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Original Studies |
Diabetes Center, West Glasgow Hospitals National Health Service Trust (M.P., M.S.); and Departments of Medicine and Therapeutics (J.R.P., C.H., M.S., J.M.C.C.), Pathological Biochemistry (N.S.), Medicine (J.R.P., G.D.O.L.), and Obstetrics and Gynecology (M.P., M.-A.L.), University of Glasgow, Glasgow G31 2ER, Scotland
Address all correspondence and requests for reprints to: Dr. Naveed Sattar, University Department of Pathological Biochemistry, Glasgow Royal Infirmary, University National Health Service Trust, Glasgow G31 2ER, Scotland. E-mail: nsattar{at}clinmed.gla.ac.uk
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Abstract |
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Introduction |
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Observational studies, which have included predominantly nondiabetic women, have suggested that postmenopausal hormone replacement therapy (HRT), may reduce the relative risk of heart disease by up to 50% (3). Cardioprotection may arise from effects on one or more of several metabolic pathways relevant to atherogenesis: insulin resistance and glycemic control, lipids and lipoprotein concentrations, and prothrombotic changes (4). Overall, there are very little data regarding HRT and coronary heart disease (CHD) in women with type 2 diabetes, although two recent studies indicate that they may derive similar benefits as nondiabetic women from HRT (5, 6). Interestingly, women with diabetes are less frequently prescribed HRT (7).
To date, short-term studies of the metabolic effects of HRT in women with type 2 diabetes have been encouraging; unopposed estradiol appears to have potentially beneficial effects on lipids, coagulation factors, and insulin sensitivity (8, 9, 10). However, this form of HRT is suitable only for those patients who have undergone hysterectomy. Currently, randomized controlled trials on the metabolic effects of combined HRT preparations in women with type 2 diabetes are lacking.
The aim of the present study was to assess the effect of transdermal estradiol (80-µg patches) in combination with continuous oral norethisterone (1 mg daily) on conventional anthropometric parameters, lipoprotein concentrations, coagulation (fibrinogen, factor VII, and fibrin D dimers), and endothelial factors [tissue plasminogen activator (t-PA), and von Willebrand factor (vWF)] in postmenopausal women with type 2 diabetes.
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Subjects and Methods |
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Laboratory methods
Plasma total cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, and high density lipoprotein (HDL) cholesterol were determined by a modification of the standard Lipid Research Clinics protocol. The intra- and interassay coefficients of variation for all lipid measures were less than 3%. Factor VIIc was determined by a one-stage clotting assay in an ACL-300 Research coagulometer (Instrumentation Laboratories, Warrington, UK), and tPA (Biopool, Stockholm, Sweden), fibrin D dimers (AGEN, Parsippany, NJ), and vWF antigens (DAKO Corp., Copenhagen, Denmark) were measured by enzyme-linked immunosorbent assay techniques. The intraassay coefficients of variation for the hemostatic indexes were all less than 5%.
Statistical analysis
The adequacy of the randomization process was checked by comparing the baseline values in the two groups (unpaired t test or Mann-Whitney U test as appropriate). Differences in changes from baseline between the two treatment groups were compared using t tests if the changes were normally distributed. Baseline values in parameters of interest and in age, smoking status, and diabetes duration were adjusted for using linear regression. Correlation analysis was performed using the Spearman rank correlation. Data are presented as the mean and SD for normally distributed data and as the median and range for data with a nonparametric distribution. Lp(a) data were log transformed before analysis, and the geometric mean and range are presented.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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;
the lipoprotein and thrombotic and endothelial factor results at
baseline and 6 months are given in Tables 2 and 3. The
patients were well matched for all parameters at baseline (data not
shown). In addition, the two groups were well matched for the
proportion of individuals receiving oral hypoglycemic (73% in active
and 71% in placebo groups (remainder treated with diet only)] and
antihypertensive treatments (59% and 57%, respectively).
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No changes in BMI, waist/hip ratio, fasting glucose, or
HbA1c (Table 1
) were detected. In addition, there
were no changes in leptin concentrations (Table 2).
Lipoproteins
Total cholesterol and triglyceride decreased by 8% and 22%, respectively, in those receiving HRT (P < 0.05 relative to placebo, after adjustment for baseline concentrations). There was a trend (P = 0.06) toward a reduction in HDL cholesterol. No changes in VLDL cholesterol, LDL cholesterol, or Lp(a) were detected.
Thrombotic and endothelial factors
Factor VII activity decreased by 16% in the active group relative to the placebo group (P < 0.001). There was also a significant reduction in vWF (P = 0.014) by about 7% in the active group. No changes in fibrinogen, t-PA, or fibrin D dimer were detected. There was no correlation between change in factor VII activity and triglyceride concentration (P > 0.1).
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Discussion |
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Two recent studies examining the metabolic effects of oral unopposed estradiol in women with type 2 diabetes (8, 9, 10) have reported increases in HDL cholesterol of about 20% together with reductions of about 15–25% in LDL cholesterol. Triglyceride concentrations remained unchanged. However, almost the reverse pattern was seen with the preparation used in this study; HDL cholesterol decreased by 8% (P = 0.06), triglyceride decreased by 22% (P = 0.014), and LDL cholesterol was unchanged relative to changes with placebo. The difference in the pattern of results probably reflects a combination of two factors. Firstly, as transdermal estradiol does not undergo hepatic first pass metabolism, effects on liver lipoprotein metabolism are less pronounced. For example, estrogens increase hepatic apolipoprotein AI synthesis (the principal protein in HDL particles) and reduce hepatic lipase activity (the key HDL catabolic pathway) (12). Estrogens also increase hepatic triglyceride synthesis. Secondly, oral norethisterone, an androgenic progestogen, is likely to have generated a net progestogenic/androgenic hepatic effect via hepatic lipase to decrease HDL cholesterol, thus neutralizing the effect of estradiol (12). Oral progestogens and androgens also appear to decrease circulating triglyceride concentrations; although the mechanism is unclear, it is likely that the hepatic ß-oxidation pathway is up-regulated, resulting in a decreased flow of nonesterified fatty acids into hepatic triglyceride assembly and synthesis. A lack of reduction of VLDL cholesterol in parallel with plasma triglyceride suggests a preferential reduction in the triglyceride-rich VLDL subfraction that is known to be elevated in insulin-resistant states such as type 2 diabetes (13).
Overall, the changes in lipid and lipoprotein concentrations with this preparation may be considered balanced or even slightly favorable. On the one hand, a reduction in triglyceride is favorable, because raised triglyceride concentrations (particularly the large triglyceride-rich fraction) are independently linked to CHD risk, particularly in women (14), and can promote endothelial damage, oxidation, and inflammatory changes in the vascular endothelium (15, 16). Against this, a small reduction in HDL cholesterol can be considered undesirable, because this particle is protective by virtue of its role in reverse cholesterol transport and its antioxidative and antiinflammatory effects (17). However, as the decrease in HDL is probably due to increased catabolism and not to a decrease in synthesis, the pathological significance may be minimal.
In contrast to previously reported improvements in glycemic indices during short-term oral estradiol treatment, we did not observe a reduction in HbA1c with the HRT preparation under study. However, the study was powered to detect only a large change in this parameter, and our finding is consistent with a study by Mosnier-Pudar et al. (18), who observed no change in plasma HbA1c or fructosamine after 6 months of unopposed transdermal estradiol therapy in women with diabetes. Interestingly, BMI was stable in this study, whereas it increased in both the above-mentioned studies using oral estradiol (9, 10).
With respect to thrombotic factors, there was a pronounced reduction in factor VII activity (by 16%) attributable to HRT in the present study. Consistent with our results, Kroon et al. noted a reduction in factor VII activity with HRT combining transdermal estradiol and oral medroxyprogesterone acetate (MPA) (10 mg) in healthy women (19). This reduction in factor VII is possibly produced by the oral norethisterone (or MPA) component, as both transdermal estradiol and oral estradiol increase factor VII activity (20). These observations are potentially important, because elevated factor VII coagulation activity has been associated with an increased risk of coronary thrombosis in men (21). To date, factor VII activity in the Heart and Estrogen/Progestin Study (11), which used oral conjugated equine estrogens plus oral MPA, has not been reported. Based on the above observations, one may speculate that an HRT that avoids an increase in factor VII activity, such as the one used in this study, might be more suitable for women with cardiovascular disease and those at high risk, such as women with type 2 diabetes.
The mechanism for the observed reduction in factor VII activity is unclear. One possible mechanism is a secondary effect of reduced triglyceride concentrations, as VLDL particles up-regulate factor VII activity (22). However, although triglyceride and factor VII activity were reduced by similar magnitudes (22% and 16%, respectively), the changes were not correlated. An alternative possible mechanism is a direct progestogenic effect, as MPA has previously been shown to reduce factor VII activity (19). Further studies are required to investigate this possibility.
There were no appreciable effects of the HRT regimen on fibrinogen, D dimers, or t-PA antigen in this study. However, there was a significant reduction in vWF antigen by 7% in the HRT group (P = 0.014). This result together with our previous report (23) of decreased CRP concentrations with the same preparation suggest that the HRT regimen used in this study may have a net antiinflammatory action. In keeping with this possibility, both progestogens and androgens generally display antiinflammatory effects on biological tissues (24, 25). In contrast, oral estrogens appear to display both pro- and antiinflammatory effects (26).
In conclusion, we have shown that HRT comprising continuous transdermal estradiol and oral norethisterone reduces plasma triglyceride and cholesterol concentrations, factor VII activity, and vWF antigen levels in women with type 2 diabetes without concomitant detectable changes in adiposity or glycemic control. These results allied with evidence from recent literature concerning procoagulant and proinflammatory effects of oral estrogen-based HRT suggest that the preparation used in this study may hold particular advantages for women at high risk of cardiovascular disease. Further comparative studies are required to test this hypothesis.
Received May 11, 2000.
Revised November 3, 2000.
Accepted November 22, 2000.
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