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expert reaction to study looking at menopausal hormone therapy and risk of developing dementia

A study published in the BMJ looks at use of menopausal hormone therapy (MHT) and risk of dementia.

 

Dr Anita McGrogan, Senior Lecturer in Pharmacy & Pharmacology, University of Bath, said:

“This is an interesting study using two primary care databases to understand whether HRT confers any change in risk of dementia or Alzheimer’s disease.  The study evaluates in detail the length of time that HRT was prescribed and different hormone combinations.  A lot of detail has been provided regarding the characteristics of the patients included but it would be helpful to know more about changes over time as recording of dementia and Alzheimer’s disease in primary care databases has increased over the course of the study.  Prescribing of HRT has also changed, as shown in the figure but does risk (or odds) of the dementia outcome remain the same?  When considering HRT as an exposure, a key confounder to include is some element reflecting socioeconomic status and the authors have adjusted for the Townsend score in the QResearch analyses but not for CPRD.  They point out the oestrogen / progestogen users are younger and live in more affluent areas (and potentially are healthier) so could this in itself alter the risk of being diagnosed with the outcome, irrespective of HRT use?  Women receiving HRT in more recent years are likely to have different characteristics to those receiving in the earlier part of the study hence it would be interesting to see these analyses run over shorter time periods to overcome any aggregating of effect of changing recording of outcomes and changing prescribing.”

 

Dr Sara Imarisio, Head of Research at Alzheimer’s Research UK, said:

“Previous research into hormone therapy and dementia risk is mixed and inconclusive.

“Studies like this, that look for patterns in medical records can be extremely useful for identifying factors linked with Alzheimer’s risk, but they can’t tell us the root cause of that link.

“When looking at the data as a whole, researchers found no link between receiving hormone replacement therapy and an increased risk of dementia.

“A smaller sub-group of the data suggests that women who received some forms of hormone therapy over a longer period of five years were slightly more likely to be diagnosed with Alzheimer’s disease, this increased risk was small, equivalent of up to seven extra dementia cases per 10,000 person years, but if any causal link exists between these two factors, it can’t be confirmed by this study.

“Hormone therapy provides important benefits to many women, helping to combat the symptoms that menopause can bring. Women who require hormone therapy should not be put off by these results, and anyone concerned about the effects of this treatment should speak to their doctor.”

 

Dr Haitham Hamoda, spokesperson for the Royal College of Obstetricians and Gynaecologists, and Chair of the British Menopause Society, said:

“Overall, this study found there were no significant links between the use of hormone replacement therapy (HRT) and the risk of developing dementia.  The study did show there was a small increased risk of developing Alzheimer’s disease if a person was on oestrogen and progesterone HRT for a long period of time.  This was equivalent to, respectively, five and seven extra cases per 10 000 woman years.  However, micronised progesterone was not specifically examined in this study and the study did not assess the impact of the timing of starting HRT (the timing hypothesis in relation to the age of starting HRT).

“Every woman experiences the menopause differently.  Symptoms can vary and be extremely debilitating, significantly impacting on their physical and psychological health, career, social life and relationships.  Sadly, many women are still suffering in silence and are reluctant to seek advice and support due to concerns around HRT.

“The findings from this research should be helpful to both women and doctors.  Overall the findings from this study do not change the recommendation that HRT should not be used to prevent dementia.  These findings should be considered in the context of overall benefits and risk associated with HRT including symptom management and improvement in quality of life as well the bone and cardiovascular benefits associated with HRT intake.”

 

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“I think this is a well-conducted large study, with appropriate use of statistical methods, and generally it’s pretty reassuring that menopausal hormone therapy (MHT, also known as hormone replacement therapy, HRT) isn’t associated with an increased risk of developing dementia.  It does report some evidence of a slight increased risk of developing Alzheimer’s disease (as opposed to other types of dementia), but only for women who took a specific hormone therapy, oestrogen-progestogen therapy, for periods of five years or more.  That increase in risk really isn’t large, though, as the authors point out; and we can’t say from this kind of study whether or not the therapy causes these cases.

“The press release and the research report, rightly, point out that this is an observational study and so cannot establish cause and effect.  So we can’t even be sure that, in the case of increased risk of Alzheimer’s in women who took oestrogen-progesterone therapy for a long time, it was the therapy that caused the increased risk.  It could have been some other factor that happens to be associated with taking that therapy.  As with all observational studies, there are sure to be many differences between the women who took different hormone therapies, or none at all, for different lengths of time, apart from the hormones they did or didn’t take.  Those other differences might be the real cause of any difference in risk of dementias, rather than the hormone therapy.  It can even go the other way – some other factors might hide an association between hormone therapy and dementia risk.  It’s possible to make statistical adjustments for other factors like this, and the researchers on this study did that for a wide range of factors.  So, while the observational nature of the study means we can’t be sure of knowing what causes what, I think the results here can still reassure us that these hormone therapies mostly aren’t associated with increased risk of dementias.  And where there is some evidence of an increased risk, the increase isn’t very big at all.

“Incidentally, the issues about interpreting observational studies also arise in a different way in this research report.  The methods used in observational studies are very important in determining the strength of evidence for the conclusions.  The researchers on this study point out that much of the concern about a possible association between some of these hormone therapies and Alzheimer’s disease came from two Finnish observational studies, which found evidence of some such associations.  But the researchers here give a convincing argument that there were issues with the methods used in those studies, particularly because the length of time for which patient data were available was not enough to provide clear enough conclusions.  This could mean that the increased risks that the Finnish researchers found were not actually true evidence of increased Alzheimer’s risk in women taking these therapies.  Because of these potential issues about the methods used in observational studies, it’s unlikely that this new study will be the very last word on this subject – but, in my view, it’s very reassuring nevertheless.”

 

 

‘Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases’ by Yana Vinogradova et al. was published in the BMJ at 23:30 UK time on Wednesday 29 September 2021.

DOI: 10.1136/bmj.n2182

 

 

Declared interests

Dr Sara Imarisio: “No conflicts.”

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  My quote above is in my capacity as an independent professional statistician.”

None others received.

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