In a nested case-control study of older Danish women with hysterectomy in 2000, estrogen-only therapy was associated with higher dementia rates. The relationship held “even in women exposed near menopause, confirming findings from the large randomized clinical trial but in a more contemporary population reflecting actual use,” the authors conclude.
The 29,104 women were 50–60 years of age when the study began, did not have histories of dementia or oophorectomy, and had no contraindications to menopausal hormone therapy. Followed until Dec. 31, 2018, death, emigration, or an exclusion criterion, the women had these outcomes during 500,000 person-years: “During follow-up, 541 women developed dementia (Alzheimer disease, 92) and were matched to 2,705 controls; 13.9% were identified only by use of antidementia medication. Median age at diagnosis was 70 years (IQR, 66-73 years). Estrogen-only users constituted 53.2% of cases and 45.0% of controls; users aged 55 years or younger constituted 15.6% and 12.3%, respectively. Median age at treatment initiation was 53 years (IQR, 51-54 years). Median treatment duration among users was 5.4 years (IQR, 1.3-8.8 years) for cases and 5.1 years (IQR, 1.7-8.6 years) for controls. Estradiol use composed 94% (9,266 of 9,858 person-years) of person-time with estrogen-only therapy, and of this, 81% (7,487 person-years) was oral and 19% (1,779 person-years) transdermal.
“Estrogen-only vs never use was associated with increased dementia rate (hazard ratio [HR], 1.55; 95% CI, 1.25-1.93); HR was 1.49 (95% CI, 1.15-1.93) for 5 years use or less and 1.62 (95% CI, 1.25-2.09) for greater than 5 years’ use. Increasing daily estradiol dose yielded increasing HRs (P trend < .003). Oral estradiol HR was 1.62 (95% CI, 1.28-2.05); and transdermal, 1.39 (95% CI, 0.97-1.99).
“The association persisted in women using estrogen only until a maximum of aged 55 years (HR, 1.58; 95% CI, 1.06-2.35). Alzheimer disease HR was 1.79 (95% CI, 0.99-3.23).”