Estrogen may be linked to a woman’s risk of developing dementia

Dementia rates have increased at an alarming rate around the world. In fact, some researchers have reported a higher incidence of dementia in women compared to men, with certain reproductive factors being associated with an increased risk of dementia. However, the use of hormones in women and their associations with dementia risk remain unclear.

A new PLOS medicine Study examines the risk of dementia from all causes, which correlates with reproductive factors in women and the number of children in both sexes. Researchers have also looked at whether this association varies with a number of factors such as smoking status, age and body mass index (BMI).

To learn: Reproductive factors and the risk of developing dementia: A cohort study with participants from the British Biobank. Photo credit: pikselstock / Shutterstock.com

background

There are 50 million people living with dementia worldwide, and that number could triple by 2050. Mitigating and modifying risk factors could reduce the population-level burden associated with dementia, as to date there are no effective disease-modifying treatments for dementia.

Estimates suggest that dementia rates are higher in women; However, the extent to which this is due to women’s longer life expectancy remains to be determined. Female-specific reproductive factors could potentially explain these gender differences.

Several endogenous estrogen changes occur over the course of a woman’s reproductive life. The use of exogenous hormones such as B. oral contraceptives, and hormone replacement therapy (HRT) can affect estrogen levels.

So far there has been a lack of research examining the long-term effect of reproductive factors on the risk of dementia. The putative mechanisms are unclear and the conclusions are far from certain.

About the study

In the new cohort study, researchers looked at women in the UK Biobank and examined reproductive factors and exogenous hormone use in relation to the risk of all-cause dementia. The association between these factors and risk of dementia was examined and correlated with a range of factors including age, socioeconomic status (SES), smoking status and BMI.

In addition, men were also included for an intersex comparison. The association between the number of children fathered by these men and the risk of dementia from any cause was assessed and compared to the results of their female counterparts.

study results

Scientists observed several associations between reproductive factors and exogenous hormone use with dementia risk. Younger age at first live birth and hysterectomy was associated with a higher risk of dementia.

A U-shaped relationship was found between risk of dementia and several factors including age at menarche, hysterectomy, and oophorectomy. A lower risk of dementia was associated with a longer reproductive span, late natural menopause, intermittent pregnancy, and a history of abortions.

With exogenous hormone exposure, oral contraceptive use was associated with a lower risk of dementia. It has been found that women with a lower SES have an increased risk of dementia. There was a U-shaped relationship between the number of children and the risk of dementia in both sexes.

Several fitted constrained cubic splines (with kernel density plots) showing HRs for dementia risk related to reproductive factors.  The blue line represents the hazard function and the blue shaded area represents the 95% CIs. The shaded gray area represents the kernel density plot for the data distribution.  After excluding values ​​from the top and bottom 2.5% of the distribution, with the median as the reference.  Splines adjusted for age, Townsend deprivation index, ethnicity, smoking status, systolic blood pressure, BMI, diabetes, total cholesterol, antihypertensive drugs, and lipid-lowering drugs.  (A) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with age at menarche.  (B) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with age at first birth.  (C) Restricted cubic spline plot with multiple fitted HRs (95% CI) for dementia of all causes related to reproductive years.  (D) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with age in natural menopause.  (E) Restricted cubic spline plot with multiple fitted HRs (95% CI) for all-cause dementia associated with age at hysterectomy.  (F) Restricted cubic spline plot with multiple fitted HRs (95% CI) for all-cause dementia associated with age at oophorectomy.  (G) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with age-related contraceptive pill use.  (H) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for dementia from all causes related to the age at which HRT was started.  (I) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with years of HRT use.  BMI, body mass index;  CI, confidence interval;  HR, hazard ratio;  HRT, hormone replacement therapy.Several fitted constrained cubic splines (with kernel density plots) showing HRs for dementia risk related to reproductive factors. The blue line represents the hazard function and the blue shaded area represents the 95% CIs. The shaded gray area represents the kernel density plot for the data distribution. After excluding values ​​from the top and bottom 2.5% of the distribution, with the median as the reference. Splines adjusted for age, Townsend deprivation index, ethnicity, smoking status, systolic blood pressure, BMI, diabetes, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. (A) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with age at menarche. (B) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia related to age at first birth. (c) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with reproductive years. (D) Constrained cubic spline plot with multiple adjusted heart rates (95% CI) for all-cause dementia associated with age in natural menopause. (E) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia related to age at hysterectomy. (F) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with age at oophorectomy. (G) Constrained cubic spline plot with multiple fitted HRs (95% CI) for all-cause dementia associated with age-related birth control pills. (H) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for dementia from all causes related to the age at which HRT was started. (I) Constrained cubic spline plot with multiple fitted heart rates (95% CI) for all-cause dementia associated with years of HRT use. BMI, body mass index; CI, confidence interval; HR, hazard ratio; HRT, hormone replacement therapy.

strengths and limitations

A large sample size with links to national medical and death records is one of the key strengths of this study. The data also included a comprehensive list of reproductive factors and exogenous hormone use, which was an added strength.

Retrospective and self-reported measurements of reproductive factors, which may be subject to bias, are a major limitation of the study. The UK Biobank population consists mainly of relatively healthy and affluent people of white ethnic background and is therefore limited in terms of representativeness.

In addition, due to the small number of events in the UK Biobank, dementia subtypes were not differentiated. A final caveat was that despite the researchers’ best attempts, some unmeasured factors could lead to residual confusion.

Conclusions

The current study highlights that various reproductive and hormonal factors can be associated with an increased risk of dementia in women. For example, SES could be an important determinant of dementia risk and other aspects of women’s health.

Given the similar observed association between the number of children and dementia in both sexes, it is unlikely that the physical experience of childbirth accounts for risk variation in women.

Taken together, the current study supports a life-course approach to dementia prevention. Here, the scientists provide new insights into potential strategies that can be used to reduce the risks of dementia associated with certain female reproductive factors. Going forward, results on exogenous hormone use should be validated by rigorous clinical trials, while identifying high-risk women for future trials.

Magazine reference:

  • Gong, J., Harris, K., Peters, SAE, & Woodward, M. (2022) Reproductive factors and the risk of developing dementia: A cohort study of British Biobank participants. PLoS Medicine 19th(4). doi:10.1371/journal.pmed.1003955.

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