Sex-specific risk of cardiovascular disease and cognitive decline: pregnancy and menopause

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Abstract

Understanding the biology of sex differences is integral to personalized medicine. Cardiovascular disease and cognitive decline are two related conditions, with distinct sex differences in morbidity and clinical manifestations, response to treatments, and mortality. Although mortality from all-cause cardiovascular diseases has declined in women over the past five years, due in part to increased educational campaigns regarding the recognition of symptoms and application of treatment guidelines, the mortality in women still exceeds that of men. The physiological basis for these differences requires further research, with particular attention to two physiological conditions which are unique to women and associated with hormonal changes: pregnancy and menopause. Both conditions have the potential to impact life-long cardiovascular risk, including cerebrovascular function and cognition in women. This review draws on epidemiological, translational, clinical, and basic science studies to assess the impact of hypertensive pregnancy disorders on cardiovascular disease and cognitive function later in life, and examines the effects of post-menopausal hormone treatments on cardiovascular risk and cognition in midlife women. We suggest that hypertensive pregnancy disorders and menopause activate vascular components, i.e., vascular endothelium and blood elements, including platelets and leukocytes, to release cell-membrane derived microvesicles that are potential mediators of changes in cerebral blood flow, and may ultimately affect cognition in women as they age. Research into specific sex differences for these disease processes with attention to an individual’s sex chromosomal complement and hormonal status is important and timely.

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Most cited references 214

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An 18-year follow-up of overweight and risk of Alzheimer disease.

Deborah Gustafson, Elisabet Rothenberg, Kaj Blennow … (2003)

Overweight and obesity are epidemic in Western societies and constitute a major public health problem because of adverse effects on vascular health. Vascular factors may play a role in the development of a rapidly growing disease of late life, Alzheimer disease (AD). Using body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), we examined whether overweight is a risk factor for dementia and AD. The relationship between BMI and dementia risk was investigated in a representative cohort of 392 nondemented Swedish adults who were followed up from age 70 to 88 years, with the use of neuropsychiatric, anthropometric, and other measurements. Multivariate Cox proportional hazards regression analyses included BMI, blood pressure, cardiovascular disease, cigarette smoking, socioeconomic status, and treatment for hypertension. During the 18-year follow-up (4184.8 risk-years), 93 participants were diagnosed as having dementia. Women who developed dementia between ages 79 and 88 years were overweight, with a higher average BMI at age 70 years (27.7 vs 25.7; P =.007), 75 years (27.9 vs 25.0; P<.001), and 79 years (26.9 vs 25.1; P =.02) compared with nondemented women. A higher degree of overweight was observed in women who developed AD at 70 years (29.3; P =.009), 75 years (29.6; P<.001), and 79 years (28.2; P =.003) compared with nondemented women. For every 1.0 increase in BMI at age 70 years, AD risk increased by 36%. These associations were not found in men. Overweight is epidemic in Western societies. Our data suggest that overweight at high ages is a risk factor for dementia, particularly AD, in women. This may have profound implications for dementia prevention.

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Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.

Zhao Chen, Simon J McGowan, Andrea LaCroix … (2003)

In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures. To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures. Randomized controlled trial (September 1993-July 2002) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years. Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk. Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction =.54). This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.

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Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.

W A Rocca, J. H. Bower, D. Maraganore … (2007)

There is increasing laboratory evidence for a neuroprotective effect of estrogen; however, the clinical and epidemiologic evidence remains limited and conflicting. We studied the association of oophorectomy performed before the onset of menopause with the risk of subsequent cognitive impairment or dementia. We included all women who underwent unilateral or bilateral oophorectomy before the onset of menopause for a non-cancer indication while residing in Olmsted County, MN, from 1950 through 1987. Each member of the oophorectomy cohort was matched by age to a referent woman from the same population who had not undergone oophorectomy. In total, we studied 813 women with unilateral oophorectomy, 676 women with bilateral oophorectomy, and 1,472 referent women. Women were followed through death or end of study using either direct or proxy interviews. Women who underwent either unilateral or bilateral oophorectomy before the onset of menopause had an increased risk of cognitive impairment or dementia compared to referent women (hazard ratio [HR] = 1.46; 95% CI 1.13 to 1.90; adjusted for education, type of interview, and history of depression). The risk increased with younger age at oophorectomy (test for linear trend; adjusted p < 0.0001). These associations were similar regardless of the indication for the oophorectomy, and for women who underwent unilateral or bilateral oophorectomy considered separately. Both unilateral and bilateral oophorectomy preceding the onset of menopause are associated with an increased risk of cognitive impairment or dementia. The effect is age-dependent and suggests a critical age window for neuroprotection.

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Author and article information

Journal

Journal ID (nlm-ta): Biol Sex Differ

Journal ID (iso-abbrev): Biol Sex Differ

Title: Biology of Sex Differences

Publisher: BioMed Central

ISSN (Electronic): 2042-6410

Publication date Collection: 2013

Publication date (Electronic): 28 March 2013

Volume: 4

Page: 6

Affiliations

[1 ]Departments of Surgery and Physiology and Biomedical Engineering, 200 1st St SW, Rochester, MN 55905, USA

[2 ]Division of Nephrology and Hypertension, 200 1st St SW, Rochester, MN 55905, USA

[3 ]Department of Radiology, 200 1st St SW, Rochester, MN 55905, USA

[4 ]Department of Anesthesiology, 200 1st St SW, Rochester, MN 55905, USA

[5 ]Department of Physiology and Biomedical Engineering, 200 1st St SW, Rochester, MN 55905, USA

[6 ]Department of Health Science Research, Division of Epidemiology, 200 1st St SW, Rochester, MN 55905, USA

[7 ]Department of Internal Medicine, Women’s Health Clinic, 200 1st St SW, Rochester, MN 55905, USA

[8 ]Department of Health Science Research, Division of Epidemiology, and Neurology, College of Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA

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Publisher ID: 2042-6410-4-6

DOI: 10.1186/2042-6410-4-6

PMC ID: 3623746

PubMed ID: 23537114

SO-VID: 0e7674ec-6005-4eaa-8c07-e8014e002df1

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Sex-specific risk of cardiovascular disease and cognitive decline: pregnancy and menopause

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Most cited references 214

An 18-year follow-up of overweight and risk of Alzheimer disease.

Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.

Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.

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