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© 1997 American Heart Association, Inc.
Articles |
Effect of 17ß-Estradiol on Plasma Lipids and LDL Oxidation in Postmenopausal Women With Type II Diabetes Mellitus
the Departments of Endocrinology and Metabolic Disease (H.E.B., H.M.J.K.) and Cardiology (A. van der L.), University Hospital Leiden, and Gaubius Laboratory (H.E.B., J.A.G.L., C.K., W. van D., R.B., H.M.G.P.), TNO-PG, Leiden, Netherlands.
Correspondence to Dr Hans M.G. Princen, Gaubius Laboratory, TNO-PG, PO Box 2215, 2301 CE Leiden, Netherlands. E-mail JMG.Princen@PG.TNO.NL.
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Abstract |
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In type II diabetes mellitus the altered hormonal state after menopause may represent an additional cardiovascular risk factor. Estrogen replacement therapy (ERT) is associated with a decreased cardiovascular risk, at least in nondiabetic postmenopausal women. We studied the effect of ERT on plasma lipids and lipoproteins and on LDL oxidation in 40 postmenopausal women with type II diabetes but with minimal vascular complications in a randomized placebo-controlled trial. Twenty patients were treated orally with 2 mg/d micronized 17ß-estradiol and 20 patients with placebo for 6 weeks. Plasma total cholesterol (-6%, P=.04), LDL cholesterol (-16%, P=.0001), and apoB (-11%, P=.001) levels decreased and HDL cholesterol (20%, P=.0001) and apoA-I (14%, P=.0001) levels increased after ERT compared with placebo. Glycated hemoglobin (HbA1c) decreased significantly after ERT (-3%, P=.03), the cholesterol content of the LDL particles decreased (-5%, P=.006), triglyceride content increased (16%, P=.01), and LDL particle size did not change significantly. ERT had no effect on parameters of LDL oxidation. We conclude that plasma levels of HDL cholesterol, apoA-I, LDL cholesterol, apoB, and glycated hemoglobin are improved in postmenopausal women with type II diabetes mellitus after treatment with 17ß-estradiol, indicative of a better metabolic control, and that ERT has no effect on LDL oxidizability.
Key Words: non–insulin-dependent diabetes mellitus • 17ß-estradiol • antioxidant • plasma lipid • LDL oxidation
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Introduction |
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Diabetes mellitus is an important risk factor for cardiovascular disease.1 2 In type II diabetes mellitus, the insulin resistance syndrome is associated with changes in the lipoprotein profile and lipid composition of the lipoprotein particles.3 4 A relative preponderance of small dense LDL particles (subclass pattern B) is also associated with the insulin resistance syndrome5 and with non–insulin-dependent diabetes mellitus.6 7 These risk factors are supposed to participate in the overall process of accelerated atherosclerosis in type II diabetes mellitus and are considered to be responsible for the increased cardiovascular risk.4
Increasing experimental and epidemiological evidence indicates that oxidative processes in vivo, including oxidative modification of LDLs, play an important role in the development of atherosclerosis8 and that these processes may occur more avidly in patients with diabetes mellitus.9 10 11 12 13 Increased oxidative stress in diabetes has been attributed to an enhanced flux of reactive oxygen species generated by auto-oxidative glycation reactions that results in a variety of changes such as glycation, glyco-oxidation, and lipid peroxidation, and ultimately leads to the formation of advanced glycation end products.10 11 14 15 16 These end products have also been reported to initiate lipid peroxidation.11 17
Several lines of evidence suggest that estrogen is an important determinant of cardiovascular risk in women. In large epidemiological studies estrogen use is associated with a reduced cardiovascular morbidity and mortality.18 ERT affects a variety of physiological processes that may in turn affect the risk of coronary atherosclerosis. Well-established risk factors like low HDL and high LDL levels are improved during ERT after menopause in healthy women.19
Estrogens are reported to exert beneficial effects on LDL oxidation parameters in vitro and in cell culture20 21 22 and ex vivo after treatment in nondiabetic postmenopausal women.23 However, data from ex vivo studies are not consistent.23 24 To our knowledge, no information is available about the effect of ERT in type II diabetes mellitus.
The aim of this study was to analyze the effect of ERT in postmenopausal women with type II diabetes mellitus but with minimal vascular complications on plasma lipid and lipoprotein levels and on the susceptibility of LDLs to oxidation ex vivo.
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Methods |
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Patients
Forty postmenopausal women with type II diabetes mellitus were enrolled in the study. Menopause was assumed to be present if the menstrual cycle had stopped for >1 year and was confirmed biochemically by low estradiol levels (<50 pmol/L) and by follicle-stimulating hormone levels >20 IU/L in plasma. Follicle-stimulating hormone levels had to be higher than luteinizing hormone levels. About 25% of the women had undergone hysterectomy. Type II diabetes mellitus was defined as diabetes characterized by a positive C peptide response after glucagon stimulation in the past or by oral hypoglycemics for >1 year without episodes of severe ketoacidotic dysregulation. Patients included in the study were treated with diet, sulfonylureum derivatives, insulin, or a combination of these treatments. Some of the subjects used antihypertensive agents, ie, angiotensin-converting enzyme inhibitors, calcium antagonists, or ß-blockers.
Only patients without abnormal liver function tests, established cardiac disease, or nephrotic syndrome and with a creatinine clearance >50 mL/min were accepted. Patients with other endocrine or metabolic abnormalities, malignant disease, thromboembolic events in the past, alcohol abuse, or use of anticonvulsant therapy, metformin, diuretics or lipid-lowering drugs were excluded.
Study Design
The patients were randomly divided in two groups. The study design was double-blind randomized and placebo controlled. Twenty patients were treated with micronized 17ß-estradiol 2 mg/d PO, and 20 received placebo treatment for 6 weeks. Estradiol intake during the trial was monitored by counting unused pills and by determination of plasma estradiol levels. All participants completed the study. During the intervention they were instructed by a dietitian to adhere to their normal eating habits. Fasting blood samples were taken at baseline and after 6 weeks. Blood was collected in EDTA-containing evacuated tubes (1 mg/mL). The blood to be used for LDL oxidation assays was placed on ice immediately and cooled to 4°C. Plasma was prepared, frozen in liquid nitrogen in small portions (leaving as little empty space in the tubes as possible), and stored at -80°C.25 26 This procedure was completed within 1 hour.
The study was approved by the local committee of medical ethics of the Leiden University Hospital. All patients in this study gave their informed consent.
Analytical Methods
Serum estradiol was determined by using a commercial radioimmunoassay (Pharmos) and follicle-stimulating hormone concentration by an immunofluorimetric method (Pharmacia). Lipoprotein profiles were assessed by using density-gradient ultracentrifugation as modified by Gevers Leuven et al.27 Cholesterol and TG were determined in isolated density-gradient fractions. Cholesterol and TG concentrations were determined enzymatically by using commercially available reagents (CHOD-PAP and GPO-PAP, respectively, Boehringer). ApoA-I and apoB were assessed by using rate immunonephelometry with an automated Beckman Array analyzer (Beckman Instruments).27 Nonesterified FAs were measured by using a NEFAC test (Wako Chemicals GmbH). C peptide concentration was determined by using a radioimmunoassay (Biolab) and HbA1c by high-performance liquid chromatography (Bio-Rad).
LDL size was determined by analyzing 10 µL plasma with 2% to 16% nondenaturing polyacrylamide gradient gel electrophoresis (Isolab-Europe).28 High-molecular-weight standards (Pharmacia) were used with a reference serum. After staining with Sudan Black B, gels were scanned with an LKB 2202 Ultrascan laser densitometer (LKB).
The FA composition of LDLs was determined by using gas-liquid chromatography with a Chrompack gas chromatograph (model 438S) equipped with a CP-Sil88 column (50 mx0.25 mm inner diameter) and a flame ionization detector.26
Preparation and Oxidation of LDLs
The procedure for preparation and lipid peroxidation of LDLs was adapted from the method described by Esterbauer et al29 with major modifications.25 26 Briefly, 2 mL of plasma from each subject that had been frozen and stored at -80°C was rapidly thawed and used for isolation of LDLs by ultracentrifugation at 4°C. To minimize the time between isolation and oxidation, the LDLs were not dialyzed. By omitting dialysis a more stable LDL preparation is obtained that can be stored in the dark at 4°C under nitrogen for several days without affecting resistance time and propagation rate.26 This improves the precision of the method, since each LDL preparation can be oxidized consecutively in triplicate. In a representative experiment, lag time was 90±2 minutes 1 hour after LDL isolation in an LDL preparation that had not been dialyzed; 24 hours after LDL isolation, lag time was 91±3 minutes (n=3). Dialysis under nitrogen for 4 hours (two changes) at 4°C against 1000 vol of an oxygen-free buffer containing 150 mmol/L NaCl and 10 mmol/L sodium phosphate, pH 7.4, resulted in lag times of 52±5 minutes directly after dialysis and 23±4 minutes after storage of these LDLs under nitrogen for 24 hours (n=3). In agreement with these observations, a loss of lipophilic antioxidants during dialysis has been reported.30
The kinetics of the LDL oxidation was followed by continuously monitoring the change of absorbance at 234 nm25 26 29 (Figure
). Absorbance curves of LDL preparations obtained from an equal number of subjects from the placebo and estradiol groups before and at the end of the intervention period were determined in parallel. Each LDL preparation was oxidized in three consecutive oxidation runs on the same day; the values shown for lag time and propagation rate are means of the three values. The intra-assay coefficients of variation for lag time and propagation rate were 2.6% and 3.1%, respectively, upon oxidation of the same LDLs in three consecutive oxidation runs on 1 day.25 26 The interassay coefficients of variation for lag time and propagation rate were 4.9% and 7.4%, respectively, and were obtained by determining the oxidation of LDLs from the same subject prepared on different days. In every oxidation run one reference LDL sample, prepared from a reference plasma stored at -80°C, was used as a control. Oxidation runs with >10% deviation from the mean lag time and propagation rate of former measurements were omitted.25 26 By using this highly standardized method we found no differences in lag times and propagation rates between LDLs prepared from plasma frozen in liquid nitrogen and from freshly collected plasma from the same subject. In addition, no differences in these parameters were found after storage of plasma at -80°C for up to 18 months.25 26 In a representative experiment, the lag time and propagation rate of a reference LDL sample prepared from freshly collected plasma were 91±2 minutes and 8.7±0.3 nmol·mg-1·min-1, respectively (n=5). After freezing of the plasma in liquid nitrogen, storage for 3 hours at -80°C, and rapid thawing at 37°C, these data were 90±3 minutes and 8.8±0.3 nmol·mg-1·min-1 (n=5) upon oxidation in the same oxidation run. After storage of the same plasma for 18 months at -80°C, the lag time and propagation rate were 92±4 minutes and 8.9±0.5 nmol·mg-1·min-1, respectively (n=4 independent oxidations on different days).
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), 300 nmol/L (
), 1 µmol/L (
), 3 µmol/L (
), and 10 µmol/L (
) 17ß-estradiol. A234 indicates absorbance at 234 nm.
In separate experiments, the effect of different concentrations of 17ß-estradiol (Sigma) on LDL oxidation was assessed after addition of the hormone directly to the oxidation assay (Figure
).
Statistical Analysis
Values are presented as mean±SD. To evaluate possible differences between baseline values from estrogen and placebo groups and to compare the effect of treatment on the variables between the two groups, a Mann-Whitney unpaired test was used. Percentage changes were calculated as 100x(posttreatment value-pretreatment value)/pretreatment value). Results were considered significant at P<.05. All data analyses were performed by using the NCSS software package, version 5.01, developed by Dr J.L. Hintze, Kaysville, Utah.
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Results |
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The characteristics of the participants are given in Table 1
. There was no difference in use of antihypertensive agents between the groups (5 patients in the placebo group and 3 in the estradiol group; P=.37). All patients completed the study and showed a good compliance as monitored by pill counts (<3% of the provided pills were returned) and by measurement of plasma estradiol levels. The plasma estradiol concentration in the estradiol group was 294±143 (range, 106 to 670) pmol/L, whereas the estradiol level in the placebo group was <40 pmol/L. Two patients from the estradiol group reported vaginal spotting, for which they were referred to the gynecology department. Otherwise, no adverse effects of intervention were reported.
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Effects of 17ß-Estradiol on Plasma Lipids and Lipoproteins and on Parameters of Metabolic Control
The baseline values of plasma lipid, lipoprotein, and apolipoprotein levels and parameters of metabolic control did not differ between the estradiol and placebo groups (Table 2). Plasma TC decreased significantly in the estradiol compared with the placebo group (-5% versus 1%; P=.04), mainly because of a decrease in LDL-C (-14% versus 2%; P=.0001). HDL-C increased significantly in the estradiol group compared with the placebo group (23% versus 3%; P=.0001). The rise could be attributed to a highly significant increase in the HDL2 subfraction (60% versus 11%; P=.0007). Estradiol therapy was not associated with significant changes in VLDL cholesterol or plasma total TG and VLDL TG concentrations. ApoA-I levels increased (17% versus 3%; P=.0001) and apoB levels decreased (-9% versus 2%; P=.001) after treatment with 17ß-estradiol.
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Plasma nonesterified FAs measured under euglycemic conditions (glucose levels were kept between 5 and 6 mmol/L for >2 hours) and fasting C peptide did not change significantly, although the fasting C peptide level tended to be lower in the estradiol than in the placebo group (Table 2). Another parameter of metabolic control, HbA1c, showed a significant decrease in the estradiol group (-7% versus -4%; P=.03).
Effect of 17ß-Estradiol Treatment on LDL Particle Size and Lipid Composition
Since LDL particle size,31 32 LDL TG content,33 and LDL FA composition34 35 are implicated as important parameters in determining the susceptibility of LDLs to oxidation, these parameters were measured. Treatment with 17ß-estradiol had no effect on LDL particle size (Table 3). 17ß-Estradiol induced a small but significant decrease in LDL-C content (-7% versus -2% after placebo; P=.006) and an increase in LDL TG content (13% versus -3% after placebo; P=.01). No significant changes in total FA content or polyunsaturated and unsaturated (ie, mono- and poly-) FA content in LDLs were found (Table 3).
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Effect of 17ß-Estradiol Treatment on LDL Oxidation
Resistance of LDLs to oxidative modification was assessed by determination of the lag time and propagation rate of the formation of conjugated dienes, which are formed by conversion of polyunsaturated FAs into FA hydroperoxides with conjugated double bonds.25 26 29 The two oxidation parameters, lag time and propagation rate, did not differ significantly between the estradiol and placebo groups after supplementation of postmenopausal women with type II diabetes mellitus in vivo with 17ß-estradiol and measurement ex vivo (Table 4). In contrast, addition of varying concentrations of 17ß-estradiol directly into the assay mixture in vitro showed a dose-dependent prolongation of the resistance time, in agreement with the results of others.20 21 22 Representative oxidation curves are shown in the Figure. Lag time was significantly increased by adding 30 nmol/L 17ß-estradiol, and the maximum rate of oxidation was significantly reduced at 1 µmol/L 17ß-estradiol (Figure and Table 5).
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To find an explanation for the discrepancy between the data obtained after adding 17ß-estradiol to the assay mixture in vitro and those found after supplementation of 17ß-estradiol in vivo, we compared plasma 17ß-estradiol concentrations and 17ß-estradiol content of LDLs with the concentrations added in the oxidation assay. Plasma concentrations of 17ß-estradiol after supplementation in the patients (maximum 0.67 nmol/L) were at least 45-fold lower than the lowest concentration at which prolongation of resistance time was observed when 17ß-estradiol was added directly to the oxidation assay (30 nmol/L). Moreover, <5% of 17ß-estradiol was associated with the LDL particle (data not shown). These data indicate that the concentration of 17ß-estradiol was too low to have a direct effect on copper-mediated LDL oxidation. Our data also exclude an indirect effect of 17ß-estradiol treatment on LDL oxidation.
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Discussion |
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We have shown that treatment with 17ß-estradiol of postmenopausal women with type II diabetes mellitus but without overt signs of vascular disease induced significant improvements in TC, LDL-C, HDL-C, plasma apoA-I and apoB levels, and HbA1c. Data on the decrease of HbA1c after estrogen treatment indicate better metabolic control in the group of women receiving ERT; they will be discussed in more detail elsewhere (H.E. Brussaard, J.A. Gevers Leuven, C. Kluft, H.M.J. Krans, unpublished data, 1994). Despite these beneficial changes, parameters of LDL oxidizability were not influenced by treatment with 17ß-estradiol.
Supplementation of the diabetic postmenopausal women with 17ß-estradiol in this study resulted in beneficial changes in the lipoprotein profile, ie, decreased TC and LDL-C and increased HDL-C levels, especially of the HDL2 subfraction, and changes in the levels of apoA-I and apoB-100, all of which were comparable with those reported in nondiabetic postmenopausal women.36 37 38 39 Notably, plasma TG levels did not differ after ERT in our study, in contrast to the elevation observed after oral estrogen treatment in nondiabetic subjects.36 No changes were found in LDL FA content and composition after ERT, but the cholesterol content of the LDL particle was slightly decreased, and LDL TGs were slightly increased. These changes may be indicative of a smaller, more dense LDL particle. However, no significant change in mean particle size, as assessed by gradient gel electrophoresis, was found after ERT. In general, a reduced mass of large, buoyant LDL particles and a shift toward intermediate-sized LDL subspecies are observed after ERT in healthy postmenopausal women,37 38 whereas no change in LDL size is found in dyslipidemic postmenopausal women.37 To our knowledge no data are available on the effect of ERT in postmenopausal diabetic women. The decreased apoB and LDL-C levels in our study indicate that the total number of LDL particles declined after ERT.
There is growing evidence that high glucose levels may generate reactive oxygen species in diabetic patients10 11 12 13 14 15 16 17 40 that lead to increased oxidative stress, as monitored by increased levels of malondialdehydes41 42 43 in some but not all studies. With respect to LDL oxidation ex vivo in diabetes mellitus, reported data are not consistent. Increased,9 12 44 decreased,45 and unchanged46 LDL oxidizability are reported with no apparent differences between patients with insulin-dependent and non–insulin-dependent diabetes mellitus. The oxidation parameters of LDLs from the diabetic women in our study appeared to be normal. Resistance time and maximum rate of oxidation at baseline in all 40 women did not differ significantly from oxidation parameters of LDLs obtained from a group of 29 healthy women of younger age (35±12 years) and with lower body mass index (24±4 kg/m2) (data not shown). Although the two groups were not matched for age and body mass index, this finding is in agreement with a preliminary report of Dean et al,46 who also found no differences in copper-mediated LDL oxidation between patients with type II diabetes and age- and body weight–matched nondiabetic control subjects. There may be many reasons for the discrepancy between the above-mentioned studies. Different procedures for LDL oxidation were used, and there may be differences in the severity of the secondary diabetic complications. It has been suggested that lipid peroxidation is only present if diabetes is accompanied by micro- or macroangiopathy.10 13 41 43 In nondiabetic patients the susceptibility of LDLs to oxidation is correlated with the severity of atherosclerosis.33 47 48 These data may indicate the necessity of atherosclerotic vascular disease for increased LDL oxidation. The patients in our study had no clinically overt cardiovascular, cerebrovascular, or peripheral occlusive artery disease or nephropathy.
Resistance time and maximum rate of LDL oxidation did not differ between the 17ß-estradiol and placebo groups after treatment. In addition, no changes in oxidation parameters were observed in the groups during the intervention trial, indicating that susceptibility of LDLs to lipid peroxidation remained constant throughout the study. We have shown that 17ß-estradiol added directly into the oxidation assay has antioxidant properties, in agreement with other reports.20 21 22 However, the concentrations at which 17ß-estradiol inhibited LDL oxidation were >30-fold above the physiological levels observed in the blood of premenopausal women (peak level, 1 µmol/L49 ) and levels found in postmenopausal women on ERT. In addition, we found that 17ß-estradiol is almost absent in the LDL particle, since <5% of the hormone was associated with LDLs. These data demonstrate that 17ß-estradiol cannot have a direct effect on and does not have an indirect effect on the susceptibility of LDLs to oxidation ex vivo. We suggest that 17ß-estradiol, due to its relatively low physiological concentrations, will not readily act as an antioxidant in vivo. In agreement with our findings, Guetta et al24 reported no significant increase in lag time using transdermal estradiol in an open-design study in nondiabetic postmenopausal women. In contrast to our findings, Sack et al23 reported an increased lag time after treatment of postmenopausal women with 17ß-estradiol. However, the latter study was not placebo controlled.
We studied the effects of unopposed oral ERT because to our knowledge, no trials with monotherapy have been performed in postmenopausal women with type II diabetes, and we wanted to introduce one variable at a time. It is common practice to prescribe combined therapy to minimize the estrogen-induced risk of endometrial carcinoma in women with an intact uterus. The effects of 17ß-estradiol opposed by a progestogen remain to be established.
In conclusion, this study demonstrates that ERT has no effect on LDL oxidation ex vivo. We suggest that the decrease in LDLs and especially the increase in HDLs may indirectly have a beneficial effect on LDL oxidation in vivo by diminishing the amount of oxidizable material, ie, LDLs, and by enhancing the number of lipid peroxide scavengers, ie, HDLs. HDLs have been shown to inhibit LDL oxidation by acting as a sink for lipid peroxides formed on the LDL particle50 51 52 and by rendering them harmless by enzymes associated with the HDL particle, such as paraoxonase.52 This may form one of the ways by which estrogen supplementation may attenuate cardiovascular risk.
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Acknowledgments |
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This work was supported by the Netherlands Diabetes Foundation, grant No. 92.137. 17ß-Estradiol pills were generously provided by Novo-Nordisk Nederland, Zoeterwoude, Netherlands. We thank Anneke Kramp-van Doorduin for skillful technical assistance.
Received January 29, 1996;
revision received June 20, 1996;
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