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HRT – confused?!

Zoe Norris - 17 Sep, 2019

I have been qualified as a GP for almost 13 years; it’s taken me at least ten of those to work out what to do with HRT. Not just the basics, but to really feel that I’ve got a handle on counselling women about the risks, benefits, types and how to swap women over from one type of another. And now it feels like it’s all change again – but is it really?

After the Women’s Health Initiative and Million Women Studies both published results in the early 2000’s which started to show risks associated with taking HRT, our prescribing of it in the UK dropped by almost 50%, and for the next decade many GPs deemed HRT as a risky drug and felt uncomfortable promoting or prescribing it. As newer types of HRT came onto the market, there was a gradual change culminating in the NICE 2015 guidance on managing the menopause which stated that HRT was “a highly effective treatment for menopausal symptoms”, and encouraging healthcare professionals to revisit its use in a wider range of women.

Since then we have continued to learn more about risks and benefits related to the length of time a woman takes HRT for, the age at which she starts using it, the type of HRT prescribed and how it is taken; all of these things being factors in working out the benefits and risks for each individual patient in front of us. As recently as this year, we had a paper published confirming significant differences in VTE risk between different types of HRT, and last year we saw evidence that the newer micronized progesterone Utrogestan seems to have a better risk profile than other progestogens used in HRT.

The latest big news was from this paper in the Lancet that made headlines across the world.

 This study was a meta-analysis of over 100,000 women with breast cancer, and their long term follow up. It looked at those women who had used HRT mostly in the early 2000s, and compared it to those who had developed breast cancer and never used HRT. The mean duration of HRT use was 7 yrs for past users, and 10 years for current users. What are the headlines?

  • The risk of developing breast cancer was the same with all types of systemic HRT; it didn’t seem to matter what type of oestrogen or progesterone was used.
  • If a woman used HRT for less than a year, her risk of breast cancer did not increase.
  • The risk of breast cancer increases the longer a woman is on HRT (roughly double the 5yr risk at 10yrs of treatment)
  • Women who have taken HRT for more than a year, remain at an increased risk of breast cancer for >10 years
  • The highest risk of breast cancer was from continuous combined HRT
  • There was no increased risk of breast cancer from topical oestrogen.

 As a standalone list, this makes for pretty scary reading. You may already have had women coming to see you concerned about the widespread news reports. But as with everything in general practice, things are rarely black and white. Let’s look at those headlines again and consider if they add anything new to what we already know.

The risk of developing breast cancer was the same with all types of systemic HRT; it didn’t seem to matter what type of oestrogen or progesterone was used.

NICE guidance talks about the increased risk of breast cancer with HRT; the risk previously quoted was +5 cases per 1000 women with a background risk of 13/1000 women (all ages). This paper gives us more detail on the different level of increased risk with different types of systemic HRT. Sequential HRT is +7/1000 cases of breast cancer, continuous combined is +10/1000, and oestrogen only +3/1000.

If a woman used HRT for less than a year, her risk of breast cancer did not increase.

This is helpful information and the next question is whether, if a woman repeatedly used short courses of HRT to control her symptoms, would she would remain at the <1 year risk or have a cumulative risk from repeated exposure? We simply don’t know, and for most women if their symptoms require HRT, experience tells us they are unlikely to need less than 12 months of treatment. But the old adage of using the lowest possible dose for the shortest possible time applies to everything we give in medicine. It remains the case here too.

The risk of breast cancer increases the longer a woman is on HRT (roughly double the 5yr risk at 10yrs of treatment).

While NICE removed the upper age limit for women to take HRT, they did talk about needing to discuss with women their individual risk/benefit at each review. While a lower risk combination of transdermal oestrogen and an IUS is the gold standard, the risk of VTE is largely age-related regardless of HRT use, and the risk of breast cancer also increases with age. Many of us have women in their 70’s or 80’s who wish to remain on HRT; this information adds to that discussion about whether the balance remains on the side of benefits or risks, and depends on multiple other factors. 

 Women who have taken HRT for more than a year, remain at an increased risk of breast cancer for >10 years.

This is a useful figure to be able to give women; and a chance to reinforce advice about breast self-examination and the importance of screening. Remember all these figures are about the risk of developing breast cancer; there is nothing to suggest women are more at risk of dying from breast cancer caused by HRT. Some evidence exists that shows those women who do develop breast cancer on HRT tend to have more well-differentiated disease which responds better to treatment. This JAMA article and data from the Women’s Health Initiative (WHI) randomised controlled trials showed no significant difference in cancer deaths in the HRT arms of the study compared to placebo. In addition, no difference was noted in all-cause mortality in the HRT arms of the study compared to placebo.

The highest risk of breast cancer was from continuous combined HRT

This is largely to do with the amount of exposure to hormones and has to be balanced against the reduction in uterine cancer risk from giving continuous combined HRT compared to sequential. Continuous combined HRT virtually eliminates any risk of endometrial cancer for the woman taking it, which is particularly relevant for women with a higher BMI which causes around 70% of uterine cancer cases. BMJ.

There was no increased risk of breast cancer from topical oestrogen.

Another welcome piece of the puzzle, confirming what we already advise many women, but potentially opening up further the conversation for breast cancer survivors who often struggle with horrific atrophic changes and face a limited choice in terms of treatment options.

Some other things to remember.

The women in this study were prescribed HRT before the NICE guidance was published, and before some newer forms of HRT was available. While all types of HRT showed an increased risk, the choice of HRT for our patients now is broader than at the time of this study. Many of us have been aware that the gold standard combination for HRT is transdermal oestrogen with separate progesterone (usually via a Mirena IUS); this paper doesn’t change that advice.

 The small increased risk of breast cancer associated with HRT use (which we can minimise by choosing lower risk HRT preparations) is far less than the increased risk of breast cancer associated with being overweight +17/1000 or from regular alcohol consumption +6/1000. Heart disease kills far more women in the Western world (~ 45%) than breast cancer (~ 4%). HRT reduces the risk of heart disease if started within ten years of menopause, below the age of 60. Primary Care Women's Health Forum article.

The biggest risk factors for breast cancer remain being female and getting older, and the best way to reduce these risks is to maintain a healthy weight, and exercise regularly (-10/1000).

Remember that these increased risks do not apply to women who have premature ovarian insufficiency (POI), and are simply having replaced hormones which should still be present, so our counselling of these women will be very different. Once they are beyond the age of 51yrs, they should be advised of the risks and benefits of HRT in the same way as any other patient.

Lots of professional groups have updated their guidance on HRT in the light of this new study, but in terms of our day to day practice, there honestly isn’t a huge change.

We should continue to offer HRT to women whose quality of life is being affected by the menopause. We should counsel them on the benefits and risks, including addressing other risk factors and choosing the lowest risk preparation of HRT. The newer micronized progesterones were not being used in patients at the time of this study, while early data showing that utrogestan (the only one currently available in the UK) is not associated with any increased breast cancer risk is reassuring it remains an area to watch. Our gold standard options for HRT therefore remain topical oestrogen for all women plus an IUS or micronized progesterone for those women with a uterus. Annual reviews with a discussion on this and any other new evidence remains vital, as does an individual approach to each and every woman.

We will be discussing this paper, plus a whole lot more on our next women's health course in Birmingham on November 19th. It is also available as a webinar here

British menopause society 


Women’s Health Concern (patients)


MHRA Patient leaflet

The Polypill - is it making a comeback?

Simon Curtis - 3 Sep, 2019

Do you remember the polypill? That iconic BMJ cover from back in 2003, claiming it would prevent 80% of heart attacks? Well, the polypill is threatening a comeback, as it has been in the news again this week following the publication of the first big randomised intervention study the PolyIran Study Lancet 2019. This was a cluster randomised controlled trial, in which 6,000 patients in rural Iran aged over 50 were randomised to taking a polypill (containing thiazide, aspirin, statin and ACEi) or having lifestyle advice.

The BBC and other media blazed the headlines that the polypill reduced major cardiovascular events by a third. Your patients may have been interested. However, before we even start on the problems of applicability between people in rural Iran and our patients, the media failed to report the absolute benefits seen. Taking the polypill reduced relative risk by a third, but in absolute terms taking the polypill every day for 5 years reduced the risk of a major CV event for an individual from 9% to 6%. Your patient may now be less interested. Therein lies the problem of applying knowledge that from a public health perspective may have a big impact but for each individual the personal gain may be too small to consider.

One of the fascinating things about doing Hot Topics for so long is seeing how ideas, drugs and medical interventions evolve over time. And in the 16 years since the BMJ made the dramatic claim, detailed in the accompanying paper, that if taken by everyone aged over 55 the polypill could prevent 80% of heart attacks, a lot has changed. Back in 2003 Richard Smith, then editor of the BMJ, wrote an editorial suggesting it was the most important paper the BMJ had published in 50 years. When we presented the ‘polypill papers’ on the Hot Topics course, it was hugely controversial amongst our delegates. Many GPs saw it is a simple, cheap and pragmatic solution to the problem of CVD prevention. Stop smoking, move more, eat healthy and if you want you can also take this pill. Easy. Many more however saw it as medicalisation gone mad, big brother ‘blunderbuss’ medicine that ignored individual biological variation and undermined personal responsibility for healthy lifestyle change. Amongst all the debate however, perhaps the biggest argument for the idea was the ‘prevention paradox’, the fact that many people who have cardiovascular events do not have hypertension or hyperlipidaemia so will be missed if only high risk people are targeted. And perhaps the biggest argument against it was that the claims were based on observational studies and epidemiological data and not on randomised, controlled intervention trials.

Sixteen years later and we are still not prescribing polypills. The zeitgeist has moved on, away from mass medicalisation and towards individualised risk assessment and informed patient choice based on absolute risks and benefits. But perhaps these concepts are the luxuries of developed nations. In low and middle income countries, such as rural Iran, this could provide a pragmatic and affordable way to offer people an intervention to lower their cardiovascular risk above and beyond lifestyle change. Polypills for HIV, TB and malaria have been developed and are widely used in developing countries. So, why not for prevention of cardiovascular disease, which after all remains the world’s biggest killer? Well, the biggest argument against so far has been the lack of evidence from intervention studies and the PolyIran study has now produced evidence of benefit.

So, will we be prescribing Polypills anytime soon? I can’t see it happening here in Europe, there are just too many variables to consider as we strive to practice personalised medicine and furthermore, we still lack intervention data relevant to our patient population. But from a public health perspective in low and middle income countries? That is an interesting idea, and the PolyIran study shows that the polypill may yet have a future.