Controversial HRT study revisited 20 years on

Controversial HRT study revisited 20 years on

Brisbane obstetrician and gynaecologist Gino Pecoraro still recalls the moment twenty years ago when he learned that a large-scale study probing the effects of hormone replacement therapy (HRT) on post-menopausal women had come to a screaming halt.

“I’ll never forget the night– I’d come home from doing a delivery, I sat down on the couch and was having a cup of coffee, watching the late news,” Associate Professor Pecoraro says.

The rolling ‘breaking news’ banner down the bottom of the screen revealed that the US-based Women’s Health Initiative (WHI) study had been prematurely stopped in its tracks due to findings suggesting it “caused” breast cancer.

“I thought I was going to vomit,” Pecoraro says. “I thought, ‘I don’t want to go to work because it’s going to be awful. It’s going to be a warzone’.”

He was right – and the casualties were menopausal women.

‘Highly unusual circumstances’

Worldwide panic meant that HRT use fell off a cliff. According to the Women’s Health Concern in the UK, the number of HRT users fell from two million to less than a million between 2003 and 2007; in Australia, HRT use fell by 55% from 2001 to 2005, a PLoS One study found.

“I thought, ‘I don’t want to go to work because it’s going to be awful. It’s going to be a warzone’.”

Associate Professor Gino Pecoraro

Dr Ginni Mansberg, a Sydney-based GP who authored The M Word: How to thrive in menopause, says countless women went back to suffering some of the worst symptoms the so-called “change of life” had in its arsenal – hot flushes, night sweats, disrupted sleep, brain fog, anxiety and depression.

Doctors were blindsided, having had no opportunity to weigh the evidence before the news hit the headlines, Pecoraro says.

“Unfortunately, they released the fact that they were stopping the trial to the media, rather than going to the medical profession, so that we didn’t have time to interpret what they said,” he explains.

Smiling blue suit photo. Jpg edited
Associate Professor Gino Pecoraro.

Up until then, observational studies had revealed that HRT could prevent major age-related diseases, especially cardiovascular disease, which is the number one killer of Australian women, according to the Heart Research Institute.

A closer look at the WHI trial revealed that it aimed to test whether starting HRT long after menopause would confer the same heart and other health benefits as seen in women closer to menopause.

The average age of menopause is 51 years, according to the Australian Menopause Society.

By contrast, 70% of women in the worrying WHI study were 60-79 years, with an average age of 63, says Robert Langer, Professor Emeritus in Family and Preventive Medicine at the University of California in San Diego.

Read more: Tackling the gap in women’s health data.

In a paper published in Climacteric in 2017, Langer, one of the WHI’s lead investigator, blew the whistle on the “highly unusual circumstances” which led to the abrupt termination of the trial due to “critical misinterpretations” of the data.

Generalising findings from an older population which was unrepresentative of typical HRT users was just one in a series of interpretive flaws, Langer wrote.

Generalising the form of HRT used in the study (continuous conjugated equine estrogens and medroxyprogesterone acetate) to all other forms of HRT was also suspect.

But the biggest blunder? Concluding that HRT led to an elevated risk of breast cancer, a finding which was “statistically unsupported”, he wrote.

“The investigators most capable of correcting the critical misinterpretations of the data were actively excluded from the writing and dissemination activities,” Langer added.

‘Quietly suffering for a generation’

Even though subsequent studies have lent considerable support to the benefits of HRT in menopausal women, in 2002, the damage was done.

“Everyone went away, and women just quietly suffered in silence for a generation,” Pecoraro says.

Part of the aftermath was that the medical profession lost a whole army of specialists and GPs, who shied away from recommending or prescribing HRT.

“We didn’t have any GPs feel comfortable because it was taken out of their curriculum,” Pecoraro says.

A further consequence was a 20-year void in research, product development and treatment.

“We didn’t have any new hormones, or pills, or oral contraceptive pills, or HRT treatments for a very, very long time,” Pecoraro says.

“When the government makes you put black box warnings about how this thing is going to give you cancer all over the box, where are the commercial incentives?”

Dr Ginni Mansberg

Meanwhile, the manufacturer of the HRT used in the trial was crushed by a rumoured $300 million in lawsuits, says Mansberg.

“Most drug companies got whacked into submission and just shut down their women’s health business,” she adds.

“So it wasn’t just that we were scared of HRT, it’s like the whole industry got tainted with (a sense) that it’s bad luck, and it’s not worth the risk, and that has really left people with a pretty bad taste in their mouths.”

Other lingering legacies of the WHI debacle include the “black box warnings” which are still retained on HRT products, along with the high cost of the products, Mansberg argues.

“Most of the best forms of HRT are not subsidized by the Pharmaceutical Benefits Scheme (PBS),” she says.

“The reason is that it costs between $300,000 to $800,000 to … apply for your drug to be included.

“When the government makes you put black box warnings about how this thing is going to give you cancer all over the box, where are the commercial incentives?”

Many women simply can’t afford HRT, an evidence-based treatment, because it’s so expensive.

“Menopause management is absolutely a wallet-based issue and, as women, we should be up in arms,” Mansberg says.

Don’t sweat it

Beyond the personal costs, menopause imposes a significant burden on the economy, given that 10% of menopausal women find its symptoms so disabling that they quit work, while another 14% reduce their hours, and a further 8% refuse a promotion, Mansberg says.

Ginni mansberg edited
Dr Ginni Mansberg, author of The M Word: How to thrive in menopause.

Those who stay can experience a dive in confidence and loss in self-perceived productivity.

“We see these women hurtling towards the C suite in their late thirties, early forties, with companies investing enormous amounts in leadership training, only to be left standing there, scratching their heads, with these women at 49, just going, ‘No, I don’t think so, I’m not doing this anymore’,” she says.

Mansberg has developed the online learning program Don’t Sweat It to help workplaces better manage issues relating to perimenopause and menopause.

Mental health issues like anxiety and depression which emerge at this time may even be more effectively treated with HRT than anti-depressant medication, Mansberg adds.

Read more: Predicting menopause: Is reproductive lifespan genetic?

“The greatest time for suicide for women is between 45 and 55,” she says.

“This is a huge issue – there’s no point saying that it’s just a cosmetic (issue) and don’t worry about it and if you’re looking for help, you’re just a loser.”

Campaigns by the likes of UK television presenter Davina McCall, along with celebrities like Gwyneth Paltrow, Angelina Jolie and Michelle Obama, have done a lot to lift the lid on menopause – putting the benefits of HRT to symptomatic women back on the agenda.

After the longest pause, pharmaceutical companies are responding, with an increasing array of options, taking HRT beyond tablet form to patches, gels, vaginal pessaries and other innovative modes of delivery, Pecoraro says.

“But women should be aware that there are options … and if you’ve got symptoms, then let us help you.”

Associate Professor Gino Pecoraro

Other chemicals that aren’t hormones are also on the way – such as a class of drugs (kappa agonists) which work on part of the brain (the KNDy neurons) to cool hot flushes.

“It’s past the rat stage, and I think it’s almost at the human stage, and when that comes out, it will be a non-hormonal treatment for hot flushes, which will be very good,” he says.

Pecoraro says that not every menopausal woman needed to be using HRT.

“But women should be aware that there are options … and if you’ve got symptoms, then let us help you.”

Cw84 promo ads

Please login to favourite this article.