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Possible link between long-term HRT use and Alzheimer’s

Study says absolute risk is small but noteworthy

Adrian O'Dowd

Thursday, 07 March 2019

Women who take oral hormone therapy for a long time may be increasing their risk of developing Alzheimer’s disease, suggests a study* carried out in Finland published today in The BMJ.

The researchers have stressed that the absolute risk is small – 9-18 extra cases per 10,000 women per year – and the age at which hormone therapy is started has no bearing on future risk.

Nevertheless, they said women should be informed of the potential risk associated with prolonged use.

Hormone therapy used to relieve menopausal symptoms can be given in different ways such as tablets containing oestrogen only or a combination of oestrogen and progestogen, as well as ‘transdermal’ treatments, such as patches, gels and creams.

Several previous studies have suggested that postmenopausal hormone therapy could protect against Alzheimer’s disease, but there has been conflicting data.

Therefore a team of researchers led by Tomi Mikkola at the University of Helsinki set out to better understand this possible association by comparing use of hormone therapy in postmenopausal women with and without a diagnosis for Alzheimer’s disease.

Using national population and drug registers, they compared data on hormone therapy use for 169,478 women, made up of 84,739 postmenopausal women diagnosed with Alzheimer’s disease between 1999 and 2013 with the same number of postmenopausal women without a diagnosis.

Results showed that in 83,688 (98.8%) women, the Alzheimer’s disease diagnosis was made at age 60 or older, and 47,239 (55.7%) women were over 80 when diagnosed.

Analysis showed that overall, use of oral hormone therapy was associated with a 9-17% increased risk for Alzheimer’s disease, whereas use of vaginal hormone therapy showed no such risk.

In absolute terms, this means that nine to 18 additional cases of Alzheimer’s disease per year will be detected in 10,000 women between 70 to 80 years of age, especially in those who had used hormone therapy for over 10 years, explained the authors.

The risk did not differ significantly between users of oestrogen only tablets and users of combined oestrogen-progestogen tablets.

Age at which hormone therapy was started did not appear to affect future risk for the condition. However, in women who were younger than 60 when they started taking hormone therapy, the increased risk was associated with exposure for over 10 years.

This was an observational study so could not establish cause.

Nevertheless, the researchers said this was one of the largest studies on the association between hormone therapy use and risk of Alzheimer’s disease and used data from a reliable nationwide register.

“Long-term use of systemic hormone therapy might be accompanied with an overall increased risk for Alzheimer’s disease, which is not related to the type of progestogen or the age at initiation,” they concluded.

“By contrast, use of vaginal estradiol shows no such risk.

“Even though the absolute risk increase for Alzheimer’s disease is small, our data should be implemented into information for present and future users of hormone therapy.”

Royal College of GPs chair Professor Helen Stokes-Lampard urged women on hormone replacement therapy (HRT) not to be alarmed by the new study.

“HRT can be of greatest benefit to many women who are suffering from some of the unpleasant side-effects of the menopause and there is a large body of evidence that shows it is an effective and safe treatment for most women,” she said.

“However, as with any medication there are risks and it's important that women are aware of them so that they can make an informed decision, with their doctor, before starting treatment.

“This new research shows an association with very long-term use of combined HRT but does not prove that there is a causal link. Nevertheless, it is a large, independent study and it is important that it is taken into account as clinical guidelines are updated and developed.”

Dr James Pickett, head of research at the Alzheimer’s Society, said: “This large and well-controlled study adds to a conflicting pool of evidence around the effect of hormone therapy on risk of developing dementia.

“In this case, some women on hormone therapy had a slight increased risk of Alzheimer’s, but this increase was so small it shouldn’t cause alarm or deter women from their prescribed treatment - particularly those taking it over a short period of time.”


*Savolainen-Peltonen H; Rahkola-Soisalo P; Hoti F; Vattulainen P; Gissler M; Ylikorkala O; and Mikkola T S. Use of postmenopausal hormone therapy and risk for Alzheimer’s disease in Finland: nationwide case-control study. BMJ 2019;364:l665. DOI:10.1136/bmj.l665

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