The WHI study is 18 years old - but is there anything to celebrate?

Fiona Clark

Happy 18th!

The WHI study on HRT has come of age. But should we be celebrating? Some doctors argue the effects of this study have cost a generation of women their long term health.

 

You may remember waking up 18 years ago to headlines emblazoned across newspapers proclaiming hormone replacement therapy (HRT) increased the risk of developing breast cancer.

If you were about to take your morning dose, you could easily be forgiven for spitting it out and then flushing it and the rest of the packet down the loo. And you wouldn’t have been alone.

The story was about a landmark trial being run by the Women’s Health Initiative (WHI) on the effects of HRT on post-menopausal women. It had followed around 26,000 for 5 years but in 2002 it announced it was stopping the trial because of the health risks it said it had discovered.

Not surprisingly, the announcement caused panic among women and doctors, and the result was a dramatic drop in prescribing. HRT use declined by 46% in the USA,  28% in Canada, and similar drops occurred in countries such as Germany and the United Kingdom.

A Lost Generation

But was this warranted?

Since then there has been an ongoing debate about the findings and the effect they have had on a generation of women. Many health professionals now claim that women’s health and quality of life has unnecessarily suffered because of the study’s flaws, and the way it was portrayed in the media.

Dr Sarah Ball, a GP with a special interest in menopause, is one of them. She has been counting down the last ten days to the study’s ‘coming of age’ on July 9 with a series of social media posts that aim to dispel the myths about HRT that still persist today.

“The WHI has led a generation of women and healthcare professionals to fear HRT. It feels like we as a gender have lost so much since 2002,” she says.

“But the truth is still emerging. This scandal is fixable.”

According to the WHI the trial was set up to evaluate if HRT was a good preventative health measure for post-menopausal women when it came to heart health.

It had decided to look at this as previous observational studies had suggested that post-menopausal hormone therapy was associated with a decreased risk of coronary heart disease. It also set about to look at bone health and osteoporosis, after reports it helped increase in bone density – which theoretically meant less fractures.

The decision to look at bones, breast and endometrial cancer (where there was a benefit) were a ‘secondary’ considerations.

The trial enrolled some 26000 women who were randomly assigned into groups who either took HRT or a placebo. The 16000 or so who had a uterus took an oral, synthetic form of estrogen (Conjugated Equine Estrogen or CEE- derived from horse pee) and progestin, and the 10000 or so who no longer had a uterus took estrogen only.

The age of the women when they were enrolled was between 50 and 79 with an average age of 63.5.

They were monitored and assessed on a variety of health parameters for 5.2 years but in 2002 it was decided that the study should be stopped after it showed an increased risk in coronary heart disease and breast cancer for those who took both hormones, and an increase in stroke for those who took the estrogen only.

According to a summary of the findings published in JAMA “Over 1 year, 10 000 women taking estrogen plus progestin compared with placebo might experience 7 more CHD events, 8 more strokes, 8 more pulmonary embolisms (PEs), 8 more invasive breast cancers and 6 fewer colorectal cancers, and 5 fewer hip fractures.”

That’s less than one person in 1000.

menopause-hrt-harley-street-emporiumDesign Flaws

By its own admission the study had limitations. It only looked at one form of HRT – the older form of equine derived estrogen, which, unlike the modern forms of HRT, is not ‘body identical’. It was taken orally and the dose was the same for everyone.

The authors conceded that you there could be a very different outcome if transdermal oestrogen had been studied.

A later re-analysis of the study found that it had many other flaws.

The age range from 50 up to 79 starting on HRT is one concern raised. Many did not have menopause symptoms so did not need HRT and many were outside of the ideal age – or the ‘window of opportunity’ – to be started on HRT which is within 10 years of your last period.

On top of that the results were only adjusted for the primary endpoint — coronary heart disease — not other factors that may have affected their health.

Despite that, the results were generalised and applied to all women – including women under 50 who were not part of the study and where clear benefits of taking HRT had been found in other studies.

To make matters worse, an explanatory article by the NHS pointed out that reporting by the media was misinterpreted. Relative risks were stated as absolute risks. Absolute risk is the risk you have of developing a disease while relative risk compares the risk between two groups – in this case those taking HRT and those who didn’t.

 

Misunderstanding the Numbers

On top of that the figures themselves were misunderstood. The WHI study found the number of cases of breast cancer increased from 30 to 38 in 10,000 women. Those extra cases represent a rise of 26% from 30 to 38 – but that does not mean that 1 in 4 women taking HRT will get breast cancer– which is what made the headlines.

The re-analysis of the WHI trial that included new studies and a meta-analysis showed that the use of HRT in younger women (50–59 years) or within early within 10 years of menopause – the last period – had a beneficial effect on the cardiovascular system, reducing coronary diseases and all-causes of death.

“Furthermore,” the authors wrote, “a large controlled trial from Denmark (reported in 2012) demonstrated that healthy women taking combined HRT for 10 years immediately after menopause had a reduced risk of heart disease and death from heart disease.

“Unfortunately, these data did not receive appropriate coverage by the media, and the fear regarding HRT has persisted,” they wrote.

heart-hrt-harley street-emporium

The Deprivation Effect

Dr Ball says that women who experience premature menopause due to surgery or other reasons have paid a very big price in the fall out of the WHI study.

For example, a woman who experiences premature menopause at say 35 will be without the protective effects of oestrogen for 16 or more years in comparison to a woman who naturally goes through menopause at 51-52 – the average age.

This means have missed “the very real benefits” it confers in reducing the risk of coronary heart disease and cardiovascular disease (heart attacks and strokes), fractures, new onset diabetes and, as Dr Ball says, “all cause mortality – that is, the chance of dying of anything including any type of cancer.”

“Tragically, it is estimated that there have been 50,000 premature deaths in women in the US alone who have had hysterectomies because they have not used or stopped using HRT because of the WHI study.”

In a recent presentation at the International Society for the Study of Women’s Sexual health (ISSWSH), Dr James A. Simon, a clinical professor in obstetrics and gynaecololgy at George Washington University in the US, claimed women are now faring much worse than men in a variety of health indicators as a result of the ongoing effects of the WHI study.

A report comparing male and female mortality  rates in the US between two periods, the mid-1990s and between 2002 and 2006  reported a reduction in male mortality but an increase in female mortality in the same timeframe.

While health and mortality rates are multifactorial, if HRT had been that bad for women’s health then you’d expect that women’s health would fare better when around 50% of perimenopausal or menopausal women stopped using it – but that doesn’t seem to have happened.

In his presentation called “How the US government and the media conspired to convince women that Menopausal Hormone Therapy was dangerous” he set out the number of times the WHI had released positive data on HRT that had never been picked up.

 

Ignored Results

In 2007, he said, it released data showing that there was no risk of heart disease from HRT and that the total mortality rate of women taking it was lower.

In 2016 it released data showing that the was a decreased risk of breast cancer in black women taking oestrogen alone.

“If I were a black woman taking oestrogen I’d want to know that,” he said.

And in 2017 – after a follow up of 18 years the WHI said it was not associated with any increased risks when it came to mortality rates from cardiovascular disease of breast cancer in women aged between 50-59.

All findings, he said, that didn’t get the airing they deserved.

As Dr Ball says in her final happy birthday post, longer term follow up shows that any risk for breast cancer from combined HRT (both oestrogen and progesterone) is so small that it’s not “statistically significant” and, she reminds us that it does not mean that HRT causes cancer or death from cancer.

“Remember,” she says, “HRT these days is even safer that that used in the WHI. Many studies prove this.”

But, is anyone listening?

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