28 July, 2014

The average age of natural menopause is about 51 years. In the absence of hormone therapy, systemic exposures to ovarian hormones are greatly reduced after menopause, with consequences that vary by organ or tissue. Health-related effects are likely to be more pronounced after premature menopause, defined by menopause at age 40 years or younger.

Potential effects of premature menopause might include an elevated risk of developing dementia later in life and greater age-related cognitive decline in the absence of dementia. Few studies, however, have considered these outcomes after premature menopause or have assessed long-term cognitive outcomes after surgical menopause (bilateral oophorectomy) separately from natural menopause. The latter is potentially important because surgical menopause is distinguished not only by younger age – by definition, surgical menopause is induced before the age at which natural menopause would have occurred – but also by abrupt transition and by lower levels of testosterone (derived in part after natural menopause from the ovarian stroma), in addition to low levels of estradiol, estrone, and progesterone [1].

These issues were examined by Ryan and colleagues in the population-based Three-City Study, based in the French cities of Montpellier, Bordeaux, and Dijon [2]. Women (n = 4868) were aged 65 years and older at the time of recruitment (mean age 75 years), and investigators examined cognitive outcomes in relation to age at menopause and to type of menopause (natural or surgical). Ten percent of women reported surgical menopause, and 7.6% reported a premature menopause. Well-defined procedures were in place to diagnose dementia and to detect cognitive decline. About 10.5% of 3739 women followed longitudinally developed dementia. Alzheimer's disease was not assessed separately from all-cause dementia, and analyses were not adjusted for multiple comparisons.

Comment

Dementia risk

Neither premature menopause (hazard ratio (HR) 1.2, 95% confidence interval (CI) 0.76–2.0, p = 0.40) nor surgical menopause (HR 0.89, 95% CI 0.51–1.4, p = 0.83) was associated with the risk of all-cause dementia. These results can be compared to findings from Olmsted County, Minnesota [3], and from a large, national cohort in Denmark [4], both focused on surgical menopause. In Olmsted County, bilateral oophorectomy below age 49 years (but not after this age) was associated with increased risk of late-life cognitive impairment or dementia (HR 1.9, 95% CI 1.3–2.8). This risk was not apparent in the subgroup of Minnesota women who used hormone therapy up until age 50 years. In the Three-City Study, however, dementia risk was unrelated to hormone therapy use.

In the Danish national cohort, the relation between surgical menopause and late-onset dementia could not be reliably assessed (incomplete datasets). For early-onset dementia, however, hysterectomy with bilateral oophorectomy was associated with increased risk (relative risk 2.3, 95% CI 1.4–3.8 for dementia before age 50; relative risk 1.3, 95% CI 1.0–1.6 for dementia between ages 50 and 59). Potential modifying effects of hormone therapy on dementia risk were not examined.

Cognition and cognitive decline

Women in the Three-City Study were serially assessed with four neuropsychological tests, yielding five cognitive outcomes. Compared to women undergoing menopause after age 50, premature menopause was associated with higher risk of poor cognitive performance (lowest quintile) on two of five tests. These were tests of verbal fluency (HR 1.6, 95% CI 1.1–1.9) and visual memory (HR 1.4, 95% CI 1.1–1.8). Verbal memory was not assessed. Interestingly, and difficult to reconcile, use of hormone therapy around the time of premature menopause was associated with even worse verbal fluency but better visual memory. Over a period of 7 years, the risk of substantial cognitive decline (lowest quintile) among women with premature menopause, when compared to women undergoing menopause after age 50 years, was increased by about a third on two neuropsychological measures: psychomotor speed (assessed with the Trail Making Test, part A; HR 1.4, 95% CI 1.1–1.7) and global cognition (Mini-Mental State examination; HR 1.4, 95% CI 1.1–1.7). Surgically menopausal women as a group (all ages combined) were not at increased risk of large decline on any measure. Women who underwent menopause between ages 41 and 49 years did not face elevated risks of substantial cognitive decline.

Conclusions

Findings from the Three-City Study [2] support the view that menopause before age 40 has adverse consequences on some cognitive skills later in life and on cognitive aging. Results, however, failed to link premature menopause – whether surgical or natural – to dementia after age 65 years. This finding is not fully congruent with prior reports [3,4], but differences in approaches and populations could be important. The overall conclusion is that long-term cognitive outcomes of premature menopause are of concern, and further research will be needed to delineate the risks more clearly. At the same time, results provide partial reassurance to women who undergo menopause after age 40 years, recognizing that findings reported from other populations are less benign.

Victor W. Henderson
Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University, USA

References

1. Henderson VW, Sherwin BB. Surgical versus natural menopause: cognitive issues. Menopause 2007;14:572-9
http://www.ncbi.nlm.nih.gov/pubmed/17476147
2. Ryan J, Scali J, Carriere I, et al. Impact of a premature menopause on cognitive function in later life. BJOG 2014 May 7. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/24802975
3. Rocca WA, Bower JH, Ahlskog JE, Grossardt BR, de Andrade M, Melton LJ, 3rd. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology 2007;69:1074-83
http://www.ncbi.nlm.nih.gov/pubmed/17761551
4. Phung TK, Waltoft BL, Laursen TM, et al. Hysterectomy, oophorectomy and risk of dementia: a nationwide historical cohort study. Dement Geriatr Cogn Disord 2010;30:43-50
http://www.ncbi.nlm.nih.gov/pubmed/20689282