Menopausal Hormone Therapy and Dementia

Thought LeadersDr. Yana VinogradovaSenior Research FellowUniversity of Nottingham

In this interview, News-Medical speaks to Dr. Yana Vinogradova about her latest research into menopausal hormone therapy (MHT) and its unassociated risk to dementia.

What provoked your latest research into menopausal hormone therapy (MHT) and dementia?

We have been involved in very large observational studies into drug risks for some time.  This is our third study investigating serious side effects associated with MHT.  Early studies had reported problems, such as venous thromboembolism (VTE) and breast cancer, and this had caused a decline in the use of the therapy, which had persisted.

In 2015, the UK’s National Institute for Clinical Excellence issued new guidelines recommending the wider use of MHT, at the same time calling for more detailed research into the risks of serious side effects.  Because they were the side effects most commonly known and discussed, our first studies into MHT addressed the additional risks of VTE and breast cancer.  This third study on dementia was triggered by existing inconsistent research findings on additional risks of developing dementia associated with MHT.

Please can you give an overview into what MHT is and how it works?

Menopause is the stage in a woman’s life when her hormone levels decrease and periods stop.  At this time, many women also experience a range of symptoms, such as hot flushes, sleep disturbances, depression, mood swings, or memory losses – sometimes so severely that they need treatment to counteract the effects.

Menopausal hormone therapy usually consists of two types of hormones– an estrogen being the key component and a progestogen added for womb protection (combined therapy).  Oestrogen-only therapy is prescribed to women who have undergone procedures involving the removal of the uterus.

Some menopausal symptoms are similar to early warnings of future dementia and biological studies have suggested both that exposure to estrogen may have a protective effect on the aging brain and that the addition of a progestogen may counteract this effect.

Menopausal hormone therapy is effective in easing menopausal symptoms, but whether women who use it were at higher or lower risk of developing dementia was unclear.

Hormone Replacement Therapy

Image Credit: Image Point Fr/Shutterstock.com

Why have a lot of studies surrounding MHT and dementia provided inconsistent findings?

Dementia is relatively rare and the number of MHT specific hormones used in different treatments is wide.  Assessing risks for different combinations of hormones, dosages, and duration of treatment requires that a very large number of women be followed up over a long time.

Previous investigations on this topic have either been too small to deliver clear results or have investigated only a few available treatment formulations.  The large Women’s Health Initiative study, for example, investigated only one combination of hormones.  A recent Finnish study on MHT and Alzheimer’s disease reported rather high risks, but the study design had some methodological weaknesses.  

Our study aimed to investigate all menopausal hormone treatments available from the National Health Service in the UK and included – as do all our studies a very large number of women, representative of the general population.

Can you describe how you carried out your latest research into MHT and dementia?

We used patient records from two of the largest primary care databases in the UK, which also have links to secondary care and other data sources, creating a rich data set with extensive information about patients, and patient histories and characteristics.  From these, we extracted information on all women aged 55 or older, who had been diagnosed with dementia in the last 20 years.

We then matched each of these cases to up to 5 women without dementia, who were from the same practice and were of the same age.  Finally, we analyzed prescription information and compared it between cases and controls taking into account all other available factors which are known to affect their risk of developing dementia.

What did you discover?

When we investigated diagnoses for generic dementia (regardless of a specific type), we found no additional risks of developing dementia associated with the use of MHT.  This was consistent across different treatment formulations, dosages, ways of administering the therapy, and duration of use.

The only elevated risk was found in an analysis of the subgroup of cases diagnosed specifically with Alzheimer’s disease (AD) and their controls.  Here we found a very small association for users of combined MHT therapy, increasing with duration of use and reaching a measurable level only among long-term users (11% uplift for use of 5 to 9 years and 19% for use of 10 years or more).  In absolute terms, the risk was equivalent to extra respectively 5 and 7 women per 10,000 per year.

It should be stressed that our estimates for the AD cohort were lower than those from the Finnish study mentioned earlier and that these risk associations are not causal.  AD is a slowly developing form of dementia and shares some symptoms with menopause.

Our findings are more like identifying a group of women with histories or characteristics that make it more likely both to require HRT for longer and to be slightly more likely to go on to develop dementia.

Dementia Concept

Image Credit: Robert Kneschke/Shutterstock.com

What were some of the limitations of your study?

The main limitation of the study is that the records for menopause were not complete and we could not know which symptoms triggered women to take MHT.  With respect to the finding for Alzheimer’s disease mentioned above, it is possible that some women had menopausal symptoms similar to signs of Alzheimer’s disease, and persistence of those made them stay on MHT for longer.

To minimize this anticipated possible indication bias, our analyses discounted all prescriptions within the three years before the diagnosis date, but there still might have been some residual confounding.

How will your findings help the wider medical community including doctors and policymakers?

The study should further reassure women about the safety of MHT treatments, particularly when not used for an extended period.  For women who do still have concerns, this information will be useful to doctors, facilitating discussions with their patients.  For policymakers, it also clarifies the situation and will help underpin their recommendations concerning HRT.

How will your research also help to reassure women who require MHT?

MHT is a medication and like any medication has some side effects.  For women suffering from severe menopausal symptoms, MHT brings relief and improves their quality of life.  Our research in this area has shown in general that risks of serious side effects are minimal (as with dementia) or very low.

The more detailed findings in our studies also help women of different ages to identify the relative risks for them of specific treatments and regimens (formulation, dosage, and/or duration).  We would always advocate that women discuss their concerns with their doctor to identify the most appropriate treatment for their needs.

Women’s health is an often neglected area of research. Why is it important to continue to research women’s health? What more can be done here?

I am not so certain of the opening premise – as a researcher into aspects of women’s health as well as more general health studies, I am aware that there are many aspects of health that need investigation or where existing findings could be improved.

My main concern is that patients’ needs should be at the center of every health study – with respect to MHT, for example, the real need for relief from severe symptoms means that effective treatments are needed, but what is also needed are studies to identify the safest treatments and so help reassure patients concerned about serious side effects.

Women

Image Credit: Rawpixel.com/Shutterstock.com

What are the next steps for you in your research?

We intend to continue research on risks and benefits from MHT treatments – primarily very large observational studies using real patient data collected in ‘real world’ treatment centers.

Our aim is to deliver outcomes observed in the general population so that our estimates reflect what ordinary patients might expect.

About Dr. Yana Vinogradova

I studied Applied Mathematics at Moscow State University (MGU) and became a Research Fellow at the Cardiology Research Centre of the Russian Academy of Medical Sciences in Moscow. After moving to the UK, I worked in the Division of Cardiology at the University of Leicester, and in the Centre for Health Service Studies (CHESS), and in the Division of Health in the Community at the University of Warwick.Dr. Yana Vinogradova

In 2005, I joined the University of Nottingham as an expert in medical statistics in 2005. I have since worked in the Division of Primary Care of the School of Medicine, where I was awarded a Ph.D. in Medicine by published works in 2017. I am now a Senior Research Fellow.

Current Research

My research involves the use of mathematical models and statistical methods to improve understanding of the dynamics and incidence of diseases, and of treatment outcomes. My work at Nottingham has largely been in the area of drug safety, focusing on two aspects – adherence to prescribed medications and drug safety, in particular looking at rare and/or slowly developing outcomes.  These require very large observational studies, and I use anonymised real patient data gathered over long periods in NHS primary care environments, which are linked to secondary care and other relevant data sources.

This allows the studies to deliver accurate and robust estimates of risk, reflective of outcomes in the general populations, and down to the level of detail of specific drug formulations, dosages, delivery measures, and exposures.  As well as my drug safety work (currently focusing on MHT,) I am involved in a wide range of collaborative research projects.

Past Research

I have been involved in a wide range of research – observational and trial studies in Moscow Cardiological Research Centre and Leicester and Warwick University.  Since joining Nottingham University, I have also worked on risk prediction modelling (QRisk) and observational studies to do with injury prevention.

Future Research

I have highly developed skills in the use of very large data sets and pioneered the use of multiple large databases (specifically QResearch and CPRD) to facilitate more detailed research into drug types and formulations and improve the accuracy of risk estimates.

My aim is to build on what I have achieved at Nottingham to continue to deliver independently-researched drug safety information of use to patients, doctors and regulators. I enjoy extending my areas of expertise and envisage researching using new machine learning and other novel techniques, though always from the perspective of utility rather than fashion.

Emily Henderson

Written by

Emily Henderson

During her time at AZoNetwork, Emily has interviewed over 150 leading experts in all areas of science and healthcare including the World Health Organization and the United Nations. She loves being at the forefront of exciting new research and sharing science stories with thought leaders all over the world.

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