Menopausal Hormone Therapy (MHT) and Dementia Risk - The Debate Continues

Bringing you the latest from the hormone therapy world

Cognitive health is front and center along with cardiovascular, bone, muscle and metabolic health in maintaining our vitality as we enter life’s second half. The use of MHT and its impact on cognitive health has been the subject of interest and debate for more than two decades with no definitive answers and conflicting results among even the most well-done studies.

Today’s post reviews the latest contribution to this debate. This Danish study by Nelsan Pourhadi et. al. aimed to address some of the gaps in the current literature surrounding MHT use and dementia risk.

The Women’s Health Initiative (WHI) Memory Study is a landmark randomized, double-blind placebo controlled trial reported that MHT was associated with an increased risk of dementia. However, the study population only included women age 65 and older. Most commonly, MHT is prescribed for younger women < age 60 within 10 years of menopause onset, so the WHI memory study could not speak to the younger population using MHT. Further, only MHT containing conjugated estrogens was studied where estradiol is more commonly used in current MHT regimens.

The authors cite other large observational studies that have reported a positive association between MHT use and dementia risk, however, some of these studies lack a full MHT exposure history. Another question that has been raised by these studies is whether progestin use in MHT regimens plays a role in dementia risk independent of the estrogen component.

The current study is another very large observational study utilizing the Denmark National Registry, which has complete patient demographic information, follows diagnoses, types of medical therapy used and documents duration of therapy use.

Menopausal hormone therapy and dementia: nationwide, nested case-control study

Nelsan Pourhadi, Lina S Morch, Ellen A Holm, Christian Torp-Pedersen, Amani Meaidi

British Medical Journal 2023:382;e072770 (Free Full Text)

Goal of the study

To assess the association between MHT use and risk of dementia according to the type of MHT, duration of use, and participant age.

Study Design

• Nationwide nested case-control study (observational study)

• Danish women age 50-60 years from the Denmark National Registry with no history of dementia or contraindications for MHT at the start of the study in 2000.

• 5589 cases of dementia were included with 55,890 age-matched women without dementia identified between 2000 -2018.

• Outcome measure: All-cause dementia defined by a first-time diagnosis or first-time use of a dementia-specific medication.

Results

• The use of MHT was associated with an increased rate of all-cause dementia.

• Increasing duration of use yielded higher hazard ratios for dementia from 1 - 12 years of use.

• This positive association was seen for continuous and cyclic regimens of MHT.

• Positive associations persisted in women who received treatment at age 55 and younger.

• Findings persisted when restricted to late-onset dementia and Alzheimer’s Disease

Author’s Conclusions

• MHT was positively associated with the development of all-cause dementia and Alzheimer’s Disease, even in women who received treatment age 55 and younger.

• Rates of dementia were similar between continuous and cyclic MHT regimens.

• More study is needed to determine if these findings represent an effect of MHT on dementia risk or rather an underlying predisposition in women who present for treatment with MHT.

Definitions:

Nested case-control study: A study design where a cohort (group) of participants or case records are selected based on a disease of interest and matched with cases without the disease. Within this group, the magnitude of the exposure of interest is analyzed in those with and without the disease of interest.

Contraindication: A circumstance that poses a significant health risk to the use of an intervention or therapy.

Hazard Ratio: A measure of how often an event (or disease) happens in one group (ex - MHT use) compared to how often it happens in another group (ex- no MHT use). A hazard ratio of 1.0 indicates no difference between groups.

Observational vs randomized studies: Observational studies look at groups of individuals based on specified characteristics (ie dementia diagnosis, use of MHT, etc.) of interest and either follow them prospectively (going forward) or retrospectively (past history). A randomized study selects participants with specific characteristics (age, symptoms, medical history) and randomly assigns the participants treatment versus no treatment and follows them forward.

In My Humble Opinion….

My first observation in analyzing this study is the inherent differences in the two study populations with and without dementia. Table 1 of baseline characteristics of the two groups was notable for a statistically significant higher rate of thyroid disease and diabetes in the group with dementia. Diabetes is a known risk factor for developing dementia. Other risk factors such as smoking and obesity were not characterized in these two groups at baseline. It is, therefore, unknown if there were significant differences in smoking habits and obesity between these two groups that could have biased the results.

Further, 40% and 46% of patients with dementia and without dementia, respectively, had achieved an education level of elementary school only. However, 42% and 50% percent, respectively, were in the highest household income range. This seems like an inconsistency in socioeconomic demographics.

These observations raise questions about the inherent differences and inconsistencies in the baseline characteristics of these two populations with and without dementia before even considering MHT use. These potential differences in confounding risk factors between these two groups and their impact on developing dementia may extend way beyond whether or not these women used or did not use MHT.

Another potential bias inherent to any observational study is user bias. Women who use MHT are typically doing so to alleviate symptoms (such as hot flashes). The question, therefore, is whether the physiology behind the symptom is a risk factor in and of itself for developing a particular disease - in this case, dementia. Multiple studies have shown a positive association between the duration and severity of hot flashes and cardiovascular disease risk. One must ask, then, whether the duration and severity of hot flashes may also correlate with dementia risk, especially since dementia is often a vascular phenomenon. This remains to be seen.

In randomized controlled trials, this user bias is controlled for by randomizing users of the placebo and treatment. A well-done randomized, double-blind, placebo-controlled trial that is appropriately statistically powered is the highest level of evidence that supports a cause-effect relationship between variables. Because observational studies are not subject to this level of control and randomization, they are therefore unable to prove cause-effect relationships . They only show associations.

To be fair, this study is still a viable contribution to the collective literature with its very large number of study cases, use of a national registry with complete treatment histories, clinically relevant study population, and a valid method of identifying dementia cases. Although their study does not support a cause-effect relationship between MHT use and dementia, the associations noted were likely not random, as evidenced by their statistical analysis. Despite the potential confounders, these findings are worth considering in the design of future studies.

So where does this leave us? The collective literature to date, along with the recommendations of the North American Menopause Society (NAMS) as well as the British Medical Society and the Royal College supports the safety and efficacy of MHT use in women < age 60 within 10 years of menopause onset for appropriate indications (treatment of hot flashes, prevention of osteoporosis, genitourinary syndrome of menopause (GSM)) and that a reduction in all-cause mortality is seen in these individuals.

The collective body of evidence over the decades suggests, however, that there is not enough definitive evidence to support MHT use for general disease prevention as there are real risks in some populations. What is needed is to better define these populations with respect to disease processes, lifestyle habits, or other circumstances that pose the greatest risk and conversely, relay the greatest benefit. What we have seen since the original NAMS position statements on Hormone Therapy from 2010 to the most recent statement in 2022 is indeed more clarity surrounding the patient populations and conditions for which the benefits of MHT outweigh the risks and this research is continuing.

Additionally, the era of Precision Medicine is upon us which looks to our DNA for these clues. A recent study in Alzheimer’s Research & Therapy reviewed here in Athletic Aging was the first of its kind to look at the APOE allele genotype and its association with cognitive health in MHT users and non-users.

No study is ever perfect. But it’s important to take the “nuggets” of these studies with their strengths and weaknesses and keep them as puzzle pieces that will, with time, create a clearer picture of these very important issues (and inevitably, raise more questions!). Until next time! Thanks for reading!