Primary Prevention of Cardiovascular Disease With HRT

Kate Maclaran; John C Stevenson


Women's Health. 2012;8(1):63-74. 

In This Article

Different Estrogens & Route of Administration

Other than estrogen dose and duration of treatment, several additional factors may influence the cardiovascular effects of HRT. In general, animal studies showing cardiovascular protection with estrogen have mainly used 17β-estradiol, in contrast to RCTs, which have predominantly used CEE. CEE and 17β-estradiol have different metabolic effects and, therefore, may exert different cardiovascular effects. CEE causes a greater rise in triglycerides than orally administered estradiol,[65] and may have differing effects on insulin and glucose metabolism.[11] Several studies have compared oral CEE with transdermal estradiol on surrogate markers of CVD;[66,67] however, these are difficult to interpret as the dose and route of administration may influence results more than type of estrogen.

Few studies have directly compared the effects of different estrogens on clinical events, but a meta-analysis did not find any difference between the effects of CEE and estradiol on risk of coronary events, stroke or VTE.[57] The currently in progress KEEPS study is comparing the effect of CEE with estradiol on surrogate markers of CVD and should provide further information regarding the effect of these different estrogens.[56] However, the doses of estrogen in the oral and transdermal groups are not really equivalent, so the comparison between routes of administration will unfortunately not be strictly valid.

As discussed, route of HRT administration can affect the risk of thrombosis due to effects on the coagulation factors such as protein C, antithrombin and tissue factor pathway inhibitor. By avoiding first-pass hepatic metabolism, the transdermal route avoids these effects on coagulation pathways.

So does the route of administration affect CHD risk? Oral and transdermal therapy results in different metabolic effects. Oral therapy has been shown to reduce LDL and increase HDL more than transdermal, and while oral therapy tends to raise triglycerides, transdermal reduces them.[65] Although both oral and transdermal estradiol reduce fasting glucose and insulin, only oral therapy appears to benefit insulin sensitivity.[17] Furthermore, oral HRT has been shown in large, randomized trials to reduce the incidence of diabetes in postmenopausal women,[68,69] whereas there are only data from a small observational study to show such an effect with transdermal estradiol.[70]

It has been suggested that the pattern of early harm observed in the WHI RCTs may have been due to transient procoagulant effects and abnormal vascular modeling. By potentially avoiding procoagulant activity, transdermal therapy would be expected to have different effects on cardiovascular risk. Unfortunately, minimal data currently exist regarding the impact of route of therapy on CHD risk. A meta-analysis showed no difference in CHD events by route of estrogen, although only a small number of trials used transdermal therapy.[57] Available data would suggest that the dose of estrogen is probably more important than the route of administration on the risk of CHD, whereas both route and estrogen dose can influence stroke and VTE risk.[71]


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