Don't Panic about the Study Suggesting an Increased Risk of Dementia with MHT

But there is a good lesson here.

A new study is making some waves as it links menopausal hormone therapy (MHT) with an increased risk of dementia, even for people taking hormones for less than a year who are under age 55. I received quite a few DMs last night and today, like these two.

But the study shouldn’t worry you.  

Here’s why.

The Background

This is a large cohort study published in the British Medical Journal or BMJ. The investigators looked at Danish women in national health registries who were between the ages of 50 and 60 between years 2000 and 2018. They then looked at the records to see who developed dementia and who did not and who took combined hormone therapy (estrogen and a progestin) and who did not. 

These kinds of studies are interesting, because in countries with good registries they can look at massive numbers of people in a “real world” setting. For example, in this registry they identified 5,589 cases of dementia and matched these cases with 55,890 controls. It’s simply not possible to enroll this many people in a clinical trial and then do 5-12 years of follow up to see who develops dementia. On the plus side, this registry system in Denmark fairly accurately captures the diagnosis of dementia. In addition, there is a prescription registry, so they can be fairly certain who received a prescription for MHT and who did not.

Another advantage of the prescription registry is the researchers were able to see who used transdermal versus oral estrogen, as well as the type of progestin and how it was used (every day as opposed to cyclic, typically meaning 12 days out of a month). All of the prescriptions were progestin, meaning a synthetic medications similar to progesterone. This is currently a less common regimen as the starting hormone of choice to protect the uterus is now progesterone (you can read more about who needs a progesterone or a progestin here). 

Side note: progestogens are the class of drugs that act like progesterone. In this class are progesterone, the hormone released by the ovary, and progestins, which are synthetic or novel compounds. They are all made the same way, from a chemical in yams or soybeans, but progesterone and progestins do have different properties, so it is important when looking at risks and benefits to be able to separate them.

Another point is the majority of estrogen prescriptions (about 90%) were oral, which is also no longer the preferred therapy.

The Findings

There was 24% increased risk of dementia among women who took estrogen and a progestin MHT for any length of time. The risk was greatest for those who took the medication for more than 12 years (a 74% increased risk), but it was even present for those who were 55 years or younger when they started hormones and for those who took the medication for less than one year. These latter two findings raise some serious red flags about interpreting the study. Because it is biologically improbable, if not impossible, that taking estrogen and progestin for less than one year raises the likelihood of developing dementia by 21%. In addition, if less than one year of estrogen increased the odds of dementia by that rate, we’d know given the data already available.  

The Interpretation

This is a cohort study, meaning groups of people who did things were evaluated and then compared with each other, and of course, we don’t know why these people did those things (meaning why they took hormones). Is it possible that the people who were worried about dementia because of family history were more likely to take hormones as they erroneously believed the hormones would lower their risk? Sure. Another important point is people who experience more hot flashes are more likely to have changes in the brain that are associated with an increased risk of dementia. Meaning might people with the worst hot flashes, meaning those at higher risk for dementia, be more likely to take to start hormones considering estrogen is the gold standard for hot flashes? Again, sure.

While researchers can control for some of the variables that impact the risk of dementia, for example smoking, and make the groups equal in that regard, they can’t account for all the factors, for example hot flash severity, diet, and social interactions, just to name a few. There could be many reasons why the two groups in this new study are not similar regarding their risk for dementia, and so it is possible that those who were more likely to develop dementia were those more like to be prescribed hormones. This is why randomized clinical trials are so important before altering recommendations.

Another very important point, previously mentioned, is the majority of people in this study took oral estrogen (about 90%), which is associated with higher blood pressures, which is a risk factor for dementia. Might this be an explanation for the link with dementia? It seems unlikely given what we know from randomized trials (we’re getting to that, so hold that thought), but we are learning more and more about the differences between oral and transdermal estrogen, so we need to be careful about comparing the two, because it’s not apples to apples.

This reminds me of another recent cohort study where taking estrogen was associated with a lower risk of Alzheimer’s that I wrote about here. In this study, among those who carried APOE4 variations (a genetic risk for Alzheimer’s) there was less loss of brain volume and fewer memory issues for those who took menopausal hormone therapy versus those who didn’t, but no difference for those who did not have the APOE4 variation. While one conclusion could be that estrogen in menopausal hormone therapy is protective brain-wise for APOE4 carriers, it’s equally possible that the benefit shown is spurious, meaning there were other reasons that the people who took estrogen might have had better outcomes brain-wise. For example, taking estrogen might be a marker for being more engaged with other activities that we know reduce the risk of dementia, but were not tracked in the study. 

Observational studies are interesting, but for cause and effect, meaning does MHT cause dementia or does it protect from dementia, ultimately randomized trials are needed. In fact, for every observational study that says estrogen protects against dementia, I’d bet I can find one that says the opposite. 

Fortunately, we HAVE randomized clinical trial data for MHT and dementia. Both the Women’s Health Initiative Memory Study (WHIMS) and the WHIMS of Younger Women (WHIMS-Y) trial evaluated oral estrogen and an oral progestin. When MHT was started for women who were 65 years or older the risk of dementia doubled and when MHT was started for women aged 50 to 55 years there was no increased risk. There are also two other randomized trials that looked at cognition and transdermal estradiol plus progesterone (the current starting regimens of choice) and found no negative effect of these hormones on cognition compared with placebo over several years.

What Does This All Mean?

It’s a good study of a large population and the data was looked at meticulously, but it can’t tell us cause and effect. As a result, it shouldn’t change the way we currently prescribe menopausal hormone therapy.

We have at least four randomized clinical trial that say the opposite of what this new study found for the group of women using MHT for 5 years or less who were 55 years or younger when they started. This represents the majority of people starting MHT today and when there is conflicting data, we go with the randomized clinical trials, which are more able to determine cause and effect. 

Most women who start MHT are not taking oral therapy or a progestin, so the regimen isn’t very applicable to today’s prescribing. The recommended starting therapy today is transdermal estradiol and oral progesterone.

We also have randomized clinical trial data that tells us the risk of dementia is higher for those who start estrogen at age 65 or older.

“What does this study mean for me?”, you may be asking yourself. Nothing. This study, while interesting for researchers, should not change anything. We need to go by the randomized clinical trial data, and the guidelines for dementia should remain unchanged. Meaning, estrogen should not be started to protect against the risk of dementia for those in menopause. For those with early menopause, premature menopause, or primary ovarian insufficiency, recommendations are different and you can read about that in my new series dedicated to the hormone menoverse

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Who Should Take Menopausal Hormone Therapy?

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Yes, I know there are some providers who tell women that the estrogen in MHT protects the brain in menopause, but what these people are doing is cherry picking observational studies to support this point of view. I too could cherry pick observational studies and freak people out, but I choose not to because I understand the literature, the guidelines, and I’m not interested in upselling estrogen so I can charge concierge prices or make a small fortune from implanting pellets (also, never get pellets). 

The lesson here is observational studies are interesting, and when we don’t have randomized controlled trials they are invaluable. This is one of those studies that is interesting for researchers, but shouldn’t change clinical guidelines. For example, I read this study and thought, “I wonder if we need to know more about long term use of oral estrogen?” I think it’s ridiculous that this study received the press that it did. It proves my point that scaring women about their health makes bank.

It is possible that one day we might find specific groups of people who are more or less likely to benefit from MHT from a dementia risk perspective? Of course, but we are not there today. Until that time, we need to follow the guidelines for hormones which are largely based on some solid randomized clinical trials:

• Don’t start estrogen for brain health in menopause, start it for other reasons, such as hot flashes. 

• Don’t start estrogen over age 60/more than 10 years from the final menstrual period. I will be explaining more about this in my hormone menoverse guide when we get to the “timing hypothesis.”

And Most Importantly

The best way to protect your brain is not with hormones, but you might consider these interventions:

• Exercise

• A healthy diet

• Not smoking

• Controlling blood pressure

• Staying socially active

• Protecting your brain from injury

• Limiting alcohol

• Correcting hearing loss

If you read the headlines and freaked out a little, I get it, hence why I wrote this article. But if it scared you (or even if it didn’t), think about this list of modifiable factors and consider how you can work on them for your own brain health. 

And the lesson? Be mindful of observational data, because with MHT it’s easy to twist in either direction.

References

Pourhadi N, et. al. Menopausal hormone therapy and dementia: nationwide, nested case-control study. BMJ 2023;381:e072770.

Kantarci K, Manson JE. Menopausal hormone therapy and dementia. A causal link remains unlikely. BMJ 2023;381:p1440.

Rasha N M Saleh, Michael Hornberger, Craig W Ritchie, Anne Marie Minihane. Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort. Alzheimers Res Ther 2023 Jan 9;15(1):10.

Yueh-Feng Sung, Chun-Teng Tsai, Cheng-Yi Kuo, et al. Use of Hormone Replacement Therapy and Risk of Dementia. A Nationwide Cohort Study. Neurology October, 2022; 99 (17).

Gleason CE, Dowling NM, Whartone W, et. al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med;2015 Jun 2;12(6):e1001833

Henderson St. John JA, Hodis HN, et. al. Cognitive effects of estradiol after Menopause. A randomized trial of the timing hypothesis. Neurology 2016. Aug 16;87(7):699-708.

Espeland MA, Shumaker SA, Leng I, et. al. Long-Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50 to 55 Years. JAMA Intern Med. 2013;173.

Mark A Espeland, Stephen R Rapp, JoAnn E Manson, et. al. Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups J Gerontol A Biol Sci Med Sci 2017 Jun 1;72(6):838-845. 

Kantarci K, et. al. Brain structure and cognition 3 years after the end of an early menopausal hormone therapy trial. Neurology 2018;90-12.