Primary Prevention of Cardiovascular Disease With HRT

Kate Maclaran; John C Stevenson


Women's Health. 2012;8(1):63-74. 

In This Article

Role of Progestogens

The progestogenic component of HRT appears to influence the cardiovascular effects, although existing data are conflicting. Comparison of the two arms of the WHI study suggests that the addition of MPA may account for the early deleterious outcomes seen in the CEE/MPA arm.[7,29]

Several studies have shown that the cardioprotective effects of estrogen are attenuated following the addition of a progestogen. When examining coronary atheroma in monkeys, CEE alone was associated with a 72% reduction in atheroma; however, there was no difference between the untreated group and those receiving CEE plus MPA.[72] In humans, estradiol was associated with beneficial effects on endothelial function, as assessed by brachial artery flow-mediated vasodilation, but the effect was negated by the addition of MPA.[23] Data using hard clinical end points are limited, although meta-analyses have shown that addition of a progestogen doubled the risk of VTE but had no impact on risk of cerebrovascular disease or CHD.[57]

Progestogens have distinct properties depending on their chemical derivatives and, therefore, different groups exert varying biological effects.

There are limited clinical data comparing the effect of different progestogens as most large RCTs have involved the use of MPA. The divergent metabolic effects of progestogens means these results cannot be expected to apply to other groups of progestogens. For example, HRT containing drosperinone has antihypertensive effects via the antimineralocorticoid properties of drosperinone.[73] Other studies have shown that MPA, but not progesterone, increases the risk of coronary vasospasm in hypercholestrolemic monkeys.[74] The androgenicity of progestogens influences their metabolic effects. Androgenic progestogens (e.g., norgestrel, levonorgestrel and MPA) reverse the HDL-raising effect of estrogen,[75] decrease triglycerides and increase insulin resistance. By contrast, nonandrogenic progestogens, such as dydrogesterone, do not appear to counteract the beneficial effects of estradiol on insulin and lipids.[76] Further studies are needed to better understand the cardiovascular effects of the different progestogens.


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