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Diabetes and Depot Medroxyprogesterone Contraception in Navajo Women
Catherine Kim, MD, MPH;
Keith W. Seidel, MD;
Elizabeth A. Begier, MD;
Yeong S. Kwok, MD
Arch Intern Med. 2001;161:1766-1771.
ABSTRACT
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Background Depot medroxyprogesterone acetate contraception is widely used in Navajo
women, a high-risk population for diabetes mellitus. However, depot medroxyprogesterone
may lead to weight gain and independently decrease insulin sensitivity. We
studied the association between depot medroxyprogesterone and development
of diabetes in Navajo women.
Methods We studied Navajo women aged 18 to 50 years who had seen a health care
provider at a Navajo Area Indian Health Service clinic at least once in 1998.
Diabetic cases (n = 284) and nondiabetic controls (n = 570) were matched by
age. Medical records were reviewed to determine contraception use before the
diagnosis date of diabetes.
Results Users of depot medroxyprogesterone were more likely to develop diabetes
than patients who had used combination estrogen-progestin oral contraception
only (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.8-7.9). The excess
risk persisted after adjustment for body mass index (OR, 3.6; 95% CI, 1.6-7.9).
Longer use was associated with greater risk of diabetes. Users of depot medroxyprogesterone
were also more likely to develop diabetes than patients who had never used
hormonal contraception, although excess risk was smaller (OR, 2.4; 95% CI,
1.4-3.6).
Conclusions Depot medroxyprogesterone contraception was associated with a greater
risk of diabetes compared with combination oral contraceptive use only. Risk
was associated with length of use and persisted after adjustment for body
mass index. Additional research is needed for confirmation, but this risk
should be considered in contraceptive choice for women at high risk for diabetes.
INTRODUCTION
SINCE ITS introduction in the 1960s, depot medroxyprogesterone acetate
has been an effective hormonal contraceptive, but results of studies of possible
side effects are inconsistent.1 Some metabolic
studies in populations at low risk for type 2 diabetes mellitus demonstrate
decreased glucose tolerance,2 increased insulin
levels,3 and weight gain1
in depot medroxyprogesterone users, but others show no change in these variables.4-5
Members of the Navajo tribe are at high risk for type 2 diabetes, with
a prevalence of diabetes between 10% and 15% in women aged 20 years and older.6-7 A recent longitudinal study in the
Navajo indicated that depot medroxyprogesterone is associated with weight
gain, a major risk factor for type 2 diabetes mellitus.8
However, depot medroxyprogesterone reduces the number of pregnancies, which
may also be a risk factor for type 2 diabetes.9-10
Therefore, the overall risk of diabetes in Navajo users of depot medroxyprogesterone
is unclear.
Depot medroxyprogesterone was first introduced on the reservation in
1971 through the Indian Health Service (IHS) hospitals and was used on a limited
basis as an alternative contraceptive until formal Food and Drug Administration
approval in 1992. Since approval, depot medroxyprogesterone use has increased
dramatically. Centralized tracking of prescription by patient is not yet available.
However, data from the Navajo Area Supply Service Center, the pharmaceutical
distribution center for all Navajo Indian Health hospitals and clinics, show
that 491 doses of depot medroxyprogesterone were distributed in 1993 and 16 308
doses were distributed in 1997.8
In this study, we determined the risk of diabetes associated with depot
medroxyprogesterone use in Navajo women compared with combination estrogen-progestin
oral contraception (OC), and whether any risk was independent of weight gain.
We chose to focus on the comparison of risk between depot medroxyprogesterone
users and combination OC users, rather than persons who did not use contraception.
We did this because, for most women, the primary choice is between varying
formulations of hormonal contraception. Hormonal contraception is the most
effective method of contraception, with the exception of the intrauterine
device and surgical sterilization, which are not recommended for nulliparous
women.11 In addition, persons who use contraception
tend to be a healthier population than those who do not use contraception.12
SUBJECTS AND METHODS
The Navajo Nation consists of more than 200 000 members and is
located in the southwestern United States in an area roughly the size of West
Virginia.13 The IHS, a branch of the Public
Health Service, provides free medical care for this population and provides
depot medroxyprogesterone contraception along with other types of contraception.
The Navajo Nation Institutional Review Board approved the study.
This case-control study included 854 patients who met the following
criteria: (1) age of 18 to 50 years, (2) membership in the Navajo Nation,
and (3) at least 1 outpatient visit to a health care provider at Gallup Indian
Medical Center, Gallup, NM, or Crownpoint Healthcare Facility, Crownpoint,
NM, between January 1, 1998, and December 31, 1998. We defined cases as eligible patients who had been diagnosed as having type 2
diabetes mellitus by December 31, 1998. We defined controls as eligible patients without a diagnosis of type 2 diabetes, age-matched
to the cases within 12 months. From a list of all eligible patients, cases
were randomly selected, and 2 controls were selected randomly for each case.
Four physicians abstracted a total of 284 cases and 570 controls from clinic
medical records. We performed a power calculation for the primary comparison
of depot medroxyprogesterone with OCs. Assuming that depot medroxyprogesterone
exposure with and without OC exposure was 7%, we calculated that 282 cases
and 564 controls were required to detect an odds ratio of 2 with a 2-sided 
= .05 and ß = 0.20. For the comparison of depot medroxyprogesterone with
no hormonal contraception use, we had a power of 0.55 to detect an odds ratio
of 2.
The information abstracted included most recent weight and height, blood
pressure, hemoglobin A1c level if available, glucose measurement
in the past year in control subjects, gestational history, number of visits
to the clinic, and hormonal and nonhormonal contraceptive history, including
type and date of last use. Contraceptive use was documented up to the date
of diabetes diagnosis for each case and her matched control subjects. Patients
who had ever used depot medroxyprogesterone were grouped together in 1 category.
Patients who had used only combination OC, which included both an estrogen
and a progestogen component, were grouped together in 1 category. Patients
who never used hormonal contraception and patients who had used levonorgestrel
(Norplant; Wyeth-Ayerst Laboratories, Philadelphia, Pa) or progestogen-only
pills were categorized separately.
Categorical variables were compared with  2 and Fisher
exact tests, and continuous variables were compared with t tests. Conditional logistic regression models were built by means
of Stata software14 and constructed according
to Kleinbaum.15 Covariates are displayed in
several stages; the first stage adjusts for age, the second stage adds most
recent body mass index (BMI; calculated as weight in kilograms divided by
the square of height in meters) measurement, the third stage adds parity,
and the fourth stage adds history of gestational diabetes mellitus diagnosed
after contraceptives were given. Data are presented as mean ± SE unless
otherwise indicated.
RESULTS
Demographics of diabetic cases and their controls are described in Table 1. Cases had a higher mean arterial
blood pressure and BMI, and more often had a history of gestational diabetes.
They also had a higher average number of visits in 1998 than nondiabetic subjects.
Number of pregnancies and births did not differ significantly between cases
and controls. About 84% (n = 477) of nondiabetic subjects had a glucose check
in 1998, the majority of which were random glucose determinations with a mean
level of 100 ± 18 mg/dL (5.6 ± 1.0 mmol/L). None of the random
glucose measurements exceeded 200 mg/dL (11.1 mmol/L). The duration of diabetes
was 6.0 ± 4.6 years.
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Table 1. Selected Measures in Patients With Diabetes and Control Subjects*
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Table 2 compares these variables
for patients who used depot medroxyprogesterone with or without combination
contraception vs patients who used combination contraception only and patients
who never used hormonal contraception. Cases were compared with cases, and
controls with controls, to preserve matching characteristics. Among controls,
depot medroxyprogesterone users gave birth to significantly more children
than combination contraception users and those who never used hormonal contraception.
Depot medroxyprogesterone users tended to be younger than patients who never
used hormonal contraception and to more frequently have had a history of gestational
diabetes mellitus. Among cases, no significant differences existed between
depot medroxyprogesterone users and combination users, although depot medroxyprogesterone
users tended to be younger than those who never used hormonal contraception
and to have had bilateral tubal ligations less frequently. Only 5 women used
levonorgestrel for an average of 33 ± 27 months, and 40 women had used
a progestogen-only pill an average of 4.9 ± 4.8 months.
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Table 2. Selected Measures in Depot Medroxyprogesterone Users, Combination
Oral Contraceptive Users, and Subjects Who Never Used Hormonal Contraception*
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The risk of diabetes with any history of depot medroxyprogesterone use
and with varying lengths of depot medroxyprogesterone use compared with combination
OC use only is shown in Table 3.
History of any depot medroxyprogesterone use was associated with roughly a
4-fold increased risk of diabetes when compared with history of combination
OC use only; this risk decreased slightly after adjustment for BMI and after
adjustment for parity, but still persisted. After adjustment for history of
gestational diabetes mellitus diagnosed after contraceptive use, risk increased
slightly.
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Table 3. Odds Ratio of Diabetes and Depot Medroxyprogesterone Acetate
Use, With Respect to Combination Oral Contraceptive Use Only*
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While ever-exposure to depot medroxyprogesterone was not associated
with greater BMI when compared with combination OC use, depot medroxyprogesterone
exposure of 12 months or more was associated with a BMI greater by 3.6 (odds
ratio, 3.6; 95% confidence interval, 0.22-7.1) when compared with combination
OC use only. Duration of depot medroxyprogesterone use in months was associated
with greater BMI when compared with no hormonal contraceptive use; for every
month of use of depot medroxyprogesterone, BMI was greater by approximately
0.1 (odds ratio, 0.12; 95% confidence interval, 0.001-0.24).
Greater risk of diabetes was associated with longer depot medroxyprogesterone
use (Table 3). While use for 3
months or less was not significantly associated with greater risk of diabetes,
risk was greater with longer periods of use. Women who used depot medroxyprogesterone
for 1 year or more had an almost 8-fold increased risk of diabetes compared
with combination OC users. When depot medroxyprogesterone use of 3 months
vs 4 to 11 months vs 12 or more months was compared, greater risk of diabetes
was associated with longer use. When compared with no history of hormonal
contraceptive use, depot medroxyprogesterone was still associated with a doubled
risk of diabetes mellitus (Table 4).
Again, greater risk of diabetes was associated with longer depot medroxyprogesterone
use. The odds ratios were lower than when combination OCs were used as the
reference group.
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Table 4. Odds Ratio of Diabetes and Depot Medroxyprogesterone Acetate
Use, With Respect to No History of Hormonal Contraceptive Use*
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Progestogen-only contraception in the form of a pill or levonorgestrel
was not significantly associated with increased risk of diabetes when compared
with combination OC use, although the study was underpowered with regard to
this type of contraception (odds ratio, 0.87; 95% confidence interval, 0.37-2.1).
When combination OC was compared with no history of any type of hormonal contraception,
there was a trend toward decreased risk of diabetes mellitus, which reached
significance after adjustment for BMI (Table 5).
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Table 5. Odds Ratio of Diabetes and Combination Oral Contraception
Use, With Respect to No History of Hormonal Contraceptive Use*
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COMMENT
We found that, when depot medroxyprogesterone was compared with combination
OC, depot medroxyprogesterone was associated with greater risk of type 2 diabetes
mellitus in Navajo women, and greater risk was associated with longer use.
The association between depot medroxyprogesterone and diabetes was partially
explained by BMI, but persisted after adjustment for BMI.
Our results must be interpreted with caution, as there are several limitations
in design. Because we conducted a clinic-based sampling of cases and controls,
the study patients may not be representative of Navajo women. Although the
IHS provides free health care to Navajo patients, it is possible that Navajo,
even those living on the reservation, receive health care at other facilities.
These patients might have received contraceptives that were not recorded in
their IHS medical record. If this undetected use occurred equally for cases
and controls, it would probably bias our results toward the null hypothesis,
but it may have magnified the association between diabetes and depot medroxyprogesterone
and resulted in selection bias if nondiabetic patients who received contraceptives
elsewhere were a healthier population and outside practitioners were more
likely to prescribe depot medroxyprogesterone than were IHS practitioners.
As a high percentage of diabetic patients may go undiagnosed,16
misclassification bias may have occurred if the nondiabetic control group
actually contained diabetic patients. Although the sensitivity of a random
plasma glucose determination has been found to be only about 50% in other
populations,17 more than 80% of our control
patients had a glucose level in 1998 that was consistent with absence of diabetes.
In addition, this form of bias would also be expected to reduce the association
between diabetes and depot medroxyprogesterone use. The association might
be magnified if depot medroxyprogesterone users were screened more often for
diabetes, resulting in surveillance bias. Depot medroxyprogesterone users
had more visits than did combination OC users in the past year, although number
of visits in the past year is not a good proxy for screening frequency. Depot
medroxyprogesterone users did have urine testing for human chorionic gonadotropin,
but this test does not include a urine glucose measurement.
Our conclusions about the relationship between depot medroxyprogesterone,
diabetes, and BMI are limited by the cross-sectional nature of the BMI measurement.
The most recent measurement was used, and this may not accurately reflect
the weight gain that occurred after initiation of contraceptive use. Therefore,
although depot medroxyprogesterone use has been associated with weight gain
in a longitudinal study of Navajo women,8 our
statistical adjustment for BMI is limited.
Patients with gestational diabetes mellitus are at high risk for developing
type 2 diabetes, and patients who used depot medroxyprogesterone were significantly
more likely to have a history of gestational diabetes.18
Although the majority were not treated with depot medroxyprogesterone before
diagnosis, our study cannot exclude the possibility that certain patient characteristics
promote the use of depot medroxyprogesterone as opposed to combination OC
use, and that these patient characteristics may be associated with diabetes
mellitus. For example, it is interesting that a reason for depot medroxyprogesterone
use in patients is theoretically poor patient compliance.19
In our study, depot medroxyprogesterone users had more children than did combination
contraceptive users, although our results cannot distinguish the chronologic
order of depot medroxyprogesterone and the pregnancies. It is possible that
satisfaction with depot medroxyprogesterone was low, and patients stopped
using contraception and subsequently became pregnant, or that patients who
had more children subsequently chose depot medroxyprogesterone as a method
with easier compliance. However, in their longitudinal study in Navajo women,
Espey and colleagues8 found that depot medroxyprogesterone–associated
weight gain persisted after adjustment for parity.
Patient and provider attitudes toward depot medroxyprogesterone prescription
have not been studied in this population. It is possible that providers perceived
certain patients to be at higher risk for pregnancy, and these characteristics
were also associated with a higher risk for diabetes. For example, patients
unable to use other methods of birth control effectively may have been selected
for depot medroxyprogesterone, but the barrier to using other birth control
could be associated with diabetes. In another scenario, patients who received
depot medroxyprogesterone may have engaged in higher-risk sexual behaviors,
which could be correlated with poor diet and exercise habits, which in turn
put them at higher risk for diabetes mellitus.
The results indicate that depot medroxyprogesterone use may have significant
consequences in Navajo women. While previous studies show variable effects
of depot medroxyprogesterone on glucose tolerance, the populations studied
were at low risk for this complication. The Navajo have a diabetes risk that
is much greater than that of the general population across all age groups.
Although the majority of diabetic patients are older than 50 years, Navajo
women of childbearing age have a 10% risk of having type 2 diabetes.6 This rate is double that for the US population as
a whole.16 Therefore, a drug affecting diabetes
prevalence has a greater effect in this population.
A mechanism explaining an association between diabetes and depot medroxyprogesterone
has not been elucidated. Recent evidence in the Navajo population suggests
that long-term depot medroxyprogesterone use is associated with significant
weight gain in this population. For patients who used depot medroxyprogesterone
for at least 1 year, weight gain was roughly 3 kg greater than in the OC group,
and for patients who used depot medroxyprogesterone for 2 years, weight gain
was 6 kg greater.8 Since the risk of diabetes
increases with BMI,6 depot medroxyprogesterone,
via weight gain and other pathways, may lead to increased risk of diabetes.
Studies of progesterone-only OCs have suggested that the progesterone component
may increase insulin resistance in a dose-dependent fashion apart from weight
gain,20-22 particularly
in populations at high risk for diabetes.18
However, these results are difficult to extrapolate to depot medroxyprogesterone
because of the pharmacokinetics of depot release and varying assays used to
measure it.23 In our study, we found no relationship
between progestogen-only pill contraception and levonorgestrel contraception
and diabetes risk, although length of use of progestogen-only contraception
was relatively short and the number of users of levonorgestrel relatively
small. Similarly, the continuity of the depot medroxyprogesterone dosing regimen
was not significant, but almost all users of multiple doses took their regimen
continuously; it is possible that 4 doses given sequentially have different
diabetogenic potential than 4 interrupted doses.
Risk of diabetes associated with depot medroxyprogesterone use was greater
when compared with risk associated with combination OC use than when compared
with risk associated with no hormonal contraception use. This suggests that
combination OCs may have a protective effect from diabetes, in addition to
depot medroxyprogesterone having a deleterious effect. Previous studies of
populations at low risk for diabetes have not found a protective effect of
OCs.24 Studies of populations at higher risk
for diabetes, such as Latina women with gestational diabetes mellitus, have
found that combination OCs seem to offer a protective effect compared with
other types of progestin-only contraception and do not increase risk of diabetes
compared with nonhormonal contraception.18
Alternatively, the patients taking combination OCs may be a healthier group
at lower risk for developing diabetes.
In Navajo women, a population at high risk for type 2 diabetes mellitus,
depot medroxyprogesterone use is associated with greater risk of diabetes.
However, depot medroxyprogesterone is an effective means of contraception,
and parity may increase risk of diabetes. Therefore, these results must be
interpreted carefully. A longitudinal study design that examines diabetes
incidence and its relationship to hormonal contraception and weight changes
would be useful to confirm the results. Centralized records tracking depot
medroxyprogesterone use would assist in understanding prescription patterns
and ascertaining sources of confounding. In the meantime, patients should
be counseled on the possible increased risk of diabetes-associated depot medroxyprogesterone
and the availability of other types of contraception.
AUTHOR INFORMATION
Accepted for publication January 11, 2001.
Dr Kim was supported by a Robert Wood Johnson Clinical Scholars fellowship.
We thank Alan G. Waxman, MD, of the Gallup Indian Medical Center for
his consultation and Thomas Koepsell, MD, MPH, for his helpful comments on
an earlier draft of the article.
Corresponding author: Catherine Kim, MD, MPH, Robert Wood Johnson
Clinical Scholars Program, Box 357183, University of Washington, Seattle,
WA 98195-7183 (e-mail: cathykim{at}u.washington.edu).
From the Robert Wood Johnson Clinical Scholars Program (Dr Kim) and
Department of Medicine (Dr Kwok), University of Washington, Seattle; and Crownpoint
Healthcare Facility, Crownpoint, NM (Drs Seidel and Begier).
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