Hormone Therapy and Dementia: Novel Insights

JoAnn E. Manson, MD, DrPH


July 28, 2023

This transcript has been edited for clarity.

This is Dr JoAnn Manson, professor of medicine at Harvard Medical School and Brigham and Women's Hospital. I'd like to talk with you about a recent report in The BMJ about menopausal hormone therapy and risk for dementia.

This observational study from Denmark has been causing a lot of alarm among clinicians and leading to many questions about whether the findings are likely to be causal or should be used in clinical decision-making about hormone therapy in early menopause. This large study from the Danish National Registry suggested that hormone therapy is linked to increased risk for dementia, whether it's used short term or long term, whether it's started in early menopause (age 50-55) or in later menopause.

My colleague, Dr Kejal Kantarci from the Mayo Clinic, and I were invited to write an editorial in The BMJ to accompany this paper. I want to share with you some of the caveats that we presented to support our belief that the findings should not be used to infer causality, for several reasons. One is that these observational study findings are at odds with several randomized clinical trials of hormone therapy and cognitive function among women in early menopause. Even the WHI Memory Study of younger women and the WHIMS-Y study in women who were randomized to hormone therapy at age 50-55 showed neutral effects of hormone therapy (both estrogen plus progestin and estrogen alone) on cognitive function. The women who were age 65 or older did have an increased risk for dementia related to hormone therapy, but not the women in early menopause. Also, the KEEPS trial, the Kronos Early Estrogen Prevention Study, showed a neutral effect of hormone therapy on cognitive function among women in early menopause, as did the ELITE trial among women who were in early menopause. There was no adverse effect, a neutral effect on cognitive function.

Now, in addition, several methodologic issues should be taken into account. In the early years of the study when women were enrolling into the registry, there was a perception that hormone therapy was a benefit for cognitive concerns. Women who had disrupted sleep and concerns about concentration may have been seeking out hormone therapy. This was prior to the results of the WHI and therefore there could be confounding by indication. We do know that more severe vasomotor symptoms and disrupted sleep have been linked to higher volumes of white matter hyperintensities in women and that this is a marker of poor vascular health.

There could also be confounding by detection and surveillance in that these women were in the medical system. They were receiving a prescription and they may have been followed more closely, may have been more likely to have early signs of dementia picked up by their clinicians than women who were not receiving regular medical care. After the results of the WHI in 2003, the WHI Memory Study findings were published. There may have been more vigilant monitoring of women who had been treated with hormone therapy. So there was also potentially some confounding by that issue.

So, overall, we feel that the results should not be used to infer causality. They are at odds with the randomized clinical trial findings and there are methodologic concerns. The study should not lead to denying hormone therapy to women in early menopause who are seeking treatment for clear indications, such as bothersome moderate to severe vasomotor symptoms, in the context of discussions with the patient and shared decision-making. Thank you so much for your attention. This is JoAnn Manson.

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