Premenopausal atherosclerosis: Setting the stage for later clinical disease


Considering the amount of experimental evidence to show that adequate amounts of endogenous premenopausal estrogen protect a woman from coronary artery disease, there's reason to believe that the hormone should still play an important role in protecting women after menopause.

Most clinicians realize that the leading cause of death among women continues to be coronary artery disease (CAD)-by a large margin. In fact we should probably think of coronary atherosclerosis as a lifelong process, the clinical onset of which varies depending on the presence or absence of specific risk factors. The landmark Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study supported this line of thought, documenting the presence of fatty streaks in adolescents, lesions that only increased as subjects grew older.1

The PDAY study also found that abnormal lipid profiles early in life play a major role in determining the age of onset and extent of atherosclerosis.2 It's important for clinicians caring for women to appreciate the importance of premenopausal atherosclerosis and to understand that appropriate medical interventions can reduce the risk of later clinical disease. Because atherosclerosis begins early in life, it's reasonable to believe that the postmenopausal risk of coronary clinical events is influenced by the degree of coronary artery atherosclerosis already present at the time of menopause.

Atherosclerosis follows a clear-cut sequence of events. The process starts with endothelial dysfunction, which leads to fatty streaks in arterial vessels, which in turn are the precursors to clinically significant lesions. The fatty streak lesions come before the fibrous plaque, developing under the endothelial surface and dominated by fat-laden macrophages (the foam cells). The damaged endothelium expresses cytokines, adhesion molecules, and other inflammatory agents that are involved in the formation of atherosclerotic plaques. The formation of a plaque is initiated by the aggregation and adherence of circulating monocytes (macrophages) to a site on the arterial endothelium, stimulating an inflammatory response. When the monocytes penetrate through the endothelium and enter the intima, they become loaded with lipids and are converted to foam cells. Modification of LDL, especially oxidation, is crucial in this conversion of monocytes to foam cells. The adherence of monocytes to endothelium can be brought on by elevated cholesterol and LDL-cholesterol in the circulation. Most of the cholesterol that accumulates in atherosclerotic plaques is derived from circulating LDL-cholesterol.

There's no question that an abnormal lipid profile contributes to the above sequence of atherosclerotic events, but how much atherosclerosis is present at menopause depends in part on estrogen exposure during the premenopausal years. If estrogen exposure earlier in life is beneficial, it would make sense to continue estrogen exposure in the early postmenopausal years.

Following the failure of secondary prevention trials to show that hormone therapy benefits older women with CAD, several investigators have argued that a healthy endothelium is needed to respond in a positive way to estrogen; that by the time the endothelium of older women has been exposed to excessive atherosclerosis, it is too late for estrogen to exert its beneficial effect. The clinical trial reports make an argument that the optimal approach to postmenopausal HT is to start treatment close to the menopause, avoiding a significant period of exposure to low estrogen levels prior to beginning therapy. This recommendation makes sense if one has an appreciation for the importance of estrogen in the premenopausal years.

What hypoestrogenemia does to premenopausal women

Women with premature ovarian failure are at increased risk for cardiovascular disease.4 In other words, there is an inverse relationship between the risk of cardiovascular disease and the age of menopause.5 Endothelial function in women with premature ovarian failure is impaired, as measured by dilation of the brachial artery in response to blood flow, a response known to be mediated by estrogen-modulated endothelial nitric oxide.6,7 This association between endothelial dysfunction and hypoestrogenemia is reinforced by the fact that HT improves endothelial dysfunction in women with premature ovarian failure.6

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