- Email: [email protected]
Early Menopause and the Risk of Silent Brain Infarction in Community-Dwelling Elderly Subjects: The Sefuri Brain MRI Study
Early Menopause and the Risk of Silent Brain Infarction in Community-Dwelling Elderly Subjects: The Sefuri Brain MRI Study Kenji Fukuda, MD, PhD,* Yuki Takashima, MD, PhD,† Manabu Hashimoto, MD, PhD,† Akira Uchino, MD, PhD,‡ Takefumi Yuzuriha, MD, PhD,† and Hiroshi Yao, MD, PhD†
Our previous study showed that the male predominance of silent brain infarction (SBI) was largely because of higher prevalence of alcohol habit and smoking in men than in women. In the present study, we further conducted an analysis of brain magnetic resonance imaging findings to examine whether early menopause contributes to SBI in community-dwelling subjects. Women were queried as to the age and cause of menopause, the total number of children, and the age at giving birth to her last child. Among 306 female subjects aged 60 years or older, univariate analysis showed that early menopause (total or natural) was significantly associated with SBI but age at natural menopause, number of children, and age at the last parity were not. In the total of 715 subjects (283 men and 432 women with a mean age of 67.2 years), the forward stepwise method of logistic analysis revealed that natural early menopause (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.07-17.11), in addition to age, hypertension, alcohol intake, and smoking, was a significant factor concerning SBI. Also in the subgroup of female subjects aged 60 years or older, natural early menopause was a significant factor concerning SBI (OR 4.35, 95% CI 1.05-18.08) adjusted for covariates. Although the prevalence of natural early menopause was low (3.3% of 306 female subjects), natural menopause before the age of 40 years may be a risk for SBI or small-vessel disease of the brain. Key Words: Silent stroke—small-vessel disease—menopause—parity—magnetic resonance imaging. Ó 2013 by National Stroke Association
Introduction The morbidity and mortality rates of symptomatic stroke are known to be lower in women than in men with the exception of subarachnoid hemorrhage.1,2 Zhang et al3 analyzed the sex ratios of men to women in stroke mortality using World Health Organization data from 27 populations, which revealed that the male
From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka; †Center for Emotional and Behavioral Disorders, National Hospital Organization Hizen Psychiatric Center, Saga; and ‡Department of Diagnostic Radiology, Saitama Medical University International Medical Center, Saitama, Japan. Received June 5, 2013; revision received July 3, 2013; accepted July 5, 2013.
predominance of stroke mortality decreased with age in many countries. Brain infarction is more common in men: male sex may be a risk factor for symptomatic stroke, whereas premenopausal women appear to be protected from cardiovascular events or stroke.4 Nevertheless, hypertension is a major risk for cardiovascular disease in both women and men, and menopause
Conflicts of interest: The authors declare no conflict of interest. Address correspondence to Hiroshi Yao, MD, Center for Emotional and Behavioral Disorders, National Hospital Organization Hizen Psychiatric Center, Mitsu 160, Yoshinogari, Kanzaki, Saga 842-0192, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.07.005
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escalates such cardiovascular risk factors and, thereby, erodes the female protection against cardiovascular morbidity and mortality.5 Although exogenous estrogen and/ or progesterone increased the risk of stroke,6,7 estrogen has beneficial effects on endothelial function and atherosclerosis in addition to the hormone’s effects on serum lipid concentrations, raising the possibility of sex differences in arterial remodeling.8 In line with this favorable effect of estrogen, early menopause was associated with an increased incidence of ischemic stroke in the Framingham Heart Study.9 With regard to parity, the ability to have children at older age may be a marker for slow aging and extreme longevity.10 On the contrary, Zhang et al11 have found that high gravidity and high parity were associated with a higher risk of ischemic stroke. Our previous study showed the male predominance of silent brain infarction (SBI), which was largely because of higher prevalence of alcohol habit and smoking in men than in women.12 Although early menopause could be a risk factor for stroke or SBI, as has been shown by the Framingham Heart Study,8 yet no study has evaluated the impact of early menopause on the presence of SBI. Therefore, we conducted a population-based, cross-sectional analysis of brain magnetic resonance imaging (MRI) findings to examine whether early menopause contributes to SBI.
Subjects and Methods Between 1997 and 2010, we contacted approximately 1200 inhabitants aged 40 years or older, living in the rural community of Sefuri village, Saga, Japan, through the village office. During this period, a total of 1272 MRI scans were performed for 755 volunteers. These subjects were living independently at home without apparent dementia. A total of 40 cases were excluded because of claustrophobia or contraindications for MRI (n 5 7), a history of stroke (n 5 15), brain tumor (n 5 1), malignant neoplasm (n 5 1), psychiatric disorders including depression (n 5 4), a history of head trauma (n 5 3), and insufficient clinical information (n 5 9). The National Hospital Organization Hizen Psychiatric Center Institutional Review Board approved the study (No. 15-1), and written informed consent was obtained from all subjects. Participants underwent a structured clinical interview, a neurologic examination, general hematology tests, biochemistry tests, and electrocardiograms. Vascular risk factors were defined as previously described.12,13 Briefly, arterial hypertension was considered present if a subject had a history of repeated blood pressure recordings above 140/90 mm Hg or the subject was being treated for hypertension. Diabetes mellitus was defined as fasting plasma glucose greater than 7.77 mmol/L and/ or HbA1c greater than 6.0% or a previous diagnosis of diabetes mellitus. Hyperlipidemia was defined as total serum cholesterol concentration greater than
5.69 mmol/L or if the subject was being treated for hyperlipidemia. We obtained information about usual alcohol intake and type of alcohol consumed from a detailed questionnaire as previously described.12 We defined 1 drink as 10 g of ethanol, calculated as follows: 350 mL beers as 1.4 drinks, 180 mL sake (rice wine) as 2.2 drinks, 180 mL shochu (white spirits) as 3.6 drinks, 60 mL whisky as 2.0 drinks, and 120 mL wine as 1.2 drinks. In the present study, we defined alcohol intake as 1 drink or more per week because the previous study from the same population revealed that even light drinkers had the similar risk for SBI as moderate drinkers. Former drinkers were considered nondrinker in the present study. Smoking was defined as present if the subject smoked at least an average of 10 cigarettes per day.
Menopause and SBI in Women Aged 60 Years or Older We asked all the female participants about items given subsequently using a questionnaire and analyzed potential risk factors for SBI in 306 women aged 60 years or older in relation to age at menopause and parity. Natural menopause was considered to occur if a woman had ceased menstruating naturally for at least 1 year. Age at natural menopause was the self-reported age at last menstrual period. Early menopause was defined as menopause before age 40. Women were also queried as to the cause of menopause (natural, surgical, or other), whether a hysterectomy was performed, number of ovaries removed, the use of hormone replacement therapy, the total number of children, and the age at giving birth to her last child.
Assessment of MRI Findings The combination of T1-weighted image (T1WI), T2weighted image (T2WI), and fluid-attenuated inversion recovery image is required to accurately detect both SBI and white matter lesions.14 Therefore, T1WI (repetition time [TR]/echo time [TE] 5 510/12 msec), T2WI (TR/ TE 5 4300/110 msec), and fluid-attenuated inversion recovery (TR/inversion time/TE 5 6750/1600/22 msec) images were obtained with a slice thickness of 6 mm with a 1-mm interslice gap with an MRI (1.0 T, Shimadzu Magnex XP, Kyoto, Japan). SBI was shown as low signal intensities on T1WI and high signal intensities on T2WI, and their size was 5 mm or larger. We differentiated enlarged perivascular spaces from SBI on the basis of their location, shape, and size.15 The white matter lesions were defined as isointense with normal brain parenchyma on T1WI and high signal intensity areas on T2WI and were classified into deep white matter lesions and periventricular hyperintensities.16
Statistical Analysis Summary statistics of clinical variables were given as median with interquartile range. For the univariate
EARLY MENOPAUSE AND SBI
analysis, the nonparametric Mann–Whitney U test for continuous variables and the chi-square test or Fishers exact test for categorical variables were used to investigate differences between groups. We chose the variables for entry into the multivariate analysis based on the clinical and neuroradiologic findings after univariate testing. Multivariate analysis was done using the forward stepwise method of logistic regression analysis. A significance level of .05 was used in all analyses. The data were analyzed with the IBM SPSS Statistics 18 software for Windows (SPSS Japan, Inc.).
Results In the 715 subjects (283 men and 432 women with a mean age of 67.2 years), SBI, deep white matter lesions, and periventricular hyperintensities were detected in 89 (12.4%), 241 (33.7%), and 154 (21.5%), respectively. The prevalence of SBI was more frequent in men (44 of 283 subjects [15.5%]) than in women (45 of 432 subjects [10.4%]). Of 89 subjects with SBI, 53 subjects (59.6%) had a single lacune. There were a total of 162 lacunes in 89 subjects: 81 were located in the basal ganglia, 21 in the thalamus, 47 in the corona radiata, 5 in the cerebellum, and 8 in the brainstem. Among 306 female subjects aged 60 years or older, the median age at menopause was 50 years, the median number of children was 3, and the median age at the last parity was 30 years (Fig 1). Although the prevalence of hypertension was not different between female subjects with or without natural early menopause, blood pressure levels at the examination were lower in subjects with natural early menopause (Table 1). Total and high-density lipoprotein cholesterol were also lower in subjects with natural early menopause. In this subgroup of elderly women, SBI was present in 34 subjects (11.1%). In addi-
Figure 1.
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tion to age, total early menopause (14.7% versus 4.8%, P 5 .04) or natural early menopause (11.8% versus 2.2%, P 5 .02) was more frequent in subjects with SBI than in those without SBI. Age at natural menopause, number of children, and age at the last parity were not significantly associated with SBI (data not shown). In the total of 715 subjects, univariate analysis showed that the presence of SBI was associated with total and natural early menopause (Table 2). The subjects with SBI were older, more hypertensive, and tended more likely to drink and smoke than subjects without SBI. In the forward stepwise method of logistic regression analysis, natural early menopause (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.07-17.11), age (OR 2.44/10 years, 95% CI 1.84-3.23), hypertension (OR 4.04, 95% CI 2.41-6.77), alcohol intake (OR 2.11, 95% CI 1.24-3.58), and smoking (OR 2.95, 95% CI 1.52-5.69) were significant factors concerning SBI (Model 2) (Table 3). Although SBI was more prevalent among men in Model 1, this sex difference disappeared after adjustment for alcohol and smoking. In the Model 3 with the same covariates as Model 2 in 306 female subjects aged 60 years or older, natural early menopause, age, and diabetes mellitus were significant factors concerning SBI. When natural early menopause was replaced with total early menopause, the results of Model 2 and 3 were similar, but the significance was attenuated (.05 , P , .1). Natural early menopause was more frequent in subjects with deep white matter lesions, but no significant association was shown in the multivariate model (data not shown).
Discussion The present study showed ‘‘natural’’ early menopause as a potential new risk factor for SBI unique to women. Age and hypertension are the most widely accepted risk factors
Distribution of age at natural menopause (A), number of children (B), and age at the last parity (C).
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Table 1. Clinical features of female subjects aged 60 years or older with or without natural early menopause Early menopause (natural)
Age, median (IQR), y Body mass index, median (IQR), kg/m2 Hypertension, n (%) Systolic BP, median (IQR), mm Hg Diastolic BP, median (IQR), mm Hg Diabetes mellitus, n (%) Hyperlipidemia, n (%) Alcohol, n (%) Smoking, n (%) Fasting blood glucose, median (IQR), mmol/L Total cholesterol, median (IQR), mmol/L High-density lipoprotein cholesterol, median (IQR), mmol/L
(1) n 5 10
(2) n 5 296
P value
76 (70-83) 22.5 (20.6-26.0) 4 (40) 127 (109-138) 69 (59-72) 2 (20) 1 (10) 2 (20) 1 (10) 5.16 (5.05-5.77) 4.58 (4.09-5.16) 1.42 (1.25-1.53)
72 (66-78) 22.9 (20.5-25.4) 133 (45) 142 (130-158) 78 (72-86) 21 (7) 79 (27) 28 (9) 4 (1) 5.11 (4.79-5.55) 5.31 (4.63-5.84) 1.58 (1.33-1.86)
.12 NS NS .01 .00 .17 NS NS .15 NS .05 .04
Abbreviations: IQR, interquartile range; BP, blood pressure; NS, nonsignificant. NS, P . .2.
for SBI, and other cardiovascular risk factors for symptomatic stroke were also found to raise the risk of SBI. Because most of silent infarcts are subcortical lacunar infarction, risk factors for SBI are similar to those of lacunar infarction or cerebral small-vessel disease. Protective effects of moderate alcohol consumption on SBI were evident in the Cardiovascular Health Study,17 whereas the Atherosclerosis Risk in Community Study18 showed no association between alcohol and MRI infarction. The Atherosclerosis Risk in Community Study showed that current smoking and hypertension both almost doubled the odds of SBI
(1.88 for current smoking, 2.00 for hypertension).19 Menopause is known to be associated with an increase in various risk factors for stroke such as abdominal obesity, increases in total and LDL cholesterol, increased fasting glucose and insulin resistance, and blood pressure.20,21 However, in the present study, natural early menopause was independently associated with SBI after adjustment for various risk factors. Although cigarette smoking, malnutrition, and lower socioeconomic status have been associated with earlier menopause, age at natural menopause is largely influenced by genetic factors.22-25
Table 2. Clinical features of subjects with or without silent brain infarction Silent brain infarction
Age, median (IQR), y Male sex, n (%) Early menopause (total), n (%) Early menopause (natural), n (%) Body mass index, median (IQR), kg/m2 Hypertension, n (%) Systolic BP, median (IQR), mm Hg Diastolic BP, median (IQR), mm Hg Diabetes mellitus, n (%) Hyperlipidemia, n (%) Alcohol, n (%) Smoking, n (%) Ischemic heart disease, n (%) Atrial fibrillation, n (%) Fasting blood glucose, median (IQR), mmol/L Total cholesterol, median (IQR), mmol/L High-density lipoprotein cholesterol, median (IQR), mmol/L
(1) n 5 89
(2) n 5 626
P value
76 (69-82) 44 (49.4) 5 (5.6) 4 (4.5) 22.8 (20.4-24.9) 61 (68.5) 146 (132-166) 78 (72-88) 13 (14.6) 16 (18.0) 40 (44.9) 20 (22.5) 11 (12.4) 5 (5.6) 5.27 (4.88-5.71) 4.99 (4.37-5.68) 1.47 (1.29-1.71)
67 (58-75) 239 (38.2) 13 (2.1) 6 (1.0) 22.9 (20.4-25.3) 208 (33.2) 136 (122-152) 80 (72-88) 57 (9.1) 142 (22.5) 219 (35.0) 82 (13.1) 35 (5.6) 11 (1.8) 5.22 (4.83-5.66) 5.13 (4.50-5.69) 1.55 (1.27-1.84)
.00 .04 .06 .03 NS .00 .00 NS .10 NS .07 .02 .02 .04 NS NS .14
Abbreviations: IQR, interquartile range; BP, blood pressure; NS, nonsignificant. NS, P . .2.
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Table 3. Potential risk factors for silent brain infarction Multivariate: Model 1
Early menopause (natural) Age (per 10 y) Sex (male) Hypertension Diabetes mellitus Alcohol Smoking
Multivariate: Model 2
Multivariate: Model 3
OR
95% CI
P
OR
95% CI
P
OR
95% CI
P
5.40 2.20 2.28 3.88
1.36-21.68 1.68-2.88 1.39-3.76 2.34-6.43
.02 .00 .00 .00
4.28 2.44
1.07-17.11 1.84-3.23
.04 .00
4.35 2.54 —
1.05-18.08 1.52-4.23 —
.04 .00 —
4.04
2.41-6.77
.00 3.26
1.09-9.77
.04
2.11 2.95
1.24-3.58 1.52-5.69
.01 .00
Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval. Model 1: early menopause, age, sex, hypertension, and diabetes mellitus were included in the forward stepwise method of logistic regression analysis; Model 2: alcohol and smoking were added to Model 1; and Model 3: same covariates as Model 2 in 306 female subjects aged 60 years or older.
Blood pressure is generally lower in premenopausal women than in age-matched men, and most women develop hypertension in their lifetime.26,27 The mechanisms responsible for postmenopausal hypertension include endothelial dysfunction, increased arterial stiffness, oxidative stress, salt sensitivity, and obesity or atherogenic adiposity.28 Although smoking is a strong risk factor for early menopause,22 natural early menopause was associated with SBI independent of smoking in the present study. Strengths of this study include that natural early menopause was independently associated with SBI after the adjustment of conventional risk factors especially age and hypertension, and this study is population based and includes a relatively large number of residents with brain MRI. The limitations of this study are the cross-sectional nature and the small number of subjects with natural early menopause. Nonetheless, 3 models of regression estimates were all positive for the independent association of natural early menopause with SBI. No study so far has investigated whether early menopause is a potential risk for SBI in community-dwelling elderly subjects. A number of cohort studies have shown inconsistent findings with regards to the association between age at menopause and stroke mortality or risk of incident stroke.23 Large prospective cohort studies showed that age at natural menopause was essentially unrelated to stroke mortality.29,30 Age at natural menopause was not significantly associated with ischemic stroke or hemorrhagic stroke,31,32 whereas early menopause increased the risk of stroke in the Framingham Heart Study.9 In the latter prospective study of 1430 women, there was an increased risk of ischemic stroke among the women who experienced natural menopause before age 42 compared with all other women.9 Studies with measures of endogenous estrogen may unravel the relationship between hormones and ischemic stroke. Although postmenopausal hormone replacement therapy had no demonstrable beneficial
effect on primary or secondary stroke prevention,6,7 the effects of endogenous estrogens on stroke remains unanswered. In a case–control study, a shorter duration of ovarian activity was independently related to a higher risk of noncardioembolic ischemic stroke.33 In contrast, age-adjusted endogenous circulating free estradiol levels were an indicator of an increased risk of stroke (2.3-fold greater odds) in older postmenopausal women.34 Recent studies on the possible relationship between parity and stroke are controversial. A large populationbased cohort study of Chinese women found that more gravidity or parity was significantly associated with an elevated risk of incident stroke.11 In a case–control study, repeated childbirth was associated with increased risk of hemorrhagic stroke in women adjusted for age, hypertension, diabetes mellitus, smoking, alcohol, and a family history of stroke.35 In contrast, in middle-aged Swedish women, parous women had a statistically significant lower risk of hemorrhagic stroke but not for ischemic stroke.36 The Adventist Health Study showed no association between parity and stroke mortality.37 The present study also found negative results with regard to parity and SBI. In conclusion, we found that natural early menopause was significantly associated with SBI in addition to common vascular risk factors such as age, hypertension, alcohol habit, and smoking. Although the prevalence of natural early menopause was low (3.3% of 306 female subjects aged 60 years or older), natural menopause before the age of 40 years may be a risk for SBI or smallvessel disease of the brain. Acknowledgments: We wish to express special thanks to Koji Yahara for statistical analysis; T. Muto, K. Akashi, and K. Kawakami for technical assistance with the laboratory examinations and the MRI scanning, and K. Muto and N. Kawahara-Ideno for registration of participants.
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References 1. Bonita R, Anderson CS, Broad JB, et al. Stroke incidence and case fatality in Australia. A comparison of the Auckland and Perth population-based stroke registers. Stroke 1994;25:552-557. 2. Stegmayr B, Asplund K, Kuulasmaa K, et al. Stroke incidence and mortality correlated to stroke risk factors in the WHO MONICA Project. An ecological study of 18 populations. Stroke 1997;28:1367-1374. 3. Zhang XH, Sasaki S, Kesteloot H. Changes in the sex ratio of stroke mortality in the period of 1955 through 1990. Stroke 1995;26:1774-1780. A. Sex differences in 4. Appelros P, Stegmayr B, TerEnt stroke epidemiology: a systematic review. Stroke 2009; 40:1082-1090. 5. Engberding N, Wenger NK. Management of hypertension in women. Hypertens Res 2012;35:251-260. 6. Kuller LH, Women’s Health Initiative. Hormone replacement therapy and risk of cardiovascular disease: implications of the results of the Women’s Health Initiative. Arterioscler Thromb Vasc Biol 2003;23:11-16. 7. Bath PM, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ 2005;330:342. 8. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005; 308:1583-1587. 9. Lisabeth LD, Beiser AS, Brown DL, et al. Age at natural menopause and risk of ischemic stroke: the Framingham heart study. Stroke 2009;40:1044-1049. 10. Perls TT, Alpert L, Fretts RC. Middle-aged mothers live longer. Nature 1997;389:133. 11. Zhang X, Shu XO, Gao YT, et al. Pregnancy, childrearing, and risk of stroke in Chinese women. Stroke 2009; 40:2680-2684. 12. Takashima Y, Miwa Y, Mori T, et al. Sex differences in the risk profile and male predominance in silent brain infarction in community-dwelling elderly subjects: the Sefuri Brain MRI Study. Hypertens Res 2010; 33:748-752. 13. Yao H, Miwa Y, Takashima Y, et al. Chronic kidney disease and subclinical lacunar infarction are independently associated with frontal lobe dysfunction in communitydwelling elderly subjects: the Sefuri brain MRI study. Hypertens Res 2011;34:1023-1028. 14. Sasaki M, Hirai T, Taoka T, et al. Discriminating between silent cerebral infarction and deep white matter hyperintensity using combinations of three types of magnetic resonance images: a multicenter observer performance study. Neuroradiology 2008;50:753-758. 15. Bokura H, Kobayashi S, Yamaguchi S. Distinguishing silent lacunar infarction from enlarged Virchow-Robin spaces: a magnetic resonance imaging and pathological study. J Neurol 1998;245:116-122. 16. Fazekas F, Kleinert R, Offenbacher H, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993;43:1683-1689. 17. Mukamal KJ, Longstreth WT Jr, Mittleman MA, et al. Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the cardiovascular health study. Stroke 2001;32:1939-1946. 18. Ding J, Eigenbrodt ML, Mosley TH Jr, et al. Alcohol intake and cerebral abnormalities on magnetic resonance imaging in a community-based population of middleaged adults: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2004;35:16-21.
19. Howard G, Wagenknecht LE, Cai J, et al. Cigarette smoking and other risk factors for silent cerebral infarction in the general population. Stroke 1998;29:913-917. 20. Matthews KA, Kuller LH, Sutton-Tyrrell K, et al. Changes in cardiovascular risk factors during the perimenopause and postmenopause and carotid artery atherosclerosis in healthy women. Stroke 2001;32:1104-1111. 21. Matthews KA, Crawford SL, Chae CU, et al. Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition? J Am Coll Cardiol 2009;54:2366-2373. 22. Mikkelsen TF, Graff-Iversen S, Sundby J, et al. Early menopause, association with tobacco smoking, coffee consumption and other lifestyle factors: a cross-sectional study. BMC Public Health 2007;7:149. 23. Lisabeth L, Bushnell C. Stroke risk in women: the role of menopause and hormone therapy. Lancet Neurol 2012;11:82-91. 24. Kok HS, van Asselt KM, van der Schouw YT, et al. Heart disease risk determines menopausal age rather than the reverse. J Am Coll Cardiol 2006;47:1976-1983. 25. Voorhuis M, Onland-Moret NC, van der Schouw YT, et al. Human studies on genetics of the age at natural menopause: a systematic review. Hum Reprod Update 2010;16:364-377. 26. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995;25:305-313. 27. Cutler JA, Sorlie PD, Wolz M, et al. Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988-1994 and 19992004. Hypertension 2008;52:818-827. 28. Coylewright M, Reckelhoff JF, Ouyang P. Menopause and hypertension: an age-old debate. Hypertension 2008; 51:952-959. 29. Jacobsen BK, Heuch I, Kv ale G. Age at natural menopause and stroke mortality: cohort study with 3561 stroke deaths during 37-year follow-up. Stroke 2004;35:1548-1551. 30. Cui R, Iso H, Toyoshima H, , et alJACC Study Group. Relationships of age at menarche and menopause, and reproductive year with mortality from cardiovascular disease in Japanese postmenopausal women: the JACC study. J Epidemiol 2006;16:177-184. 31. Hu FB, Grodstein F, Hennekens CH, et al. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med 1999;159:1061-1066. 32. Choi SH, Lee SM, Kim Y, et al. Natural menopause and risk of stroke in elderly women. J Korean Med Sci 2005; 20:1053-1058. 33. de Leci~ nana MA, Egido JA, Fern andez C, , et alPIVE Study Investigators of the Stroke Project of the Spanish Cerebrovascular Diseases Study Group. Risk of ischemic stroke and lifetime estrogen exposure. Neurology 2007;68:33-38. 34. Lee JS, Yaffe K, Lui LY, , et alStudy of Osteoporotic Fractures Group. Prospective study of endogenous circulating estradiol and risk of stroke in older women. Arch Neurol 2010;67:195-201. 35. Jung SY, Bae HJ, Park BJ, , et alAcute Brain Bleeding Analysis Study Group. Parity and risk of hemorrhagic strokes. Neurology 2010;74:1424-1429. 36. Yang L, Kuper H, Sandin S, et al. Reproductive history, oral contraceptive use, and the risk of ischemic and hemorrhagic stoke in a cohort study of middle-aged Swedish women. Stroke 2009;40:1050-1058. 37. Jacobsen BK, Knutsen SF, Oda K, et al. Parity and total, ischemic heart disease and stroke mortality. The Adventist Health Study, 1976-1988. Eur J Epidemiol 2011; 26:711-718.
Our previous study showed that the male predominance of silent brain infarction (SBI) was largely because of higher prevalence of alcohol habit and smoking in men than in women. In the present study, we further conducted an analysis of brain magnetic resonance imaging findings to examine whether early menopause contributes to SBI in community-dwelling subjects. Women were queried as to the age and cause of menopause, the total number of children, and the age at giving birth to her last child. Among 306 female subjects aged 60 years or older, univariate analysis showed that early menopause (total or natural) was significantly associated with SBI but age at natural menopause, number of children, and age at the last parity were not. In the total of 715 subjects (283 men and 432 women with a mean age of 67.2 years), the forward stepwise method of logistic analysis revealed that natural early menopause (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.07-17.11), in addition to age, hypertension, alcohol intake, and smoking, was a significant factor concerning SBI. Also in the subgroup of female subjects aged 60 years or older, natural early menopause was a significant factor concerning SBI (OR 4.35, 95% CI 1.05-18.08) adjusted for covariates. Although the prevalence of natural early menopause was low (3.3% of 306 female subjects), natural menopause before the age of 40 years may be a risk for SBI or small-vessel disease of the brain. Key Words: Silent stroke—small-vessel disease—menopause—parity—magnetic resonance imaging. Ó 2013 by National Stroke Association
Introduction The morbidity and mortality rates of symptomatic stroke are known to be lower in women than in men with the exception of subarachnoid hemorrhage.1,2 Zhang et al3 analyzed the sex ratios of men to women in stroke mortality using World Health Organization data from 27 populations, which revealed that the male
From the Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka; †Center for Emotional and Behavioral Disorders, National Hospital Organization Hizen Psychiatric Center, Saga; and ‡Department of Diagnostic Radiology, Saitama Medical University International Medical Center, Saitama, Japan. Received June 5, 2013; revision received July 3, 2013; accepted July 5, 2013.
predominance of stroke mortality decreased with age in many countries. Brain infarction is more common in men: male sex may be a risk factor for symptomatic stroke, whereas premenopausal women appear to be protected from cardiovascular events or stroke.4 Nevertheless, hypertension is a major risk for cardiovascular disease in both women and men, and menopause
Conflicts of interest: The authors declare no conflict of interest. Address correspondence to Hiroshi Yao, MD, Center for Emotional and Behavioral Disorders, National Hospital Organization Hizen Psychiatric Center, Mitsu 160, Yoshinogari, Kanzaki, Saga 842-0192, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.07.005
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2013: pp 1-6
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escalates such cardiovascular risk factors and, thereby, erodes the female protection against cardiovascular morbidity and mortality.5 Although exogenous estrogen and/ or progesterone increased the risk of stroke,6,7 estrogen has beneficial effects on endothelial function and atherosclerosis in addition to the hormone’s effects on serum lipid concentrations, raising the possibility of sex differences in arterial remodeling.8 In line with this favorable effect of estrogen, early menopause was associated with an increased incidence of ischemic stroke in the Framingham Heart Study.9 With regard to parity, the ability to have children at older age may be a marker for slow aging and extreme longevity.10 On the contrary, Zhang et al11 have found that high gravidity and high parity were associated with a higher risk of ischemic stroke. Our previous study showed the male predominance of silent brain infarction (SBI), which was largely because of higher prevalence of alcohol habit and smoking in men than in women.12 Although early menopause could be a risk factor for stroke or SBI, as has been shown by the Framingham Heart Study,8 yet no study has evaluated the impact of early menopause on the presence of SBI. Therefore, we conducted a population-based, cross-sectional analysis of brain magnetic resonance imaging (MRI) findings to examine whether early menopause contributes to SBI.
Subjects and Methods Between 1997 and 2010, we contacted approximately 1200 inhabitants aged 40 years or older, living in the rural community of Sefuri village, Saga, Japan, through the village office. During this period, a total of 1272 MRI scans were performed for 755 volunteers. These subjects were living independently at home without apparent dementia. A total of 40 cases were excluded because of claustrophobia or contraindications for MRI (n 5 7), a history of stroke (n 5 15), brain tumor (n 5 1), malignant neoplasm (n 5 1), psychiatric disorders including depression (n 5 4), a history of head trauma (n 5 3), and insufficient clinical information (n 5 9). The National Hospital Organization Hizen Psychiatric Center Institutional Review Board approved the study (No. 15-1), and written informed consent was obtained from all subjects. Participants underwent a structured clinical interview, a neurologic examination, general hematology tests, biochemistry tests, and electrocardiograms. Vascular risk factors were defined as previously described.12,13 Briefly, arterial hypertension was considered present if a subject had a history of repeated blood pressure recordings above 140/90 mm Hg or the subject was being treated for hypertension. Diabetes mellitus was defined as fasting plasma glucose greater than 7.77 mmol/L and/ or HbA1c greater than 6.0% or a previous diagnosis of diabetes mellitus. Hyperlipidemia was defined as total serum cholesterol concentration greater than
5.69 mmol/L or if the subject was being treated for hyperlipidemia. We obtained information about usual alcohol intake and type of alcohol consumed from a detailed questionnaire as previously described.12 We defined 1 drink as 10 g of ethanol, calculated as follows: 350 mL beers as 1.4 drinks, 180 mL sake (rice wine) as 2.2 drinks, 180 mL shochu (white spirits) as 3.6 drinks, 60 mL whisky as 2.0 drinks, and 120 mL wine as 1.2 drinks. In the present study, we defined alcohol intake as 1 drink or more per week because the previous study from the same population revealed that even light drinkers had the similar risk for SBI as moderate drinkers. Former drinkers were considered nondrinker in the present study. Smoking was defined as present if the subject smoked at least an average of 10 cigarettes per day.
Menopause and SBI in Women Aged 60 Years or Older We asked all the female participants about items given subsequently using a questionnaire and analyzed potential risk factors for SBI in 306 women aged 60 years or older in relation to age at menopause and parity. Natural menopause was considered to occur if a woman had ceased menstruating naturally for at least 1 year. Age at natural menopause was the self-reported age at last menstrual period. Early menopause was defined as menopause before age 40. Women were also queried as to the cause of menopause (natural, surgical, or other), whether a hysterectomy was performed, number of ovaries removed, the use of hormone replacement therapy, the total number of children, and the age at giving birth to her last child.
Assessment of MRI Findings The combination of T1-weighted image (T1WI), T2weighted image (T2WI), and fluid-attenuated inversion recovery image is required to accurately detect both SBI and white matter lesions.14 Therefore, T1WI (repetition time [TR]/echo time [TE] 5 510/12 msec), T2WI (TR/ TE 5 4300/110 msec), and fluid-attenuated inversion recovery (TR/inversion time/TE 5 6750/1600/22 msec) images were obtained with a slice thickness of 6 mm with a 1-mm interslice gap with an MRI (1.0 T, Shimadzu Magnex XP, Kyoto, Japan). SBI was shown as low signal intensities on T1WI and high signal intensities on T2WI, and their size was 5 mm or larger. We differentiated enlarged perivascular spaces from SBI on the basis of their location, shape, and size.15 The white matter lesions were defined as isointense with normal brain parenchyma on T1WI and high signal intensity areas on T2WI and were classified into deep white matter lesions and periventricular hyperintensities.16
Statistical Analysis Summary statistics of clinical variables were given as median with interquartile range. For the univariate
EARLY MENOPAUSE AND SBI
analysis, the nonparametric Mann–Whitney U test for continuous variables and the chi-square test or Fishers exact test for categorical variables were used to investigate differences between groups. We chose the variables for entry into the multivariate analysis based on the clinical and neuroradiologic findings after univariate testing. Multivariate analysis was done using the forward stepwise method of logistic regression analysis. A significance level of .05 was used in all analyses. The data were analyzed with the IBM SPSS Statistics 18 software for Windows (SPSS Japan, Inc.).
Results In the 715 subjects (283 men and 432 women with a mean age of 67.2 years), SBI, deep white matter lesions, and periventricular hyperintensities were detected in 89 (12.4%), 241 (33.7%), and 154 (21.5%), respectively. The prevalence of SBI was more frequent in men (44 of 283 subjects [15.5%]) than in women (45 of 432 subjects [10.4%]). Of 89 subjects with SBI, 53 subjects (59.6%) had a single lacune. There were a total of 162 lacunes in 89 subjects: 81 were located in the basal ganglia, 21 in the thalamus, 47 in the corona radiata, 5 in the cerebellum, and 8 in the brainstem. Among 306 female subjects aged 60 years or older, the median age at menopause was 50 years, the median number of children was 3, and the median age at the last parity was 30 years (Fig 1). Although the prevalence of hypertension was not different between female subjects with or without natural early menopause, blood pressure levels at the examination were lower in subjects with natural early menopause (Table 1). Total and high-density lipoprotein cholesterol were also lower in subjects with natural early menopause. In this subgroup of elderly women, SBI was present in 34 subjects (11.1%). In addi-
Figure 1.
3
tion to age, total early menopause (14.7% versus 4.8%, P 5 .04) or natural early menopause (11.8% versus 2.2%, P 5 .02) was more frequent in subjects with SBI than in those without SBI. Age at natural menopause, number of children, and age at the last parity were not significantly associated with SBI (data not shown). In the total of 715 subjects, univariate analysis showed that the presence of SBI was associated with total and natural early menopause (Table 2). The subjects with SBI were older, more hypertensive, and tended more likely to drink and smoke than subjects without SBI. In the forward stepwise method of logistic regression analysis, natural early menopause (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.07-17.11), age (OR 2.44/10 years, 95% CI 1.84-3.23), hypertension (OR 4.04, 95% CI 2.41-6.77), alcohol intake (OR 2.11, 95% CI 1.24-3.58), and smoking (OR 2.95, 95% CI 1.52-5.69) were significant factors concerning SBI (Model 2) (Table 3). Although SBI was more prevalent among men in Model 1, this sex difference disappeared after adjustment for alcohol and smoking. In the Model 3 with the same covariates as Model 2 in 306 female subjects aged 60 years or older, natural early menopause, age, and diabetes mellitus were significant factors concerning SBI. When natural early menopause was replaced with total early menopause, the results of Model 2 and 3 were similar, but the significance was attenuated (.05 , P , .1). Natural early menopause was more frequent in subjects with deep white matter lesions, but no significant association was shown in the multivariate model (data not shown).
Discussion The present study showed ‘‘natural’’ early menopause as a potential new risk factor for SBI unique to women. Age and hypertension are the most widely accepted risk factors
Distribution of age at natural menopause (A), number of children (B), and age at the last parity (C).
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Table 1. Clinical features of female subjects aged 60 years or older with or without natural early menopause Early menopause (natural)
Age, median (IQR), y Body mass index, median (IQR), kg/m2 Hypertension, n (%) Systolic BP, median (IQR), mm Hg Diastolic BP, median (IQR), mm Hg Diabetes mellitus, n (%) Hyperlipidemia, n (%) Alcohol, n (%) Smoking, n (%) Fasting blood glucose, median (IQR), mmol/L Total cholesterol, median (IQR), mmol/L High-density lipoprotein cholesterol, median (IQR), mmol/L
(1) n 5 10
(2) n 5 296
P value
76 (70-83) 22.5 (20.6-26.0) 4 (40) 127 (109-138) 69 (59-72) 2 (20) 1 (10) 2 (20) 1 (10) 5.16 (5.05-5.77) 4.58 (4.09-5.16) 1.42 (1.25-1.53)
72 (66-78) 22.9 (20.5-25.4) 133 (45) 142 (130-158) 78 (72-86) 21 (7) 79 (27) 28 (9) 4 (1) 5.11 (4.79-5.55) 5.31 (4.63-5.84) 1.58 (1.33-1.86)
.12 NS NS .01 .00 .17 NS NS .15 NS .05 .04
Abbreviations: IQR, interquartile range; BP, blood pressure; NS, nonsignificant. NS, P . .2.
for SBI, and other cardiovascular risk factors for symptomatic stroke were also found to raise the risk of SBI. Because most of silent infarcts are subcortical lacunar infarction, risk factors for SBI are similar to those of lacunar infarction or cerebral small-vessel disease. Protective effects of moderate alcohol consumption on SBI were evident in the Cardiovascular Health Study,17 whereas the Atherosclerosis Risk in Community Study18 showed no association between alcohol and MRI infarction. The Atherosclerosis Risk in Community Study showed that current smoking and hypertension both almost doubled the odds of SBI
(1.88 for current smoking, 2.00 for hypertension).19 Menopause is known to be associated with an increase in various risk factors for stroke such as abdominal obesity, increases in total and LDL cholesterol, increased fasting glucose and insulin resistance, and blood pressure.20,21 However, in the present study, natural early menopause was independently associated with SBI after adjustment for various risk factors. Although cigarette smoking, malnutrition, and lower socioeconomic status have been associated with earlier menopause, age at natural menopause is largely influenced by genetic factors.22-25
Table 2. Clinical features of subjects with or without silent brain infarction Silent brain infarction
Age, median (IQR), y Male sex, n (%) Early menopause (total), n (%) Early menopause (natural), n (%) Body mass index, median (IQR), kg/m2 Hypertension, n (%) Systolic BP, median (IQR), mm Hg Diastolic BP, median (IQR), mm Hg Diabetes mellitus, n (%) Hyperlipidemia, n (%) Alcohol, n (%) Smoking, n (%) Ischemic heart disease, n (%) Atrial fibrillation, n (%) Fasting blood glucose, median (IQR), mmol/L Total cholesterol, median (IQR), mmol/L High-density lipoprotein cholesterol, median (IQR), mmol/L
(1) n 5 89
(2) n 5 626
P value
76 (69-82) 44 (49.4) 5 (5.6) 4 (4.5) 22.8 (20.4-24.9) 61 (68.5) 146 (132-166) 78 (72-88) 13 (14.6) 16 (18.0) 40 (44.9) 20 (22.5) 11 (12.4) 5 (5.6) 5.27 (4.88-5.71) 4.99 (4.37-5.68) 1.47 (1.29-1.71)
67 (58-75) 239 (38.2) 13 (2.1) 6 (1.0) 22.9 (20.4-25.3) 208 (33.2) 136 (122-152) 80 (72-88) 57 (9.1) 142 (22.5) 219 (35.0) 82 (13.1) 35 (5.6) 11 (1.8) 5.22 (4.83-5.66) 5.13 (4.50-5.69) 1.55 (1.27-1.84)
.00 .04 .06 .03 NS .00 .00 NS .10 NS .07 .02 .02 .04 NS NS .14
Abbreviations: IQR, interquartile range; BP, blood pressure; NS, nonsignificant. NS, P . .2.
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Table 3. Potential risk factors for silent brain infarction Multivariate: Model 1
Early menopause (natural) Age (per 10 y) Sex (male) Hypertension Diabetes mellitus Alcohol Smoking
Multivariate: Model 2
Multivariate: Model 3
OR
95% CI
P
OR
95% CI
P
OR
95% CI
P
5.40 2.20 2.28 3.88
1.36-21.68 1.68-2.88 1.39-3.76 2.34-6.43
.02 .00 .00 .00
4.28 2.44
1.07-17.11 1.84-3.23
.04 .00
4.35 2.54 —
1.05-18.08 1.52-4.23 —
.04 .00 —
4.04
2.41-6.77
.00 3.26
1.09-9.77
.04
2.11 2.95
1.24-3.58 1.52-5.69
.01 .00
Abbreviations: OR, odds ratio; 95% CI, 95% confidence interval. Model 1: early menopause, age, sex, hypertension, and diabetes mellitus were included in the forward stepwise method of logistic regression analysis; Model 2: alcohol and smoking were added to Model 1; and Model 3: same covariates as Model 2 in 306 female subjects aged 60 years or older.
Blood pressure is generally lower in premenopausal women than in age-matched men, and most women develop hypertension in their lifetime.26,27 The mechanisms responsible for postmenopausal hypertension include endothelial dysfunction, increased arterial stiffness, oxidative stress, salt sensitivity, and obesity or atherogenic adiposity.28 Although smoking is a strong risk factor for early menopause,22 natural early menopause was associated with SBI independent of smoking in the present study. Strengths of this study include that natural early menopause was independently associated with SBI after the adjustment of conventional risk factors especially age and hypertension, and this study is population based and includes a relatively large number of residents with brain MRI. The limitations of this study are the cross-sectional nature and the small number of subjects with natural early menopause. Nonetheless, 3 models of regression estimates were all positive for the independent association of natural early menopause with SBI. No study so far has investigated whether early menopause is a potential risk for SBI in community-dwelling elderly subjects. A number of cohort studies have shown inconsistent findings with regards to the association between age at menopause and stroke mortality or risk of incident stroke.23 Large prospective cohort studies showed that age at natural menopause was essentially unrelated to stroke mortality.29,30 Age at natural menopause was not significantly associated with ischemic stroke or hemorrhagic stroke,31,32 whereas early menopause increased the risk of stroke in the Framingham Heart Study.9 In the latter prospective study of 1430 women, there was an increased risk of ischemic stroke among the women who experienced natural menopause before age 42 compared with all other women.9 Studies with measures of endogenous estrogen may unravel the relationship between hormones and ischemic stroke. Although postmenopausal hormone replacement therapy had no demonstrable beneficial
effect on primary or secondary stroke prevention,6,7 the effects of endogenous estrogens on stroke remains unanswered. In a case–control study, a shorter duration of ovarian activity was independently related to a higher risk of noncardioembolic ischemic stroke.33 In contrast, age-adjusted endogenous circulating free estradiol levels were an indicator of an increased risk of stroke (2.3-fold greater odds) in older postmenopausal women.34 Recent studies on the possible relationship between parity and stroke are controversial. A large populationbased cohort study of Chinese women found that more gravidity or parity was significantly associated with an elevated risk of incident stroke.11 In a case–control study, repeated childbirth was associated with increased risk of hemorrhagic stroke in women adjusted for age, hypertension, diabetes mellitus, smoking, alcohol, and a family history of stroke.35 In contrast, in middle-aged Swedish women, parous women had a statistically significant lower risk of hemorrhagic stroke but not for ischemic stroke.36 The Adventist Health Study showed no association between parity and stroke mortality.37 The present study also found negative results with regard to parity and SBI. In conclusion, we found that natural early menopause was significantly associated with SBI in addition to common vascular risk factors such as age, hypertension, alcohol habit, and smoking. Although the prevalence of natural early menopause was low (3.3% of 306 female subjects aged 60 years or older), natural menopause before the age of 40 years may be a risk for SBI or smallvessel disease of the brain. Acknowledgments: We wish to express special thanks to Koji Yahara for statistical analysis; T. Muto, K. Akashi, and K. Kawakami for technical assistance with the laboratory examinations and the MRI scanning, and K. Muto and N. Kawahara-Ideno for registration of participants.
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