Effect of estrogen on endothelial dysfunction in postmenopausal women with diabetes

Treatment with estrogen causes increased release of nitric oxide and this appears to be an important mechanism involved in the cardioprotective effect of estrogen. Previous studies have clearly shown that estrogen has an acute vasodilatory effect. Recently, abnormality of flow mediated endothelial dilation, which is defined as an endothelial dysfunction, has been proposed as an early manifestation of atherogenesis. However, its effect in type 2 diabetes is unknown. Stimulus-provoked endothelium dependent dilatation, using high-resolution external vascular ultrasound, is a useful method in the measurement of endothelial function. The main advantages of this method are that it is completely non-invasive, accurate and reproducible. This classical method for the measurement of endothelial dysfunction, utilizing non-invasive, high-resolution ultrasonography, has some limitations especially in terms of reproducibility. To improve the accuracy and reproducibility of this method, measurements made for this study involved the use of an additional attachment. This device was an ultrasound probe that was attached to the arm of patient. In addition, this study evaluated not only a change in diameter in terms of flow mediated vasodilation, but also initial and peak response times during this test. The aims of this study are: (1) to evaluate the flow mediated peak vasoreactivity (FMD), the lag time from base line to initiation of vasodilation (IRT) and the peak response of endothelial dependent vasodilation in a control group and in young diabetic patients; and (2) to evaluate the effect of estrogen treatment on flow mediated vasodilation in postmenopausal women with diabetes.

Measurements were taken for flow mediated vasodilation (endothelial dependent vasodilation: FMD), endothelial independent vasodilation (EID) and lag time from base line to initial reaction of FMD. The aforementioned non-invasive method and attachment were used. Subjects for the experiment were 12 young people with diabetes (six male and six female, mean age 26.3) and 12 age-matched healthy controls (six male and six female, mean age 25.6). In addition, measurements were taken for FMD, EID and lag time in the brachial artery before and after estrogen supplementation (Premarin 0.625 mg for 7 days). Subjects for the experiment were 16 normal postmenopausal women and 18 age-matched postmenopausal women with type 2 diabetes.

There is no significant difference in BMI (body mass index), mean age, or blood pressure between the control group and the young diabetic group. There were no differences in age, total and LDL cholesterol levels or body mass index between the groups of postmenopausal women (P<0.05). However, the HDL cholesterol level was found to be significantly lower in postmenopausal women with diabetes than in normal postmenopausal women (respectively, a mean+/-SD; 38.95+/-11.96 mg/dl vs. 52.20+/-9.55 mg/dl, P<0.05). The FMD of young diabetic patients is slightly lower than that of age-matched young healthy controls (healthy control: 8.9+/-2.7%, young diabetic patients: 6.3+/-2.1%, P<0.05). There was no difference in endothelial independent vasodilation between the control group and the young diabetic group. The IRT of FMD was significantly shorter in the healthy control group than in the young diabetic group (healthy control: 20.4+/-2.8 s, diabetic group: 29.5+/-5.4 s, P<0.0001). In contrast, the IRT of EID was no different between the two groups. The IRT of FMD showed a significant negative correlation with FMD (r=-0.61, P<0.01) and a significant negative correlation with high-density lipoprotein (HDL) cholesterol (r=-0.68, P<0.0001). The basal endothelium dependent vascular reactivity was significantly decreased in postmenopausal women with diabetes compared with normal postmenopausal women (8.0+/-3.9 vs. 13.7+/-6.2%, P<0.05). Estrogen supplementation increased endothelium dependent vasodilation not only in postmenopausal women with diabetes (from 8.0+/-3.9 to 15.1+/-4.0%, P<0.05) but also in normal postmenopausal women (from 13.7+/-6.2 to 20.1+/-4.7%, P<0.05). In contrast, the responses to sublingual nitroglycerin were comparable between postmenopausal women with diabetes (from 21.1+/-6.0 to 22.1+/-4.1%, P>0.05) and normal postmenopausal women (from 25.8+/-7.8 to 25.2+/-4.5%, P>0.05), both before and after estrogen supplementation.

These findings indicate that in addition to the percentage change in FMD, lag time from base line to initial response time (IRT) of FMD is a good indicator for evaluation of endothelial dysfunction. Also, this new parameter may be a more sensitive parameter for differentiation between the diseased state and the normal state of the endothelium than percentage changes in FMD. In terms of postmenopausal women, endothelial dysfunction was prominent in women with diabetes and was significantly improved by estrogen 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 mellitus.