Short-Term Menopausal Hormone Therapy Has No Lasting Cognitive Effects

Short-term menopausal hormone therapy (mHT) does not have long-term cognitive effects when given to women in early postmenopause, according to new research from Mayo Clinic scientists. This may provide reassurance on its long-term safety, but also suggests that mHT does not improve cognitive function.

The study is published in PLOS Medicine.

Investigating potential negative effects on cognition

Around three-quarters of women will experience unpleasant symptoms linked to menopause, such as “hot flashes” and disturbed sleep; but a quarter describe their symptoms as moderate to severe.

In these cases, mHT can be used to relieve the more challenging symptoms. Also known as hormone replacement therapy (HRT), the treatment replaces hormones estrogen or progesterone, or both. However, its safety has been questioned. “Concern about the safety of mHT stems in part from the unexpected findings from the Women’s Health Initiative study and its ancillary Memory Study (WHIMS),” the senior author of the new study, Kejal Kantarci, told Technology Networks.

“WHIMS found that mHT exhibited deleterious effects on global cognitive function and risk for cognitive impairment, with one formulation in particular demonstrating an association with risk of incident mild cognitive impairment and dementia,” said Kantarci, professor of radiology and Katherine B. Andersen Endowed Professor in Women’s Health at the Mayo Clinic.

The Kronos Early Estrogen Prevention Study (KEEPS) found no benefits or harms on cognition after four years of mHT for women in early postmenopause in good cardiovascular health, compared to placebo. However, not much is known about the potential for long-term effects after even short-term use.

“Women who were enrolled in KEEPS received mHT and were recently postmenopausal. Therefore, they were too young (average age of 53 years) to exhibit cognitive decline, which may happen later in life,” Kantarci said.

The KEEPS Continuation Study was designed to follow-up with the KEEPS participants nearly 10 years after the original study to investigate any potential long-term effects of mHT.

“They were at an ideal age to assess cognitive decline associated with dementia after 4 years of mHT use and 10 years of follow-up at an average age of 67 years,” Kantarci explained.

Long-term follow-up saw no ill effects

The continuation study followed up with 275 participants who received four years of mHT that began within three years of menopause. This included both estrogen in pill-form and in a transdermal form that is absorbed through the skin.

Short-term mHT did not have a long-term negative cognitive impact, though it also failed to protect against cognitive decline. Previous studies have suggested that transdermal estrogen may have long-term benefits for cognition, leading Kantarci to hypothesize it would demonstrate benefits compared to a placebo.

“mHT was not associated with cognitive benefits, nor did mHT prevent cognitive decline. Our data indicates that mHT should not be recommended as an intervention to preserve cognitive function in postmenopausal women,” Kantarci summarized.

“Furthermore, our data indicates that short-term mHT use does not increase the risk of cognitive decline in women with good cardiovascular health.”

The findings are not without their limitations, though, as Kantarci explained: “This study was conducted in women who did not have cardiovascular disease; therefore, the findings are limited to women with good cardiovascular health.”

The results may reassure women who are considering mHT, but more research may determine if the findings also apply to women with a higher risk of cardiovascular disease.

The researchers plan to continue their work in a similar vein to investigate other potential side effects: “We will continue to study other potential long-term health outcomes associated with mHT, beyond cognitive performance. Future studies could focus on areas such as mood and Alzheimer’s disease biomarkers,” Kantarci concluded. 

Reference: Gleason CE, Dowling NM, Kara F, James TT, Salazar H, Ferrer Simo CA, et al. Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study. PLoS Med. 2024. 21(11): e1004435. doi: 10.1371/journal.pmed.1004435

About the interviewee:

Dr. Kejal Kantarci is Katherine B. Andersen Endowed Professor and professor of radiology in the Division of Neuroradiology at Mayo Clinic Rochester. She is the director of the Women’s Health Research Center and associate director of the Mayo Clinic Alzheimer’s Disease Research Center. Her research focuses on the neuroimaging, neuroscience and clinical aspects of aging and dementia, particularly in women’s cognitive health and Lewy body dementias. She is leading an NIH-funded multi-center program on determining the long-term effects of early menopausal hormone therapy on Alzheimer’s pathophysiology. In 2023, she received the Distinguished Investigator Award from the Academy for Radiology and Biomedical Imaging Research. She has authored over 300 publications.