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Oral Contraceptive Use and Hormone Replacement Therapy Are Associated With Microalbuminuria
Taco B. M. Monster, MPharmSc;
Wilbert M. T. Janssen, MD, PhD;
Paul E. de Jong, MD, PhD;
Lolkje T. W. de Jong-van den Berg, MPharmSc, PhD;
for the Prevention of Renal and Vascular End Stage Disease Study Group
Arch Intern Med. 2001;161:2000-2005.
ABSTRACT
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Background Controversy exists regarding the adverse and beneficial effects of oral
contraceptive use and hormone replacement therapy. Microalbuminuria is associated
with increased risk of renal and cardiovascular disease.
Objective To examine the association between oral contraceptive use or hormone
replacement therapy and microalbuminuria.
Methods We performed a case-control study of the baseline data and historical
pharmacy data of 4301 female subjects of the Prevention of Renal and Vascular
End Stage Disease study cohort, aged 28 to 75 years, excluding women who were
pregnant or had type 1 diabetes mellitus. The main outcome measure was microalbuminuria,
defined as a urinary albumin excretion of 30 to 300 mg per 24 hours (recorded
as the mean of two 24-hour urine collections).
Results After adjusting for age, hypertension, diabetes, obesity, hyperlipidemia,
and smoking, the odds ratio (OR) for having microalbuminuria was 1.90 (95%
confidence interval [CI], 1.23-2.93) for premenopausal oral contraceptive
users and 2.05 (95% CI, 1.12-3.77) for postmenopausal hormone replacement
therapy users. The point estimate increased in a dose-dependent fashion, albeit
insignificantly, according to the estrogen content of the oral contraceptives
(<30 µg ethinyl estradiol: OR, 1.11; 95% CI, 0.14-8.56; 30 to <50
µg: OR, 1.83; 95% CI, 1.17-2.87; and 50 µg: OR, 2.72; 95% CI,
0.81-9.08). The OR was greater in oral contraceptives with a second-generation
(OR, 2.04; 95% CI, 1.28-3.25) vs a third-generation progestin (OR, 1.39; 95%
CI, 0.63-3.06). The OR increased with the duration of hormone replacement
therapy ( 5 years, OR, 1.28; 95% CI, 0.37-4.50; >5 years, OR, 2.56; 95%
CI, 1.32-4.97).
Conclusion Regular and long-term oral contraceptive use and hormone replacement
therapy are associated with an increased risk for microalbuminuria and cardiovascular
disease.
INTRODUCTION
HORMONE therapy, defined as treatment with estrogens, progestin, or
a combination of them, is widely used among women of all ages. Premenopausal
oral contraceptive use and postmenopausal hormone replacement therapy are
associated with a risk for cardiovascular diseases. This is the most frequently
reported adverse effect of hormonal oral contraceptives1-3
but is affected by the presence of known risk factors, such as smoking, hypertension,
and diabetes.4-6
Moreover, the incidence of this adverse effect may also be related to the
estrogen and progestin content of the oral contraceptive.1-3,7
Observational data8-11
show a beneficial effect of hormone replacement therapy on cardiovascular
risk factors and mortality rates. Randomized clinical trials, however, do
not support this beneficial role of hormone replacement therapy. The first
randomized controlled trial of the effect of hormone replacement therapy on
cardiovascular disease (Heart and Estrogen/progestin Replacement Study)12 showed that this therapy does not reduce the overall
incidence of coronary heart disease in postmenopausal users with established
coronary disease. Recently, the results of the Estrogen Replacement and Atherosclerosis
study13-14 confirmed these findings.
Microalbuminuria is a marker for early vascular endothelial damage,15 and studies16-19
show that microalbuminuria is associated with an increased cardiovascular
risk in subjects with and without diabetes. We therefore questioned whether
premenopausal and postmenopausal use of hormonal preparations heightened the
risk for microalbuminuria, hypothesizing that measurement of microalbuminuria
might discriminate between women who are and who are not at risk for cardiovascular
events. To that end, we studied the association of oral contraceptive use
and hormone replacement therapy with microalbuminuria in the female subjects
of the Prevention of Renal and Vascular End Stage Disease population, an ongoing
study on the effect of microalbuminuria in the general population.
SUBJECTS AND METHODS
STUDY POPULATION AND DESIGN
We used the data of the Prevention of Renal and Vascular End Stage Disease
cohort, consisting of 8592 subjects, aged 28 to 75 years, from Groningen,
the Netherlands. This group was investigated for the presence of increased
urinary albumin excretion.20 From this study
cohort, only women were included (n = 4301).
The participants completed a questionnaire, from which information was
gathered on menopausal status, duration of oral contraceptive use and hormone
replacement therapy, tobacco use, and whether they were medically treated
for hypertension, hyperlipidemia, or diabetes.
Body weight was measured to the nearest 0.5 kg, using a balance scale
(seca Vogel & Halke GmbH & Co, Hamburg, Germany) after removal of
shoes and heavy clothing. Height was measured to the nearest 0.5 cm using
a statiometer measuring board with right angle. Body mass index was calculated
as weight in kilograms divided by the square of height in meters. In the supine
position, blood pressure in the right arm was measured at 2 visits, every
minute for 10 minutes using an automatic blood pressure monitoring device
(Dinamap XL 9300; Johnson & Johnson, Arlington, Tex). Systolic and diastolic
blood pressure was calculated as the mean of the last 2 measurements at both
visits. At the second visit, fasting blood samples were drawn for direct measurement
of glucose and cholesterol levels. The subjects also provided two 24-hour
urine collections at the second visit.
Plasma glucose, serum cholesterol, and serum and urinary creatinine
levels were recorded based on findings of an automated dry chemistry analyzer
system (Kodak Ectachem; Eastman Kodak, Rochester, NY). Creatinine clearance
was defined as the mean of 2 creatinine clearances, based on 24-hour urinary
creatinine excretion, divided by plasma creatinine. Urinary albumin concentration
was determined by nephelometry (Dade Behring Diagnostics, Marburg, Germany),
with a threshold of 2.3 mg/L and intra- and interassay coefficients of variation
of less than 4.3% and 4.4%, respectively. Leukocyte and erythrocyte counts
of the urine were determined based on urine stick findings. Subjects were
excluded from analysis in cases of erythrocyturia greater than 50 per microliter
or leukocyturia greater than 75 per microliter, or leucocyturia of 75 or more
per microliter and erythrocyturia greater than 5 per microliter.
DEFINITIONS
If subjects reported last menstruating more than 1 year previously or
if using hormone replacement therapy for postmenopausal conditions, they were
classified as postmenopausal, otherwise they were considered premenopausal.
Microalbuminuria was defined as a urinary albumin excretion of 30 to 300 mg
per 24 hours, measured as the mean of two 24-hour urine collections. A urinary
albumin excretion greater than 300 mg per 24 hours was defined as macroalbuminuria.
Hypertension was defined as systolic blood pressure of 160 mm Hg or greater,
diastolic blood pressure of 95 mm Hg or greater, or use of antihypertensive
drugs. Diabetes was defined as having a fasting glucose level of 140.5 mg/dL
or greater ( 7.8 mmol/L), a nonfasting glucose level of 200 mg/dL or greater
(11.1 mmol/L), or use of antidiabetic medication. We also analyzed our
data using current definitions of hypertension (blood pressure, 140/90
mm Hg) and diabetes (fasting glucose, 126.1 mg/dL [7.0 mmol/L]), resulting
in similar findings. A body mass index of 30 or higher was classified as obesity.
Hyperlipidemia was defined as a serum cholesterol level of 308.9 mg/dL or
greater (8.0 mmol/L), or 193.1 mg/dL or greater (5.0 mmol/L) if the
person had suffered a myocardial infarction, or use of lipid-lowering medication.
Subjects were classified as smokers if they reported current smoking or had
stopped smoking less than 1 year previously; otherwise, they were classified
as nonsmokers.
PHARMACY RECORDS
Pharmacy records were collected at community pharmacies. Because Dutch
patients usually register at a single community pharmacy, use of pharmacy
records provides an almost complete listing of a subject's prescribed drugs.21 The pharmacy data contain, among others, the name
of the drug, number of units dispensed, prescribed daily dose, date the drugs
were obtained, and Anatomical Therapeutical Chemical classification code of
the drug. It was determined whether subjects had been dispensed oral contraceptives
or hormone replacement therapy during the year preceding the baseline investigation
with the urine collections. A subject was considered using a drug if she had
at least one prescription for the drug during this year.
Oral contraceptives were defined as preparations containing ethinyl
estradiol and a progestin. They were classified according to their ethinyl
estradiol content in micrograms, as 50, sub-50 (30 to <50), or sub-30 tablets.
Progestins were classified as second generation (levonorgestrel, lynestrenol,
and norethindrone) or third generation (desogestrel, gestodene, and norgestimate).
Hormone replacement therapy was defined as oral preparations containing conjugated
estrogens or estradiol valerate, or transdermal preparations containing estradiol.
Hormone replacement therapy was subdivided into therapies with or without
additional progestin. Vaginal preparations, defined as creams or vaginal tablets
containing estriol or dienestrol, were not considered hormone replacement
therapy.
STATISTICAL ANALYSIS
Analyses were performed using commercially available statistical software
(SPSS version 9.0; SPSS Inc, Chicago, Ill). Continuous data are reported as
mean ± SD. Differences between continuous variables were tested using t tests. Differences in proportions were assessed by  2 and Fisher exact tests. Logistic regression analysis was performed
to determine the association between oral contraceptive use or hormone replacement
therapy and microalbuminuria, using a regression model with variables that
included age; presence of hypertension, obesity, diabetes, or hyperlipidemia;
and smoking status. Odds ratios (ORs) and corresponding 95% confidence intervals
were calculated as approximations of relative risk. P<.05
was considered statistically significant; all P values
were 2-tailed.
RESULTS
Subjects were excluded if they had erythrocyturia or leucocyturia (n
= 360) or macroalbuminuria (n = 39), if they could not be classified as premenopausal
or postmenopausal (n = 205), or if pharmacy data could not be obtained (n
= 392), leaving 3305 subjects for analysis.
The characteristics of women with microalbuminuria, according to their
menopausal status, are shown in Table 1. In women who were premenopausal, oral contraceptive use was significantly
more prevalent in those with microalbuminuria compared with those without.
Microalbuminuria in the premenopausal group was also associated with hypertension,
obesity, and higher creatinine clearance. In women who were postmenopausal,
there was a tendency toward more hormone use in the group with microalbuminuria
compared with those without. Also in the postmenopausal group, those with
microalbuminuria were older and had a higher prevalence of hypertension, diabetes,
obesity, and hyperlipidemia compared with those without microalbuminuria.
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Table 1. Subject Characteristics According to Menopausal Status and
Presence of Microalbuminuria*
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Table 2 shows the characteristics
of subjects, according to menopausal status and oral contraceptive use or
hormone replacement therapy. Premenopausal oral contraceptive users were significantly
younger and had a higher prevalence of microalbuminuria compared with nonusers,
although the cardiovascular risk factors did not differ between the groups.
In women who were postmenopausal, oral contraceptive and hormone replacement
therapy users were significantly younger than nonusers. Interestingly, users
of oral contraceptives (P = .18) and hormone replacement
therapy (P = .40) scored better on most risk factors
associated with microalbuminuria (Table
1), but still had a higher, though nonsignificant, prevalence of
microalbuminuria than nonusers. Creatinine clearance was also higher in women
using oral contraceptives or hormone replacement therapy compared with nonusers.
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Table 2. Subject Characteristics According to Menopausal Status and
Use of Oral Contraceptives (OC) or Hormone Replacement Therapy (HRT)*
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Table 3 gives the crude
ORs for having microalbuminuria, ORs adjusted for age alone, and ORs adjusted
for age, hypertension, diabetes, obesity, hyperlipidemia, and smoking. Adjustment
for age alone and for all factors increased the ORs for microalbuminuria in
premenopausal oral contraceptive users and in postmenopausal hormone replacement
therapy users. Oral contraceptive use and hormone replacement therapy were
independently associated with microalbuminuria. Of the adjustment factors,
age demonstrated the largest effect.
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Table 3. Crude and Adjusted Odds Ratios (ORs) for Microalbuminuria*
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In the premenopausal group using hormone therapy, we calculated ORs
for different estrogen dosages, progestin types, and durations of use (Table 4). There was a tendency toward an
association between microalbuminuria risk and estrogen content in oral contraceptives.
Furthermore, women using oral contraceptives containing second-generation
progestins had a higher risk than users of third-generation progestins. However,
neither the estrogen (P = .25) nor the progestin
(P = .36) difference was statistically significant.
The results were similar for women using oral contraceptives longer than 5
years vs 5 years or less. To determine whether the increased albumin excretion
was related to creatinine clearance, we added this variable to the regression
model. The association of oral contraceptive use with microalbuminuria, however,
did not change after addition of this factor (OR, 1.88; 95% confidence interval,
1.22-2.90).
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Table 4. Adjusted Odds Ratios (ORs) for Microalbuminuria (MA) According
to Different Hormonal Preparations*
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In the postmenopausal group, users of hormone replacement therapy and
oral contraceptives showed an increased OR for having microalbuminuria. Findings
were similar in users of hormone replacement therapy with and without addition
of progestins. Women using hormone replacement therapy for more than 5 years
had a higher risk of having microalbuminuria compared with those using this
therapy for 5 years or less. Use of estrogens or progestins in general was
also associated with microalbuminuria (OR, 2.36; confidence interval, 1.53-3.65).
The association of hormone replacement therapy with microalbuminuria was not
related to higher creatinine clearance; addition of this variable to the regression
model hardly changed the association (OR, 1.99; confidence interval, 1.08-3.67).
COMMENT
This study gives the first epidemiological evidence that the risk for
having microalbuminuria is increased in women using oral contraceptives before
and after menopause, and in women using hormone replacement therapy after
menopause. Because microalbuminuria is an early marker for increased risk
of cardiovascular disease,17-19
users of estrogen preparations may have an increased risk for cardiovascular
morbidity and mortality. The association between oral contraceptive use or
hormone replacement therapy and microalbuminuria is dependent on several factors:
(1) the age of the subject and, for hormone replacement therapy, the number
of years of use; (2) the type of progestin in an oral contraceptive, but not
the addition of a progestin to hormone replacement therapy; and (3) the estrogen
content in the oral contraceptive used.
Our findings regarding the association between oral contraceptive use
and microalbuminuria are in agreement with those of Ribstein et al,22 who found that a group of 57 oral contraceptive users
had a higher prevalence of microalbuminuria compared with a group of 57 matched
nonusers. They also showed this difference to be independent of blood pressure
readings. The finding of an increased risk of microalbuminuria among users
of hormone replacement therapy raises further questions about the cardiovascular
benefits of oral contraceptive use and hormone replacement therapy.13-14 Based on observational studies,8-11 hormone
replacement therapy was reported to be protective against cardiovascular events.
However, the first randomized clinical trial12
failed to show a beneficial effect of estrogens against secondary cardiovascular
events in postmenopausal users. Furthermore, recent investigations in healthy
women who are postmenopausal have shown that hormone replacement therapy is
associated with an impaired procoagulant-anticoagulant balance23
and a rise in C-reactive protein,24 another
marker that is predictive of cardiovascular events in healthy men and women.25
Our observation that duration of hormone replacement therapy longer
than 5 years increases the risk for microalbuminuria is important, because
most observational data are representative of 5 years or less. Differences
in duration of hormone replacement therapy may thus bias the results. The
association between estrogen preparations and microalbuminuria in women, regardless
of menopausal status, remained after adjustment for age, hypertension, diabetes,
obesity, hyperlipidemia, and smoking, factors considered to be associated
with microalbuminuria. It has been suggested that microalbuminuria reflects
generalized vascular endothelial dysfunction.15
However, based on our data, it is not possible to conclude whether there is
a direct effect on the vascular endothelium, or whether it is secondary to
unknown effects of oral contraceptive use or hormone replacement therapy on
vascular endothelial function and structure.23
An alternative explanation is that estrogens induce glomerular hyperfiltration,
which via a greater tubular load of albumin, and perhaps in combination with
an altered tubular albumin handling, could lead to an elevated albumin excretion.
Our data demonstrated that oral contraceptive use and hormone replacement
therapy are associated with an elevated creatinine clearance. This is in agreement
with the data of Ribstein et al.22 It has recently
been shown that, as in persons with diabetes, glomerular filtration rate (measured
as creatinine clearance and using the Cockcroft and Gault formula) is elevated
in subjects without diabetes with microalbuminuria, but more so in subjects
with high-normal urinary albumin excretion (15-30 mg/24 h).20
However, in our study, adjustment for creatinine clearance did not change
the observed association between oral contraceptive use or hormone replacement
therapy and microalbuminuria, making this a less likely explanation.
Our study has several shortcomings. First, it is a cross-sectional analysis
and therefore does not allow us to draw conclusions on a cause and effect
relationship between oral contraceptive use or hormone replacement therapy
and microalbuminuria. A long-term prospective follow-up of our cohort, with
monitoring of pharmacy records, will show whether urinary albumin excretion
increases with continued use of estrogen-containing preparations. Second,
even though we studied 3305 women, of whom 762 used hormonal preparations,
the number of women in the various subgroups, analyzed for effects of different
therapies, was limited. These small numbers and the adjustment for several
confounders prevented us from drawing definite conclusions about the effects
in subgroups. Third, this study was limited to women 28 years and older, rendering
our findings inconclusive regarding younger women. Younger women increasingly
are using newer oral contraceptives, while most oral contraceptive users in
this study used sub-50 oral contraceptive preparations. Therefore, a comparison
between estrogen strengths is hard to make, and the present data do not allow
us to recommend the use of sub-30 vs sub-50 oral contraceptives. Moreover,
older women who are premenopausal are more likely to have used oral contraceptives
longer, although our findings did not suggest that the duration of oral contraceptive
use was significant.
Finally, our finding that second- but not third-generation oral contraceptives
are associated with microalbuminuria is relevant in the debate whether second-generation
progestins should be preferred, because of the greater risk for venous thromboembolism
with the third-generation progestins. A lower risk for microalbuminuria, and
possibly for atherosclerotic events, with the use of third-generation oral
contraceptives6 may outweigh the benefits of
the second-generation ones.
In conclusion, oral contraceptive use either before or after menopause
and hormone replacement therapy after menopause, are associated with microalbuminuria,
a predictor of cardiovascular risk. These data shed new light on the potential
effects of these treatments on cardiovascular morbidity and mortality.
AUTHOR INFORMATION
Accepted for publication February 22, 2001.
This study was supported in part by grant E.013 from the Dutch Kidney
Foundation (Nierstichting Nederland), Bussum, the Netherlands.
We thank Frans Helmerhorst, MD, and Kerry Anne Birbeck, PhD, for critically
reading the manuscript, Marnon Haas, PhD, for doing a literature search, and
the public pharmacies in Groningen, the Netherlands, for helping with the
collection of pharmacy data.
In addition to the authors, the Prevention of Renal and Vascular End
Stage Disease investigators are: University Hospital of Groningen, Groningen,
the Netherlands: Division of Nephrology, Department of Internal Medicine:
Gerjan Navis, MD, Sara-Joan Pinto-Sietsma, MD, Arnold H. Boonstra, MD; Department
of Internal Medicine: Reinold O. B. Gans, MD, Andries J. Smit, MD; Department
of Cardiology: Harry J. G. M. Crijns, MD, Ad J. van Boven, MD. University
of Groningen, Groningen: Department of Clinical Pharmacology: Wiek H. van
Gilst, MD, Dick de Zeeuw, MD, Hans L. Hillege, MD; Department of Social Pharmacy
and Pharmacoepidemiology: Maarten Postma, PhD; Department of Medical Genetics:
Gerard J. te Meerman, PhD. Municipal Health Department, Groningen: Jan Broer,
MD. Julius Center for Patient Oriented Research, University Medical Center,
Utrecht, the Netherlands: Annette A. A. Bak, PhD, Diederick E. Grobbee.
Corresponding author: Lolkje T. W. de Jong–van den Berg, MPharmSc,
PhD, Department of Social Pharmacy and Pharmacoepidemiology, Groningen University
Institute for Drug Exploration, University of Groningen, A Deusinglaan 1,
9713 AV Groningen, the Netherlands (e-mail: L.T.W.de.Jong-van.den.Berg{at}farm.rug.nl).
From the Department of Social Pharmacy and Pharmacoepidemiology (Mr
Monster and Dr de Jong-van den Berg), and Division of Nephrology, Department
of Internal Medicine (Drs Janssen and de Jong), Groningen University Institute
for Drug Exploration, University of Groningen, Groningen, the Netherlands.
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