Reproductive history and cardiovascular disease risk in postmenopausal women: A review of the literature
Introduction
Postmenopausal women seem to be at a higher risk of developing cardiovascular diseases than premenopausal women of approximately the same age [1], [2], [3]. Studies have shown that menopause influences several risk factors of cardiovascular disease. It has been associated with a 2–20% increase in total serum cholesterol and a 2–35% increase in triglycerides, irrespective of the subject’s age [1], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Menopause is furthermore associated with significant increases in the levels of antithrombin III, factor VII, and fibrinogen in plasma [13], [14] as well as an increase in the waist-hip ratio [15], [16].
The most important hormonal change at menopause is the decrease in oestrogen, in particular 17β-oestradiol. This hormone is believed to be responsible for the change in cardiovascular risk factors and cardiovascular morbidity risk. This oestrogen hypothesis is supported by observations that hormone replacement therapy (oestrogen alone or with a progestogen) leads to changes in cardiovascular disease risk factors in experimental animal studies and in studies using human subjects. Hormone replacement therapy increases high-density lipoprotein (HDL) cholestrol levels, decreases low-density lipoprotein (LDL) cholestrol and decreases fibrinogen levels [17], [18], [19]. Studies have shown that the amount of atherosclerosis was decreased after hormonal replacement therapy in both the arteries of monkeys [20] and the coronary arteries of humans [21]. Almost all observational studies have indicated that cardiovascular risk decreased among postmenopausal women using hormone replacement therapy [22]. The first randomized trials on hormone replacement therapy and cardiovascular disease have started [23] and results of the first secondary prevention trial were recently published (HERS) [24]. The relative risk of cardiovascular disease in hormone replacement therapy users after four years of treatment was one compared with nonusers. There was, however, a trend in the last two years of the study showing a decreasing risk in the active treatment group. This trial was conducted in postmenopausal women with coronary heart disease and therefore the results cannot be automatically generalized to healthy women. The biological explanation of a protective effect of oestrogen can be found in the favourable changes in lipoprotein metabolism. This can, however, only partially explain the beneficial effects on atherosclerosis [25]. Although changes in haemostatic factors do occur during hormone replacement therapy use, the effects that haemostasis has on clinical end-points are not clear. The haemostatic changes probably represent the direct effect of oestrogen. Oestrogen also directly affects the vessel wall. Functionally competent oestrogen receptors have been identified in vascular smooth muscle cells and specific binding sites have been demonstrated in the endothelium [26], [27]. Studies involving human subjects as well as those on experimental animals have shown oestrogen administration to directly promote vasodilation, in part by stimulating prostacyclin and nitric oxid syntheses [28], [29], [30].
The loss of ovarian function results in a very low level of 17β-oestradiol in postmenopausal women. Nevertheless, it is possible, that postmenopausal women still benefit from the endogenous 17β-oestradiol produced during their reproductive history, due to the effects it exerted on conventional cardiovascular risk factors. Reproductive events during a woman’s life influence endogenous oestrogen levels. Before menarche, for example, oestrogen levels are very low. During a menstrual cycle they vary considerably, depending on the ovulation and the length of the cycle [31]. Oestrogen levels show a great increase during pregnancy [32] but decrease to almost zero during breast-feeding [33]. After menopause, oestrogen levels are once again low. Given the effects of oestrogen on lipoproteins and other cardiovascular risk factors, it would appear reasonable to expect that the duration of exposure to endogenous oestrogen in premenopausal life (lasting from menarche until menopause) and the level of oestrogen during this period would influence the risk of cardiovascular disease in postmenopausal women.
Postmenopausal women are already known to have a high risk of developing cardiovascular disease. A 50-year-old woman has a 46% lifetime probability of developing cardiovascular disease and a 31% probability of cardiovascular death. Small changes in relative risk can, therefore, cause a substantial change in incidence. In this paper, we present an overview of the studies that investigate the relationship between the reproductive history of postmenopausal women and the risk of developing cardiovascular disease. Age at menarche, menstrual cycle length and regularity, gravidity and parity, number of pregnancy losses, duration of breast-feeding, and age at menopause are the major determinants of a woman’s reproductive history. Past use of oral contraceptives is excluded from this study, because the effects of exogenous oestrogen are not the objective of this review. Furthermore, we will not focus on intermediate endpoints. Each reproductive factor will be presented separately in relation to cardiovascular risk.
Section snippets
Article selection and method of evaluation
We searched the scientific literature for all epidemiological studies pertaining to the relationship between reproductive factors and cardiovascular disease endpoints. The reproductive factors we searched for included age at menarche, menstrual cycle length and regularity, breast-feeding, gravidity, parity, pregnancy losses and age at menopause. Included were all observational studies that involved human subjects and that identified cardiovascular disease or death as an outcome variable and
The epidemiological studies
We reviewed 32 original publications, based on 28 different studies, concerning cardiovascular disease as it relates to reproductive history. A cross-sectional or case-control study design was used in 17 publications (Table 1) and a follow-up design in the remaining 15 (Table 2). Four publications studied age at menarche (Table 3), two menstrual regularity, seven gravidity (i.e. total number of pregnancies) (Table 4), 16 parity (i.e. total number of children) (Table 5), four the number of
Discussion
It is widely believed that oestrogen protects women from cardiovascular disease, because it has a direct effect on vessels and an indirect effect on several risk factors for the disease. It is unknown, however, whether the duration of exposure to endogenous oestrogen and the total amount of endogenous oestrogen to which a woman is exposed during her lifetime influence the risk of cardiovascular disease. It is impossible to measure endogenous oestrogen levels during the premenopausal phase of a
Acknowledgements
This review has been supported by a grant of the Dutch Heart Foundation.
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