Depot medroxyprogesterone acetate is a highly effective, long-acting method of birth control. Use of this contraceptive by young women, however, has been associated with a number of adverse effects, such as irregular menstrual bleeding1–3 and loss of bone mineral density.4–11 It also has been suggested that depot medroxyprogesterone acetate may adversely affect serum glucose and insulin levels. For example, Fahmy12 observed that 20 Egyptian women who used depot medroxyprogesterone acetate for 12 months exhibited increases in their serum glucose levels both in the fasting state and during an oral glucose tolerance test. Additional studies have similarly shown an adverse effect of depot medroxyprogesterone acetate on glucose and insulin levels.12–19 However, others have not shown any effect.15,20,21 Although a number of these previous studies suggest that depot medroxyprogesterone acetate has an adverse effect on glucose–insulin metabolism, the results of all these investigations must be interpreted with caution because they were based on small sample sizes,12,14,15,17,19–21 were cross-sectional,13,18 or had short follow-up intervals.12,15–17,19–21 In addition, most did not include a control group for comparison.12,14–17,19–21 Finally, none took into account the potential effects of obesity, which has been shown to affect insulin and glucose levels.
Similarly, it is not clear whether use of very-low-dose oral contraceptive pills (OCPs) containing desogestrel adversely affect insulin–glucose metabolism. This third-generation progestin has been used in newer birth control pills because it is less androgenic and thus should have less effect on carbohydrate metabolism than previously marketed oral contraceptives. However, most published studies that have evaluated this progestin when used in an OCP containing only 20 micrograms ethinyl estradiol are based on small sample sizes or did not include a control group.22–28 As a result, a recent Cochrane review of interventional studies related to hormonal contraception stated that results are conflicting with regards to the effects of desogestrel on carbohydrate metabolism.29
The purpose of this study was to estimate the effects of depot medroxyprogesterone acetate and an OCP containing 20 micrograms ethinyl estradiol and 0.15 mg desogestrel over 3 years on fasting insulin and glucose levels using longitudinal data with a control group.
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. The methods for the larger study are reported in detail elsewhere.5 Briefly, recruitment was conducted to achieve a sample that was balanced by age group (16–24 years and 25–33 years), race (African American, white, Hispanic), and contraceptive method (nonhormonal, oral contraceptives, and depot medroxyprogesterone acetate injections). Of the 805 women who signed a consent form for the larger study, five withdrew before completing their first visit and 97 were excluded because of 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) regarding age, marital status, parity, or education (all P>.05). Written informed consent was obtained from all participants; parental consent was obtained for participants younger than 18 years of age. All procedures were approved by the Institutional Review Board at the University of Texas Medical Branch at Galveston.
After counseling on the different types of contraception available and their efficacies, women were allowed to select one of three types of birth control: 245 chose oral contraceptive (0.15 mg desogestrel plus 20 micrograms ethinyl estradiol used for 21 days, followed by 2 days of placebo and 5 days of 10 micrograms ethinyl estradiol); 240 chose depot medroxyprogesterone acetate; and 218 chose nonhormonal method. Contraception was dispensed every 3 months. 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.
At each visit, weight was measured with a digital scale accurate to the nearest 0.1 kg while women were wearing light indoor clothing. Height was measured using a wall-mounted stadiometer accurate to the nearest 0.001 m. Body mass index was calculated as weight (kg)/height (m)2. Participants completed questionnaires containing demographic and behavioral measures every 6 months. To obtain estimates of dietary intake, a registered dietician conducted a 24-hour recall interview with each participant. Using food models to estimate portion sizes, nutrient calculations were performed using the Nutrition Data System for Research software. Physical activity was assessed using the Exercise Module of the Behavioral Risk Factor Surveillance System Questionnaire.30 This measure lists 56 common activities that women were asked to report the frequency and duration of up to two activities performed during the past month.
Serum glucose and insulin levels were measured at baseline and every 6 months thereafter for 3 years. All blood samples were collected between 7:00 am and 10:00 am after an overnight fast. Serum insulin assays were performed on the Access immunoassay system using the ultrasensitive insulin chemiluminescent immunoassay and the manufacturer's reagents and calibrators. Serum glucose assays were performed using the VITROS 5.1 FS chemistry system using the manufacturer's reagents and calibrators. Serum glucose level was measured using the VITROS GLU slides, along with the VITROS chemistry products calibrator kit 1. Each slide analyzed 10 microliters of serum using a multi-layered analytical element coated on a polyester support with oxidative coupling, producing a dye. The intensity of the dye was measured by reflective light. Coefficients of variation for serum insulin and glucose levels were 4.0% and 1.5%, respectively, using a single lot of reagents calibrated weekly. Samples were assayed in batches at the University of Texas Medical Branch laboratory after the study was completed between March and November 2009. Participants were not screened for diabetes mellitus at the beginning of the study because this is not part of our protocol for contraceptive care. When conducting the assays at the conclusion of the study, four participants were noted to have a fasting glucose level of 126 mg/dL or higher at baseline indicative of diabetes. Therefore, these four women (three depot medroxyprogesterone acetate users and one oral contraceptive user) were excluded from these analyses on glucose and insulin levels.
One-way analysis of variance with Bonferroni correction for continuous variables and χ2 test for categorical variables were performed to compare the three contraceptive groups at baseline. We used longitudinal analyses to compare changes in blood glucose and serum insulin 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 (Stata, xtmixed module), 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 patients 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 glucose and insulin levels. To examine the overall effect of method, race, and time, our models included contraceptive method (oral contraceptive, depot medroxyprogesterone acetate, or nonhormonal), race or ethnicity, and duration of contraceptive use (time) as main effects after adjusting for other covariates. Interaction terms (method×race or ethnicity; method×time) were then included in the model. Age, parity, previous use of pills and depot medroxyprogesterone acetate, lifestyle variables (smoking, alcohol use, and physical exercise), and socioeconomic variables were also examined and retained if P<.2. Separate mixed models were constructed to examine the effect (adjusted by total calories) of daily intake of protein, fat, and carbohydrates (based on 12-month follow-up data) on glucose and insulin levels. All analyses were performed using Stata 11.
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) was Hispanic (predominately Mexican American), and 35% (n=247) was non-Hispanic white. The number of women in each racial or ethnic group and in each age category (16–24 years and 25–33 years) did not significantly differ by contraceptive method (Table 1). Furthermore, there were no significant differences between contraceptive groups in baseline height, weight, body mass index, total fat mass, percent body fat, age at menarche, previous use of birth control pills, and serum insulin and glucose levels (Table 1). Nonhormonal users did have a higher mean parity, oral contraceptive users were less likely to have used depot medroxyprogesterone acetate in the past, and depot medroxyprogesterone acetate users were more likely to smoke. As previously reported, follow-up data were available for 424, 290, and 182 women at 12, 24, and 36 months, respectively,5 after excluding the four patients with elevated baseline glucose levels.
Over the course of 3 years, depot medroxyprogesterone acetate users experienced increases in levels of glucose and insulin that were greater than those experienced by nonhormonal (P<.001) and oral contraceptive users (P<.05; Table 2, Fig. 1). These patterns differed somewhat by the type of assay. Glucose steadily increased during the first 30 months of depot medroxyprogesterone acetate use, although the greatest increase occurred during the first 6 months (2 mg/dL at 6 months to 3 mg/dL at 30 months). Serum insulin increased approximately 3 units during the first 6 months of depot medroxyprogesterone acetate use and an additional 1 unit during next 12 months but then leveled off. In contrast, nonhormonal and oral contraceptive users exhibited little change in their glucose and insulin levels over the course of the 36 months. Both groups experienced approximately 1 mg/dL increase in their mean glucose level over the course of 36 months. With regard to insulin levels, nonhormonal users experienced less than a 1-unit increase during the 3 years of follow-up, whereas oral contraceptive users had approximately a 2-unit increase. Few participants had abnormal (more than 27 international units/mL) levels of serum insulin (nonhormonal 3, depot medroxyprogesterone acetate 1, oral contraceptive 3) at baseline. Overall, six depot medroxyprogesterone acetate users had an abnormally high level of insulin after 6 months of use and nine participants had an abnormal insulin level after 18 months. However, in the majority of these women, the serum insulin level was noted to be normal at a subsequent visit. Only two depot medroxyprogesterone acetate users (compared with none of the nonhormonal users) were noted to have a normal baseline insulin level that became elevated within 6 months and remained high at subsequent visits.
Body mass index affected both glucose and insulin levels, irrespective of the contraceptive method used. Depot medroxyprogesterone acetate users exhibited a significantly greater increase than did nonhormonal users in glucose and insulin levels with each increase in body mass index category (Fig. 2). Obese depot medroxyprogesterone acetate users had an average increase of 4 units of glucose and 5 units of insulin over the course of 36 months. The respective increase observed in glucose and insulin levels among overweight and normal-weight depot medroxyprogesterone acetate users were 3 units and 3 units, and 2 units and 2 units. However, changes in oral contraceptive and nonhormonal users varied between 0 and 2 units in different weight categories over the course of 36 months. No racial differences were observed with regard to the effect of contraception on glucose and insulin levels. With regard to age, those 25–33 years old had lower insulin levels (1.4 units lower) compared with those 16–24 years old, irrespective of contraceptive method over the course of 36 months. Baseline values also affected results, with women with higher levels of glucose and insulin at baseline more likely to demonstrate higher values after 36 months of contraceptive use. Overall, there was a positive trend of glucose, but not insulin levels, over the course of 36 months. Changes in percentage of calories obtained in the diet from protein, fat, and carbohydrates per day did not predict any changes in glucose or insulin levels. However, total caloric intake was positively associated with insulin levels.
We observed that depot medroxyprogesterone acetate use resulted in slightly higher levels of both glucose and insulin. Furthermore, the magnitude of this increase in insulin and glucose levels was higher among obese depot medroxyprogesterone acetate users compared with obese nonhormonal and oral contraceptive users. Although we did observe an increase, both glucose and insulin levels remained within a normal range for all depot medroxyprogesterone acetate users who exhibited normal levels at baseline. Furthermore, the magnitude of increase in fasting glucose levels we observed is actually less than that reported in some previous studies. For example, in a study of 20 depot medroxyprogesterone acetate users, Fahmy et al12 observed an increase of 10 units of fasting glucose within 12 months of depot medroxyprogesterone acetate use, whereas Vermeulen et al17 observed 7 units within 7 months of use in 20 women. Variation in serum glucose levels between studies may be attributable to differences in sample sizes, baseline characteristics of the participants, study duration, or assay methods.
The mechanism by which depot medroxyprogesterone acetate causes an increase in insulin and glucose levels has yet to be elucidated. One possible mechanism is a compensation for increased insulin resistance. Tuttle et al31 reported increased free fatty acids after a glucose challenge among medroxyprogesterone users, a condition usually associated with insulin resistance.32 A direct stimulation of pancreatic B-cells was also speculated. Other possible mechanisms for depot medroxyprogesterone acetate-associated elevation of insulin-glucose are related to weight gain associated with depot medroxyprogesterone acetate or the glucocorticoid-like activity of progestogen.21
In contrast to previous reports on third-generation OCPs, we observed no differences in fasting insulin and glucose levels between nonhormonal contraception and oral contraceptives after 36 months of use. In fact, third-generation birth control pills containing norgestimate, desogestrel, or gestodene were designed to minimize adverse effects associated with the androgenic activity of oral contraceptives, including unfavorable effects on lipid and carbohydrate metabolism. Since their introduction, several studies have confirmed that their effects on carbohydrate metabolism are less than those observed with first- and second-generation birth control pills.29,33 This study confirms that this formula does not cause significant changes in fasting insulin or glucose levels.
This study has several limitations. First, we did not randomly assign women to a contraceptive method because the three types undergoing study have different efficacies and randomization could have led to unintended pregnancies. Second, we did not have data on glucose or insulin levels during an oral glucose tolerance test, which would have given us a more complete picture of the effect of these contraceptives on glucose metabolism. Finally, we studied only one formulation of oral contraceptive, so our findings cannot be generalized to other types of birth control pills 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.
It is important to remember that the reason women use depot medroxyprogesterone acetate and oral contraceptives is to avoid pregnancy. When counseling women about contraception, the provider and the patient must weigh potential adverse effects of each method against the risk of unintended pregnancy. Overall, we conclude that women receiving depot medroxyprogesterone acetate may experience mild increases in fasting insulin and glucose levels, which are probably not clinically meaningful, and those receiving very-low-dose oral contraceptives with desogestrel will not experience any change in fasting levels. Thus, data from this longitudinal study are reassuring overall regarding the effects of these two contraceptives on insulin–glucose metabolism.
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