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Original Article

The Effects of Different Formulations of Oral Contraceptive Agents on Lipid and Carbohydrate Metabolism

List of authors.
  • Ian F. Godsland, B.A.,
  • David Crook, Ph.D.,
  • Ruth Simpson, B.Sc.,
  • Tony Proudler, M.Sc.,
  • Carl Felton, Ph.D.,
  • Belinda Lees, B.Sc.,
  • Victor Anyaoku, B.Sc.,
  • Maxeen Devenport, M.B., B.S.,
  • and Victor Wynn, M.D.

Abstract

Background.

Oral contraceptives can induce changes in lipid and carbohydrate metabolism similar to those associated with an increased risk of coronary heart disease, including increased serum triglyceride, low-density lipoprotein (LDL) cholesterol, and insulin levels and decreased high-density lipoprotein (HDL) cholesterol levels. In this study, we examined whether modification of the type or dose of progestin in oral-contraceptive preparations diminishes these changes.

Methods.

We measured plasma lipoprotein levels and performed oral glucose-tolerance tests in a cross section of 1060 women who took one of nine types of oral contraceptives for at least three months and 418 women who took none. Seven of the contraceptive formulations contained various doses and types of progestin: levonorgestrel in low (150 μg), high (250 μg), and triphasic (50 to 125 μg) doses; norethindrone in low (500 μg), high (1000 μg), and triphasic (500 to 1000 μg) doses; and a new progestin, desogestrel, in one dose (150 μg). All seven contained 30 to 40 μg of ethinyl estradiol. Two additional formulations contained progestin alone.

Results.

As compared with controls, women taking combination drugs did not have increased serum total cholesterol levels but did have increases of 13 to 75 percent in fasting triglyceride levels. Levels of LDL cholesterol were reduced by 14 percent in women taking the combination containing desogestrel and by 12 percent in those taking low-dose norethindrone. Levels of HDL cholesterol were lowered by 5 percent and 16 percent by the combinations containing low-dose and high-dose levonorgestrel, respectively; these decreases were due to reductions of 29 percent and 43 percent, respectively, in the levels of HDL subclass 2. The combination pill containing high-dose norethindrone did not affect HDL cholesterol levels, whereas that containing low-dose norethindrone increased HDL cholesterol levels by 10 percent. The desogestrel combination increased HDL cholesterol levels by 12 percent. Levels of apolipoproteins A-I, A-II, and B were generally increased by combination drugs. Depending on the dose and type of progestin, combination drugs were associated with plasma glucose levels on the glucose-tolerance test that were 43 to 61 percent higher than in controls, insulin responses 12 to 40 percent higher, and C-peptide responses 18 to 45 percent higher. Progestin-only formulations had only minor metabolic effects.

Conclusions.

The appropriate dose and type of progestin may reduce the adverse effects of oral contraceptives on many metabolic markers of risk for coronary heart disease. Progestin-only formulations or combinations containing desogestrel or low-dose norethindrone were associated with the most favorable profiles. (N Engl J Med 1990; 323:1375–81.)

Introduction

ORAL contraceptive agents can induce substantial metabolic changes that resemble those seen in persons at increased risk for premature coronary heart disease.1 These changes include raised serum triglyceride and low-density lipoprotein (LDL) cholesterol levels, reduced high-density lipoprotein (HDL) cholesterol levels, impairment of glucose tolerance, and elevated insulin levels.2 , 3 Although the contribution of these changes to the increased risk of coronary heart disease in users of oral contraceptives is uncertain,4 it would seem prudent to minimize these disturbances. We have studied lipid and carbohydrate markers of risk in users of oral contraceptives containing the progestins levonorgestrel, norethindrone, and desogestrel. Desogestrel (not yet available in the United States) is structurally related to levonorgestrel but has diminished metabolic side effects.5 Two formulations contained levonorgestrel or norethindrone alone. Oral contraceptives combining progestin with estrogen were classified as monophasic if the steroid dose was held constant throughout the cycle or as triphasic if three different doses of the estrogen and progestin were taken during the cycle. All combinations contained 30 to 40 μg of ethinyl estradiol and thus differed primarily in their progestin content.

Interrelations between risk markers have been overlooked in studies of oral contraceptives. In the present study we evaluated lipid and carbohydrate risk markers. We also measured plasma C-peptide concentrations, since they can provide a sensitive indicator of disturbances in insulin secretion6 and have rarely been measured in studies of oral contraceptives.

Methods

Subjects

We studied 1478 white women who were 18 to 45 years old and within 20 percent of their ideal body weight (according to Metropolitan Life tables); 1060 used oral contraceptives, and 418 did not. The participants were recruited mainly through local family-planning clinics and general practitioners, were not paid, and gave written informed consent. The study was approved by the ethics committees of the Paddington and North Kensington Health Authority and the Wynn Institute for Metabolic Research. The women had no known medical conditions, were not taking medications known to affect lipid or carbohydrate metabolism, and had not been pregnant within the previous six months. Oral-contraceptive users had taken their current formulation for at least three months; nonusers had not taken sex hormones for at least three months.

Table 1. Table 1. Oral-Contraceptive Formulations.

The compositions and proprietary names of the oral contraceptives are given in Table 1. Combination drugs containing levonorgestrel were classified according to progestin content as high dose (250 μg), low dose (150 μg), or triphasic (50 to 125 μg). Similarly, norethindrone combinations were classified as high dose (1000 μg), low dose (500 μg), or triphasic (500 to 1000 μg). The triphasic levonorgestrel combination contained the lowest dose of the three formulations containing levonorgestrel. The triphasic norethindrone combination contained a progestin dose intermediate between the two monophasic formulations. Women using progestin-only formulations containing 30 or 37.5 μg of levonorgestrel were treated as a single group. Those taking progestin-only formulations containing norethindrone or ethynodiol diacetate were also treated as a single group, since ethynodiol diacetate is converted to norethindrone before becoming biologically active.

Procedures

The subjects were instructed to consume more than 200 g of carbohydrate daily in their diet for three days as preparation for a glucose-tolerance test, to fast overnight (more than 12 hours), and to take only water and refrain from cigarette smoking on the morning of the test. Metabolic tests were performed between 9 and 10 a.m. on the days progestogenic effects would be expected to dominate: days 15 to 21 of the pill-taking cycle (users) or days 21 to 27 of the menstrual cycle (nonusers). Women were asked to bring the packet of pills they were currently using. If they did not do this, they were presented with a range of oral-contraceptive packages and asked to identify the type they used. Height, weight, and blood pressure were measured on arrival, and a general medical history was taken by a clinician, including details of reproductive history, current and past oral-contraceptive use, alcohol and tobacco consumption, exercise habits, and family history of diabetes and heart disease.

Of the 1478 subjects, 782 users of oral contraceptives and 346 nonusers had the oral glucose-tolerance test (OGTT). After the subjects had rested for 15 minutes in a semirecumbent position, an indwelling cannula was inserted into an antecubital vein. Prolonged venous stasis was avoided. Blood samples for the measurement of the fasting serum lipoproteins were obtained and placed in plastic tubes containing plastic granules. The samples were mixed and allowed to stand at room temperature for one hour before the serum was separated by low-speed centrifugation. Two successive blood samples, taken 10 minutes apart, were drawn into tubes treated with lithium and heparin for the measurement of fasting plasma glucose, insulin, and C-peptide levels. The subjects then immediately drank a glucose solution (1 g of glucose per kilogram of body weight, given as a 50 percent [wt/vol] solution of dextrose), and additional blood samples were obtained every 30 minutes for the next 3 hours.

Serum total cholesterol and triglycerides were measured by enzymatic procedures.7 , 8 Concentrations of HDL and HDL subclass 3 (HDL3) cholesterol were measured after sequential precipitation with heparin and manganese ions9 and dextran sulfate,10 respectively. The serum concentration of HDL subclass 2 (HDL2) cholesterol was calculated as the difference between the HDL and HDL3 cholesterol levels. The Friedewald equation11 was used to calculate LDL cholesterol levels. Apolipoproteins A-I, ATI, and B were measured by immunoturbidimetry.12 This technique became available in our laboratory during the course of the study, and as a consequence values were not available for all subjects. Plasma glucose was measured by a glucose oxidase procedure.13 Samples stored at 4°C were analyzed within one day (glucose) or four days (total lipids, lipoproteins, and apolipoproteins). Plasma insulin was measured in samples stored at —20°C according to the radioimmunoassay procedure of Albano et al.,14 and C peptide was measured with a Guildhay radioimmunoassay kit (Surrey, United Kingdom).

Quality control was monitored by the use of commercially available lyophilized serum and by participation in national quality-control programs. The overall coefficients of variation were 1 to 2 percent for serum total cholesterol and triglycerides, 2 to 4 percent for HDL cholesterol, 5 to 7 percent for HDL3 cholesterol, 6 to 9 percent for HDL2 cholesterol, 3 to 4 percent for apolipoprotein A-I, 1 to 3 percent for apolipoprotein A-II, 2 to 4 percent for apolipoprotein B, 1 to 2 percent for plasma glucose, 4 to 6 percent for plasma insulin, and 7 to 9 percent for plasma C peptide.

Statistical Analysis

Triglyceride and insulin concentrations were logarithmically transformed to normalize their distributions. Mean fasting plasma glucose, insulin, and C-peptide concentrations were taken as the average of the two samples obtained before the OGTT. The total area under the profiles of the glucose, insulin, and C-peptide concentrations in the OGTT was calculated in the following manner: total area = (MFc/2) + 30′c + 60′c + 90′c + 120′c + 150′c + (180′c/2), where t′c is the concentration at time t′ and MFc is the mean fasting concentration. We then used the incremental area (which is the total area — (6 × MFc)) under the curve as a measure of the response to the OGTT. The incremental area is the area between the concentration profile of the OGTT and the fasting level and thus reflects the magnitude of the response.

We used BMDP Statistical Software (Los Angeles) for statistical analyses. Multiple linear-regression analysis was performed with metabolic measures as dependent variables. The independent variables included the type and duration of current use of the oral contraceptive, age, percentage of ideal body weight, number of pregnancies, current and previous cigarette smoking, alcohol use, exercise, and family history of diabetes and heart disease. Results were standardized to the mean value for each independent variable in the study population with the regression-analysis coefficients. Comparisons between mean standardized values in users and nonusers of oral contraceptives were made with Student's unpaired t-test (two-tailed). Analyses using matched groups of users and nonusers and standardization for selected variables gave essentially the same results. Results are given as means ±SD unless otherwise noted.

Results

The mean (±SD) ages of users of combined oral contraceptives (28.0±5.0 years) and progestin-only agents (34.9±5.8) were significantly different from that of nonusers (32.5±6.7, P<0.001). The percentages of ideal body weight, alcohol use, and other variables were similar in all groups, although users had had fewer pregnancies (P<0.001). The mean duration of current use varied from 1.5 years (triphasic norethindrone combination) to 4 years (high-dose monophasic levonorgestrel combination).

Table 2. Table 2. Serum Lipid and Lipoprotein Cholesterol Levels in Users and Nonusers of Oral Contraceptives.*

Serum total cholesterol levels were not affected by combination oral contraceptives, whereas serum triglyceride levels were increased by 13 to 75 percent (Table 2). LDL cholesterol levels were reduced by 14 percent by the monophasic desogestrel combination and by 12 percent by the low-dose (500 μg) norethindrone combination. Monophasic, but not triphasic, levonorgestrel combinations lowered HDL cholesterol levels. Monophasic high-dose (1000 μg) and triphasic norethindrone combinations had no effect on HDL cholesterol levels, whereas the low-dose monophasic norethindrone and the desogestrel combinations raised HDL cholesterol levels.

HDL2 was the most sensitive discriminator of the type and dose of progestin taken by users of combination oral contraceptives. Levonorgestrel combinations lowered HDL2 cholesterol levels by 15 to 43 percent, with the highest dose inducing the greatest decrease. The high-dose monophasic norethindrone combination lowered HDL2 cholesterol levels by 27 percent, whereas the low-dose monophasic combination had no effect. Triphasic levonorgestrel and norethindrone combinations lowered HDL2 levels by 15 percent and 8 percent, respectively. In the case of the triphasic norethindrone combination, this decrease was not significant (P = 0.066) in the standardized analysis but was significant (P = 0.020) when a matched-control-group analysis was used. The monophasic desogestrel combination did not affect HDL2 cholesterol levels. HDL3 cholesterol levels were increased by all combination oral contraceptives except the high-dose monophasic levonorgestrel combination.

Table 3. Table 3. Serum Apolipoprotein Levels in Users and Nonusers of Oral Contraceptives.*

Serum apolipoprotein B levels were increased by all levonorgestrel combinations (Table 3) and by high-dose and triphasic norethindrone combinations. Apolipoprotein A-I levels were decreased by the high-dose monophasic levonorgestrel combination but increased by all other combination drugs. Apolipoprotein A-II levels were increased by all combination drugs.

Levonorgestrel-only formulations had no effect on lipid metabolism. Norethindrone-only formulations lowered HDL cholesterol levels and apolipoprotein A-I and A-II levels.

Table 4. Table 4. Fasting Levels and Incremental Areas of the Oral Glucose-Tolerance Test for Plasma Glucose, Insulin, and C-Peptide Concentrations in Users and Nonusers of Oral Contraceptives.*

Fasting plasma glucose levels were reduced in users of the low-dose monophasic levonorgestrel and triphasic norethindrone combinations (Table 4). Fasting insulin and C-peptide levels were generally increased by combination oral contraceptives. Combination drugs increased incremental areas for glucose by 43 to 61 percent. Incremental areas for insulin and C peptide were increased by 12 to 40 percent and 18 to 45 percent, respectively. There were trends in the effects of the type and dose of progestin taken: the levonorgestrel combinations had greater effects than those containing norethindrone or desogestrel. Norethindrone-only formulations did not affect carbohydrate metabolism; levonorgestrel-only formulations increased the incremental area for glucose.

Figure 1. Figure 1. Percent Differences in HDL and LDL Cholesterol Levels and in the Incremental Area for Insulin in Response to the OGTT between Women Taking One of Seven Combination Oral Contraceptives and Those Not Taking Oral Contraceptives.

The T bars indicate 1 SD. The asterisk (P<0.001), dagger (P<0.01), and double dagger (P<0.05) indicate significant differences between users and nonusers in the mean values for the principal metabolic variables. The oral-contraceptive codes are given in Table 1.

Figure 2. Figure 2. Percent Differences in the Incremental Area for C Peptide in Response to the OGTT between Women Taking One of Seven Combination Oral Contraceptives and Those Not Taking Oral Contraceptives.

The T bars indicate 1 SD. The asterisk (P<0.001 ) and the dagger (P<0.05) indicate significant differences between users and nonusers. The oral-contraceptive codes are given in Table 1.

Trends with progestin dose in the incremental area for insulin and in LDL and HDL cholesterol levels are shown in Figure 1, and in the incremental area for C peptide in Figure 2.

Discussion

Oral administration of estrogen and progestin provides an effective, reversible means of contraception. There has been controversy, however, about the possible risks, including coronary heart disease and myocardial infarction,4 , 15 16 17 of this treatment. The progestin component of oral contraceptives combining progestin and estrogen is primarily responsible for the contraceptive action, but it has been implicated as a risk factor for coronary heart disease,15 , 18 perhaps through the promotion of potentially adverse changes in lipid and carbohydrate metabolism.3 , 19

Low levels of HDL increase the risk of coronary heart disease,20 especially in women.21 Ethinyl estradiol raises HDL cholesterol levels.22 Conversely, progestins can lower HDL cholesterol levels19 , 23 24 25 by increasing hepatic lipase activity.26 In our study, the estrogen-induced elevation of HDL cholesterol levels was opposed by levonorgestrel in a dose-dependent manner and by high-dose and triphasic norethindrone combinations. Monophasic desogestrel combinations as well as low-dose norethindrone combinations, which lowered LDL cholesterol levels, increased HDL cholesterol levels, indicating the predominance of the estrogen over the progestin. Reduced HDL cholesterol levels were seen with monophasic levonorgestrel combinations and with norethindrone given alone. The lack of effect of levonorgestrel when given alone may reflect the very low dose used in the formulation we tested.

The HDL2 subclass may be a more sensitive indicator of risk than total HDL cholesterol,27 although this has yet to be demonstrated in prospective studies. Much of the variation in HDL cholesterol levels appears to be due to the HDL2 subclass.22 We found that combination drugs generally lowered HDL2 cholesterol levels and increased HDL3 cholesterol levels. Measurement of HDL cholesterol levels alone may lead to an underestimation of the metabolic effect, since the triphasic levonorgestrel combination modified the relative levels of the HDL subclasses but did not affect overall HDL cholesterol levels. Generally, trends in apolipoprotein A-I levels reflected the trends in HDL cholesterol levels. In cases in which HDL cholesterol levels were unchanged, apolipoprotein A-I and apolipoprotein A-II levels were increased, confirming compositional changes in the HDL cholesterol spectrum.

High levels of LDL cholesterol are associated with an increased risk of coronary heart disease,28 but the association is weaker in women than in men.21 Oral estrogen reduces LDL cholesterol levels,22 , 29 and progestins may oppose this effect. Combination oral contraceptives can increase LDL cholesterol levels.19 , 23 In contrast, we found that monophasic desogestrel and low-dose norethindrone combinations lowered LDL cholesterol levels, although levels of apolipoprotein B — the protein component of LDL — were unchanged. With the other combination drugs, LDL cholesterol levels were unchanged and apolipoprotein B levels increased. The relative merits of the measurement of LDL cholesterol and apolipoprotein B as predictors of the risk of coronary heart disease are controversial.30

The status of elevated serum triglyceride levels as an independent predictor of coronary heart disease is also uncertain31; elevated triglyceride levels are not associated with increased risk if HDL cholesterol levels are also high.32 Ethinyl estradiol increases hepatic secretion of triglyceride-rich lipoproteins.33 The differences we found in triglyceride levels among users of combination oral contraceptives reflect the ability of the progestin component to oppose this increase. Norethindrone and desogestrel appear to be relatively weak in their opposition to this action, and their use as progestins in combination drugs was associated with the highest serum triglyceride levels. In contrast, levonorgestrel combinations more strongly opposed the action of estrogen and did so in a dose-dependent manner.

Deterioration in glucose tolerance is associated with an increased risk of coronary heart disease, particularly in women.34 The insulin concentration is a strong risk factor for coronary heart disease in men35 but has been poorly studied in women. Deterioration in glucose tolerance combined with elevated insulin levels indicates insulin resistance. Insulin resistance, which has been proposed as having a central role in the metabolic disturbances associated with the development of coronary heart disease,36 is directly related to the response of insulin to the OGTT.37 We observed an increased insulin response in all the women taking combination oral contraceptives, but this increase varied according to the type and dose of progestin, with monophasic levonorgestrel combinations having the greatest effects. Normalization of such disturbances in glucose homeostasis is mediated by increased secretion of insulin by the pancreas, and the plasma C-peptide response can provide a better indicator of secretion than does the insulin level.6 Figure 2 illustrates the effect of the dose and type of progestin on C-peptide responses to the OGTT. Progestin-only formulations had minor effects on carbohydrate metabolism, consistent with the relatively low dose of progestin in these drugs.

Even at the low doses in current use, progestins may have unwanted metabolic side effects when combined with estrogen. We found marked variation in such side effects depending on the type and dose of progestin, with the greatest effects seen with monophasic levonorgestrel combinations and the least with monophasic desogestrel and low-dose norethindrone combinations. Our study has confirmed that a reduction in the dose of progestin and a change in the type of progestin can bring about a substantial reduction in risk markers for coronary heart disease in users of oral contraceptives containing low doses of estrogen. These developments represent important advances in oralcontraceptive practice.

Funding and Disclosures

Supported by the U.S. National Institute of Child Health and Human Development (contract NO1-HD-52907).

Presented in part at the XII World Congress of Gynecology and Obstetrics, Rio de Janeiro, 1988.

We are indebted to Shyamala Punniamoorthy, Dr. R. Niththyananthan, and Joanna Nolan for technical assistance; to Fiona Borth and Penny Griffin for data analysis; to Tom Marshall and Cecily Kelleher for statistical advice; to Dr. Jeffrey Perlman of the U.S. National Institute of Child Health and Human Development for support and encouragement; to the Margaret Pyke Centre (London) for assistance in recruitment; to the nursing and secretarial staff associated with the project; and to the women who participated in this study.

Author Affiliations

From the Wynn Institute for Metabolic Research, 21 Wellington Rd., St. John's Wood, London NW8 9SQ, England, where requests for reprints should be addressed to Professor Wynn.

References (38)

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Citing Articles (307)

    Figures/Media

    1. Table 1. Oral-Contraceptive Formulations.
      Table 1. Oral-Contraceptive Formulations.
    2. Table 2. Serum Lipid and Lipoprotein Cholesterol Levels in Users and Nonusers of Oral Contraceptives.*
      Table 2. Serum Lipid and Lipoprotein Cholesterol Levels in Users and Nonusers of Oral Contraceptives.*
    3. Table 3. Serum Apolipoprotein Levels in Users and Nonusers of Oral Contraceptives.*
      Table 3. Serum Apolipoprotein Levels in Users and Nonusers of Oral Contraceptives.*
    4. Table 4. Fasting Levels and Incremental Areas of the Oral Glucose-Tolerance Test for Plasma Glucose, Insulin, and C-Peptide Concentrations in Users and Nonusers of Oral Contraceptives.*
      Table 4. Fasting Levels and Incremental Areas of the Oral Glucose-Tolerance Test for Plasma Glucose, Insulin, and C-Peptide Concentrations in Users and Nonusers of Oral Contraceptives.*
    5. Figure 1. Percent Differences in HDL and LDL Cholesterol Levels and in the Incremental Area for Insulin in Response to the OGTT between Women Taking One of Seven Combination Oral Contraceptives and Those Not Taking Oral Contraceptives.
      Figure 1. Percent Differences in HDL and LDL Cholesterol Levels and in the Incremental Area for Insulin in Response to the OGTT between Women Taking One of Seven Combination Oral Contraceptives and Those Not Taking Oral Contraceptives.

      The T bars indicate 1 SD. The asterisk (P<0.001), dagger (P<0.01), and double dagger (P<0.05) indicate significant differences between users and nonusers in the mean values for the principal metabolic variables. The oral-contraceptive codes are given in Table 1.

    6. Figure 2. Percent Differences in the Incremental Area for C Peptide in Response to the OGTT between Women Taking One of Seven Combination Oral Contraceptives and Those Not Taking Oral Contraceptives.
      Figure 2. Percent Differences in the Incremental Area for C Peptide in Response to the OGTT between Women Taking One of Seven Combination Oral Contraceptives and Those Not Taking Oral Contraceptives.

      The T bars indicate 1 SD. The asterisk (P<0.001 ) and the dagger (P<0.05) indicate significant differences between users and nonusers. The oral-contraceptive codes are given in Table 1.

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