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Use of postmenopausal hormone therapy ups risk of Alzheimer’s disease

Stephen Padilla
14 Mar 2019

Long-term use of systemic hormone therapy may increase the risk of Alzheimer’s disease in postmenopausal women, which is not associated with progestogen type or age at initiation of said therapy, according to a Finnish study. On the other hand, use of vaginal oestradiol does not appear to increase such risk.

“The present study indicates that the use of systemic hormone therapy, once claimed to be protective against Alzheimer’s disease, is accompanied with a 9–17-percent increase in the risk of the disease in postmenopausal women, whereas the exclusive use of vaginal oestradiol shows no risk,” researchers said.

Alzheimer’s disease was diagnosed in 83,688 (98.8 percent) women at the age of 60 years and in 47,239 (55.7 percent) at age >80 years. An association was found between use of systemic hormone therapy and a 9–17-percent increased risk of Alzheimer’s disease. [BMJ 2019;364:l665]

There was no difference in disease risk between users of oestradiol only (odds ratio [OR], 1.09; 95 percent CI, 1.05–1.14) and those of oestrogen-progestogen (OR, 1.17; 1.13–1.21). Risk increases in users of oestrogen-progestogen therapy were not associated with various progestogens (ie, norethisterone acetate, medroxyprogesterone acetate or other progestogens).

However, in women aged <60 years at hormone therapy initiation, such risk increases correlated with hormone therapy exposure over 10 years. In addition, age at therapy initiation did not appear to be a key determinant for the increase in Alzheimer’s disease risk. Furthermore, such risk was not affected by the exclusive use of vaginal oestradiol (OR, 0.99; 0.96–1.01).

Interestingly, previous studies have found a reduced risk of Alzheimer’s disease and all-cause dementia in hormone therapy users, but these analyses can be criticized for their lack of a placebo arm and the possible bias of healthy women among users. [Lancet 1996;348:429-432; Neurology 1999;52:965-970; JAMA 2002;288:2123-2129; Neurology 2012;79:1846-1852; Maturitas 2017;98:7-13; Neurology 2017;88:1062-1068; Epidemiol Rev 2014;36:83-103]

“This criticism gained strong support from the placebo-controlled WHIMS trial, reporting an increased risk of impaired cognition and probable dementia in women who used conjugated equine oestrogens with and without medroxyprogesterone acetate,” researchers said. [JAMA 2003;289:2651-2662; JAMA 2004;291:2947-2958]

However, the WHIMS trial was also criticized because, “unlike in normal clinical practice, hormone therapy was initiated for women older than 65, many years after the onset of menopause,” and it failed to “differentiate Alzheimer’s disease from other dementia or cognitive decline,” they added.

The present nationwide case-control study included postmenopausal women in Finland who were diagnosed with Alzheimer’s disease and were identified from a national drug register between 1999 and 2013. Control women without a diagnosis were matched by age and hospital district.

Researchers obtained data on hormone therapy from the Finnish national drug reimbursement register. Conditional logistic regression analysis was conducted to calculate ORs and 95 percent CIs for Alzheimer’s disease.

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