Correspondence

Early age at natural menopause and risk of cardiovascular and all-cause mortality: A meta-analysis of prospective observational studies

To systematically review the evidence on the association between age at natural menopause (NM) and reproductive factors such as age at menarche, parity and ever use of oral contraceptives.

A literature search was carried out in PubMed, Scielo, Scopus and LILACS databases, without restriction of publication year until July 6, 2017. We excluded clinical trials, case-control studies, case reports and studies using statistical methods other than Cox proportional hazard models to assess the factors associated with age at NM. Cross-sectional studies evaluating women aged <50 years were also excluded. Random-effects models were used to pool the estimates. We registered the systematic review in the International Prospective Register of Systematic Review (PROSPERO) in August 2018, CRD42018099105.

We identified 30 articles to include in the meta-analysis. We found that previous ever use of oral contraceptives (OC) (HR = 0.87, CI = 0.82, 0.93), age at menarche ≥13 years (HR = 0.90, CI = 0.84, 0.96), and having at least one live birth (HR = 0.79, CI = 0.74, 0.85) were associated with a later age of NM.

Despite differences in results between countries and study design, our findings suggest that previous use of OC, age at menarche ≥13 and having at least one live birth are associated with later menopause. The results suggest that these factors could be markers of later ovarian aging.

Although both age at menarche and age at menopause may independently affect the risk of cardiovascular diseases and all-cause mortality, their joint association with mortality is less clear. The objectives of this study were to address the relationship between ages at menarche and at menopause with mortality among postmenopausal women.

The study included 75,359 U.S. postmenopausal women aged 50–78 years from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. Information on ages at menarche and menopause was self-reported and collected at baseline, by questionnaire.

All-cause, cardiovascular and cancer mortality.

After a median follow-up of 13 years, we identified 7826 deaths among 75,359 women in the PLCO cohort. Compared with women with an age at menarche of 12–13 years and an age at menopause of 45–54 years, the adjusted hazard ratios (95% confidence interval) for all-cause mortality for women with early menarche (≤11 years) and menopause (≤44 years) and those with late menarche (≥14 years) and menopause (≥55 years) were 1.20 (1.09, 1.32) and 0.82 (0.71, 0.96), respectively. This association remained significant in a sensitivity analysis that excluded women who did not undergo natural menopause. The indexes for the additive effect of the combined association showed no excess risk due to an interaction.

Early menarche and early menopause seemed to have an exactly additive effect on all-cause mortality. The findings suggest that it is important to evaluate ages at both menarche and menopause rather than to consider either variable on its own in assessing the risk of mortality.

While a mean age at menopause of 51 years has been reported in the United States (U.S.), some U.S. women experience menopause before age 45, possibly increasing risk of cardiovascular mortality; however, the role in all-cause and cerebrovascular-related mortality is unclear. The purpose of this study was to investigate the association between age at menopause and all-cause and cause-specific mortality by race, hormone replacement therapy (HRT) use, and smoking status. REasons for Geographic and Racial Differences in Stroke (REGARDS) is a population-based study of 30,239 participants aged ≥45 years enrolled between 2003 and 2007 of whom 14,361 were postmenopausal women. Age at menopause was defined as <45 (early) or ≥45. All-cause and cause-specific mortality were ascertained through 2013. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between age at menopause and mortality, adjusting for baseline measures. Of 11,287 eligible women (6403 white; 4884 black), mean menopause age was 45.2 (SD 7.9) with 1524 deaths over 7.1 years. Significant interactions were detected between early age at menopause (39%) and HRT use in association with all-cause mortality (p < 0.01), mortality from coronary heart disease (p = 0.06), and mortality from all other causes (p = 0.04). An association between early age at menopause and all-cause mortality was observed among ever-HRT users (HR = 1.31, 95% CI: 1.10–1.56), but not never-HRT users (HR = 1.01, 95% CI: 0.85–1.20). There were no differences in associations examined by race or smoking status. Increased all-cause mortality risk was observed for ever-HRT users with menopause before age 45.

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in women in spite of the overall reduction in age-adjusted CVD mortality in the past few years. Although traditional risk factors for CVD are predictors of increased risk in both men and women, risk factors that are unique to women and related to their reproductive history have recently been considered to be important. The development of CVD in women may correlate with specific events taking place throughout a woman's obstetric and gynaecological history. Gynaecological conditions such as polycystic ovary syndrome, premature ovarian failure, surgical and spontaneous menopause, and conditions related to pregnancy, i.e. gestational diabetes, preeclampsia, intrauterine growth restriction, miscarriages, and preterm birth, may affect the onset, clinical features, and prognosis of CVD later in women's lives. These pathological conditions that develop during the fertile period of life or peri-menopause have been suggested to be early markers of future CVD; their presence presents a unique opportunity for the early identification of women who may be at an increased risk of CVD. The assessment of CV risk in women should not just focus on conventional risk factors but also on different aspects of the gynaecological history to allow specific preventive and therapeutic strategies to be established.

This paper reviews the various pathological conditions occurring in women during their fertile period of life and peri-menopause, which have been identified to potentially increase CVD risk.

To conduct a survival analysis according to age at natural menopause (NM) in a representative sample of elderly women from the municipality of São Paulo, Brazil.

We analyzed data from the Health, Well-Being and Aging study (SABE), a cohort that started in 2000. Mortality data up to September 2016 were obtained by linkage from the Program for Mortality Information of São Paulo (PRO-AIM).

We used Cox regression to analyze all-cause and cause-specific mortality rates for cardiovascular diseases, respiratory diseases and cancer, according to age at menopause, categorized as <40, 41–44, 45–49, 50–54 (reference) and ≥55.

After 16 years of follow-up, there were 444 deaths, of which 199 were from cardiovascular diseases, 73 from respiratory diseases and 65 from cancer. After adjustment for socioeconomic, reproductive and lifestyle factors, having an early menopause (at age 41–44) was associated with an increased risk of all-cause mortality (HR = 1.48, 95% IC: 1.03, 2.14) relative to NM at 50–54 years. Women aged 41–44 and 45–49 at NM had twice the risk of cancer mortality of the reference group. We did not find significant associations between age at NM and cause-specific mortality for respiratory and cardiovascular diseases.

Our findings suggest that early menopause is associated with all-cause mortality in the largest city of Latin America. In addition, earlier age at NM was associated with cancer mortality. These results suggest that age at NM may be a biomarker for mortality, irrespective of country of residence.