. The disposition index (DI) was calculated to determine if pancreatic β-cell secretion was adequate to overcome the level of insulin resistance. The DI is the product of SI and AIRg (24).

Measurement of percent body fat

Percent body fat measurements were performed with a Hologic QDR 4500A dual energy x-ray absorptiometer in the array mode, using software version 5.71 (Hologic, Inc., Bedford, MA).

Statistical analysis

Data are presented as mean ± SD. Comparisons between OCP users and controls were performed using unpaired t tests. Parameters that were not normally distributed were transformed before analysis by log or square root as appropriate. {chi}2 tests were used for comparisons of categorical variables. The likelihood of having impaired glucose tolerance was determined in OCP users and controls by calculating the odds ratio. Multiple regression analyses were performed with either 2-h glucose or fasting TG as dependent variables, and BMI, age, and OCP use as the independent variables. A P value less than or equal to 0.05 was considered significant. The statistical analyses were performed using statistical data analysis software STATA version 10.0 (StataCorp LP, College Station, TX).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the participants are listed in Table 2Go. Compared with controls, OCP users were younger (P = 0.05). OCP users had a trend toward lower BMI and lower percent body fat than controls, albeit the difference did not reach statistical significance. Family history of diabetes and the social factors that can influence glucose metabolism such as alcohol use, cigarette smoking, and physical activity did not differ between OCP users and controls (Table 2Go).


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  		TABLE 2. Characteristics of study population

 
Fasting glucose was not different by OCP use (P = 0.27), but 2-h glucose obtained from the oral glucose tolerance tests was higher in OCP users than controls (135 ± 23 vs. 120 ± 25 mg/dl; P = 0.01). Similarly, the DI (the product of SI and AIRg) was significantly lower in OCP users compared with controls (P = 0.01) (Table 2Go).

Both TGs and HDL-cholesterol were higher in OCP users than controls (P ≤ 0.02), but total cholesterol and LDL-cholesterol did not differ (Table 2Go).

SHBG levels were higher in OCP users than controls (P = 0.01). Estradiol levels were lower in OCP users than controls (P = 0.01).

Multiple regression analysis revealed that BMI, age, and OCP use were significant determinants of 2-h glucose with adjusted R2 = 0.37 (P < 0.001) (Table 3Go). Similarly, BMI, age, and OCP use were significant determinants of TG levels with adjusted R2 = 0.21 (P < 0.05). As BMI was a significant determinant of both 2-h glucose and TG, we examined how BMI categories modified the effect of OCP use on cardiovascular risk factors. Women were divided into two categories [nonobese (BMI < 30) and obese (BMI ≥ 30)], and the analyses were repeated.


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  		TABLE 3. Regression analyses showing the independent contributions of BMI, OCP use, and age to 2-h glucose and TG

 
Metabolic and hormonal profile in nonobese women

Compared with controls, OCP users were younger (P = 0.05) (Table 4Go). OCP users were more insulin resistant than controls, as evidenced by their higher fasting insulin levels (P = 0.05), higher 2-h glucose (P = 0.01), and lower SI (P = 0.03). Consequently, the prevalence of glucose intolerance was higher in OCP users than in controls (36 vs. 9%; P = 0.01). Similarly, OCP users had a higher likelihood of having glucose intolerance than controls (odds ratio = 5.7; 95% confidence interval 1.4–24; P = 0.01).


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  		TABLE 4. Characteristics of nonobese subjects

 
In addition, compared with controls, OCP users had higher TGs and HDL-cholesterol (P < 0.01), but total cholesterol and LDL-cholesterol were not statistically different (Table 4Go). OCP users had higher SHBG levels (P = <0.01) and lower estradiol levels (P < 0.01).

Metabolic and hormonal profile in obese women

In contrast to the nonobese women, obese OCP users compared with obese controls had no difference in age, fasting insulin, 2-h glucose, SI, TG, or HDL-cholesterol. Consequently, the prevalence of glucose intolerance in obese OCP users and controls was similar (57 vs. 42%; P = 0.46).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We are the first to examine the association between cardiovascular risk factors and OCP use specifically in African-American women. Our investigation revealed that compared with controls, African-American women taking low-dose OCP have worse glucose tolerance and higher fasting TG levels. Most importantly, the differences between OCP users and controls in cardiovascular risk factors were greatest in the subgroup of nonobese women. Previous studies in white women have suggested that among women taking the OCP, those at highest risk for developing glucose intolerance were obese (25, 26). Our observation of significantly worse glucose tolerance and TG elevations in nonobese African-American users of the OCP suggests that for nonobese African-American women, OCP may pose additional health risks.

Although elevations in both fasting and 2-h glucose levels are associated with increased cardiovascular risk, 2-h glucose may be a better predictor of cardiovascular disease risk than fasting blood glucose (27, 28). In our study, whereas fasting glucose was unaffected by OCP use, 2-h glucose levels were higher in users compared with controls. Consistent with our findings, Sheu et al. (29) showed in Chinese women that OCP use did not affect fasting glucose but was associated with higher 2-h glucose. Interestingly, this pattern has also been observed with HRT in postmenopausal women (30).

Elevation in 2-h glucose is an indication of glucose intolerance. Glucose intolerance results from both insulin resistance and decreased β-cell function. OCP use promotes glucose intolerance by affecting both pathways (15). The exact mechanism by which OCP use leads to insulin resistance has not been fully elucidated. However, a proposed mechanism is reduced insulin receptor binding (31). This phenomenon has been demonstrated by comparing insulin receptor binding and affinity in monocytes isolated from OCP users and controls. In the normal menstrual cycle, insulin receptor binding and affinity are lower in the luteal than the follicular phase, suggesting that insulin resistance is worse in the luteal than follicular phase (32). De Pirro et al. (31) demonstrated that OCP users have lower insulin binding and affinity similar to that observed in the luteal phase of the menstrual cycle in normal women.

In addition to promoting insulin resistance, OCP use leads to impaired β-cell function (15). The relationship between insulin secretion and insulin resistance is best represented by the DI. The DI is a measure of whether insulin secretion by the β-cell is sufficient to compensate for the level of insulin resistance. Watanabe et al. (15) have shown in white women that the DI is lower in OCP users than controls, suggesting that OCP use in white women is associated with compromised β-cell function. Our study of African-American women also found impaired β-cell function with OCP use because the DI was lower in the OCP users than controls (Table 2Go).

Besides altering glucose metabolism, OCP use leads to an increase in both TGs and HDL-cholesterol. With exposure to estrogen, hepatic synthesis and secretion of TG-rich particles increase (33, 34). Many studies have demonstrated that increased TG levels are an independent risk for cardiovascular disease (35, 36, 37). Hokanson and Austin (36) reported that especially in women, elevations in TGs are associated with an increased risk of cardiovascular disease, even after adjusting for HDL-cholesterol levels. Therefore, by causing an increase in TG levels, OCP use may be worsening cardiovascular risk.

HDL-cholesterol levels increase with OCP use because estrogen inhibits hepatic lipase activity, the enzyme responsible for clearing HDL-cholesterol from the circulation (33, 38). In contrast, hepatic lipase activity is promoted by the androgenic effect of progesterone, leading to an increased clearance of HDL-cholesterol and lower circulating HDL-cholesterol levels (33, 38, 39). However, with OCP use the overall net effect favors estrogen’s inhibition of hepatic lipase, resulting in an increase in HDL-cholesterol levels. Because OCP use leads to increased HDL-cholesterol, it would be anticipated that cardiovascular risk might be lower with OCP use. However, definitive evidence that pharmacologically increased HDL-cholesterol improves cardiovascular outcomes is not available (9, 40).

Different preparations of the OCP do not equally affect cardiovascular risk. Because the participants in our study were on 11 different preparations, we cannot address this issue or distinguish the relative effect of the estrogen and progestin components. The negative effect of the progestin component may be directly related to the type and dose of progesterone. Identifying the risk associated with different progestin preparations has been a major emphasis of European investigators (7, 39).

The major weaknesses of our study are the sample size, cross-sectional design, and the number of different OCP preparations used. However, despite our sample size, our findings of significantly higher 2-h glucose, worse insulin resistance, higher TGs and HDL, and a lower DI in OCP users are consistent with reports in larger cohorts (15, 16, 17, 29). Furthermore, SHBG and estradiol, both of which are known to be affected by OCP use, were significantly different in OCP users than controls. We also carefully examined family history and the social factors that could potentially confound our results such as smoking and alcohol, and they did not differ between OCP users and controls. It is our belief that our results justify the design of larger prospective studies of African-American women taking the OCP.

In evaluating sample size, we must also consider the risk of OCP use in relation to body size and age. After the study population was divided into nonobese and obese groups, the difference in risk factors was significant only in the nonobese women. Thus, nonobese women who should not have had these risk factors now may do so because of their OCP use. For obese women the situation is different. As obesity itself increases the baseline risk for insulin resistance and dyslipidemia, a larger sample size would be needed to detect a difference, if one exists, between obese OCP users and controls. In addition, the OCP users were younger than the controls. By virtue of being younger, it would be expected that the OCP users would have lower TGs and less glucose intolerance. The fact that OCP users had higher TGs and more glucose intolerance again magnifies the importance of the differences between users and controls.

In African-American women, low-dose OCP use was associated with an increased risk of insulin resistance, glucose intolerance, and elevated TGs. As each of these factors may promote adverse cardiovascular outcomes (27, 36), it is possible that the OCP is presenting a risk to African-American women. Assessing the risks and benefits of OCP use is complex and requires careful consideration in African-American women.


   Acknowledgments
 
We thank Drs. Pamela Stratton and Lynnette Nieman for their thoughtful and critical review of the manuscript. We also thank the participants for their time and effort.


   Footnotes
 
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program.

Disclosure Information: The authors have nothing to declare.

First Published Online March 11, 2008

Abbreviations: AIRg, Acute insulin response to glucose; BMI, body mass index; DI, disposition index; HDL, high-density lipoprotein; HERS, Heart and Estrogen/Progestin Replacement Study; HRT, hormone replacement therapy; LDL, low-density lipoprotein; OCP, oral contraceptive pill; PEPI, Postmenopausal Estrogen/Progestin Interventions; SI, insulin sensitivity index; TG, triglyceride; WHI, Women’s Health Initiative.

Received November 27, 2007.

Accepted March 5, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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