HRT 'can shrink the brain'

“Common forms of hormone replacement therapy (HRT) can shrink the brains of post-menopausal women,” reports Channel 4 News.

The story comes from analysis of an earlier study in which women were given one of two forms of HRT or a dummy placebo pill. This trial was stopped early because women given HRT showed an increased risk of dementia. Three years later, researchers performed brain scans on some of the participants of this earlier study and found that two key areas of the brain were smaller in the women who were given HRT rather than the placebo pill.

This new research has shortcomings, including the study’s design and the fact that researchers did not have brain volume measurements prior to the women starting HRT. Consequently, it cannot be proved that the treatment caused changes in brain volume. Stating that “HRT can shrink women’s brains” may therefore be misleading.

Also, the findings of this research may not apply to younger women or those who use one of the several different forms of HRT treatment.

Where did the story come from?

This study was conducted by Drs SM Resnick and colleagues from the Laboratory of Personality and Cognition at the Biomedical Research Centre in Baltimore.

The publication uses results from two randomised controlled trials that were funded by the National Heart, Lung and Blood Institute of the NIH, the US Department of Health and Human Services, and in part by Wyeth Pharmaceuticals. The study was published in the peer-reviewed medical journal Neurology .

What kind of scientific study was this?

This was a cross-sectional study of women who were asked to participate in two previous randomised control trials. These earlier studies were part of the Women’s Health Initiative Memory Study (WHIMS).

The WHIMS study assessed the effects of certain HRT treatments on cognition and dementia risk in women aged over 65 years. The HRT treatments used were either “conjugated equine oestrogens” (CEE) or a combined treatment of medroxyprogesterone with CEE.

In the first trial, women were randomly assigned to take CEE medication or a placebo pill. In the second trial women took a combined treatment or a placebo pill.

The trial had found that those taking either form of HRT were at increased risk of dementia and negative effects on their cognition. Also, there was no reduction in risk of mild cognitive impairment. This was particularly evident in women who had low cognitive function prior to the start of the trial. These studies were stopped early because of these adverse events.

In this later study, researchers investigated the effects of the hormone replacement treatments on brain volume. This investigation used a subset of the women who had participated in the WHIMS studies.

The researchers were interested in whether the adverse events seen in the WHIMS study reflected differences in the women’s brain volumes. They also wanted to examine whether any brain volume changes were linked to cognitive levels before the WHIMS study.

Brain scans were performed on 1,403 participants from the WHIMS studies trial after completion. The researchers were interested in whether total brain volume, volume of hippocampus and of the frontal lobe differed between those who had been taking HRT compared to those who had taken a placebo. Brain volumes were measured using MRI scans.

Various baseline factors, including BMI, education, and cognitive function score were collected and considered in an analysis. These factors were used to adjust the analysis because they may be linked to cognitive function and changes in brain volume changes over time.

What were the results of the study?

Women from the WHIMS studies were contacted and asked to agree to a brain scan. Consent was given by 883 women in the combined treatment arm of the WHIMS study. Of these, 436 took the combined treatment and 447 took a placebo.

Of the women in the CEE arm of the WHIMS trial, 520 agreed to have brain scans. This broke down into 257 who had received CEE medication, and 263 who had received a placebo.

Overall, women who had received CEE or combined treatment were found to have lower brain volumes in the frontal region and in the hippocampus. The link between HRT use and hippocampal brain volume was stronger in those women with lower cognitive function at baseline.

The researchers also found that cognitive decline seen in the WHIMS study persisted until the time the brain scans were taken. Lower brain volume was also linked to older age, lower BMI, uncontrolled high blood pressure, prior cardiovascular disease and diabetes, as well as higher educational levels.

What interpretations did the researchers draw from these results?

The researchers say that their findings “emphasise the need for continued investigation of the joint effects of brain volume changes and vascular changes to further the understanding of HRT effects on cognition and brain ageing”.

What does the NHS Knowledge Service make of this study?

This study was set up to explore further the WHIMS trial’s unexpected findings that women taking a particular HRT treatment were at increased risk of dementia and that treatment did not prevent mild cognitive decline. Researchers were interested in whether brain volume may differ between women who had been treated with these drugs compared to those taking a placebo.

Points to note when interpreting the results of this study and its subsequent press coverage:

• Firstly, the design of the study design renders it impossible to make definite conclusions about whether the treatment caused reduction in brain volume.
• Another problem is that brain volume was not measured before the study started. This meant the researchers were comparing only the post-treatment results of women who had participated in a study up to three years previously. There is no way of knowing whether brain volume prior to receiving treatment contributed to lower brain volume after treatment. A more accurate assessment could be made by comparing the change in brain volume during treatment.
• This study found that reduction in brain volume was more evident in women who had lower cognitive scores prior to the WHIMS study. This may support the findings of the WHIMS study that women with lower initial cognitive scores were more likely to experience cognitive decline during treatment and were at greater risk of dementia.

Most importantly, these findings (and the findings of the original study) are not applicable to younger women who use HRT.

It is also worth noting that there are various different HRT preparations, and these use different types and doses of oestrogen and progestogen. This means not all women in the UK will be using the particular preparations used in this study.

Given this, a statement that “HRT shrinks the brain” is too strong a conclusion to make.