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Reactions: study associates hormone therapy for menopause with possible development of dementia

The use of hormonal replacement therapy (HRT) for menopause is associated with the development of dementia and Alzheimer's disease, even for short prescriptions before the age of 55, according to an analysis of data from the Danish national registry published in The BMJ. The research - which observes associations and cannot determine causality - also shows that the use of progesterone alone and vaginal oestrogen are not associated with the development of dementia.

29/06/2023 - 00:30 CEST
Expert reactions

Cindy Farquhar - THS y demencia EN

Cindy Farquhar

Postgraduate Professor of Obstetrics and Gynaecology at the University of Auckland (New Zealand) and Coordinating Editor, Cochrane Gynaecology and Fertility

Science Media Centre Spain

This observational study reports on Danish registry data. The data suggest an association between the prescribing of combined oestrogen and progesterone preparations (mostly oral) and the diagnosis of dementia including Alzheimer’s. The age of starting hormone therapy was <55 years in 80% of the cases and the duration of use associated with all-cause dementia was 1 or more years or > 1 year for the subgroup of women with Alzheimers. There appears to be increasing likelihood of dementia with increasing years of use. No association was reported for oestrogen only (any route) or progesterone only use. 

The evidence to date has been concerning but also confusing. WHIMS study published randomised data in 2004 and reported an increase in dementia for women >65 years. Other randomised studies of selected populations did not report an increase. Recent observational studies also reported an increase for Alzheimer’s diagnoses only.   

The life time risk of dementia for women aged 65 is generally reported as 1 in 5. Women with symptoms, particularly hot flushes and sleep disturbance, need to consider the findings of this study and weigh up the benefits (symptom improvement) against the potential harms, which include the increased risk of developing dementia and Alzheimer’s. Women may choose to continue to use hormone therapy but limiting use to one year at the lowest dose that improves symptoms may be advisable. There is an adage that probably applies here - ‘the best medicine is the least medicine’. 

Further research could focus on use of oestrogen only and progesterone as this was not associated with an increased risk of dementia.

“I have no commercial conflicts of interest. I am the author of a Cochrane review of randomised studies of hormone therapy.”


Sarah-Naomi James - THS y demencia EN

Sarah-Naomi James

Senior Research Fellow at the MRC Unit for Lifelong Health and Ageing at University College London (UK)

Science Media Centre UK

[T]he study has strengths in utilising nationwide data it has available and their effort to try to differentiate between different types and duration of HRT use is admirable, well-needed and seems fairly robust. 

However, the study has fundamental limitations in its ability to interpret and understand the true underlying causal pathways of the observed association, as both the exposure (why you would be prescribed HRT in the first place, and why you would be prescribed certain types and duration of medication use) and the outcome (dementia diagnosis) have many things in common that influence them, and so this association may be artificial. 

For example, changes in sleep or mood are very common symptoms of menopause and reasons to seek out HRT; meanwhile we are starting to understand that sleep and mood may play an important role in in the expression and progression of dementia.  

The best way to understand whether HRT medication itself causes dementia comes from clinical trials, and to date, there is not enough evidence to support a direct link from the medication itself, and this new study alone should not change practice.  

What is clear from this study is that more research is warranted to understand the exacerbated risk of AD in women, including the role and patterns of HRT on diseases that cause dementia, but also to understand the wider context, encompassing menopausal symptoms, as well as life course and sociocultural influences that impact women in this transitional period of their life.

The author has not responded to our request to declare conflicts of interest

Amanda Heslegrave - THS y demencia EN

Amanda Heslegrave

Senior Research Fellow at the UK Dementia Research Institute

Science Media Centre UK

This is a large observational study and the data from a health registry should be of a good quality. It is important to note that the data was not collected specifically for this study. 

 I don’t believe you can suggest a causal link from this data, it is known that many women who seek HRT at or around menopause do so because of concerns around memory and cognition, potentially confounding data. 

 There is research that suggests HRT can be protective with respect to dementia, also other research that the paper cites, that HRT is associated with dementia – this suggests to me that we really don’t know the whole story and targeted research is required. 

We cannot tell from this study whether or not different routes of administration have the same apparent effect – this too needs to be investigated. [...] 

This research may cause alarm for women taking HRT, but it highlights just how much we still don’t know about the effects of hormones on women’s brain health and with promising treatments on the horizon it should be a call to action to make this a priority area of research.

The author has declared they have no conflicts of interest
Menopausal hormone therapy and dementia: nationwide, nested case-control study
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