Endothelial dysfunction is the hallmark of diabetes and is regarded as an early manifestation of atherogenesis. In postmenopausal women with diabetes, multiple pathophysiological processes may contribute to endothelial dysfunction. These are diabetes- related, as a result of hyperglycemia and obesity/insulin resistance and menopause-related as a result of loss of the protective effect of estrogen, as discussed earlier.
Despite the importance of the endothelium, there is limited data on the effects of HRT on endothelial dysfunction in postmenopausal women with diabetes. In a recent study comparing healthy and diabetic postmenopausal women, Lim and associates (109) found that, although cutaneous vasodilation was impaired in postmenopausal women, it was able to be improved by HRT in nondiabetic subjects, but the improvement was less apparent in the diabetic cohort. However, the use of HRT in women with diabetes was associated with lower soluble ICAM levels, suggesting an attenuation in endothelial activation. There was a considerable variability in the HRT regimens used in this study and the number of participants small, so the study was unable to ascertain whether a particular form of HRT was superior in terms of improving endothelial function.
In a further study, Lee and associates (162) also confirmed that endothelial dysfunction was prominent in women with diabetes and significantly improved by estrogen (premarin 0.625 mg) but not reversed. These results suggest that other factors, in addition to estrogen deficiency, play a role in endothelial dysfunction in postmenopausal women with diabetes and they cannot be reversed by estrogen therapy alone.
An additional small study examined the vascular effects of CEE (0.625 mg) or placebo for 8 weeks in type 2 diabetic postmenopausal women in a randomized double-blinded, placebo-controlled crossover design. The authors concluded that the effects of estrogen on vascular dilatory function and vascular adhesion molecules were less apparent in type 2 diabetic postmenopausal women, despite a beneficial effect of estrogen on lipoprotein levels (163).
Taken together, the above findings suggest, that in regard to endothelial dysfunction, there is some resistance to HRT in diabetic postmenopausal women compared to healthy postmenopausal women. However, a more recent study challenges this suggestion. Perera and associates (164) examined endothelium-dependent and independent vascular relax ation in a small cohort of postmenopausal women with diabetes before and 6 months after transdermal 17^-estradiol (80 mg twice weekly) in combination with oral nonethisterone (1 mg daily). The authors concluded that this particular HRT regimen had potentially beneficial effects on vascular relaxation. Data were consistent with improvements in endothelial function, vascular smooth muscle function, or both. Abnormal responses to endothelium-independent agonists have been reported in type 2 diabetes by other workers (165) but there have been no previous reports of augmented endothelium-independent responses after HRT in women with or without type 2 diabetes.
Finally, despite evidence for a beneficial effect of HRT on indexes of arterial load and ambulatory BP, previously reported in normal subjects, a recent study reported no change in arterial stiffness and ambulatory BP in a small cohort of diabetic postmenopausal women (166). However, another study reported that ERT or HRT may produce beneficial effects on BP responses to psychological stress and on plasma renin activity in women with type 2 diabetes (167).
It appears, therefore, that data on the effect of HRT on endothelial function in post-menopausal women with diabetes are conflicting but the weight of evidence is that there may be a degree of resistance to HRT in diabetes.
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