Experts Respond to Article on Hormone Therapy and Dementia

Posted on June 30, 2023

Source: The Menopause Society

Alzheimer disease is twice as common in women than in men; therefore, midlife exposures that might influence its risk in women are of considerable interest. An observational study by Nelsan Pourhadi and colleagues published in BMJ (June 28, 2023) using Danish registries investigated the associations of hormone therapy (HT) with dementia later in life and found an increased risk of dementia with either short-term or long-term use.

In an editorial also published in BMJ, Drs. JoAnn Manson and Kejal Kantarci commented on the study.

We have invited esteemed colleagues and experts in the field, Drs. JoAnn Manson and Kejal Kantarci to provide information for our members.

The Women’s Health Initiative Memory Study (WHIMS)—a randomized trial published in 2003—reported that estrogen plus progestin treatment was associated with a two-fold increase in the risk of dementia in women aged older than 65 years. Risk did not increase in women starting HT aged 50 to 55 years in the WHIMS of Younger Women (WHIMS-Y) trial, published in 2013. Two other randomized trials tested the effects of estrogen and progestogen treatment on cognitive function in women who started treatment shortly after menopause; in both trials, cognitive function was not affected by HT compared with placebo.

Pourhadi and colleagues’ new study reported an association with increased risk of dementia even in women using HT before age 55 years for 5 years or less, which is within the age range recommended by The Menopause Society. Their findings contradict those of the WHIMS-Y trial and other trials that reported no effect on cognitive function in women who were randomly assigned to HT in early menopause.

Confounding factors could be producing a spurious signal for higher dementia risk in younger women using HT for either a short or long duration. In particular, increased dementia risk with less than 1 year of HT is not biologically plausible, further supporting the presence of confounding factors.

Approximately two-thirds of women have subjective cognitive difficulties during the menopause transition and may experience a temporary decline in cognitive processing speed. Women with subjective cognitive complaints, vasomotor symptoms, and sleep disturbances would likely seek HT more often than those who do not experience these symptoms.

Confounding by indication may also affect observational findings because vasomotor symptoms, particularly during sleep, are associated with a higher volume of white matter hyperintensity—a marker of poor brain vascular health.

The records from the entire population of Denmark were available for this study, including detailed ascertainment of HT prescriptions, which distinguishes this study from most other observational studies. Furthermore, the authors were able to investigate cyclic and continuous estrogen plus progestogen formulations separately, as well as age at initiation of HT and length of treatment, which allowed for secondary analyses of exposure of women aged younger than 55 years, according to treatment duration.

Previous observational studies have reported conflicting findings on the risks and benefits of HT with respect to cognitive function and dementia. Although Pourhadi and colleagues’ study was done carefully using national registries, the observed associations could be artefactual and should not be used to infer a causal relationship between HT and dementia risk. These findings, therefore, cannot inform shared decision-making about the use of HT for menopause symptoms.