Menopausal hormone therapy and dementia: nationwide, nested case-control study

Abstract

Objectives: To assess the association between use of menopausal hormone therapy and development of dementia according to type of hormone treatment, duration of use, and age at usage.

Design: Nationwide, nested case-control study.

Setting: Denmark through national registries.

Participants: 5589 incident cases of dementia and 55 890 age matched controls were identified between 2000 and 2018 from a population of all Danish women aged 50-60 years in 2000 with no history of dementia or contraindications for use of menopausal hormone therapy.

Main outcome measures: Adjusted hazard ratios with 95% confidence intervals for all cause dementia defined by a first time diagnosis or first time use of dementia specific medication.

Results: Compared with people who had never used treatment, people who had received oestrogen-progestogen therapy had an increased rate of all cause dementia (hazard ratio 1.24 (95% confidence interval 1.17 to 1.33)). Increasing durations of use yielded higher hazard ratios, ranging from 1.21 (1.09 to 1.35) for one year or less of use to 1.74 (1.45 to 2.10) for more than 12 years of use. Oestrogen-progestogen therapy was positively associated with development of dementia for both continuous (1.31 (1.18 to 1.46)) and cyclic (1.24 (1.13 to 1.35)) regimens. Associations persisted in women who received treatment at the age 55 years or younger (1.24 (1.11 to 1.40)). Findings persisted when restricted to late onset dementia (1.21 (1.12 to 1.30)) and Alzheimer's disease (1.22 (1.07 to 1.39)).

Conclusions: Menopausal hormone therapy was positively associated with development of all cause dementia and Alzheimer's disease, even in women who received treatment at the age of 55 years or younger. The increased rate of dementia was similar between continuous and cyclic treatment. Further studies are warranted to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments.

Fig 1

Adjusted hazard rate ratios with 95% confidence intervals (CI) of all cause dementia, late onset dementia, and Alzheimer’s disease according to cumulative duration of oestrogen-progestin hormone therapy use. Two regression models for each outcome (one for ever use and one for cumulative use). Adjusted for education, income, cohabitation, hypertension, diabetes, and thyroid disease at index date. Never use accounted for women who had never received oestrogen-progestin hormone treatment, systemic oestrogen only treatment, vaginal oestrogen treatment, or progestin only treatment (including the levonorgestrel releasing intrauterine device) from the ages of 45-55 years until index date. Estimates for systemic oestrogen only, vaginal oestrogen only, or progestin only treatment are not shown

Fig 2

Adjusted hazard rate ratios with 95% confidence intervals (CI) of all cause dementia according to regimen of oestrogen-progestin treatment and duration of use. Two regression models (one for ever use and one for cumulative use). Adjusted for education, income, cohabitation, hypertension, diabetes and thyroid disease at index date. Never use accounted for women who had never received oestrogen-progestin hormone treatment, systemic oestrogen only treatment, vaginal oestrogen treatment, and progestin only therapy (including the levonorgestrel releasing intrauterine device from the ages 45-55 years until index date. Estimates for women having used both continuous and cyclic combined menopausal hormone therapy before index date (31.4% of all who received treatment) are not shown nor for women with unidentifiable method of treatment (5.3%). Estimates for systemic oestrogen only, vaginal oestrogen only, or progestin only therapy are not shown

Fig 3

Adjusted hazard rate ratios with 95% confidence intervals (CI) of all cause dementia according to hormone therapy use exclusively for women 55 years and younger. Two regression models (one for ever use and one for cumulative use). Adjusted for education, income, cohabitation, hypertension, diabetes and thyroid disease at index date. All cases and controls either never received treatment or finalised their oestrogen-progestin treatment at 55 years of age or before. Estimates for systemic oestrogen only, vaginal oestrogen only, or progestin only treatment are not shown