Women who have taken hormone replacement therapy for menopausal symptoms will be relieved by findings from a large British case-control study reporting no overall increased risk of dementia as long as exposure is not long term.
Dr. Yana Vinogradova
Publishing results online Sept. 29 in BMJ, ( Yana Vinogradova, PhD, a senior research fellow at the University of Nottingham (England), and colleagues made this observation after conducting nested case-control studies involving more than 700,000 women in two U.K. primary care databases. The investigators undertook the study to clarify disparate findings over the past 2 decades on dementia risk associated with menopausal hormone replacement,
“The findings show that menopausal hormone therapy, or MHT, is generally safe for women who require it,” Dr. Vinogradova said in an interview. “A small risk association was found for future development of Alzheimer’s disease increasing with the length of menopausal hormone treatment.” This finding applied only to combined treatments of estrogen plus progestin and became measurable only after long-term use of 5 years or more. “These risk associations, only for long-term use of MHT, are in line with findings related to breast cancer risk,” she said.
The findings also align with previous biological speculations that estrogen combined with progestin may have a harmful effect on the aging brain, she added, “but we also cannot completely rule out other possible factors from our study. For example, some women who were in fact suffering from early signs of Alzheimer’s disease similar to menopausal symptoms may have continued with their menopausal therapy for longer than other women.”
Concerns about the risk of dementia with MHT date back to 2003 when data from the Women’s Health Initiative Memory Study showed that incidence of all-cause dementia doubled in women age 65 years and older after treatment with conjugated equine estrogens and medroxyprogesterone acetate for an average of 4 years. More recently, Finnish research has yielded conflicting data about risks.
The study
The investigators used two U.K. primary care databases (QResearch and CPRD) to analyze MHT prescriptions for 118,501 women age 55 and older diagnosed with dementia between 1998 and 2020 and 497,416 female controls matched by age and general practice, but with no record of dementia.
The cohort was older: mean age of cases was 83.5 years and mean duration of treatment was 16 years for an average age of 67.7 at first captured prescription, considerably later than when most women begin MHT. Relevant factors such as family history, smoking, alcohol consumption, preexisting conditions, and other prescribed drugs were taken into account.
Overall, 16,291 (14%) dementia cases and 68,726 (14%) controls had been exposed to MHT in the period up to 3 years before diagnosis.
After adjusting for potentially confounding factors, the researchers found no overall associations between hormone therapy and risk of dementia, regardless of hormone type, application, dose, or duration of treatment. Within the subgroup of women younger than 80 years who had been taking estrogen-only therapy for 10 years or more, a slightly decreased risk of dementia emerged: odds ratio, 0.85; 95% confidence interval, 0.76-0.94.
However, an analysis of dementia cases with a diagnosis specifically of Alzheimer’s disease showed a slight increase in risk associated with estrogen-progestin therapy. Increased risks of developing specifically Alzheimer’s disease emerged in those who had used combination therapy for 5-9 years (OR, 1.11; 95% CI, 1.04-1.20) and also for 10 years or more (OR, 1.19; 95% CI, 1.06-1.33). This risk rose gradually with each year of exposure, reaching an average 11% increased risk for use from 5-9 years and an average 19% for use 10 years or more – equivalent to, respectively, five and seven extra cases per 10,000 woman-years.
Dr. Jill M. Rabin
According to Jill M. Rabin, MD, a professor at the Feinstein Institutes for Medical Research and an ob.gyn. with Northwell Health in Manhasset, N.Y., the findings make sense for two reasons. “First, there are other health issues noted in women taking long-term combination hormonal therapy such as an increased risk of breast cancer,” she said in an interview. “Second, progesterone is recommended for women who have retained their uterus in order to counteract the potential effects of estrogen on the uterine lining causing possible overgrowth. There are systemic effects however of progesterone, as it counteracts estrogen, potentially decreasing its benefit on the neurological system.”
She added that this analysis is synchronous with other biological studies demonstrating possible neuroprotective effects of estrogen on the brain, especially among younger women. “The vascular system in the newly menopausal female is noted to have less endothelial and intimal thickening, better blood flow and oxygenation, and in general less vascular damage. Estrogen in these relatively younger, newly menopausal women may help to stabilize the vasculature as well as the neurologic system. On the other hand, estrogen therapy over the age of 80 may be delivered to a neurovasculature damaged with age and time, may be somewhat less beneficial.” Older women also have fewer estrogen receptors and, in general, other medical comorbidities.
According to the authors, the findings will be helpful to policy-makers, doctors, and patients when making choices about hormone therapy.
In an accompanying editorial, two U.S. researchers called the findings reassuring. Pauline M. Maki, PhD, of the University of Illinois at Chicago, and JoAnn E. Manson, MD, DrPH, of Brigham and Women’s Hospital, Harvard Medical School, and Harvard T.H. Chan School of Public Health in Boston, however, pointed out that the current study with its older cohort and older age at MHT initiation could not address the important issue of the “timing hypothesis” – namely, that earlier initiation of hormone therapy might confer greater protection against Alzheimer’s disease, compared with later use.
And while the current observations do not change the recommendation that MHT should not be used to prevent dementia, they are helpful for providers to put dementia findings in context for patients. “The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason,” they wrote.
This study was funded by the U.K. National Institute for Health Research School for Primary Care Research.
Coauthor Dr. Julia Hippisley-Cox is a director of QResearch, EMIS Health, which supplies the QResearch database used for this work, and is a founder and shareholder of ClinRisk., which produces software to implement clinical risk algorithms.