Primary Prevention of Cardiovascular Disease With HRT

Kate Maclaran; John C Stevenson


Women's Health. 2012;8(1):63-74. 

In This Article

Timing Hypothesis

These findings of differing effects of estrogen on younger, healthy, recently postmenopausal women compared with older women led to the development of the timing hypothesis, initially suggested almost a decade ago.[46] This hypothesis suggests that there is a window of opportunity where HRT may be beneficial for prevention of CVD in younger women, but that in older women, it does not appear to have the same benefits.

Biological plausibility exists to explain the timing hypothesis. Early in the atherosclerotic disease process the beneficial effects of estrogen predominate. However, diseased arteries with advanced atheroma appear to respond less well to estrogen and are, therefore, more vulnerable to the proinflammatory and thrombotic effects.[47] The anti-inflammatory effect of estrogen is somehow blocked by atheroma, either due to downregulation of estrogen receptors in the endothelium due to age or in the plaques themselves.[48] This can result in reduced vasodilatation, increased inflammation and plaque instability, potentially causing a prothrombotic effect in older women with underlying atherosclerosis.

Potential mechanisms through which estradiol may have a negative effect on plaque stability include increasing proinflammatory cyctokine release, stimulation of angiogenesis, inhibition of smooth muscle migration[49] and via the estrogenic effect on matrix metalloproteinases (MMPs). Increased expression of MMPs is associated with plaque rupture and hemorrhage, and MMPs are increased by estradiol, especially at higher doses.[50] Increased MMP levels would only likely cause a deleterious effect in arteries with advanced atheroma and, therefore, although MMP would also be increased in younger women, it would not cause harm.

Although these potentially adverse effects of estrogen have been identified, it has been suggested they are not harmful except when inappropriately high doses of estrogen are used,[51] or in the presence of certain progestogens, particularly MPA, which acts to negate the beneficial effects of estrogen and may cause vasospasm.[49]

The timing hypothesis has been demonstrated in nonhuman primate studies. In a series designed to investigate the effects of postmenopausal estrogen on nonhuman primates, cynomolgus monkeys were divided into three life stages.[46] Group 1 had little or no atherosclerosis prior to oophorectomy. Immediately after oophorectomy they commenced CEE for 30 months and were fed a moderately atherogenic diet. In this group, estrogen given at the time of oophorectomy was associated with a significant reduction in coronary artery atherosclerosis of 70% compared with placebo. Group 2 had moderate atherosclerosis prior to menopause, but again, early use of CEE was associated with 50–70% less atherosclerosis compared with controls. In group 3, however, monkeys with little or no atherosclerosis underwent oophorectomy and were treated with an atherogenic diet for 2 years prior to estrogen treatment. In this group with a delayed start to HRT (equivalent to 6 human years) no difference compared with placebo was observed in amount of atherosclerosis.[46]

In humans, there is an absence of direct testing of the timing hypothesis because, although the WHI showed a trend towards cardioprotection in younger women, it was underpowered to detect a cardiovascular benefit in this age group.[52] However, ongoing postintervention follow-up observed a significant reduction of CHD (HR: 0.59, 95% CI: 0.38–0.90) and total myocardial infarction (HR: 0.54, 95% CI: 0.34–0.86) in younger postmenopausal women.[10]

These findings were in keeping with further analysis of the NHS data, which showed that the cardioprotective nature of estrogen was restricted to those starting HRT near the time of menopause (RR: 0.66, 95% CI: 0.54–0.8), whereas there was no significant reduction in CHD in women initiating therapy at least 10 years after menopause (RR: 0.87, 95% CI: 0.60–1.10).[34] The timing hypothesis may also help explain why secondary prevention studies have failed to show any benefit from HRT.[53]

Further clinical data in support of the timing hypothesis come from an influential randomized, placebo-controlled trial investigating the effect of 2–3 years treatment with HRT on cardiovascular mortality and severity of atherosclerosis in younger postmenopausal women.[54] The study involved 1458 postmenopausal women, with an average age of 55.8 years, who were followed for an average of 9.8 years. HRT (various combinations of estrogen plus progestin) was associated with a 46% reduction in mortality from CVD (HR: 0.54, 95% CI: 0.29–0.98) and significantly reduced aortic calcification.

Salpeter et al. performed a meta-analysis to examine the timing hypothesis in a larger population.[55] They examined 23 RCTs with a total of 39,049 subjects over 191,340 patient years. Subjects were classified into early postmenopause (<10 years postmenopause or <60 years of age) and late postmenopause. Results showed that HRT use was associated with significantly fewer CHD events (myocardial infarction or cardiac death) in the early postmenopausal group (odds ratio [OR] 0.68, 95% CI: 0.48–0.96), but not in older women (OR: 1.03, 95% CI: 0.91–1.16). In older women, HRT was associated with increased events in the year 1 (OR: 1.47, 95% CI: 1.12–1.92), but then reduced events after 2 years (OR: 0.79, 95% CI: 0.67–0.93).

The results of two randomized, placebo-controlled trials will hopefully provide further insight into the timing hypothesis, although both of these studies are examining surrogate markers rather than clinical events. The ELITE study is investigating the effect of oral 17β-estradiol plus vaginal progesterone in two different age groups – those less than 6 years postmenopausal and those more than 10 years.[204] The primary outcome is the rate of change of coronary artery IMT. Unfortunately, the dose of estrogen is the same in both groups, and hence the effect of a lower dose in older women will not be tested. The KEEPS study is investigating the effect of oral CEE or transdermal estradiol plus progesterone in women starting within 3 years of the menopause on carotid artery IMT and coronary artery calcium.[56]


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