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HRT: clarity after controversy

Five years ago a trial suggested the risks of HRT outweighed the benefits and prescriptions plummeted. Now a re-analysis is restoring confidence in the therapy, says gynaecologist Dr Nick Panay

Five years ago a trial suggested the risks of HRT outweighed the benefits and prescriptions plummeted. Now a re-analysis is restoring confidence in the therapy, says gynaecologist Dr Nick Panay

The recent adverse media coverage of hormone replacement therapy (HRT), still the most effective treatment available for the alleviation of menopausal symptoms, could not have come at a worse time. The population is ageing, but even now, more than 30% of women are aged 50 years or over.

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This makes maintenance of peri- and postmenopausal health of paramount importance if we are to minimise the economic impact on society in this and future centuries. The controversy surrounding the pros and cons of HRT has left menopausal women, doctors and society in general confused as to how to deal with both the short- and long-term sequelae of the menopause.

The often debilitating immediate symptoms and the long-term sequelae such as osteoporosis, still need to be dealt with, and will take on ever-increasing importance.

The controversy

Until five years ago, HRT was used by more than a third of postmenopausal women for symptoms and prophylaxis against the long-term sequelae of the menopause. However, as a result of reports on the possible breast and cardiovascular risks of HRT arising from the Women's Health Initiative (WHI) and Million Women studies in 2002 and 2003, there was a sharp fall in HRT use, which dropped by up to 50% in some countries including the UK.1-4

The past couple of years have hopefully laid the ground for a stabilisation of use, after recent favourable data on cardiovascular and breast cancer risks and life expectancy.5 Encouraged by clinicians and menopause societies, about a third of women who came off their HRT asked to restart because of a return of symptoms.6-7

Just as the dust was starting to settle, menopausal women and their GPs were confronted with further confusing data and the resultant media headlines. First, falling breast cancer rates in some areas of the USA were equated to falling HRT usage rates since 2002.8 This extrapolation was criticised by the menopause advocacy groups. They pointed out that the fall in rates may not have been in former HRT users – rates were starting to fall prior to 2002 anyway and this may have occurred because fewer women were attending for breast screening having come off HRT.

In April 2007, data from the reanalysis of the joint data from the combined and oestrogen alone WHI studies were published. These data showed there was no increase in coronary heart disease risk for the youngest cohort of participating women (50-59 years) and a 30% decrease in all cause mortality, significant at the p<0.05 level.9 These data supported the concept that HRT does not cause harm, and may even be protective, when given to younger women in whom the arterial endothelium is still intact.10

In June, a cross-sectional study was published in the New England Journal of Medicine looking at the degree of coronary artery calcification by computerised tomography in women from the 50- to 59-year-old cohort of the unopposed oestrogen arm of the WHI study. There was a statistically significant lower calcification score in women on active therapy compared with those on placebo – 83.1 v 123.1 – supporting a potential cardioprotective effect of oestrogen.11

Further analysis of data from the Million Women Study (MWS) suggested that HRT may increase the risk of ovarian cancer diagnosis and mortality.

The data were alarmingly represented by Cancer Research UK in The Lancet – and consequently the media – as the total number of cases of ovarian cancer (1,300) linked to HRT usage over 14 years.

Data were only collected for five years from 1996-2001 by the MWS but controversially, extrapolation was carried out using HRT usage rates from 1991-2005. The absolute risk was rather less alarming at one case per 2,500 users and one death per 3,300 users.12 The observational questionnaire methodology of the MWS once again came under scrutiny as the randomised prospective WHI study had not indicated a problem with ovarian cancer.

Although the regulatory authorities – the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK and the European Agency for the Evaluation of Medicinal Products (EMEA) – still advocate the use of HRT, they stipulate it should be at the minimum effective dose for the shortest possible duration with annual re-evaluation. The guidelines have not changed since October 2004 but following the most recent data, the MHRA has indicated there will be a revision of the guidelines in the near future.

Practical implications for GPs

New data suggest the benefits of HRT can be maintained with lower doses than previously used while minimising risks and possibly side-effects. A recent study showed preservation of oestrogenic benefits at a dose as low as 0.5mg of 17‚ oestradiol.13 The importance of androgen replacement is also emerging, with the recent licensing of the first transdermal testosterone preparation for women with low libido after surgical menopause.

There has also been a move towards alternative or complementary medicines such as phytoestrogens. This is a largely unregulated area with products that often have little or no efficacy and questionable safety – for example, there have been recent reports of liver failure in users of black cohosh. However, there is more promising evidence backing some red clover and soy products.14


Dr Nick Panay is a consultant gynaecologist at the West London Menopause & PMS Centre, Queen Charlotte's and Chelsea and Chelsea and Westminster Hospitals

Competing interests Dr Panay has received honoraria for lecturing and advisory board work from various pharmaceutical companies

Key websites

British Menopause Society
Women's Health Concern
Menopause Matters
North American Menopause Society
International Menopause Society
Medicines and Healthcare Regulatory Agency

Timeline: Ups and downs of HRT

2001
• RCGP study estimates a third of UK women aged 50-64 use HRT

2002
• WHI trial of oestrogen plus progesterone HRT suggests benefits outweighed by increased risk of breast cancer, stroke and DVT
• GP prescribing of HRT starts to plummet

2003
• Million Women Study suggests HRT increases breast cancer risk and that the risk goes up with longer duration of use.

2004
• WHI oestrogen-only trial shows no increase in CV events and suggests benefit in women aged 50-59
• Meta-analysis suggests HRT reduces mortality in trials with women aged <60>

2005
• European Menopause Society study suggests that confidence in the use of HRT is returning

2006
• Falling breast cancer rates in US equated with fall in HRT usage
• Reanalysis of WHI combined and oestrogen-only data confirms no increase in CHD risk in younger women and 30% cut in all-cause mortality

Take home points HRT

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