Age at menopause and cause-specific mortality in South Korean women: Kangwha Cohort Study

Maturitas 56 (2007) 411–419

Age at menopause and cause-specific mortality in South Korean women: Kangwha Cohort Study Jae Seok Hong a,f , Sang-Wook Yi b , Hee Chung Kang a , Sun Ha Jee a , Hyung Gon Kang c , Gombojav Bayasgalan d , Heechoul Ohrr e,∗ b

a Graduate School of Public Health, Yonsei University, Republic of Korea Department of Preventive Medicine and Public Health, Kwandong University College of Medicine, Republic of Korea c Department of Preventive Medicine, College of Medicine, Pochon Cha University, Republic of Korea d Department of Public Health, The Graduate School, Yonsei University, Republic of Korea e Department of Preventive Medicine and Public Health, Yonsei University College of Medicine, 134 Shinchon-dong Seodaemun-gu, Seoul 120-752, Republic of Korea f Health Insurance Review Agency, Republic of Korea

Received 4 July 2006; received in revised form 31 October 2006; accepted 8 November 2006

Abstract Objective: The purpose of this study was to examine the relation between age at natural menopause and all-cause and causespecific mortality among women. Methods: This study used the data of the Kangwha Cohort that was followed up from 1985 to 2001, in particular, for the group of 55 years or older women (n = 2658). We calculated the hazard ratio of mortality by the group of age at menopause using the Cox proportional hazards model with adjustment for age, alcohol consumption, education, age at first birth, self-cognitive health level, chronic disease, marital partner, parity, age at menarche, oral contraceptive use and hypertension. Results: The mean (standard deviation) age at menopause was 46.9 (4.9) years, and the median age was 48 years. After adjusting for the relevant variables, the risk of total death in the early menopause group (<40 years at menopause) was 1.32 times higher than that of the reference group (45–49 years at menopause) (95% confidence interval [CI], 1.05–1.66, p = 0.02). For the early menopause group, relative to the reference group, the adjusted hazard ratios of death due to cardiovascular disease and cancer were 1.53 (95% CI, 1.00–2.39, p = 0.04) and 2.01 (95% CI, 1.06–3.82, p = 0.03), respectively. Conclusion: Through this study, the age at menopause was found to be different between Asian and Caucasian women and the association of age at menopause with death, particularly caused by cardiovascular disease and cancer, was validated. Our study is one of rare studies regarding the age at menopause of Asian women and their risk of mortality, which could be considered to be meaningful. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Menopause; Mortality; Cancer; Cardiovascular disease; Cohort studies

∗

Corresponding author. Tel.: +82 2 2228 1865; fax: +82 2 392 8133. E-mail address: [email protected] (H. Ohrr).

0378-5122/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2006.11.004

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1. Introduction Menopause is diagnosed after 12 months of amenorrhea resulting from the permanent cessation of ovarian function [1]. A major reason of recent increased emphasis on the health problems of menopausal women is because the survival of postmenopausal woman is increased with the prolonged life-span of women [2,3]. According to previous studies, the risks of coronary heart disease, osteoporosis and osteoporotic fracture were increased in postmenopausal women due to the decrease of estrogen [1,4–6]. Because of this, it is probable that the mortality rate of early menopause women is higher than that of normal menopause women. Previous studies also reported the risk of mortality was higher in early menopause women than in other groups [7–15]. However, a statistically significant association has been detected only in a small number of studies [7,8,12,15]. Besides total deaths, cardiovascular disease such as coronary heart disease or stroke has been reported to occur more frequently in early menopause women than in normal menopause women, and the association of cancer deaths with age at menopause has been shown in many reports [7,8,16,17]. Numerous studies regarding the association of age at menopause with mortality have been conducted on Caucasian women. But such studies on Asian women are very rare. Particularly, studies that examined its association with death caused by specific disease such as cardiovascular disease and cancer are even rarer. As a result, references regarding the relation between age at menopause and the risk of death in Asian women are extremely difficult to search. In our study, the data obtained through the 15 years and 10 months followup was applied to elucidate the relation between age at menopause and mortality in Korean women, especially its association with the risk of death caused by specific disease such as cardiovascular disease and cancer.

2. Methods

the development of various cancers and resulting deaths and also other causes of death in the elderly population. Population recruited for the Kangwha Cohort Study was 55 years or older residents (born before 1930) of Kangwha County on 28 February 1985 based on their resident registration records (total: 9378, male: 3938, female: 5440), and the number of participants was 6372: male 2724, female 3648. They were interviewed and took a medical examination in March 1985 [18]. In this study, the initial study population was set as 3648 women in the Kangwha Cohort Study. Of them, those who had no information on age at menopause (n = 105) and had smoking history (n = 874) were excluded. Women with smoking history included current smokers (n = 798) as well as ever-smokers (n = 76). Smoking is the most important confounding variable in a study on the relation between age at menopause and death. Smoking decreases woman’s age at menopause by approximately 2 years on average [19,20]. Moreover, confounding by smoking remained after controlling for smoking in a multivariate model in a study of age at menopause and coronary heart disease [21]. Lastly, 11 women who had not been followed up after first interview were omitted from this study, and the final study population was determined as 2658. 2.2. Baseline data collection and follow-up Baseline data for the Kangwha Cohort Study were collected over a month in March 1985. The investigation team interviewed each subject using a structured questionnaire to collect data on marital status, occupation, education level, health condition and diseases at the time of interview, smoking, drinking, dietary habits, etc. The trained investigators measured their blood pressure, height, and weight. The follow-up period of each subject was calculated in months starting from 15 March 1985. Since the exact date of interview was not recorded, all interviews were presumed to have taken place on 15 March, the middle of the month. The last day of this study was 31 December 2001 and thus the period of follow-up for death was 15.8 years.

2.1. Study population 2.3. Outcome definition This study used the data of the ‘Kangwha Cohort Study’ conducted in March 1985. The Kangwha Cohort was first established to examine risk factors influencing

The outcome of this research is total death and cause of death. Data on deaths and the causes of death from 1

J.S. Hong et al. / Maturitas 56 (2007) 411–419

January 1992 to 31 December 2001 were obtained from the Statistics on the Causes of Death of Korea. Data on those who died from 15 March 1985 to 31 December 1991 were collected through calls, visits and records of burial. The International Classification of Disease 10th edition (ICD10) was applied to define the cause of death, which was classified into total cardiovascular disease (ICD10: I00–I99), all cancer disease (ICD10: C00–C76.9 and C80.0–97.9) or others. 2.4. Statistical analysis To examine the relation between age at menopause and cause-specific mortality, subjects were divided into four groups by age at menopause: under 40 years, between 40 and 44 years, between 45 and 49 years, and 50 and above years. Among them, women who experienced menopause under 40 were defined as the early menopause group and those who went into menopause in 45–49 years were defined as the reference group. Cox proportional hazards model was used to estimate hazard ratio (HR) of mortality by the group of age at menopause with adjusting for age, alcohol consumption (ever, never), education (ever, never), age at first birth, self-cognitive health level (alike, more good, more bad), chronic disease (ever, never), marital partner (yes, no), parity, age at menarche, oral contraceptive use (never, ever) and hypertension (SBP = 140, DBP = 90). In addition, similar analyses were performed for attained age groups: attained age <80 years and attained age ≥80 years at 2001. As statistical software, SAS Windows Version 6.12 was used.

3. Results The mean (standard deviation) age at menopause of the whole study subjects was 46.9 (4.9) years, and their median age was 48 years. There was no significant difference in mean age and mean menarche age among groups of age at menopause (Table 1). No significant difference by age at menopause was observed in body mass index (BMI), age at first childbirth, parity, drinking, chronic diseases, marital partner, oral contraceptive use, and hypertension as well. Exceptionally the group of 40–44 years at menopause had lower proportion of education than other groups (p < 0.01).

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Table 2 showed the hazard ratio of death due to all-causes, cardiovascular disease and cancer by age at menopause. Total number of deaths was 1193, of whom 297 persons died with cardiovascular disease and 112 persons died due to cancer. In terms of allcauses death, the hazard ratio of the early menopause group (<40 years at menopause) relative to the reference group (45–49 years at menopause) was 1.32 (95% CI, 1.05–1.66, p = 0.02) with adjustment for education level, body mass index, age at first childbirth, parity history, age at menarche, smoking, chronic diseases, marital partner, self-cognitive health level, history of use of oral contraceptives, and hypertension. And nearly same hazard ratio was shown after adjustment for age in this group (HR = 1.33; 95% CI, 1.07–1.65, p = 0.01). The risk of mortality due to cardiovascular disease was higher in the early menopause group than in other groups. Compared to the reference group, the hazard ratio of death due to cardiovascular disease of the early menopause group was 1.58 (95% CI, 1.04–2.41, p = 0.03) with adjustment for age only and 1.53 (95% CI, 1.00–2.39, p = 0.04) with adjustment for age and other variables. In case of coronary heart disease, a subtype of cardiovascular disease, the hazard ratio of the early menopause group was elevated to 5.43 (95% CI, 1.48–19.93, p = 0.01) after adjustment for age and 8.77 (95% CI, 2.07–37.16, p < 0.01) after adjustment for age and other variables. The risk of mortality due to cancer was greatest in the early menopause group. After adjusting for age, the risk of death from cancer of the early menopause group was 1.86 times (95% CI, 1.00–3.46, p = 0.05) higher than that of the reference group; after adjusting for other variables in addition to age, 2.01 times higher (95% CI, 1.06–3.82, p = 0.03). And looking at deaths due to stomach cancer (C16) and colon, rectum and anus cancer (C18–21), subtypes of total cancer, we found the early menopause group had 2.73 times (95% CI, 1.05–7.12, p = 0.04) and 12.20 times (95% CI, 2.22–67.08, p < 0.01), respectively, higher risk than the reference group after adjustment for age; 3.53 times (95% CI, 1.30–9.56, p = 0.01) and 14.26 times (95% CI, 2.42–83.96, p < 0.01), respectively, after multivariate adjustment (Table 2). To examine the association of age at menopause with the risk of death by age group, study population was classified and analyzed based on the attained

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Table 1 Socio-demographic characteristics by age at menopause (%) Age at menopause (years)

Age at entry (years)a Education Ever Never

Total, n = 2658

<40, n = 198

66.0 ± 8.2

65.8 ± 8.3

p-Value 40–44, n = 489 66.8 ± 8.0

45–49, n = 1023

>50, n = 948

65.8 ± 8.2

65.8 ± 8.3

0.14

578 (21.8) 2080 (78.2)

48 (24.2) 150 (75.8)

84 (17.2) 405 (82.8)

210 (20.5) 813 (79.5)

236 (24.9) 712 (75.1)

<0.01

430 (16.5) 931 (35.8) 610 (23.5) 629 (24.2)

28 (14.6) 68 (35.4) 38 (19.8) 58 (30.2)

87 (18.3) 170 (35.7) 119 (25.0) 100 (21.0)

165 (16.4) 360 (35.8) 254 (25.3) 227 (22.6)

150 (16.2) 333 (36.0) 199 (21.5) 244 (26.4)

0.14

Age at first birth (years) Less than 20 ≥20

618 (23.9) 1972 (76.1)

45 (23.2) 149 (76.8)

119 (25.1) 356 (74.9)

245 (24.6) 753 (75.4)

209 (22.6) 714 (77.4)

0.70

Parity No live births Any live births

44 (1.7) 2597 (98.3)

2 (1.0) 194 (99.0)

9 (1.8) 477 (98.2)

16 (1.6) 1001 (98.4)

17 (1.8) 925 (98.2)

0.86

Body mass index (kg/m2 ) Less than 20.0 20.0–22.9 23.0–24.9 >24.9

Age at menarche (years)a

17.6 ± 1.7

17.7 ± 1.8

17.6 ± 1.7

17.6 ± 1.7

17.6 ± 1.7

0.73

Alcohol consumption Ever Never

162 (6.1) 2495 (93.9)

8 (4.0) 190 (96.0)

22 (4.5) 467 (95.5)

64 (6.2) 958 (93.7)

68 (7.2) 880 (92.8)

0.13

Chronic disease Ever Never

1288 (48.5) 1370 (51.5)

107 (54.0) 91 (46.0)

246 (50.3) 243 (49.7)

470 (46.0) 553 (54.0)

465 (49.1) 483 (50.9)

0.12

Marital partner Ever Never

1388 (52.2) 1269 (47.8)

103 (52.0) 95 (48.0)

244 (49.9) 245 (50.1)

541 (52.9) 481 (47.1)

499 (52.6) 449 (47.4)

0.76

Oral contraceptive use Ever Never

26 (1.0) 2632 (99.0)

0 (0.0) 198 (100.0)

3 (0.6) 486 (99.4)

9 (1.0) 1014 (99.1)

14 (1.5) 934 (98.5)

0.16

424 (16.0)

32 (16.0)

74 (15.1)

172 (16.8)

146 (15.4)

0.79

Hypertension (SBP ≥ 140, DBP ≥ 90) a

ANOVA.

age of 80 years as at 2001 (Table 3). In the analysis of 80 years or older women, the risk of total death and death due to cardiovascular disease of the early menopause group was 1.39 times (95% CI, 1.08–1.79, p = 0.01) and 1.92 times (95% CI, 1.19–3.11, p = 0.01), respectively, higher than that of the reference group after adjusting for age; 1.42 times (95% CI, 1.09–1.86, p = 0.01) and 1.97 times (95% CI, 1.19–3.27, p = 0.01), respectively, after adjusting for other variables together with age. In particular, the early menopause group had 7.35 times (95% CI, 1.57–34.14, p = 0.01) higher risk of death due to coronary heart disease and 2.40 times (95% CI, 1.29–4.45, p = 0.01) higher risk of

death due to cerebrovascular disease than the reference group; after multivariate adjustment, 12.73 times (95% CI, 2.22–72.89, p < 0.01) and 2.29 times (95% CI, 1.20–4.36, p = 0.01), respectively. As for under 80 years old women, the hazard ratio of death due to cancer of the early menopause group, relative to the reference group, was 3.59 (95% CI, 1.69–7.62, p < 0.01) after adjusting for age and other variables. In case of stomach cancer and colon, rectum and anus cancer, the hazard ratios of the early menopause group were 4.96 (95% CI, 1.60–15.39, p < 0.01) and 7.80 (95% CI, 1.30–46.67, p = 0.02), respectively, after adjusting for age; 9.33 (95% CI,

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Table 2 Hazard ratios of age at menopause and mortality Age at menopause

No. died

Person-year of follow-up

Hazard ratio All-causes <40 40–44 45–49 ≥50

100 244 443 406

Multivariate adjustmenta

Adjusted for age 95% CI

Hazard ratio

95% CI

30544 76088.5 164718 149804

1.33 1.13 1.00 1.01

1.07–1.65 0.97–1.32 – 0.88–1.15

1.32 1.13 1.00 1.03

1.05–1.66 0.97–1.34 – 0.90–1.19

All cardiovascular diseases (ICD10: I00–I99) <40 27 22822 40–44 55 55427.5 45–49 114 129717 ≥50 101 120490

1.58 1.17 1.00 1.00

1.04–2.41 0.84–1.62 – 0.76–1.30

1.53 1.15 1.00 1.13

1.00–2.39 0.82–1.60 – 0.86–1.49

Coronary heart disease (I20–I25.9) <40 4 40–44 2 45–49 6 ≥50 4

20384 49657.5 117688 109.397

5.43 0.85 1.00 0.79

1.48–19.93 0.17–4.24 – 0.22–2.81

8.77 1.08 1.00 0.76

2.07–37.16 0.21–5.63 – 0.18–3.23

Cerebrovascular disease (I60–I69.9) <40 16 40–44 36 45–49 72 ≥50 66

21372 53577.5 125017 116588

1.69 1.22 1.00 1.06

0.98–2.93 0.82–1.83 – 0.76–1.49

1.56 1.22 1.00 1.21

0.89–2.73 0.81–1.84 – 0.86–1.71

Other circulatory diseases (I00.0–I19.9, I26.0–I59.9, and I70.0–I99) <40 7 20560 40–44 17 50927.5 45–49 36 120334 ≥50 31 112239

1.47 1.21 1.00 1.00

0.65–3.31 0.68–2.17 – 0.62–1.62

1.33 1.08 1.00 1.10

0.55–3.22 0.59–1.97 – 0.67–1.82

All cancers (ICD10: C00–C76.9 and C80.0–97.9) <40 13 21080 40–44 22 51987.5 45–49 44 121271 ≥50 33 111492

1.86 1.16 1.00 0.82

1.00–3.46 0.70–1.93 – 0.53–1.31

2.01 1.26 1.00 0.96

1.06–3.82 0.75–2.13 – 0.60–1.53

Stomach cancer (C16) <40 40–44 45–49 ≥50

20508 49682.5 118317 109396

2.73 0.80 1.00 0.68

1.05–7.12 0.29–2.19 – 0.30–1.55

3.53 0.87 1.00 0.79

1.30–9.56 0.31–2.46 – 0.34–1.88

Colon, rectum and anus cancer (C18–21) <40 4 20079 40–44 4 49929.5 45–49 2 117012 ≥50 5 109484

12.20 4.65 1.00 2.70

2.22–67.08 0.85–25.40 – 0.52–13.90

14.26 4.64 1.00 4.38

2.42–83.96 0.83–26.02 – 0.82–23.53

6 5 15 9

a Adjusted variables: age, alcohol consumption (ever, never), education (ever, never), age at first birth, self-cognitive health level (alike, more good, more bad), chronic disease (ever, never), marital partner (yes, no), parity, age at menarche, oral contraceptive use (never, ever) and hypertension.

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Table 3 Hazard ratios of age at menopause and mortality by attained age Age at menopause

Attained age ≥80

Attained age <80 No. died

Multivariate adjustmenta

Adjusted for age 95% CI

Hazard ratio

95% CI

1.17 1.15 1.00 0.88

0.76–1.80 0.83–1.60 – 0.67–1.17

1.07 1.16 1.00 0.90

0.67–1.70 0.83–1.64 – 0.67–1.21

75 191 335 318

1.39 1.12 1.00 1.05

1.08–1.79 0.94–1.34 – 0.90–1.22

1.42 1.12 1.00 1.07

1.09–1.86 0.93–1.35 – 0.91–1.25

All cardiovascular diseases (ICD10: I00–I99) <40 6 0.94 40–44 16 1.19 45–49 33 1.00 ≥50 26 0.82

0.39–2.23 0.65–2.16 – 0.49–1.37

0.86 1.20 1.00 0.81

0.35–2.14 0.64–2.26 – 0.48–1.36

21 39 81 75

1.92 1.12 1.00 1.07

1.19–3.11 0.77–1.65 – 0.78–1.46

1.97 1.17 1.00 1.27

1.19–3.27 0.80–1.73 – 0.92–1.76

Coronary heart disease (I20–I25.9) <40 1 40–44 0 45–49 2 ≥50 2

2.59 – 1.00 0.99

0.24–28.54 – – 0.90–1.87

– – 1.00 –

– – – –

3 2 4 2

7.35 1.24 1.00 0.62

1.57–34.14 0.22–6.89 – 0.11–3.39

12.73 1.69 1.00 0.74

2.22–72.89 0.26–10.79 – 0.12–4.42

Cerebrovascular disease (I60–I69.9) <40 3 40–44 12 45–49 23 ≥50 20

0.69 1.27 1.00 0.91

0.21–2.28 0.63–2.56 – 0.50–1.65

0.61 1.35 1.00 0.92

0.18–2.11 0.65–2.81 – 0.50–1.70

13 24 49 46

2.40 1.17 1.00 1.13

1.29–4.45 0.72–1.92 – 0.75–1.69

2.29 1.24 1.00 1.37

1.20–4.36 0.75–2.05 – 0.90–2.08

Other circulatory diseases (I00.0–I19.9, I26.0–I59.9, and I70.0–I99) <40 2 1.29 0.27–6.05 40–44 4 1.27 0.38–4.23 45–49 8 1.00 – ≥50 4 0.53 0.16–1.76

1.35 1.15 1.00 0.56

0.28–6.58 0.30–4.43 – 0.17–1.89

5 13 28 27

1.58 1.14 1.00 1.15

0.61–4.09 0.58–2.21 – 0.68–1.95

1.40 1.14 1.00 1.31

0.48–4.10 0.57–2.25 – 0.75–2.29

All cancers (ICD10: C00–C76.9 and C80.0–97.9) <40 12 2.73 40–44 10 1.17 45–49 22 1.00 ≥50 18 0.88

1.35–5.52 0.55–2.48 – 0.47–1.65

3.59 1.56 1.00 1.22

1.69–7.62 0.72–3.41 – 0.63–2.36

1 12 22 15

0.45 1.25 1.00 0.83

0.06–3.35 0.61–2.54 – 0.43–1.60

0.48 1.15 1.00 0.88

0.06–3.64 0.56–2.38 – 0.44–1.74

Stomach cancer (C16) <40 40–44 45–49 ≥50

4.96 0.42 1.00 0.53

1.60–15.39 0.05–3.50 – 0.13–2.10

9.33 0.79 1.00 0.91

2.51–34.68 0.09–7.24 – 0.20–4.14

0 4 9 6

– 0.99 1.00 0.78

– 0.30–3.25 – 0.28–2.21

– 0.72 1.00 0.64

– 0.21–2.48 – 0.21–1.90

7.80 2.37 1.00 1.01

1.30–46.67 0.33–16.83 – 0.14–7.17

15.21 3.54 1.00 2.16

1.73–133.88 0.45–27.98 – 0.27–16.96

1 2 0 3

– – 1.00 –

– – – –

– – 1.00 –

– – – –

25 53 108 88

6 1 6 3

Colon, rectum and anus cancer (C18–21) <40 3 40–44 2 45–49 2 ≥50 2

95% CI

Multivariate adjustmenta

Adjusted for age

Hazard ratio

95% CI

a Adjusted variables: age, alcohol consumption (ever, never), education (ever, never), age at first birth, self-cognitive health level (alike, more good, more bad), chronic disease (ever, never), marital partner (yes, no), parity, age at menarche, oral contraceptive use (never, ever) and hypertension.

J.S. Hong et al. / Maturitas 56 (2007) 411–419

Hazard ratio All-causes <40 40–44 45–49 ≥50

Hazard ratio

No. died

J.S. Hong et al. / Maturitas 56 (2007) 411–419

2.51–34.68, p < 0.01) and 15.21 (95% CI, 1.73–133.88, p = 0.01), respectively, after multivariate adjustment.

4. Discussion This study showed that the risk of total death was higher in early menopause women (<40 years) than in normal menopause women, and their risk of death caused by cardiovascular disease and cancer was much higher. Such association was particularly evident in coronary heart disease (I20–I25.9) among cardiovascular diseases and in stomach cancer and colon, rectum and anus cancer among cancers. The result was similar to previous studies conducted on Caucasian women [7,8,12,15–17]. The association between early age at menopause and the risk of death caused by cardiovascular disease and cancer is explained by several biologic mechanisms. First, estrogen receptors are found in most tissues including vascular endothelial cells, smooth muscle cells, myocardial cells, bone, bladder, urethra, and ovary [1,4], indicating that all of these tissues may be affected by a decrease in estrogen like that observed in postmenopausal women [7]. Second, estrogen may play a role in the maintenance of immune function; it has been shown that women who underwent surgically induced menopause developed impaired immune function that returned once they were given estrogen replacement therapy [7,22]. Consequently, the mortality rate of early menopause women whose estrogen is decreased at an earlier time is higher than that of normal menopause women. In recent previous studies, the mean age at menopause was 51 years [1]. In our study, the mean age at menopause was 47 years, approximately 4 years earlier than previous reports. This shows there is a difference in age at menopause between Caucasians and Asians. Therefore, unlike previous studies on Caucasians that defined the reference group as 50–54 years, in our study the reference group was defined as 45–49 years. Also it has been reported that menopause occurs 1–2 years earlier in women who are with smoking history or currently smoking, under malnutrition condition, or residing in a high mountain [3,7,11,19,20,23,24]. Particularly, confounding by smoking remained after controlling for smoking in a multivariate model in a study of age at menopause and

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coronary heart disease [7,21]. Therefore, in our study women who are with smoking history or currently smoking were excluded from the analysis. Regarding total death or death due to cardiovascular disease, the association of age at menopause with the risk of death was detected in older women (80 years or over). On the other hand, in case of death due to cancer, the association was detected in younger women (under 80). Such result is contradictory to the study reported by Jacobsen et al. [9], but in conformity with the study by Mondul et al. [7]. Difference by age in the overall association between age at menopause and mortality may be due to a different distribution of causes of death in younger versus older women [7]. Most evidences regarding estrogens and cancer risk deal with exogenous estrogens and suggest an increased risk of (fatal) breast and endometrial cancer among hormone replacement therapy users [25,26]. However, several studies indirectly provide support for the association between the exposure to endogenous estrogens and the increased risk of breast cancer, endometrial cancer, and ovarian cancer [27,28]. Late age at menopause is known to be a risk factor for breast and endometrial cancer [7,29–31]. The higher breast and endometrial cancer risk in women with late menopause is most likely explained by both the longer duration and higher level of exposure to estrogen and progesterone experienced by these women. They also may experience a larger number of anovulatory cycles resulting in a lack of cyclic progesterone. The effect of hormonal milieu on breast cancer during anovulatory cycle is less clear [32]. In this study, however, the risk of death due to cancer was higher in early menopause women and the inverse association between age at menopause and cancer death was shown unlike the previous studies in Western countries. It seems to have resulted from difference in major cancers between Korean women and Caucasian women. According to the Statistics on the Causes of Death publicized by the Korean National Statistical Office, three major cancers in Korean women are stomach cancer (mortality: 17/100,000), trachea, bronchus and lung cancer (C33–34) (mortality: 12.9/100,000), and liver and intrahepatic bile ducts cancer (C22) (mortality: 10.4/100,000) [33]. But the mortality rate of breast cancer is relatively low (5.0/100,000), and quite low if compared with Western women (99.0/100,000)

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[34]. Cervix uteri cancer (C53) has very low death rate (3.4/100,000). In case of this study, deaths caused by stomach cancer comprised 31.3% (n = 35) of all cancer deaths (n = 112), the largest proportion; colon, rectum and anus cancer 13.4% (n = 15); liver and intrahepatic bile ducts caner and pancreas cancer (C25) each 8% (n = 9). But deaths by breast cancer and cervix uteri cancer took only each 4% (n = 4). Previous studies in Western countries reported that age at menopause and breast and endometrial cancer were positively associated [7,29–31]. Since a major cancer in Caucasian women is breast cancer, total cancer has shown similarly positive association with age at menopause. In this study, however, the proportion of breast cancer deaths against total cancer deaths was very small, while those of stomach cancer and colon, rectum and anus cancer were very large. Since strong inverse association was shown in the latter, total cancer seems to have shown inverse association similarly. Besides, the number of cancer deaths in this study itself was relatively small. Accordingly the examination of relation between age at menopause and mortality was limited to total cancer, stomach cancer and colon, rectum and anus cancer. Therefore, additional examination will have to be made against breast cancer or endometrial cancer later. As the life-span of women becomes longer, they are expected to live approximately 30 years further after menopause. Studies on major diseases developing after menopause and the risk of death have been actively conducted. However, most of such studies have been done on Caucasian women, while studies on Asian women are extremely rare. Considering that the cause of death and the development of diseases are different by race, it is necessary to examine the effect of age at menopause of Asian women on mortality and the development of diseases. In that sense, our study is a rare one that examined the age at menopause in Asian women and their risk of death, particularly, due to cardiovascular disease or cancer, which could be considered to be significant. The advantage of our study is that the association of age at menopause with death, particularly from cancer, was examined through a long-term follow-up (15.8 years). For the collection of data, instead of sending a simple questionnaire to the subjects, trained surveyors visited them directly and helped them prepare the questionnaire, and also their height, weight

and blood pressure were measured directly. Thus the probable information bias due to self-report was minimized. The shortcoming of this study is that the survey relied only on the memory of responders regarding menopause. Since it would not be easy for elderly study subjects to recall their age at menopause precisely, the misclassification bias might occur in the classification of the groups by age at menopause. Nevertheless, in previous studies the recall of age at menopause has been reported to be accurate to a certain degree [35,36]. Through this study, the association of age at menopause with the risk of death, particularly due to cardiovascular disease and cancer, was validated, and the difference in mean age at menopause between Asian and Caucasian women was confirmed. Since this study was conducted on Korean subjects, it might be inadequate to apply it to all Asian women. Nevertheless, it is a rare and meaningful study conducted on Asian women regarding the relation between age at menopause and the risk of death based on the data of a long-term cohort study. Therefore, this study is expected to be utilized as an important basic data when postmenopausal health condition in Asian women and their major causes of death are examined. References [1] Greendale GA, Lee NP, Arriola ER. The menopause. Lancet 1999;353(9152):571–80. [2] Hill K. The demography of menopause. Maturitas 1996;23(2):113–27. [3] Mckinlay SM, Bifano NL, Mckinlay JB. Smoking and age at menopause in women. Ann Intern Med 1985;103(3):350–6. [4] Gruber CJ, Tschugguel W, Schneeberger C, Huber JC. Production and actions of estrogens. N Engl J Med 2002;346(5):340–52. [5] Huston JE, Linka LD. Perimenopause ‘change in women’s health after 35’. New Harbinger Publications, Inc.; 1997. [6] Rozenbaum H. Why has menopause become public health problem? Therapie 1998;53(1):49–59. [7] Mondul AM, Rodriguez C, Jacobs EJ, Calle EE. Age at natural menopause and cause-specific mortality. Am J Epidemiol 2005;162(11):1089–97. [8] Ossewaarde ME, Bots ML, Verbeek AL, et al. Age at menopause, cause-specific mortality and total life expectancy. Epidemiology 2005;16(4):556–62. [9] Jacobsen BK, Heuch I, Kvale G. Age at natural menopause and all-cause mortality: a 37-year follow-up of 19,731 Norwegian women. Am J Epidemiol 2003;157(10):923–9.

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