Is menopausal hormone therapy linked with dementia risk? Studies offer conflicting views
Click Here to Manage Email Alerts
Key takeaways:
- There is no evidence for long-term cardiovascular, metabolic or cognitive benefits with menopausal HT, nor evidence for adverse effects.
- More research is needed in women with cardiovascular disease.
PHILADELPHIA — The short-term effects of postmenopausal hormone therapies on the vascular system and the brain may differ from long-term effects and could be influenced by HT formulation and administration route, according to a speaker.
Observational studies have reported conflicting findings on the risks and benefits of HT with respect to cognitive function; however, there may be confounding factors and biases associated with observational studies looking for treatment effects, Kejal Kantarci, MD, MS, professor of radiology and director at Mayo Clinic Women’s Health Research Center and associate director at Mayo Clinic Alzheimer’s Disease Research Center, said during a plenary presentation at the Annual Meeting of The Menopause Society. Such factors could include women with subjective complaints, hot flashes and sleep disturbances seeking HT more often.
“One of the timepoints when women may have a higher or a modifiable risk for dementia is during the menopause transition, which corresponds to midlife years that determine how women age later in life,” Kantarci said. “Two-thirds of women have subjective cognitive difficulties during the menopausal transition with clinically intact cognitive performance. During the menopause transition, there is a subtle and temporary decline in processing speed, verbal encoding and verbal episodic memory.”
Age at initiation matters
After the early termination of the Women’s Health Initiative HT trial because of an increased risk for cerebrovascular events, breast cancer and dementia in the combined estrogen plus progestin arm among women aged 65 years and older, researchers investigated whether HT for recently postmenopausal women was associated with similar risks, Kantarci said. Data from the WHI Memory Study of Younger Women, which included women aged 50 to 55 years, showed no association between HT and cognitive function, Kantarci said. Multiple observational studies followed, with some suggesting increased risk for Alzheimer’s disease among older women initiating HT, though some suggested cognitive risk even among recently postmenopausal women.
Kantarci said randomized clinical trials provide the strongest evidence on the effect of HT on dementia risk; findings from observational studies should not inform shared decision-making about menopausal HT.
“Women who received menopausal HT at ... age 50 to 55 years were less vulnerable, suggesting that perhaps age at initiation is an important factor for cognitive health,” Kantarci said. “The observational studies and WHI Memory Study of Younger Women generally showed a reduced risk or a neutral risk for early postmenopausal HT and late-life cognitive impairment and dementia.”
Assessing brain changes with HT
The Kronos Early Estrogen Prevention Study (KEEPS) enrolled 727 women aged 42 to 58 years who were within 36 months of their last menses and had no prior cardiovascular disease events. Women received 0.45 mg oral conjugated equine estrogen pills (Premarin, Pfizer) daily or a 50 ug transdermal 17-beta-estradiol patch (Climara, Bayer) or placebo pills or patch. Oral micronized progesterone was given to active treatment groups 12 days each month.
Within the trial, 118 participants at the Mayo Clinic site also participated in a neuroimaging study to assess the effects of HT on imaging biomarkers of cognitive health. The women underwent MRI and cognitive testing at baseline, 18, 36 and 48 months. Participants also underwent MRI and cognitive testing 3 years after the trial concluded.
Scans at 48 months showed no difference in the decline in brain volume for HT users vs. the placebo groups, whereas women who received oral HT had a greater increase in ventricular expansion vs. placebo. However, 3 years after the trial ended, there was no difference in the rate of increase of ventricular expansion, suggesting the rate of change disappears after HT ends, Kantarci said. No change in cognitive function was found between the groups.
Unanswered questions
Although decades of follow-up may be needed to determine the risk for dementia for a clinical trial conducted during midlife, brain imaging biomarkers might help to identify the effects of HT on dementia pathophysiology at an earlier stage, Kantarci said. Such biomarkers could make assessing the influence of HT on dementia risk in trials with recently postmenopausal women feasible, Kantarci said.
“We need to understand the risks and benefits of HT in women with poor cardiovascular health [and] of different diverse racial backgrounds,” Kantarci said. “We have to also understand better the increased risk for dementia for women who undergo premenopausal bilateral oophorectomy before the age of 46 years. What are the risks for women who undergo spontaneous premature and early menopause? What is the ideal HT treatment for these women to prevent cognitive decline and dementia? Those are some of the questions we still cannot answer.”