Menopause Live (09 January, 2012) from IMS

Tom and colleagues have recently reported that a later age at natural menopause was associated with increased all-cause and cardiovascular mortality [1]. The authors conducted an analysis of the data of the Iowa cohort of the Established Populations for the Epidemiologic Study of the Elderly (EPESE). The EPESE cohort is a longitudinal population-based study of adults aged 65 years and older in the United States. The study began in the early 1980s in several states. The Iowa cohort was the only EPESE cohort to ascertain information on menopause. A total of 2253 female study participants enrolled at baseline in 1981–1983. The presented analysis included 1684 women with complete data on menopause and all covariates.

Women were personally interviewed at baseline, where they reported the type and timing of their menopause. Type of menopause could only be categorized as natural or surgical; no request was made for further details on hysterectomy or ovariectomy. Women who reported another cause of menopause, did not know the cause, or did not answer the question were excluded from the analysis (n = 290). Information on vital status and cause of death was obtained through linkage with the National Death Index; follow-up was complete until 31 December 2005. Endpoints studied were total mortality and total cardiovascular mortality. The role of type of menopause was studied in all women, and the role of age at menopause only in naturally menopausal women.

Over a follow-up of 24 years, 1477 (87.7%) women died, and 41% of deaths could be attributed to cardiovascular diseases. Type of menopause was not related to all-cause, cardiovascular, or non-cardiovascular mortality. The risk of all-cause mortality moderately increased with older age at natural menopause (p = 0.03 for linear trend). Women with age at natural menopause ≥ 55 years had a 29% increased rate of cardiovascular mortality (hazard ratio 1.29; 95% confidence interval 1.02–1.63), compared with women with natural menopause at age 50–54 years. Further adjustment of confounding variables did not attenuate this relationship. Age at surgical menopause was not related to mortality risk.

Comment
The fact that type of menopause was not related to mortality might be explained by the fact that natural menopause could only be contrasted with surgical menopause, which only occurred in women with a combination of hysterectomy and ovariectomy. 

The findings of Tom and colleagues for age at natural menopause seem to be in contradiction with what has been previously reported [2-7]. However, this study differs in more respects to the previously published data than just the results. Data on 25% of the population had to be discarded because there was no information on menopause. This is a substantial part of the population, and it is unclear whether this was differential and how this may have affected the findings. As was also mentioned by the authors, women had to remember their age at menopause late in life, which may have been difficult and not fully correct, in particular for women with a young age at natural menopause. The Iowa EPESE cohort included women from age 65 and older. Most of the previous studies included women at younger ages. Women who died before the age of 65 were by definition not included in the Iowa EPESE study. If this early mortality was related to early menopause, a different association might have been found if those women had been included. Looking closely at the previously published studies, it appears that several others have suggested that the association of age at menopause with mortality risk is not stable over the total lifetime. The Dutch study estimated the effect of each year of delay in menopause as a reduction in annual hazard of 3% for a woman of biological age 65, 2% for a 70-year-old, 1% for a 75-year-old, and no reduction for an 80-year-old [2]. Also, the Norwegian study shows that the inverse relationship between age at menopause and mortality risk was weaker in women aged 70–79 years, whereas, in older women no relationship was indicated. A test for a linear change in the effect of age at menopause with advancing age was statistically significant (p = 0.01) [3]. 

After Jacobsen and colleagues reported some evidence of a U-shaped association, i.e. an increased risk of ischemic heart disease also in women with a very late menopause (> 55 years) [5] in the Adventist Health Study, they re-analyzed the Norwegian data in this particular respect. Although the data were not fully clear, the data did support a U-shaped association in women between 70 and 79 years. On women aged 80 and over, no association was present at all [6]. Therefore, the observation that an early age at menopause is a risk mainly for women under 70 seems to be pretty consistent. Whether the risk increases at later ages or fades out remains to be elucidated. How to explain this finding is still unknown, although it is also known for some time for other cardiovascular risk factors that associations are not constant with age. An analysis from another EPESE cohort established in Connecticut reported a lack of an association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years [8]. Also blood pressure and body mass index have different relationships with mortality in older persons [9,10]. Thus, at closer inspection, Tom’s findings seem to be consistent with the current evidence base, although explanations remain to be found.

Yvonne T. van der Schouw
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

References
1. Tom SE, Cooper R, Wallace RB, Guralnik JM. Type and timing of menopause and later life all-cause and cardiovascular mortality among women in the Iowa EPESE cohort. J Womens Health (Larchmt) 2011 Oct 4. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/21970557
2. van der Schouw YT, van der Graaf Y, Steyerberg EW, Eijkemans JC, Banga JD. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996;347:714-18.
http://www.ncbi.nlm.nih.gov/pubmed/8602000
3. Jacobsen BK, Nilssen S, Heuch I, Kvåle G. Does age at natural menopause affect mortality from ischemic heart disease? J Clin Epidemiol 1997;50:475-9.
http://www.ncbi.nlm.nih.gov/pubmed/9179106
4. Cooper GS, Sandler DP. Age at natural menopause and mortality. Ann Epidemiol 1998;8:229-35.
http://www.ncbi.nlm.nih.gov/pubmed/9590601
5. Jacobsen BK, Knutsen SF, Fraser GE. Age at natural menopause and total mortality and mortality from ischemic heart disease: the Adventist Health Study. J Clin Epidemiol 1999;52:303-7.
http://www.ncbi.nlm.nih.gov/pubmed/10235170
6. Jacobsen BK, Heuch I, Kvåle G. Age at natural menopause and all-cause mortality: a 37-year follow-up of 19,731 Norwegian women. Am J Epidemiol 2003;157:923-9.
http://www.ncbi.nlm.nih.gov/pubmed/12746245
7. Ossewaarde ME, Bots ML, Verbeek AL, et al. Age at menopause, cause-specific mortality and total life expectancy. Epidemiology 2005;16:556-62.
http://www.ncbi.nlm.nih.gov/pubmed/15951675
8. Krumholz HM, Seeman TE, Merrill SS, et al. Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years. JAMA 1994;272:1335-40.
http://www.ncbi.nlm.nih.gov/pubmed/7772105
9. Boshuizen HC, Izaks GJ, van BS, Ligthart GJ. Blood pressure and mortality in elderly people aged 85 and older: community based study. BMJ 1998;316:1780-4.
http://www.ncbi.nlm.nih.gov/pubmed/9624064
10. Breeze E, Clarke R, Shipley MJ, Marmot MG, Fletcher AE. Cause-specific mortality in old age in relation to body mass index in middle age and in old age: follow-up of the Whitehall cohort of male civil servants. Int J Epidemiol 2006;35:169-78.
http://www.ncbi.nlm.nih.gov/pubmed/16284405