Berenson, Abbey B. MD1,2; Rahman, Mahbubur MBBS, PhD1,2; Wilkinson, Gregg PhD, FACE2,3
Although a number of investigations have been conducted on the relationship between depot medroxyprogesterone acetate (DMPA) and lipid levels, results are not consistent between studies. For example, some have demonstrated that DMPA does not affect serum lipids whereas others have shown an adverse relationship.1–4 Two others report a beneficial effect.5,6 Findings from all these studies are limited because they are cross-sectional in design3,6–8 or have very small sample sizes.1,4,5,9–12 Only three large trials have been published that followed women for an extended period, and they disagree in their findings.13–15 Furthermore, none of these three studies took into account the effect of diet on lipid levels.
Moreover, data are limited on the effects of oral contraceptives (OCs) containing only 20 micrograms ethinyl estradiol (E2) and 0.15 mg desogestrel on the lipid profile. This third-generation progestin has been used in newer OCs because it is less androgenic and thus should have less effect on carbohydrate metabolism and lipid levels. It is not certain, however, whether this actually occurs with use of OCs containing only 20 micrograms ethinyl E2 and 0.15 mg desogestrel because only three longitudinal studies have included more than 30 women using this formulation16–18 and none included a control group not using hormonal contraception. Furthermore, these studies are limited in their generalizability to non-white populations because they included very few of these women or did not conduct analyses by race/ethnicity.
The purpose of this study was to fill these gaps in the literature by estimating the effect of DMPA as well as OCs containing 20 micrograms ethinyl E2 and 0.15 mg desogestrel on serum lipid levels over 3 years of contraceptive use in non-Hispanic white, non-Hispanic African American, and Hispanic women. In addition, we measured serum lipids after DMPA discontinuation to estimate whether any observed changes were reversible after discontinuation of this method.
MATERIALS AND METHODS
As part of a larger study, 805 non-Hispanic African- American, non-Hispanic white, and Hispanic women between 16 and 33 years of age were recruited between October 9, 2001, and September 14, 2004.19 Recruitment was conducted to achieve a sample that was balanced by age group (16–24 years and 25–33 years), race/ethnicity (white, African American, Hispanic), and contraceptive method (OC, DMPA, nonhormonal contraceptive). This 3×2×3 grid depicted target sample sizes within each of 18 cells that were based on the overall sample size. Once the targeted number was achieved in a given cell, the cell essentially was closed to recruitment. All women underwent eligibility screening, including a medical interview, anthropometry, and fasting phlebotomy during the follicular phase of their menstrual cycles. Criteria for exclusion included current pregnancy or breastfeeding, pregnancy planned within the next 3 years, use of DMPA within the previous 6 months, use of OCs within the previous 3 months current use of a hormonal intrauterine device, contraindication to hormonal contraception, lack of menses for more than 3 months within the previous year, bilateral oophorectomy, use of over-the-counter phytoestrogen supplements, dietary isoflavone intake exceeding 84 mg/d, use of glucocorticoids, illness or medication known to affect bone mineral density, eating disorder, and strict vegetarian diet. No participants were using statins.
Of 2,999 women who responded to advertisements, 1,404 met general inclusion criteria and matched an open recruitment cell (age group× race×contraceptive method). Of these, 805 women provided written consent (and parental consent if younger than 18 years) to undergo further screening for the larger study. Of these, five withdrew before completing their first visit and 97 had abnormal laboratory or bone-scan results. Thus, 703 women were invited to participate in the longitudinal study. Those excluded (n=102) did not differ from women included in the longitudinal study (N=703) on age, marital status, parity, or education (all P>.05).
After counseling, women were allowed to select one of three types of birth control: 245 chose OCs (0.15 mg desogestrel+20 micrograms ethinyl E2 taken for 21 days followed by 2 days of placebo and 5 days of 10 micrograms ethinyl E2), 240 chose DMPA, and 218 chose nonhormonal contraception. Contraception was dispensed every 3 months. At baseline and every 6 months thereafter, women were weighed wearing light indoor clothing with a digital scale accurate to the nearest 0.1 kg, and height was measured using a wall-mounted stadiometer (Heightronic, Snoqualmie, WA) accurate to the nearest 0.001 m. To obtain estimates on daily calorie intake along with amount of protein, fat, and carbohydrates consumed, a registered dietician conducted a 24-hour dietary recall interview with each participant at baseline and every 12 months thereafter at a scheduled visit. Nutrient calculations were performed using the Nutrition Data System for Research 4.05 (Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN).20 All participants received free well-woman care and contraception during the study as well as monetary compensation. Those who did not return for scheduled visits were reminded by phone and certified letters.
Serum lipids were measured at baseline and every 6 months thereafter. All blood samples were collected between 7:00 am and 10:00 am after an overnight fast. Assays were performed on the VITROS 5,1 FS Chemistry System (Ortho-Clinical Diagnostics, Raritan, NJ) using the manufacturer’s reagents and calibrators. The triglyceride and total cholesterol tests were performed using the VITROS TRIG and CHOL slides, respectively, along with the VITROS chemistry products calibrator kit 2. Each slide analyzed 5.5 microliters of serum using a multilayered, analytical element coated on a polyester support with colorimetric detection and analysis based on an enzymatic method. Direct high-density lipoprotein (HDL) cholesterol was measured using the VITROS dHDL slide with the VITROS chemistry products calibrator kit 25. Each slide used 10 microliters of serum and employed a colorimetric test on a multilayered analytical element coated on a polyester support. Analyses are based on a non-HDL precipitation method followed by enzymatic detection. Coefficients of variation for triglycerides, total cholesterol, and direct HDL were 0.9%, 1.5%, and 3%, respectively, and were determined using a single lot of reagents calibrated weekly. Indirect lipid measures for low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol were calculated based on values obtained for total cholesterol and direct HDL. Samples were assayed in batches (total of 37) at the University of Texas Medical Branch Laboratory between December 2007 and June 2008 after the study was completed.
Participants also completed a written questionnaire containing demographic and behavioral measures. Demographic information obtained included age, race/ethnicity, marital status, education, income, and parity. Behavioral measures included prior breastfeeding and hormonal contraceptive use, smoking, alcohol use, and physical activity. Tobacco use was measured with questions from the MONICA Smoking Assessment.21 For analytic purposes, current smokers were those who reported regular or occasional smoking and nonsmokers were those who currently did not smoke. Alcohol use was calculated from questions on the Diet History Questionnaire regarding how often participants drank alcohol (either beer, wine or wine coolers, or liquor or mixed drinks) during the previous 12 months and the amount usually consumed when drinking.22 Weight-bearing physical activity was taken from a measure that included a list of 56 common activities and questions on the frequency and duration of up to two physical activities performed during the previous month.
Data were available for 186 women for the entire 36 months of study duration. Overall, 137 women discontinued the study because they desired a different contraceptive method, 257 women were lost to follow-up, and 123 women did not complete the study for other reasons. Overall, study discontinuation after 36 months was not statistically different among the contraceptive methods (77% in nonhormonal contraception, 76% in DMPA, and 68% in OC users).
We examined whether abnormal lipid levels at baseline were related to attrition over the 36 months of study duration. Users of OCs who declined to participate in the continuation portion of the study at 18 and 24 months had higher abnormal triglyceride levels (triglyceride more than 170 mg/dL) at baseline compared with those who did continue (11% compared with 4% at both occasions, P<.05). Similarly, nonhormonal-contraceptive users who discontinued this portion of the study at 12 and 18 months had higher abnormal baseline LDL levels (160 mg/dL or higher) compared with study continuers (11% compared with 4%, P<.05, and 10% compared with 4%, P=.066, respectively). However, the opposite was true for DMPA users with regard to levels of HDL (35 mg/dL or less) and the LDL:HDL ratio (more than 3.5). Users of DMPA who discontinued the follow-up portion at 18 months had lower abnormal HDL levels at baseline (12% compared with 22%, P<.05); those who did so at 18 and 30 months had lower abnormal LDL:HDL ratios (18% compared with 8% and 21% compared with 10%, respectively, P<.05).
Of the 240 initial DMPA users, 182 discontinued this method, 68 of whom remained in the study for up to 2 additional years to participate in the reversibility portion of the study. There were no differences in baseline characteristics between DMPA users who remained in the study (n=68) and those who did not (n=114) with regard to age, race/ethnicity, height, weight, age at menarche, lifestyle variables, or calcium intake (P>.05). Of the 68 women who were followed after DMPA discontinuation, 44 began OCs and were given the same formulation used in the study; the remaining 24 chose nonhormonal contraception. All procedures were approved by the institutional review board of the University of Texas Medical Branch.
One-way analysis of variance with Bonferroni correction for continuous variables and χ2 test for categorical variables was performed to compare the three contraceptive groups at baseline. We used longitudinal analyses to compare changes in serum lipid levels for each contraceptive method along with their predictors over time. To accommodate the repeated measurements, the data were modeled with the use of a mixed-effects regression procedure (xtmixed module, Stata Corporation, College Station, TX), which allowed us to obtain regression coefficients for various predictors while adjusting for the estimated errors for the repeated measurements. This class of model also allows inclusion of time-dependent covariates and accommodates participants with incomplete data because of variation in number and spacing in observations over the period of follow-up, which frequently occurs in longitudinal studies. The primary outcomes were serum lipid levels and the LDL:HDL ratio. To examine the overall effect of method, race, and time, our models included contraceptive method (OC/DMPA/nonhormonal contraception), race/ethnicity, and duration of contraceptive use (time) as main effects after adjusting for other covariates. Interaction terms (method×race/ethnicity; method×time) then were included in the model. Age, age at menarche, parity, previous use of OCs and DMPA, and lifestyle variables (smoking, alcohol use, and physical activity) were included as fixed covariates. The effect of socioeconomic variables (such as income, education, marital status, and previous breastfeeding) also was examined and retained if found to be statistically significant. Similar mixed models also were constructed to estimate the changes in serum lipids and the LDL:HDL ratio after discontinuation of DMPA. Separate mixed models were constructed to examine the effect of appetite change and daily intake of protein, fat, carbohydrates, and total calories (based on 12-month follow-up data) on serum lipid levels and the LDL:HDL ratio.
Generalized estimating equations models23 also were constructed to examine the risk of abnormal serum lipid levels and the LDL:HDL ratio by contraceptive method after adjusting for baseline status. This method can be considered a linear regression technique, which models repeated effects for individual study participants over time. Each model allowed us to estimate odds ratios for the predictors while adjusting for the estimated errors due to repeated measurements. All analyses were performed using Stata 10 (Stata Corporation, College Station, TX).
The mean age of the entire sample was 24±5 years. Twenty-nine percent of the sample (n=200) was non-Hispanic African American, 36% (n=256) Hispanic (predominately Mexican American), and 35% (n=247) non-Hispanic white. The number of women in each racial/ethnic group and in each age category (16–24 years and 25–33 years) did not differ significantly by contraceptive method (Table 1). Furthermore, there were no significant differences among contraceptive groups in baseline height, weight, body mass index, total fat mass, percent body fat, age at menarche, previous use of OCs, or amount of alcohol use or weight-bearing exercise (Table 1). Nonhormonal-contraceptive users did have a higher mean parity, OC users were less likely to have used DMPA in the past, and DMPA users were more likely to smoke. Furthermore, DMPA users had higher serum levels of total cholesterol and LDL than did nonhormonal-contraceptive users at baseline. The LDL:HDL ratio was lower among women who used hormonal contraception than among those who used nonhormonal contraceptives as well. These baseline differences were controlled in the multivariable models.
Over the 3 years of study duration, OC users experienced increases in levels of triglycerides, total cholesterol, VLDL, and HDL that were greater than those experienced by nonhormonal-contraceptive users (P<.001, Fig. 1). The patterns differed somewhat by the type of assay. Triglycerides, VLDL, and HDL all steadily increased over the 36 months of study duration, although the greatest increase occurred during the first 6 months of OC use. Total cholesterol levels increased during the first 6 months of OC use but then leveled off. In contrast, nonhormonal-contraceptive users exhibited little change in their triglyceride and total cholesterol levels over the 36 months. The LDL levels of OC users increased initially from 107 to 112 mg/dL between baseline and 6 months but then fell to 104 mg/dL by 36 months. This change differed from that observed in LDL levels among nonhormonal-contraceptive users, who experienced a large decrease during the same time period (113 to 100 mg/dL, P<.002). Over the 3 years, OC users were more likely than nonhormonal-contraceptive users to demonstrate abnormal levels of triglycerides, total cholesterol, and LDL (Table 2). No differences were observed between DMPA and nonhormonal-contraceptive users in triglycerides, total cholesterol, LDL, or VLDL levels.
With regard to changes noted among DMPA users, mean HDL levels dropped from 45 mg/dL at baseline to 41 mg/dL at the 6-month visit but then steadily rose over the remainder of the follow-up period. By 36 months, the level had increased to its baseline value. Nonhormonal-contraceptive users demonstrated an increase of 45 to 51 mg/dL over 36 months, which was different when compared with DMPA and OC users (P<.001). Furthermore, DMPA users were 2.5 times more likely than nonhormonal-contraceptive users to demonstrate a level of HDL of 35 mg/dL or less over the 36 months of the study period. In contrast, OC use was protective against developing an abnormally low HDL level (Table 2).
Calculation of the LDL:HDL ratio demonstrated a decrease in all three contraceptive groups over 36 months. Users of DMPA demonstrated an initial increase in this ratio at 6 months (2.4 to 2.6 mg/dL) followed by a drop back to baseline over the next 18–24 months. By the 36-month visit, the ratio had dropped further to 2.3 mg/dL. This decrease was less than that observed among nonhormonal-contraceptive users over the 36-month interval (2.6 to 2.1 mg/dL, P<.001). Overall, those who chose DMPA were 2.4 times more likely than nonhormonal-contraceptive users to demonstrate an abnormally high ratio of more than 3.5 over the 36 months. In contrast, OC users experienced a greater decrease in their LDL:HDL ratio than did nonhormonal-contraceptive users (P<.001).
Percentage of body fat and race both affected the lipid profile regardless of contraceptive method. White and Hispanic women had higher levels of triglycerides, total cholesterol, LDL, and VLDL and lower HDL levels than did African-American women. Body fat also had an adverse effect on the lipid profile. Irrespective of method, increased parity had a beneficial effect on total cholesterol and LDL but an adverse effect on HDL. Women with abnormal levels at baseline were not at increased risk of adverse changes to their lipid profiles as a result of using these contraceptives. Changes in appetite, total caloric intake, and amount of protein, fat, and carbohydrates consumed per day did not predict any changes in serum lipid level or LDL:HDL ratio.
Multivariable analyses were performed on both the entire sample (N=703) and only those who completed all 36 months of follow-up (n=186). The results did not significantly differ when analyses were conducted using only the 186 completers as compared with the entire sample (data not shown).
After DMPA was discontinued, triglyceride, total cholesterol, VLDL, and HDL levels increased more in women who used OCs than in those who chose nonhormonal contraception (P<.05, Fig. 2). The patterns of those who switched from DMPA to OCs were very similar to those observed among OC users during the continuation portion of the study. No differences were observed between OC users and nonhormonal-contraceptive users after DMPA discontinuation in the LDL:HDL ratio.
Third-generation OCs containing norgestimate, desogestrel, or gestodene were designed to minimize adverse effects associated with the androgenic activity of previous OCs, including unfavorable effects on lipid metabolism. A number of studies have confirmed that, since their introduction, their effects on lipids are indeed less than those observed with first-generation and second-generation OCs.24,25 In fact, a comprehensive review of 23 studies on OCs containing desogestrel reports that total cholesterol changes resulting from use of these pills were small.26 Our findings differed somewhat; we observed an increase in total cholesterol of 20 mg/dL after 36 months of use. This variation in findings between our study and those published previously may be explained by differences in methodology. For example, prior studies have not controlled for the time of the menstrual cycle in which lipids were measured as we did. This is problematic because LDL can decline as much as 10–15 mg/dL during the cycle.27 Also, we required a 3-month washout period in which no hormonal contraception was used. This is in contrast to prior studies in which the length of time that women were not exposed to hormonal contraception may not have been adequate to assure that the effect measured was not from prior drug use. Finally, prior studies often compared women using these OCs with those using another formulation rather than with a control group using nonhormonal contraception as we did. These improvements in study methods allowed us to elucidate that use of OCs containing desogestrel can elevate total cholesterol levels.
However, this rise in total cholesterol may not indicate an increased risk of atherosclerosis—we also observed some positive changes among OC users. Our finding that LDL improved by approximately 2% overall is similar to that reported by the above-cited review article of OCs containing desogestrel. Of interest, we noted an even greater drop in LDL among nonhormonal-contraceptive users. The reason for this decrease among women using nonhormonal contraception is unclear, but we do know that, among women using nonhormonal contraception, there was more attrition among those with abnormal LDL levels than among those with normal levels at 12 and 18 months. This did not occur among OC and DMPA users with regard to LDL levels and thus may explain our findings.
Similar to prior reports on third-generation pills,26,28,29 we observed a steady rise over time in HDL levels among OC users. This is due to suppression of hepatic lipase by ethinyl E2, which slows the transport to the liver of HDL-bound cholesterol. Desogestrel is less androgenic than first-generation and second-generation progestins, so it does not counteract the estrogen effects. As a result, the LDL:HDL ratio was lower in OC users than in nonhormonal-contraceptive users over the 36 months of study duration. This is an important finding because the LDL:HDL ratio has been reported to have more prognostic value than either value alone and is especially accurate for predicting coronary heart disease risk among those with elevated triglyceride levels.30 Thus, the changes we observed in the lipid profile with use of this OC may not contribute to an increased risk of atherosclerosis.
With regard to triglycerides, we detected a 43% rise over 36 months among OC users. This is consistent with prior reports that ethinyl E2, the estrogen component of the OC we studied, increases the secretion of triglycerides by the liver. This is not a concern, however, because it has been shown that a rise in estrogen-induced triglycerides does not increase the risk of coronary heart disease when accompanied by a rise in HDL.31
In contrast, we observed that DMPA users were at increased risk of developing an abnormally low HDL level as well as an abnormally high LDL level and an increase in the LDL:HDL ratio. In fact, DMPA users were two to three times more likely than nonhormonal-contraceptive users to develop abnormal values at some point during the 36 months of the study period. However, these adverse effects on serum lipids were temporary, and levels improved over time even if DMPA was continued.
This study has several limitations. First, we did not assign women randomly to a contraceptive method because the three types under study have different efficacies and randomization could have led to unintended pregnancies. Second, data were not available to examine the effects of OC discontinuation on serum lipids. Third, discontinuation rates for all contraceptive methods were high. However, this is common in contraceptive studies because there are many reasons women may choose to change or discontinue their method.32–34 Fourth, too few women were followed after DMPA discontinuation to stratify our analysis by important variables. Finally, we studied only one formulation of OC, so our findings cannot be generalized to other types of OCs with different amounts of estrogen or other progestins. Together, these limitations could affect the overall generalizability of our findings, and selection bias cannot be ruled out.
Overall, we concluded that any adverse effects of DMPA we observed on the lipid profile were temporary and reversible. Consistent with our findings, an international, multicenter, case–control study on hormonal contraception conducted by the World Health Organization concluded that there was little or no increased risk of cardiovascular disease among current users of injectable contraceptives.35 However, one small study did observe arterial impairment using magnetic resonance imaging among women using DMPA for more than 1 year, which suggests that long-term use could increase the risk of cardiovascular disease.36 In addition, a prior study by our research team demonstrated that DMPA may elevate the risk by increasing the percentage of body fat and truncal obesity.37 Additional studies with larger sample sizes are needed to clarify this issue. When counseling women about contraception, efficacy rates and ease of use also must be considered because these may be more critical issues in many cases. In all cases, individualized counseling will determine the best method for each patient.
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