NEW ORLEANS—The effect of estrogen replacement therapy on the vasculature may depend on the timing of its initiation. As reported by Louise D. McCullough, MD, PhD, at the 2008 International Stroke Conference, the evidence for the beneficial effect of estrogen replacement is stronger for coronary end points than for stroke in previous observational trials. It has been suggested that the timing of hormone replacement is critical in determining the effect of hormones on the vasculature.
“There is a lot of evidence coming out now that protective effects of estrogen predominate before vascular damage occurs, so starting right at menopause may be of some use,” said Dr. McCullough, Associate Professor of Neurology and Neuroscience and Director of Stroke Research at the University of Connecticut Health Center in Farmington. In contrast, once atherosclerosis, and thus a proinflammatory state, is established, “[estrogen] is probably going to cause some problems,” she added.
Early Studies of Hormone Therapy
Before the era of randomized controlled studies of hormone therapy, observational studies showed protection from both stroke and coronary artery disease in hormone therapy users. These data were accompanied by preclinical and experimental evidence of the “robust neuroprotective effects in vivo and in vitro,” said Dr. McCullough.
Early randomized controlled clinical trials of hormone therapy in postmenopausal women with established coronary artery disease, however, showed no decline in stroke or total cardiovascular events. To the contrary, there was an early increase with hormone therapy in vascular events, mostly venous thromboembolism. The Estrogen Replacement and Atherosclerosis study, however, found no difference in atherosclerosis progression in women randomized to hormone therapy or placebo.
The Women’s Estrogen for Stroke Trial was the first trial with stroke as a primary end point in women with established cardiovascular disease. To be eligible, postmenopausal women had to have experienced a stroke or transient ischemic attack within 90 days of randomization. The average age of participants was 71. Women randomized to estrogen had an increase in the rate of stroke, disabling stroke, and stroke death. However, Dr. McCullough noted that the dosage of estrogen used in the trial was 1 mg/day, substantially higher than doses traditionally used.
The combined results suggest a “proinflammatory effect of hormone therapy on diseased vessels,” she said. “There is some suggestion that estrogen can reduce events at early stages of atherosclerosis where you have foam cells and macrophage activation, but when you develop atheroma, a fibrous plaque that is a significant complicated lesion, estrogen has a significant proinflammatory effect.”
The Effect of hs-CRP
In healthy women, 70% of the increase in stroke risk occurs in women in the highest quartile of high-sensitivity C-reactive protein (hs-CRP) levels, explained Dr. McCullough. One study of women older than 65 indicated that the relationship between estrogen and inflammation (as measured by CRP) was dose-dependent. Although the women randomized to low-dose estrogen (0.25 mg/day) experienced a decrease in levels of hs-CRP, those randomized to a high dose (1.0 mg/day) demonstrated a 65% increase in hs-CRP that persisted three to four months after terminating estrogen therapy. This finding is important, she said, because many studies of hormone therapy use supraphysiologic doses of estrogen.
Prevention of Cardiovascular Events
The Women’s Health Initiative (WHI) was designed to determine whether hormone therapy might be beneficial for primary prevention of cardiovascular events, as the women enrolled were free of known vascular disease. The portion of WHI that randomized women to estrogen-progestin therapy or placebo was stopped early because of a significant increase in ischemic stroke risk. This was seen in women in all age-groups, independent of how long ago they had entered menopause. The estrogen-only arm of WHI was also stopped early for a similar reason.
However, some researchers pointed out that the average age of women in the trial was between 63 and 64, whereas observational studies that have shown a cardiovascular benefit of estrogen therapy included women treated early in menopause, many of whom were taking hormone therapy for the treatment of hot flashes and other perimenopausal symptoms.
Preclinical studies in monkeys also support the suggestion that timing of initiation may be crucial. Oopherectomized monkeys fed an atherogenic diet do not develop atherosclerosis if started on hormone therapy right after removal of their ovaries, said Dr. McCullough. In contrast, “if you wait before starting on hormones, there’s actually a higher rate of disease,” she continued. “It suggests that estrogen’s protective effects are lost when you have prolonged estrogen deficiency.” Mouse models show a similar loss of beneficial effect of estrogen with a prolonged period of low estrogen.
Dr. McCullough also noted that the route of administration of hormone therapy may be important. Transdermal estrogen, which bypasses the liver, may be less hypercoagulable, she said. Newer studies with venous thromboembolism as an end point suggest that transdermal estrogen does not have the same clotting risk as oral estrogen.