Serum lipid parameters show an overall beneficial change on HRT in postmenopausal diabetic women. Unopposed oral estradiol increases HDL-C and reduces LDL-C, whereas the addition of norethisterone may not alter this beneficial effect (132,148). Oral CEE 0.625 mg daily has been shown to reduce total and LDL-Cin women with diabetes, although increasing HDL-C (149). In one study, the increase in HDL-C was less than among nondiabetic women (150). Not all studies have shown an increase in triglycerides with oral CEE (149), although one showed a greater increase among women with diabetes
(150). When MPA is added to the CEE regimen, the beneficial effect on HDL-C is attenuated (149).
Transdermal estradiol combined with oral norethisterone significantly decreases total cholesterol and serum triglycerides without significantly affecting LDL-C and HDL-C
(151). A recent publication from the Third National Health and Nutrition Examination Survey (NHANES III) reported that, although HDL was found to be higher among nondiabetic women who were currently taking HRT than among never users of HRT, this finding was not observed among diabetic women. Total cholesterol and non-HDL-C, however, were significantly lower among diabetic women currently on HRT than among never or previous users. These findings were not observed in non diabetic women (152). This divergent result may indicate differential effects of HRT on lipid metabolism in diabetic compared with nondiabetic women.
Regarding Lp(a), no significant differences were found among the groups studied in the NHANES III survey. However, in a randomized controlled study combined continuous HRT (CEE + MPA) has shown beneficial effects on Lp(a) in postmenopausal women with type 2 diabetes (153). Also, a significant reduction in Lp(a) and triglycerides has been reported following treatment with tibolone (154).
Overall, the use of HRT by women with type 2 diabetes appears to reduce total and LDL-C with variable effects on HDL-C and triglycerides. As a note of caution, diabetic women may already have mild hypertriglyceridemia and this could be exacerbated by HRT. A cross-sectional study reported that nearly 8% of diabetic women currently using HRT had triglyceride levels greater than 400 mg/dL, compared with 0.6% of nondiabetic users (150). Additionally, severe exacerbation of hypertriglyceridemia can result when women with primary familial hypertriglyceridemia are given HRT (155). The researchers advised against using ERT in women with triglyceride levels greater than 750 mg/dL, to avoid pancreatitis (155).
Whether the observed hypertriglyceridemia in diabetic women may be offset by improvement in other risk factors such as HDL and insulin sensitivity with HRT is not known. However, the hypertriglyceridemia associated with ERT/HRT appears to result from an increased production of large, triglyceride-rich, very LDL, which may be less atherogenic than smaller and denser particles (150).
Additionally, it has been argued that the use of progestogens may also offset the unfavorable increase in triglycerides with estrogen. Indeed, a trend toward lower triglycerides with HRT has been reported (156).
Oral HRT preparations, unlike transdermal estrogen, are subject to first-pass metabolism by the liver and the clinical differences in impact on lipid and carbohydrate metabolism may be secondary to this effect (157). Oral preparations were also reported to have a more favorable influence on plasma lipoproteins and HbA1c in diabetic women (158). At the same time, however, oral preparations increase triglycerides which may be detrimental to diabetic women. Thus, it has been recommended that, when oral ERT/HRT is prescribed to diabetic women, triglyceride levels should be monitored before and after treatment. If hypertriglyceridemia occurs or worsens, a transdermal preparation can be substituted.
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