HRT might be linked to dementia: study

A large Danish study published in The BMJ has shown a possible link between menopausal hormone therapy (commonly known as HRT) and an increased risk of dementia.

The increase was seen not only in long-term users of menopausal hormone therapy, but also in short-term users around the age of menopause (55 years or younger) as is currently recommended.

In a linked editorial, however, expert commentators have cautioned that, while the study has several strengths, the observed associations should not be used to infer a causal relationship between hormone therapy and dementia risk.

HRT is used to relieve common menopausal symptoms such as hot flashes and night sweats. Treatments include tablets containing oestrogen only, or a combination of oestrogen and progestogen, as well as skin patches, gels and creams.

Large observational studies have shown that long-term use of menopausal hormone therapy is associated with development of dementia, confirming findings from the Women’s Health Initiative Memory Study, the largest clinical trial on this topic.

But the effect of short-term use of menopausal hormone therapy around the age of menopause remains to be fully explored, as does the effect of different treatment regimens on risk of dementia.

To try and fill these knowledge gaps, researchers in Denmark assessed the association between use of combined oestrogen and progestin (synthetic progestogen) therapy and development of dementia according to type of hormone treatment, duration of use and age at use.

Drawing on national registry data, they identified 5589 cases of dementia and 55,890 age-matched dementia-free controls between 2000 and 2018 from a population of all Danish women aged 50–60 years in 2000 with no history of dementia and no underlying reason preventing them from using menopausal hormone therapy. Other relevant factors, including education, income, hypertension, diabetes and thyroid disease, were also taken into account.

The average age at diagnosis was 70 years. Before a diagnosis, 1782 (32%) cases and 16,154 (29%) controls had received oestrogen–progestin therapy from an average age of 53 years. The average duration of use was 3.8 years for cases and 3.6 years for controls.

The results show that, compared with people who had never used treatment, people who had received oestrogen–progestin therapy had a 24% increased rate of developing all-cause dementia and Alzheimer’s disease, even in women who received treatment at the age of 55 years or younger. Rates were higher with longer use, ranging from 21% for one year or less to 74% for more than 12 years of use.

Use of progestin-only therapy and vaginal oestrogen-only therapy were not associated with the development of dementia.

This is an observational study, so can’t establish cause, and the researchers were not able to isolate vascular dementia from other types of dementia or distinguish between tablets and other ways to take hormone therapy, such as patches. They also couldn’t rule out the possibility that women using hormone therapy have a predisposition to both menopausal vasomotor symptoms (eg, hot flashes, night sweats) and dementia.

However, this was a large study based on high-quality treatment data with a long follow-up time.

The researchers concluded: “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.”

This view was supported by US researchers in a linked editorial, who said that “confounding factors could be producing a spurious signal for higher dementia risk in younger women using hormone therapy for either a short or long duration.”

They added, “These findings cannot inform shared decision-making about use of hormone therapy for menopausal symptoms. Randomised clinical trials provide the strongest evidence on the effect of hormone therapy on dementia risk.”

Commenting on the study, Gino Pecoraro, Associate Professor of Obstetrics and Gynaecology at The University of Queensland and President of the National Association of Specialist Obstetricians and Gynaecologists (NASOG), said, “This is an interesting addition to ongoing research around menopause and its treatment.

“Unfortunately, it raises more questions than it answers and caution needs to be applied in interpreting its results.

“The major conclusion is that women taking menopausal hormone therapy, be that combined oestrogen and progesterone, oestrogen only or progesterone only, was associated with an extra four cases per 1000 women of dementia being diagnosed, compared to women who did not take hormones.”

Pointing out that the particular hormones used in this population study, and their delivery systems, were not necessarily the same hormones and delivery systems used in Australia, Pecoraro said, “These results confirm the need for ongoing research into how best to manage menopausal symptoms but should not be used as a reason to stop or change treatments we offer in Australia.”

Image credit: iStock.com/Vladimir Vladimirov