HRT and dementia: cause or cure?

YOUR BRAIN ON MENOPAUSE: In this seven-part series, I explore menopause from a brain health perspective with a particular focus on the neurobiology of hot flashes, sleep, mood and memory, the role of hormone therapies and their long-term effects on the brain. This is Part 7.

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This is a long and detailed read. Click here to download the series as a PDF to read offline.

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Women are at greater risk for developing dementia compared to men.

And as Jen Gunter points out,

“…When women develop these conditions they often develop them earlier. Women with a later menopause (longer lifetime exposure to estrogen) have a lower risk of dementia, and women with menopause before age forty-five are at higher risk.”

Jen Gunter The Menopause Manifesto.

You can read more about some of the reasons why women are at greater risk than men, in one of my earlier blog post: Is Alzheimer’s Disease a Women’s Health Problem?)

What is dementia?

Dementia is an umbrella term used to describe the symptoms of a large group of illnesses that cause a progressive decline in a person’s functioning.

There are over 100 diseases that cause dementia symptoms including AD, Frontotemporal Dementia (FTD), Vascular dementia, Parkinson’s disease, Dementia with Lewy bodies, Huntington’s disease, alcohol-related dementia (Korsakoff’s syndrome) and Creutzfeldt-Jacob disease.

AD is the most common form of dementia and accounts for 50 to 70% of all cases, which is why the two terms are often used interchangeably. Women are more at risk of AD than men (but men’s rates are catching up). Men are more at risk of vascular dementia than women.

Early signs of dementia are subtle and vague. Symptoms may include:

• Progressive and frequent memory loss
• Confusion
• Personality change
• Apathy and withdrawal
• Anger and aggression
• Loss of ability to perform everyday tasks.

Clearly, these symptoms are common for a number of conditions such as vitamin and hormone deficiencies, depression, infections and brain tumours, and … menopause.

Over the past five years (its now March 2024), the perception of menopausal hormone therapy (MHT aka HRT) has undergone a significant transformation. What once was approached with fear and avoidance has shifted towards FOMO, with many now considering the benefits of MHT for alleviating menopause symptoms.

Given the myriad of opinions and loud voices dominating the conversation around menopause, it’s understandable to question how dementia fits into the context of MHT.

Fears that MHT/HRT causes dementia are based on old research

There are good reasons to be confused about the data!

Biological studies have suggested possible neuroprotective effects of oestrogen on the brain. However, data from studies following women into their 80s and 90s are mixed.

The fear that menopause hormone therapy (MHT) caused dementia arose from the results of the Women’s Health Initiative Memory Study (WHIMS), which was a sub-group with WHI. For the 4,532 women included in the trial, MHT worsened cognitive function and increased the risk for AD.

But bear in mind that this was the WHI, and women were enrolled at the average age of 72, roughly 15 to 20 years after their menopause, and well beyond the critical window of opportunity in which MHTis of benefit (see our previous blog for a discussion of the ‘window of opportunity’). Unfortunately, WHIMS came to the incorrect conclusion that MHT was detrimental to brain health and caused AD.

MHT and dementia risk: 2021 updates

In a comprehensive study published by the British Medical Journal in September 2021, researchers examined 16,291 women diagnosed with dementia alongside 68,726 healthy women, all of whom were undergoing menopausal hormone therapy (MHT).

After accounting for a wide array of potential confounding factors, the study concluded that there was no significant link between MHT and the risk of dementia. This finding held true across various hormone types, administration methods, doses, and treatment durations.

In summary, in this trial, the data found that MHT did not cause dementia.

As the authors conclude,

Evidence is reassuring for women using hormone therapy to treat menopausal symptoms.

Vinogradova et al BMJ 2021.

However, it gets a little more complex as they found a reduced risk of dementia among women under the age of 80 who had been on oestrogen-only MHT for a decade or more. They found a slight increase in the risk of developing Alzheimer’s disease, in women who had used combined oestrogen and progestogen therapy for over five years. To quantify this, the risk translated to an additional 5 to 7 cases of Alzheimer’s disease per 10,000 woman-years.

It’s important to note, the risks are different for combined oestrogen + progestogen versus oestrogen-only MHT. This distinction adds complexity to the discussion, especially considering that progestogen is almost always prescribed alongside oestrogen for women with uteruses to mitigate the risk of endometrial cancer. Only those women who’ve had a hysterectomy to remove their uterus (or using the Mirena IUD) are given oestrogen-only MHT.

MHT and dementia risk: 2023 updates

In 2023 a systematic review and meta-analysis of MHT and dementia risk was published by Lisa Mosconi and her team. This included data from the largest clinical trial to date, the WHI (including all its problems), and other observational studies, which are not considered to have the highest level of evidence for clinical decision-making but nonetheless are the best we’ve got.

Mosconi and her team looked at the risk for dementia in women who used oestrogen-only MHT or combined MHT during midlife versus dementia risk when oestrogen-only MHT or combined MHT was used by older women. Click here to view figure.

This raises a few more points (or gaps in our knowledge, if you will),

1. Different MHT formulations (combinations of hormones) and routes of administration (via the skin or as a pill) might yield different results.
2. Women taking different MHT formulations who start or stop therapy at different ages or stages of menopause might experience different levels of risk.
3. Women currently taking MHT in what is assumed to be the best dose/formulation/age/length of time aren’t yet old enough to start showing an increased or decreased risk for dementia.

Professor Susan Davis, Director of the Monash University Women’s Health Research Program, commented on some of the complexities of observational studies, combinations of hormones, and routes of administration in this piece for the RACGP (this is most relevant for Australian women). Click here to read.

As Lisa Mosconi concludes in her 2024 book, The Menopause Brain,

“For now, in the absence of more definitive findings, HRT is not recommended to prevent or treat cognitive decline or dementia. While we’re not there yet, I hope these recommendations will shift and evolve further as we gather more evidence.”

Lisa Mosconi, The Menopause Brain.

This statement is supported by global menopause societies, which are well aware of the intense interest in MHT, menopause, and healthy brain ageing. Their statements clearly reflect the ‘gaps’ but they can only make recommendations based on solid data.

“In the absence of more definitive findings, hormone therapy is not recommended at any age to prevent or treat a decline in cognitive function or dementia.”

North American Menopause Society HRT position statement

I’ll also give a shout-out, once again, to Jen Gunter, who uses a traffic light system to consider MHT risks and benefits based on the strength of available data.

Mind the gap of midlife.

Carl Jung once wrote,

“The afternoon of human life must also have a significance of its own and cannot merely be a pitiful appendage to life’s morning.”

Jung

Apart from menopause, we tend to think of midlife as a still period that lies between the turmoil of adolescence and the decline of old age. Yet midlife is when we’re at the peak of parenting, decision-making, self-confidence, self-esteem, our capacity to earn and contribute to the community.

Midlife is also when the early warning signs for poor mental or physical health emerge, but when there is still time to delay, minimise, or even prevent some of the changes in biological, psychological, and social functioning that typically occur in later life.

Midlife is a unique window of opportunity in which to invest in future-proofing your brain. It’s time to stop, take stock, and invest in a healthy future.

And as she always says it best, I shall conclude this series with yet another Jen Gunter quote,

Many women have been conditioned to fear menopause as an expiration date for relevance and as a sign of weakness only because that is what men thought.

In fact, we have this amazing data that tells us that menopause is the opposite—a time when historically women contributed great things to society because of their knowledge and their age.

Yes, menopause has symptoms and is associated with medical concerns, but there is help and it’s certainly not a pre morbid state.

The story I want you to remember is about value, agency, and voice and the knowledge to keep yourself in the best of health…

Jen Gunter, The Menopause Manifesto.

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This is a long and detailed read. Click here to download the series as a PDF to read offline.

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