Menopause: The Journal of The North American Menopause Society Vol. 22, No. 1, pp. 1/3 DOI: 10.1097/gme.0000000000000385 * 2014 by The North American Menopause Society
EDITORIAL Early menopause and subsequent cardiovascular disease
C
ardiovascular disease (CVD) kills one in three women worldwide.1 Although the risk of CVD in women before menopause is relatively low, the risk increases markedly after the cessation of ovarian function in menopause.2 Whether the loss of cardioprotection is entirely attributable to the dramatic decline in estradiol levels after menopause, however, remains unclear. Menopausal transition is recognized as a time of significant changes in the vascular system, body fat distribution, blood pressure, and blood lipid levels,3 all of which contribute to increasing the risk of CVD. These observations have subsequently led to interest in understanding how the timing of menopause impacts CVD. Menopause occurs, on average, at age 51 years in Western populations, but age at onset is wide-ranging (approximately 40-60 y).4 Approximately 10% of women experience menopause before age 45 years, indicating either early cessation of reproductive function or culmination of accelerated reproductive aging throughout the premenopausal years. Women with early menopause consequently have a shorter total duration of premenopausal estrogen exposure than women with later menopause and are hypothesized to have an elevated risk of CVD. This relationship has indeed been observed for coronary heart disease,5,6 ischemic stroke,6,7 and total CVD.8 To date, few previous analyses have addressed whether early menopause also predicts heart failure (HF). HF is responsible for approximately a third of CVD deaths in women and is among the top causes of hospital admissions.1 Despite its high prevalence, relatively little attention has been paid to understanding sex differences in the etiology and presentation of HF, which are pronounced.9 The present study, conducted by Rahman et al,10 addressed the relationship of early onset of menopause with incidence of HF, with special consideration of the impact of smoking history. Study participants were members of the Swedish Mammography Cohort, which was established in 1987-1990. The present analysis included 22,256 women who, as of 1997, (1) had reached menopause; (2) had no history of HF, myocardial infarction, or cancer; (3) had not had a hysterectomy or bilateral oophorectomy; and (4) did not report menopause before age 40 years or after age 60 years. During approximately 14 years of follow-up, 2,216 women experienced an incident hospitalization for HF, and an additional 316 women died of HF, as identified through Swedish health registries. Rahman et al10 observed that early menopause was significantly associated with HF. In analyses adjusted for age, smoking, body mass index, hypertension, and a host of other factors, women experiencing menopause at ages 40 to 45 years
had a significant 36% higher risk of HF than women reporting menopause at ages 50 to 54 years (hazard ratio [HR], 1.36; 95% CI, 1.16 to 1.60). Risk was also modestly but significantly elevated in women reporting menopause at ages 46 to 49 years (HR, 1.13; 95% CI, 1.02 to 1.26). In analyses evaluating age at menopause continuously, each 1-year increase in menopausal age was associated with a 2% decrease in risk of HF (HR, 0.98; 95% CI, 0.96 to 0.99). Results did not suggest that smoking was an important modifier of these relations, as risk of HF in women reporting menopause at ages 40 to 45 years was nearly identical in those with and those without a history of smoking. However, among women reporting menopause at ages 46 to 49 years, risk of HF was elevated in ever smokers (HR, 1.28; 95% CI, 1.09 to 1.50), but not in never smokers (P for interaction = 0.02). Rahman et al10 concluded that women who experience menopause at younger ages are at increased risk for HF and that smoking can increase risk among women undergoing menopause at ages 46 to 49 years. These results are remarkably consistent with those observed by Ebong et al11 in the Multi-Ethnic Study of Atherosclerosis. To our knowledge, this is the only other study of menopause timing and HF risk conducted to date. Among 2,947 women in the Multi-Ethnic Study of Atherosclerosis who were followed for approximately 12 years, those reporting menopause before age 45 years had a 66% higher risk of HF compared with those with later menopause (HR, 1.66; 95% CI, 1.01 to 2.73). Each 1-year increase in age at menopause was associated with a 4% lower risk of HF (HR, 0.96; 95% CI, 0.94 to 0.99). Together, these two studies provide convincing evidence that early menopause is associated with increased risk of HF, as it is associated with increased risk of other cardiovascular conditions. The identification of early menopause as a predictor of CVD sets the stage for a second phase of investigation. The first essential question that must be addressed concerns temporality and how early menopause coincides with the natural history of CVD progression. Specifically, does early cessation of reproductive function or accelerated ovarian aging, as marked by early menopause, etiologically increase risk of CVD? Alternatively, does latent CVD cause reproductive aging and accelerate the onset of menopause? While acknowledging the potential for reverse causation to impact their findings, Rahman et al10 and Ebong et al11 were not able to address this phenomenon directly, as both studies included participants who were already postmenopausal at the start of follow-up. The potential for cardiovascular risk factors to lead to early menopause has been considered specifically in Menopause, Vol. 22, No. 1, 2015
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
1
EDITORIAL
an elegant work conducted by Koh et al12 in the Framingham Heart Study. In this cohort, 695 premenopausal women provided measures of relative weight, total cholesterol, systolic blood pressure, and diastolic blood pressure biennially from baseline; for each woman, between 2 and 13 sets of measurements were collected before menopause. This wealth of data permitted a comprehensive evaluation of how individual CVD risk profiles changed during the premenopausal period and how patterns of change affected menopause timing. Koh et al12 found that increases in cholesterol, relative weight, systolic blood pressure, and diastolic blood pressure before menopause were each associated with significant decreases in future age at menopause, even after adjustment for smoking. For example, in women whose total cholesterol increased during their premenopausal years, each 20-mg/dL increase was associated with a 2.6-year advance in the onset of menopause (A = j2.6; 95% CI, j4.06 to j1.14). Although these data do not preclude the possibility of a multidirectional relationship, they provide intriguing support for the hypothesis that cardiovascular health may contribute to menopause timing, and not solely the reverse. Recent studies also raised the question of whether a relationship between early menopause and CVD may be explained primarily by shared risk factors. Although relatively few prospective studies have evaluated how diet and lifestyle are associated with early menopause, accumulating data suggest that several established CVD risk factors may also affect menopause timing. For example, smoking has been associated with both early menopause and overall age at menopause in many studies.13 Because of the strong relationship of smoking with CVD risk, Rahman et al10 specifically evaluated in the present study whether the association between early menopause and HF risk was explained by smoking. Overall, their results did not support the hypothesis that smoking explained all of the observed associations but suggested that smoking history may have modified the impact of menopausal age on HF risk to some extent. In assessing whether menopause timing is an important predictor of CVD risk and therefore should be incorporated into prediction models, it is essential to better understand the role of CVD risk factors in early menopause. If relations are explained largely by the higher prevalence of smoking, physical inactivity, atherogenic diet, and other CVD risk factors among women with early menopause, then adding information on menopause timing to screening protocols will contribute little new information that is useful for CVD prevention. However, two alternatives are possible: (1) accelerated reproductive aging may be associated with CVD risk through other etiologic mechanisms, and this information may provide the foundation for novel interventions to improve cardiovascular health; or (2) accelerated reproductive aging, as marked by menstrual cycle changes in the 30s and menopause before age 45 years, may be among the earlier sentinels of elevated CVD risk. In this case, recognition of women with early reproductive decline as a high-risk population can move the window of opportunity for intervention substantially earlier.
2
Menopause, Vol. 22, No. 1, 2015
Both of these possibilities underscore the need to further evaluate how reproductive aging and CVD health intersect in premenopausal women. Addressing these questions will undoubtedly require large-scale prospective studies enrolling younger premenopausal women and following them through menopause and well into older life. These efforts will also be strengthened by expanding the evaluation of biomarkers of reproductive aging. Recent studies have focused on the role of antimu¨llerian hormone (AMH), a glycoprotein produced by granulosa cells of primary follicles during follicular maturation.4 In premenopausal women, AMH is strongly correlated with the size of the antral follicle pool and has been established as a sensitive biomarker of ovarian reserve and ovarian age.14 Population-based studies have consistently found AMH level to be a better predictor of time to menopause than chronologic age.15
EDITORIAL Early menopause and subsequent cardiovascular disease
C
ardiovascular disease (CVD) kills one in three women worldwide.1 Although the risk of CVD in women before menopause is relatively low, the risk increases markedly after the cessation of ovarian function in menopause.2 Whether the loss of cardioprotection is entirely attributable to the dramatic decline in estradiol levels after menopause, however, remains unclear. Menopausal transition is recognized as a time of significant changes in the vascular system, body fat distribution, blood pressure, and blood lipid levels,3 all of which contribute to increasing the risk of CVD. These observations have subsequently led to interest in understanding how the timing of menopause impacts CVD. Menopause occurs, on average, at age 51 years in Western populations, but age at onset is wide-ranging (approximately 40-60 y).4 Approximately 10% of women experience menopause before age 45 years, indicating either early cessation of reproductive function or culmination of accelerated reproductive aging throughout the premenopausal years. Women with early menopause consequently have a shorter total duration of premenopausal estrogen exposure than women with later menopause and are hypothesized to have an elevated risk of CVD. This relationship has indeed been observed for coronary heart disease,5,6 ischemic stroke,6,7 and total CVD.8 To date, few previous analyses have addressed whether early menopause also predicts heart failure (HF). HF is responsible for approximately a third of CVD deaths in women and is among the top causes of hospital admissions.1 Despite its high prevalence, relatively little attention has been paid to understanding sex differences in the etiology and presentation of HF, which are pronounced.9 The present study, conducted by Rahman et al,10 addressed the relationship of early onset of menopause with incidence of HF, with special consideration of the impact of smoking history. Study participants were members of the Swedish Mammography Cohort, which was established in 1987-1990. The present analysis included 22,256 women who, as of 1997, (1) had reached menopause; (2) had no history of HF, myocardial infarction, or cancer; (3) had not had a hysterectomy or bilateral oophorectomy; and (4) did not report menopause before age 40 years or after age 60 years. During approximately 14 years of follow-up, 2,216 women experienced an incident hospitalization for HF, and an additional 316 women died of HF, as identified through Swedish health registries. Rahman et al10 observed that early menopause was significantly associated with HF. In analyses adjusted for age, smoking, body mass index, hypertension, and a host of other factors, women experiencing menopause at ages 40 to 45 years
had a significant 36% higher risk of HF than women reporting menopause at ages 50 to 54 years (hazard ratio [HR], 1.36; 95% CI, 1.16 to 1.60). Risk was also modestly but significantly elevated in women reporting menopause at ages 46 to 49 years (HR, 1.13; 95% CI, 1.02 to 1.26). In analyses evaluating age at menopause continuously, each 1-year increase in menopausal age was associated with a 2% decrease in risk of HF (HR, 0.98; 95% CI, 0.96 to 0.99). Results did not suggest that smoking was an important modifier of these relations, as risk of HF in women reporting menopause at ages 40 to 45 years was nearly identical in those with and those without a history of smoking. However, among women reporting menopause at ages 46 to 49 years, risk of HF was elevated in ever smokers (HR, 1.28; 95% CI, 1.09 to 1.50), but not in never smokers (P for interaction = 0.02). Rahman et al10 concluded that women who experience menopause at younger ages are at increased risk for HF and that smoking can increase risk among women undergoing menopause at ages 46 to 49 years. These results are remarkably consistent with those observed by Ebong et al11 in the Multi-Ethnic Study of Atherosclerosis. To our knowledge, this is the only other study of menopause timing and HF risk conducted to date. Among 2,947 women in the Multi-Ethnic Study of Atherosclerosis who were followed for approximately 12 years, those reporting menopause before age 45 years had a 66% higher risk of HF compared with those with later menopause (HR, 1.66; 95% CI, 1.01 to 2.73). Each 1-year increase in age at menopause was associated with a 4% lower risk of HF (HR, 0.96; 95% CI, 0.94 to 0.99). Together, these two studies provide convincing evidence that early menopause is associated with increased risk of HF, as it is associated with increased risk of other cardiovascular conditions. The identification of early menopause as a predictor of CVD sets the stage for a second phase of investigation. The first essential question that must be addressed concerns temporality and how early menopause coincides with the natural history of CVD progression. Specifically, does early cessation of reproductive function or accelerated ovarian aging, as marked by early menopause, etiologically increase risk of CVD? Alternatively, does latent CVD cause reproductive aging and accelerate the onset of menopause? While acknowledging the potential for reverse causation to impact their findings, Rahman et al10 and Ebong et al11 were not able to address this phenomenon directly, as both studies included participants who were already postmenopausal at the start of follow-up. The potential for cardiovascular risk factors to lead to early menopause has been considered specifically in Menopause, Vol. 22, No. 1, 2015
Copyright © 2014 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
1
EDITORIAL
an elegant work conducted by Koh et al12 in the Framingham Heart Study. In this cohort, 695 premenopausal women provided measures of relative weight, total cholesterol, systolic blood pressure, and diastolic blood pressure biennially from baseline; for each woman, between 2 and 13 sets of measurements were collected before menopause. This wealth of data permitted a comprehensive evaluation of how individual CVD risk profiles changed during the premenopausal period and how patterns of change affected menopause timing. Koh et al12 found that increases in cholesterol, relative weight, systolic blood pressure, and diastolic blood pressure before menopause were each associated with significant decreases in future age at menopause, even after adjustment for smoking. For example, in women whose total cholesterol increased during their premenopausal years, each 20-mg/dL increase was associated with a 2.6-year advance in the onset of menopause (A = j2.6; 95% CI, j4.06 to j1.14). Although these data do not preclude the possibility of a multidirectional relationship, they provide intriguing support for the hypothesis that cardiovascular health may contribute to menopause timing, and not solely the reverse. Recent studies also raised the question of whether a relationship between early menopause and CVD may be explained primarily by shared risk factors. Although relatively few prospective studies have evaluated how diet and lifestyle are associated with early menopause, accumulating data suggest that several established CVD risk factors may also affect menopause timing. For example, smoking has been associated with both early menopause and overall age at menopause in many studies.13 Because of the strong relationship of smoking with CVD risk, Rahman et al10 specifically evaluated in the present study whether the association between early menopause and HF risk was explained by smoking. Overall, their results did not support the hypothesis that smoking explained all of the observed associations but suggested that smoking history may have modified the impact of menopausal age on HF risk to some extent. In assessing whether menopause timing is an important predictor of CVD risk and therefore should be incorporated into prediction models, it is essential to better understand the role of CVD risk factors in early menopause. If relations are explained largely by the higher prevalence of smoking, physical inactivity, atherogenic diet, and other CVD risk factors among women with early menopause, then adding information on menopause timing to screening protocols will contribute little new information that is useful for CVD prevention. However, two alternatives are possible: (1) accelerated reproductive aging may be associated with CVD risk through other etiologic mechanisms, and this information may provide the foundation for novel interventions to improve cardiovascular health; or (2) accelerated reproductive aging, as marked by menstrual cycle changes in the 30s and menopause before age 45 years, may be among the earlier sentinels of elevated CVD risk. In this case, recognition of women with early reproductive decline as a high-risk population can move the window of opportunity for intervention substantially earlier.
2
Menopause, Vol. 22, No. 1, 2015
Both of these possibilities underscore the need to further evaluate how reproductive aging and CVD health intersect in premenopausal women. Addressing these questions will undoubtedly require large-scale prospective studies enrolling younger premenopausal women and following them through menopause and well into older life. These efforts will also be strengthened by expanding the evaluation of biomarkers of reproductive aging. Recent studies have focused on the role of antimu¨llerian hormone (AMH), a glycoprotein produced by granulosa cells of primary follicles during follicular maturation.4 In premenopausal women, AMH is strongly correlated with the size of the antral follicle pool and has been established as a sensitive biomarker of ovarian reserve and ovarian age.14 Population-based studies have consistently found AMH level to be a better predictor of time to menopause than chronologic age.15
