Elsevier

Maturitas

Volume 33, Issue 1, 24 September 1999, Pages 7-36
Maturitas

Reproductive history and cardiovascular disease risk in postmenopausal women: A review of the literature

https://doi.org/10.1016/S0378-5122(99)00038-9Get rights and content

Abstract

Objectives: it is widely believed that oestrogen protects postmenopausal women from cardiovascular disease. It is unknown, however, whether reproductive history, which affects endogenous oestrogen levels during a woman’s life, also influences cardiovascular disease risk in postmenopausal women. We present an overview of the studies which investigate the relationship between reproductive history and risk for cardiovascular disease in women. Methods: we conducted a Medline search of literature pertaining to age at menarche, age at menopause, parity and gravidity, breast-feeding, and length and regularity of the menstrual cycle in relation to cardiovascular diseases. Data extraction and synthesis were performed by comparing odds ratios and relative risks presented or calculated. Results: age at menarche was not found to influence cardiovascular disease risk, while menstrual cycle irregularity was associated with this risk. The studies pertaining to parity presented conflicting results: protection against as well as an increase in the risk of cardiovascular disease were found in parous women. Pregnancy loss appeared to be related to cardiovascular disease risk. Age at menopause proved to be the reproductive factor most clearly related to cardiovascular disease risk. Conclusions: only menstrual cycle irregularity, pregnancy losses, and age at menopause are possibly related to cardiovascular disease risk in postmenopausal women. All reproductive factors need to be studied together in order to assess reproductive history in a proper manner. Research of this kind will be essential if we are to further increase our knowledge regarding the nature of the effects of endogenous oestrogen on cardiovascular disease.

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.

References (75)

  • W. Winkelstein et al.

    Age trend of mortality from coronary artery disease in women and observations on the reproductive patterns of those affected

    Am. Heart J.

    (1964)
  • W. Winkelstein et al.

    Occurrence of pregnancy, abortion and artificial menopause among women with coronary artery disease

    J. Chron. Dis.

    (1958)
  • E. Talbott et al.

    Biologic and psychosocial risk factors of sudden death from coronary heart disease in white women

    Am. J. Cardiol.

    (1977)
  • G.S. Cooper et al.

    Age at natural menopause and mortality

    Ann. Epidemiol.

    (1998)
  • B.K. Jacobsen et al.

    Does age at natural menopause affect mortality from ischemic heart disease?

    J. Clin. Epidemiol.

    (1997)
  • W.B. Kannel et al.

    Menopause and the risk of cardiovascular disease: the Framingham study

    Ann. Intern. Med.

    (1976)
  • T. Gordon et al.

    Menopause and coronary heart disease: the Framingham study

    Ann. Intern. Med.

    (1978)
  • G.A. Colditz et al.

    Menopause and the risk of coronary heart disease in women

    N. Engl. J. Med.

    (1987)
  • N.S. Weiss

    Relationship of menopause to serum cholesterol and arterial blood pressure: the United States’ Health Examination Survey of adults

    Am. J. Epidemiol.

    (1972)
  • M.C. Hjortland et al.

    Some atherogenic concomitants of menopause: the Framingham Study

    Am. J. Epidemiol.

    (1976)
  • Bush TL, Cowan L, Heiss G, Chambliss L, Wallace R. Ovarian function and lipid/lipoprotein levels. Results from the...
  • J.C.M. Witteman et al.

    Increased risk of atherosclerosis in women after the menopause

    BMJ

    (1989)
  • Z. Wu et al.

    Relationship of menopausal status and sex hormones to serum lipids and blood pressure

    Int. J. Epidemiol.

    (1990)
  • K.A. Matthews et al.

    Menopause and risk factors for coronary heart disease

    N. Engl. J. Med.

    (1989)
  • E.C.H. Beresteijn van et al.

    Perimenopausal increase in serum cholesterol. a 10–year longitudinal study

    Am. J. Epidemiol.

    (1993)
  • T.W. Meade et al.

    Antithrombin III and procoagulant activity: sex differences and effects of the menopause

    Br. J. Haematol.

    (1990)
  • D.A.W. Edwards

    Differences in the distribution of subcutenaous fat with sex and maturity

    Clin. Sci.

    (1951)
  • B.W. Walsh et al.

    Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins

    N. Engl. J. Med.

    (1991)
  • A.A. Nabulsi et al.

    Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women

    N. Engl. J. Med.

    (1993)
  • M.R. Adams et al.

    Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone

    Arteriosclerosis

    (1990)
  • J.M. Sullivan et al.

    Postmenopausal estrogen use and coronary atherosclerosis

    Ann. Intern. Med.

    (1988)
  • The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors...
  • S. Hulley et al.

    Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women

    J. Am. Med. Assoc.

    (1998)
  • T.L. Bush et al.

    Cardiovascular mortality and noncontraceptive use of estrogen in women. Results from the Lipid Research Clinics Program Follow-up Study

    Circulation

    (1987)
  • C.D. Venkov et al.

    Identification of authentic estrogen receptor in cultured endothelial cells. A potential mechanism for steroid hormone regulation of endothelial function

    Circulation

    (1996)
  • M.Y. Farhat et al.

    The vascular protective effects of estrogen

    Faseb J.

    (1996)
  • J.K. Williams et al.

    Estrogen modulates responses of atherosclerotic coronary arteries

    Circulation

    (1990)
  • Cited by (94)

    • Association between duration of endogenous estrogen exposure and cardiovascular outcomes: A population – based cohort study

      2019, Life Sciences
      Citation Excerpt :

      Given that serum levels of estrogen (E2) and the expression of its receptors differ between genders, the lower prevalence of CVD in women may be partly explained by higher serum levels of E2 [20]. Contradictory results from several previous studies show that age at menarche, and menopause, parity and gravidity, breast-feeding and menstrual cycle may be considered as influential factors impacting CVD [4,8,15,16,21–26]. However it remains unclear how women's reproductive histories affect cumulative endogenous estrogen levels during their life span [27]; hence it has been suggested that the overall impact of all reproductive factors on CVD risk be investigated in women [15].

    View all citing articles on Scopus
    View full text