Menopausal hormone therapy is positively linked with the development of all cause dementia and Alzheimer’s disease, according to recent findings, even in females who are treated at the 55 years of age or younger.¹

These findings resulted from new research into full exposure history of menopausal hormone treatment including short term use. Recent large scale observational studies before this new research were shown to have found a positive association between menopausal hormone therapy use and Alzheimer’s disease in long term users who began prior to age 60, but were not as expansive.²

To examine these effects in greater detail, the research was conducted, and it was authored by Nelsan Pourhadi, MD, from the Danish Dementia Research Centre in the Department of Neurology at Copenhagen University Hospital in Denmark.

“We report a nationwide study on the association between menopausal hormone therapy and development of dementia,” We distinguish between cyclic and continuous regimens of oestrogen-progestogen therapy as well as analyses in short term users aged 55 years or younger as currently recommended.”

Background and Findings

The investigators performed a nationwide, nested case-control study using Danish national registries. They also identified incident dementia cases and age-matched dementia-free controls among Danish females in the age bracket of 50 - 60 years with specific exclusion criteria related to medical history.

Dementia diagnoses and management occurred in hospitals, particularly in specialized memory clinics. The researchers utilized the National Registry of Patients, which contains information on hospital diagnoses, and the National Prescription Registry, which records filled prescriptions since 1995.

Dementia cases were identified based upon the initial diagnosis or the redemption of a specific dementia-related drug. Each case was then matched by the research team with 10 female controls without dementia by birth year.

The primary exposure of interest was the use of estrogen and progestogen combination treatment. Information about the timing, amount, and type of purchased menopausal hormone therapy was obtained from the National Prescription Registry.
The researchers assessed the history of hormone therapy from ages 45 - 55 until 2 years before a dementia diagnosis or matching, aiming to reduce protopathic bias. They estimated the duration of estrogen-progestogen use using a program called medicinMacro.

The investigators used conditional logistic regression to analyze the association between hormone treatment use and all-cause dementia, considering type, duration, and timing of treatment.

The research team conducted subgroup analyses for late-onset dementia and Alzheimer's disease. Various potential confounding variables were included in the statistical models. Sensitivity analyses were performed with different lag time windows.

Compared to individuals who had never undergone treatment, the investigators noted that those who had received estrogen-progestogen therapy were found to have had a higher rate of all-cause dementia, with a hazard ratio of 1.24 (95% CI; 1.17 - 1.33).

The risk of dementia increased with longer durations of use, ranging from a hazard ratio of 1.21 (1.09 - 1.35) for one year or less of use to 1.74 (1.45 - 2.10) for over 12 years of use. Both continuous (1.31 (1.18 - 1.46)) and cyclic (1.24 (1.13 - 1.35)) regimens of estrogen-progestogen therapy were associated with an increased risk of dementia.

The association the team identified was shown to have persisted for women who received treatment at or before the age of 55 years (1.24 (1.11 - 1.40)). These findings remained consistent when analyzing late onset dementia (1.21 (1.12 - 1.30)) and Alzheimer's disease (1.22 (1.07 - 1.39)).

“This study is of an observational design, therefore, we cannot exclude residual bias such as residual confounding by indication (i.e., that women using hormone therapy have a predisposition to both menopausal vasomotor symptoms and dementia),” they wrote. “Further studies are warranted to explore if the observed association in this study between menopausal hormone therapy use and increased risk of dementia illustrates a causal effect.”

References

1. ^{Pourhadi N, Mørch LS, Holm EA, Torp-Pedersen C, Meaidi A. Menopausal hormone therapy and dementia: nationwide, nested case-control study. BMJ. 2023;381. doi:10.1136/bmj-2022-072770. Published June 28, 2023.}
2. ^{Vinogradova Y, Dening T, Hippisley-Cox J, Taylor L, Moore M, Coupland C. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ2021;374:n2182. doi:10.1136/bmj.n2182. pmid:34588168.}