Premature Natural Menopause Research Articles

The role of sex hormone binding globulin levels in the association of surgical and natural premature menopause with incident type 2 diabetes

ObjectiveTo examine associations of surgical and natural menopause before the age of 40 years with the risk of type 2 diabetes (T2D) in women. MethodsA total of 273,331 women from the United Kingdom were recruited between 2006 and 2010 in the UK Biobank (UKB) study, and 146,343 women aged 40 to 69 years who were postmenopausal at baseline were included in the analysis. Surgical menopause and natural premature menopause were defined as bilateral oophorectomy before the age of 40 and menopause before the age of 40 without oophorectomy, respectively. Multivariable Cox regression models were used to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between premature menopause and the incidence of T2D. ResultsDuring a median follow-up of 10.4 years, 47 women with surgical premature menopause, 244 women with natural premature menopause, and 4724 women without premature menopause developed T2D. Compared with women without premature menopause, both surgical premature menopause (adjusted HR = 1.46, 95 % CI: 1.09–1.95; P = 0.01) and natural premature menopause (adjusted HR = 1.20, 95 % CI: 1.06–1.37; P < 0.01) were associated with higher risks of incident T2D in the multivariable-adjusted models. Additionally, we observed a significant interaction between levels of sex hormone binding globulin (SHBG) (Pinteraction < 0.01) and the effects of premature menopause on incident T2D. The association between premature menopause and T2D risk appeared to be stronger in women with higher SHBG levels. Furthermore, a joint association was detected between premature menopause and the genetic risk score (GRS) of T2D, with a higher score indicating a higher risk of developingT2D. The highest risk of T2D was observed with higher T2D GRS and surgical premature menopause (adjusted HR = 2.61, 95 % CI: 1.65–4.12; P < 0.01). ConclusionsSurgical menopause and natural menopause before the age of 40 years were associated with an increased risk of T2D among postmenopausal women. The findings also suggest potential interactions of premature menopause with SHBG levels, with the association appearing to be stronger in higher SHBG levels, as well as a joint association between menopause status and genetic risk factors on T2D incidence.

Natural premature menopause relates to higher risk of mild cognitive impairment and Alzheimer’s disease and related dementias in APOE‐ε4 carriers only

AbstractBackgroundOverall risk of Alzheimer’s disease (AD) and APOE‐ε4‐related risk for AD is higher among women than men, but the sex‐specific biological underpinnings of these sex differences are unknown. Earlier age at menopause has been associated with higher risk of AD and related dementias (ADRD); however, it is unclear whether this relationship holds among naturally menopausal (versus surgically menopausal) women only or whether it is impacted by APOE‐ε4 genetic risk. We examined the association of natural premature (occurring ≤40 years of age) menopause with MCI and ADRD risk among older women and whether this relationship was moderated by APOE‐ε4 genotype.MethodThis study included 3,557 older women (age range: 65‐79 years at baseline; all White; 5.3% premature menopause; 25.5% APOE‐ε4 carriers) from the Women’s Health Initiative Memory Study (WHIMS) who experienced menopause spontaneously and not as a result of hysterectomy or bilateral oophorectomy. All participants had data on reproductive history, APOE genotype and longitudinal cognitive evaluations, and were cognitively unimpaired at baseline (follow‐up time: range = 0.92‐24.19, mean = 9.92 years). Incident MCI and ADRD were determined with a comprehensive neuropsychological battery and centrally adjudicated by a panel of specialists with expertise in dementia diagnosis. A set of Cox regression models was applied to determine whether premature menopause and its interaction with APOE‐ε4 carrier status was associated with risk of MCI or ADRD, adjusting for age, education, cardiovascular risk factors, parity, age at menarche, past contraceptive use and current or past hormone therapy use and the timing of initiation relative to menopause.ResultThe APOE‐ε4 X premature menopause interaction was significant (p = .04). Among APOE‐ε4 allele carriers, premature (vs. non‐premature) menopause was associated with an approximate two‐fold increased risk of MCI/ADRD (HR = 2.05, 95%CI: 1.22‐3.44). No such association was present among women without an APOE‐ε4 allele (HR = 1.16, 95%CI: 0.72‐1.86).ConclusionNatural premature vs non‐premature menopause was associated with two‐fold higher risk of MCI/ADRD but only among APOE‐ε4 carriers. Results suggest interactive effects of premature menopause and the APOE‐ε4 genotype. Future studies are needed to determine whether the menopause and APOE‐ε4 pathophysiological mechanisms of dyslipidemia, inflammation and brain metabolism deficiencies may explain this association.

Premature menopause among women in India: Evidence from National Family Health Survey-IV.

Women who experience premature menopause either due to biological or induced reasons have a longer duration of exposure to severe symptoms and adverse health consequences when compared to those who undergo menopause at later age. Despite the fact that premature menopause has a profound effect on the health of women, there has been limited study on this issue. Therefore, this study attempted to determine the prevalence and factors associated with premature menopause among 302 557 women aged 25-39 years in India. This study utilized secondary data from the fourth round of the National Family Health Survey-IV (NFHS-4), conducted during 2015-2016 in India. Descriptive statistics and multinomial logistic regression were used for statistical analyses of the data. The results revealed that the prevalence of premature menopause in this sample of Indian women was 3.7%, out of which 2.1% of women had experienced natural premature menopause, whereas 1.7% had surgical premature menopause. The prevalence of premature menopause was highest in the southern region of India. Factors like age, education, wealth index, place of residence, smoking status, children ever born, age at first birth, use of hormonal contraception, sterilization, and body mass index were found to be associated with premature menopause in India. A sizeable proportion of women in India are attaining menopause prematurely. Furthermore, the percentage and likelihood of experiencing premature menopause are relatively high among rural women, women with higher parity, early age at childbearing, and women who smoke.

Impact of premature natural menopause on body composition and physical function in elderly women: A Korean frailty and aging cohort study.

Induced premature menopause accelerates the rate of body composition changes (decrease in skeletal muscle mass and increase in fat mass) and deteriorating physical function. However, few studies have focused on the impact of premature natural menopause. This study aimed to investigate the impact of age at natural menopause (ANM) on body composition and physical function in elderly women.Using data from the Korean Frailty and Aging Cohort Study, 765 community-dwelling elderly women aged 70 to 85 years who experienced natural menopause were recruited in this study. Body composition was measured using dual-energy X-ray absorptiometry. Physical function was evaluated by grip strength, the timed up and go test (TUG), and the short physical performance battery (SPPB). Participants were categorized into 4 groups according to their ANM: <40 (premature natural menopause, PNM), 40 to 44 (early natural menopause, ENM), 45 to 54 (normal menopause, NM), and ≥55 (late menopause, LM) years.There were no significant differences in the body composition parameters, such as the appendicular skeletal muscle mass index (PNM: 5.90 ± 0.90 vs ENM: 5.91 ± 0.70 vs NM: 5.85 ± 0.73 vs LM: 5.90 ± 0.75, kg/m2, P = .75) and trunk fat mass index (PNM: 19.4 ± 3.9 vs ENM: 19.9 ± 4.4 vs NM: 19.9 ± 3.9 vs LM: 20.0 ± 3.8, %, P = .87) between the groups. In the physical function evaluation, there was no significant difference between the groups in grip strength (PNM: 19.8 ± 0.6 vs ENM: 20.3 ± 0.4 vs NM: 20.6 ± 0.2 vs LM: 20.6 ± 0.4, kg, P = .53). However, in the TUG (PNM: 11.8 ± 0.4 vs ENM: 10.3 ± 0.3 vs NM: 10.6 ± 0.1 vs LM: 10.2 ± 0.3, seconds, P < .01) and SPPB (PNM: 10.0 ± 0.2 vs ENM: 10.5 ± 0.2 vs NM: 10.6 ± 0.1 vs LM: 10.8 ± 0.2, points, P < .05), the PNM group showed significantly lower values than the other groups did. There was no difference in physical function between the groups except the PNM.Premature natural menopause did not affect the body composition in elderly women but was associated with physical function deterioration. Therefore, more attention should be paid to the prevention of the physical function deterioration caused by premature natural menopause in elderly women.

Abstract 012: Association Between Premature Menopause And Lifetime Risk Of Coronary Heart Disease: Lifetime Risk Pooling Project

Introduction: Menopause before the age of 40 years is recognized as a risk enhancer for coronary heart disease (CHD) by the 2019 AHA/ACC Primary Prevention guidelines. Race-specific prevalence of premature menopause and its association with lifetime risk of CHD morbidity and mortality have not been well described in Black and White women, and could inform risk stratification and intensity of prevention efforts. Hypothesis: We hypothesized that Black and White women who experience premature menopause (&lt;40 years) will have similarly elevated lifetime burden of CHD compared with women of the same race who do not have premature menopause. Methods: We pooled individual-level data from Black and White postmenopausal women aged 55-69 years from 6 US population-based cohorts. We included women without CHD at baseline and excluded women who reported surgical menopause. We defined premature menopause as age &lt;40 years. We performed (1) modified Kaplan Meier analysis and (2) competing Cox models to estimate joint cumulative risk for CHD or non-cardiovascular death adjusted for age, smoking, education, obesity, hypertension, and diabetes. Results: Of the 3522 Black women and 6514 White women, mean ages were 61.2 ± 4.3 and 60.0 ± 4.4 years, respectively. Premature menopause (&lt;40 years) occurred more commonly in Black (15.5%) compared with White (4.8%) women. Lifetime risk of CHD was higher in Black and White women with premature menopause ( Figure ). Hazard ratios adjusted for risk factors and accounting for competing risk of death were higher in Black (1.41 [1.04, 1.90]) and White (1.39 [1.03, 1.87]) women with premature menopause compared those Black and White women without premature menopause, respectively. Conclusions: Black women are three times more likely to experience premature natural menopause (&lt;40 years) than White women. Premature menopause is independently associated with 40% higher risk of CHD in both Black and White women and should be assessed as a risk-enhancing feature in clinical prevention decisions.

The Impact of Premature Menopause on Future Risk of Cardiovascular Disease

Cardiovascular disease remains the leading cause of morbidity and mortality for women in the USA. Recent multi-society guideline updates endorse using a history of premature menopause, defined as occurring before age 40 years, as a risk-enhancing factor for atherosclerotic cardiovascular disease risk assessment in women. Here, we review recent literature on cardiovascular disease risk in women with premature menopause, possible mechanisms linking premature menopause to cardiovascular disease, and the role of menopausal hormone therapy in postmenopausal women. Large cohort studies and meta-analyses have demonstrated significant associations between premature menopause and development of diverse cardiovascular diseases. In addition to atherosclerotic cardiovascular disease, recent studies have noted accelerated development of valvular heart disease and venous thromboembolism. Surgical premature menopause may be associated with greater risk of cardiovascular disease compared with natural premature menopause; further research to clarify differential risk and relevant underlying mechanisms is needed. Although the cardiovascular risks of menopausal hormone therapy appear largely restricted to women over age 60 years and more than 10 years post-menopause, data do not demonstrate convincing cardiovascular protective benefit in any age group. Premature menopause is associated with elevated future risk of diverse cardiovascular diseases. Further studies are needed to further elucidate mechanisms and identify novel preventive strategies.

Abstract 15887: Clonal Hematopoiesis Links Premature Menopause to Cardiovascular Disease

Introduction: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. Methods: We included postmenopausal women from the UK Biobank (N=11,509) aged 40-70 years with whole exome sequences and from the Women’s Health Initiative (WHI, N=8,111) aged 50-79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of (1) any CHIP and (2) CHIP with variant allele fraction (VAF) &gt;0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components, smoking, diabetes mellitus, and hormone therapy use. Results: Across cohorts, prevalence of CHIP in women with vs. without a history of premature menopause was 8.8% vs. 5.5% (P&lt;0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP, driven by associations with natural premature menopause (OR for all CHIP: 1.73, 95% CI 1.23-2.44; OR for CHIP with VAF &gt;0.1: 1.91, 95% CI 1.30-2.80; Figure ). In gene-specific analyses, DNMT3A CHIP had a strong association with natural premature menopause but no association with surgical premature menopause. Among postmenopausal middle-aged women in the UK Biobank and WHI, CHIP was independently associated with incident coronary artery disease (meta-analyzed HR 1.52, 95% CI 1.17-1.99). Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP. CHIP may contribute to the excess cardiovascular risk associated with premature menopause.

Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.

Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. We included postmenopausal women from the UK Biobank (n=11 495) aged 40 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of any CHIP and CHIP with variant allele frequency >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease. The sample included 19 606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with versus without a history of premature menopause was 8.8% versus 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; P=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; P=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; P=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; P<0.001) but smaller and nonsignificant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; P=0.012; hazard ratio associated with CHIP with variant allele frequency >0.1: 1.48 [95% CI, 1.13-1.94]; P=0.005). Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.

Association of Premature Natural and Surgical Menopause With Incident Cardiovascular Disease

Recent guidelines endorse using history of menopause before age 40 years to refine atherosclerotic cardiovascular disease risk assessments among middle-aged women. Robust data on cardiovascular disease risk in this population are lacking. To examine the development of cardiovascular diseases and cardiovascular risk factors in women with natural and surgical menopause before age 40 years. Cohort study (UK Biobank), with adult residents of the United Kingdom recruited between 2006 and 2010. Of women who were 40 to 69 years old and postmenopausal at study enrollment, 144 260 were eligible for inclusion. Follow-up occurred through August 2016. Natural premature menopause (menopause before age 40 without oophorectomy) and surgical premature menopause (bilateral oophorectomy before age 40). Postmenopausal women without premature menopause served as the reference group. The primary outcome was a composite of incident coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism. Secondary outcomes included individual components of the primary outcome, incident hypertension, hyperlipidemia, and type 2 diabetes. Of 144 260 postmenopausal women included (mean [SD] age at enrollment, 59.9 [5.4] years), 4904 (3.4%) had natural premature menopause and 644 (0.4%) had surgical premature menopause. Participants were followed up for a median of 7 years (interquartile range, 6.3-7.7). The primary outcome occurred in 5415 women (3.9%) with no premature menopause (incidence, 5.70/1000 woman-years), 292 women (6.0%) with natural premature menopause (incidence, 8.78/1000 woman-years) (difference vs no premature menopause, +3.08/1000 woman-years [95% CI, 2.06-4.10]; P < .001), and 49 women (7.6%) with surgical premature menopause (incidence, 11.27/1000 woman-years) (difference vs no premature menopause, +5.57/1000 woman-years [95% CI, 2.41-8.73]; P < .001). For the primary outcome, natural and surgical premature menopause were associated with hazard ratios of 1.36 (95% CI, 1.19-1.56; P < .001) and 1.87 (95% CI, 1.36-2.58; P < .001), respectively, after adjustment for conventional cardiovascular disease risk factors and use of menopausal hormone therapy. Natural and surgical premature menopause (before age 40 years) were associated with a small but statistically significant increased risk for a composite of cardiovascular diseases among postmenopausal women. Further research is needed to understand the mechanisms underlying these associations.

Bempedoic Acid for Lowering LDL Cholesterol

Importance Recent guidelines endorse using history of menopause before age 40 years to refine atherosclerotic cardiovascular disease risk assessments among middle-aged women. Robust data on cardiovascular disease risk in this population are lacking. Objective To examine the development of cardiovascular diseases and cardiovascular risk factors in women with natural and surgical menopause before age 40 years. Design, Setting, and Participants Cohort study (UK Biobank), with adult residents of the United Kingdom recruited between 2006 and 2010. Of women who were 40 to 69 years old and postmenopausal at study enrollment, 144 260 were eligible for inclusion. Follow-up occurred through August 2016. Exposures Natural premature menopause (menopause before age 40 without oophorectomy) and surgical premature menopause (bilateral oophorectomy before age 40). Postmenopausal women without premature menopause served as the reference group. Main Outcomes and Measures The primary outcome was a composite of incident coronary artery disease, heart failure, aortic stenosis, mitral regurgitation, atrial fibrillation, ischemic stroke, peripheral artery disease, and venous thromboembolism. Secondary outcomes included individual components of the primary outcome, incident hypertension, hyperlipidemia, and type 2 diabetes. Results Of 144 260 postmenopausal women included (mean [SD] age at enrollment, 59.9 [5.4] years), 4904 (3.4%) had natural premature menopause and 644 (0.4%) had surgical premature menopause. Participants were followed up for a median of 7 years (interquartile range, 6.3-7.7). The primary outcome occurred in 5415 women (3.9%) with no premature menopause (incidence, 5.70/1000 woman-years), 292 women (6.0%) with natural premature menopause (incidence, 8.78/1000 woman-years) (difference vs no premature menopause, +3.08/1000 woman-years [95% CI, 2.06-4.10]; P Conclusions and Relevance Natural and surgical premature menopause (before age 40 years) were associated with a small but statistically significant increased risk for a composite of cardiovascular diseases among postmenopausal women. Further research is needed to understand the mechanisms underlying these associations.

Premature natural menopause and cognitive function among older women in Indonesia

ABSTRACT We examine the association between premature natural menopause and cognitive function among older women in Indonesia. Data come from Indonesia Family Life Survey (IFLS) 2014 (N = 1,031 menopausal women). Multilevel ordered logistic regression was used to take into account unobserved factors in the women’s communities, also considering a range of potential confounding factors including their reproductive histories, lifestyles, and sociodemographic characteristics. The findings show that premature natural menopause was significantly associated with lower cognitive function in later life (ß = −0.97, P< .01, CI −1.61-(−0.33)). The findings were robust against potential confounding factors including reproductive history, lifestyle, and sociodemographic characteristics.

Early menarche and premature natural menopause in Indonesia

Background: An association has been suggested between early menarche and premature natural menopause. However, existing studies in developed countries show mixed findings.Aim: This study examined whether early menarche (first menstrual period ≤11 years old) is a factor for premature natural menopause (final menstrual period <40 years old) in the context of a developing country.Subjects and methods: Data came from the Indonesia Family Life Survey (IFLS) 2014, which consists of 1608 post-menopausal women.Results: Results of hierarchical logistic regression show that women who experienced early menarche (first menstrual period ≤11 years old) were found to be at higher risk of premature natural menopause (β = 0.94, p < 0.01, CI = 0.24–1.63). The results are robust against potential confounding factors including individual reproductive history, lifestyle and sociodemographic characteristics, as well as unobserved factors at the household and community levels.Conclusion: The findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with premature natural menopause.

Frequency of premature menopause in women who carry a BRCA1 or BRCA2 mutation

To evaluate the impact of carrying a BRCA1 or BRCA2 mutation on the probability of experiencing premature natural menopause. Observational study. Patients in an academic research environment. Women who carry a BRCA1 or BRCA2 mutation (case subjects) and women who do not carry a mutation (control subjects). Survey about reproductive history administered on study entry and every 2 years thereafter. The impact of carrying a BRCA mutation on age at menopause and other factors, including parity, age at first birth, age at last birth, and self-reported fertility. A total of 908 matched pairs were identified. The mean age at natural menopause was 48.8 years for BRCA1 carriers, 49.2 years for BRCA2 carriers, and 50.3 years for control subjects. Women who carried a BRCA mutation had parity similar to noncarriers and were as likely as noncarriers to have a child after age 35 years. Similar proportions reported a history of fertility problems (12.5% vs. 13.7%) and use of fertility medication (6.0% vs. 7.0%). Women who carry a BRCA mutation experience menopause earlier, on average, than women who do not have a mutation, but the difference is small and does not appear to affect fertility.

Clinical review 162: cardiovascular endocrinology 3: an epidemiologist looks at hormones and heart disease in women.

More than 100 yr ago, Osler (1) noted that heart disease was almost entirely a disease of men. Fifty years ago, the most popular explanations for sex differences in heart disease were lifestyle, particularly cigarette smoking (which was mainly a male habit until World War II), or differences in stress (i.e. men in the workforce and women at home, or what I like to call the “happy homemaker hypothesis”) (2). Although behavior and occupation differences may play a role, neither has emerged as a satisfactory explanation for women’s favored cardiovascular status. As shown in Fig. 1, women in every country, whether heart disease rates are high or low, are at lower risk of fatal coronary heart disease (CHD) compared with men, despite diverse lifestyles, diets, and workplace options (3). Indeed, within countries women have less heart disease than men when stratified by similar levels of classical heart disease risk factor levels. In the Renfrew and Paisley Survey (4), for example, sex-specific coronary death rates separately adjusted for cholesterol, blood pressure, body mass index, cigarette smoking, and social class showed that women had lower absolute rates at every age, although the relative risks associated with these risk factors were similar. This is also true for one factor that differs by sex, i.e. women’s higher high-density lipoprotein (HDL) cholesterol levels; within the same HDL strata, women have less heart disease than men (5). These results between and within populations and consistent across risk factors support the hypothesis that women are protected by an intrinsic factor, presumably female sex hormones. Several types of epidemiological evidence suggest that women’s universal protection against CHD is explained by estrogen (6, 7). The main observations are that CHD is 1) uncommon in women before the age of menopause, 2) more common in women who have a premature natural menopause, 3) more common in young women who have had both ovaries removed, and 4) less common in women who take hormone therapy (HT) after menopause. Population-based evidence that heart disease death rates increase after menopause is actually weak. An exponential increase in heart disease rates by age as observed in standard plots becomes a step-wise linear association when heart disease death rates are plotted on a semilogarithmic scale. There is no evidence of a different slope around age 50 yr, the usual age at menopause, as shown in Fig. 2 (8). As also shown in Fig. 2, this is in striking contrast to the midlife change in the semilogarithmic slope for breast cancer, an estrogen-dependent disease. These results could mean that estrogen is not such a primary player in heart disease etiology as it is for breast cancer, or that heart disease has a much more multifactorial etiology, making it more difficult to observe estrogen’s central role, or that estrogen is not the intrinsic factor. Some prospective epidemiological studies of individual women have shown small albeit significant associations of cardiovascular disease death with age at natural menopause (9, 10). These types of studies of menopause-CHD associations could be weak because the last menstrual period may not be accurately noted or because the lag to clinically manifest CHD is highly variable, because coronary disease has many other contributing risk factors. Note that these associations could also be an artifact due to confounding by cigarette smoking, the commonest cause for premature menopause and a powerful CHD risk factor. If premenopausal estrogen levels are cardioprotective, then premature menopause, with fewer years of exposure to premenopausal estrogen levels, should magnify risk. As reviewed elsewhere (6), many autopsy studies have demonstrated an excess of coronary artery atherosclerosis in young women who have had an oophorectomy. However, these observational studies of surgical menopause could be confounded by each woman’s reason for or reaction to early menopause, the reason for the autopsy, and possibly by the concomitant loss of other hormones (e.g. testosterone) after oophorectomy. Theoretically, studies of endogenous estrogen levels and Abbreviations: CEE, Conjugated equine estrogen; CHD, coronary heart disease; CI, confidence interval; HDL, high-density lipoprotein; HERS, Heart and Estrogen/Progestin Replacement Study; HT, hormone therapy; IMT, intimal medial thickness; LDL, low-density lipoprotein; MI, myocardial infarction; MP, micronized progesterone; MPA, medroxyprogesterone acetate; WHI, Women’s Health Initiative. 0021-972X/03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(9):4031–4042 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2003-030876

Bone density patterns after normal and premature menopause

Objectives: The investigation of the effect of time and type of menopause on bone mineral density (BMD) at different ages. Methods: Five hundred and fourteen women, who had never received any hormonal substitution were studied in a cross-sectional design: 177 with normal (NMP), 210 with surgical (SUMP) and 127 with premature natural (EMP) menopause. Age at menopause was 49.1±3.9, 38.3±4.7 and 38.1±4.2 years (mean±1 S.D.), respectively. BMD was measured at L2–L4 vertebrae and proximal femur by the DEXA method. Results: EMP women presented significantly lower vertebral BMD than NMP women in the 45–55-years segments ( P<0.001), but did not differ from SUMP women. This group exhibited lower vertebral BMD than NMP between 45 and 50 years ( P<0.001). Regarding femoral neck, EMP women exhibited lower values than SUMP in the 45–50 and 55–65 age segments ( P<0.001) whereas SUMP women presented significantly higher BMD values than NMP women after 55 years of age ( P<0.001). The percentages of women with vertebral BMD ( T-score values) in the osteoporotic range were significantly greater in EMP compared with either NMP or SUMP groups (both P<0.001) whereas in femoral neck lower in SUMP than the other two categories. Conclusions: Women with either natural or surgical premature menopause exhibit lower BMD of trabecular bone compared with normal menopause women at the age segments 45–55 and 45–50, respectively. However, surgical menopause women exceed normal menopause women in their mixed bone BMD values after 60 years as well as premature natural menopause women at almost all age segments.