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Has the pendulum against HRT swung too far?

New analyses of apparently damning studies have made GP Dr Imogen Shaw question the current orthodoxy on HRT

New analyses of apparently damning studies have made GP Dr Imogen Shaw question the current orthodoxy on HRT

For the past five years, since the publication of the Women's Health Initiative (WHI) trial which concluded that combined HRT resulted in an increase in CHD, stroke, blood clots and breast cancer, there has been widespread adverse publicity about HRT1. Not surprisingly, given the headlines, this resulted in a great deal of concern among women and a huge drop in GP prescribing.

But the pendulum may have swung too far. The WHI results were recently re-analysed and showed that the risks for coronary disease with combined HRT were not significantly increased, and were actually lower with oestrogen-only HRT, especially in women in their 50s or who had taken HRT in the 10 years since the menopause2. As is often the case with ‘negative' studies, this new analysis failed to attract the same media attention.

The question for GPs is how to give accurate information and help patients make sense of all the conflicting evidence. Most patients will not understand the difference between relative and absolute risk, so it helps to describe any risk in both ways. It can also help to present the information graphically.

There are also some important questions hanging over the two large-scale trials whose findings fuelled the controversy.

The WHI study was a randomised controlled trial looking at different strategies for primary prevention of common causes of mortality and morbidity. The women in the study were asymptomatic postmenopausal women with a mean age of 63 from the midwest USA. Some 30% were obese, hypertensive or diabetic, so they are not strictly comparable with the younger healthy women early in their menopause who typically take HRT in the UK.

The Million Women Study (MWS) was an observational study providing information about various HRT formulations in women with a mean age of 57 attending the NHS breast-screening programme – a highly selected group3 representing only 25% of the total of women this age.

Breast cancer was diagnosed after a mean 1.2 years and deaths within an average of 1.7 years, which is biologically questionable as it is thought that it takes a minimum of two years for a cell to become cancerous. The pathologists reviewing the histology of tumours were also not blinded to whether the woman was taking HRT or not.

It is also important to consider the risk of HRT alongside other risks.

A BMI of over 30 confers a relative risk (RR) of MI of 3.3, which compares with a RR with HRT of 1.23 (according to the WHI study). So being overweight is almost three times more dangerous than being on HRT; and a women with menopausal symptoms could still be offered treatment.

There was extensive media coverage of data from the MWS that suggested that since 1991 HRT has resulted in 1,300 additional ovarian cancers and 1,000 additional deaths in the UK4.

But the absolute risk for ovarian cancer makes for a less alarming figure: one extra case per 2,500 users after five years and, for ovarian cancer mortality, one extra death per 3,300 users over five years in the context of a lifetime risk of 1.7% in the general population.

HRT users get more vaginal bleeding needing investigation by ultrasound, which may reveal incidental ovarian mass, and this would explain the increased risk only in current users and not past users.

The WHI study appeared to show no coronary benefit of HRT use. However the results are different when broken down by age bands and years since the menopause in the 2007 re-analysis2.

They showed that CHD events were reduced for women starting HRT in their 50s and 60s,and increased for women in their 70s. This effect was most marked for women in their 50s where the relative risk of CV mortality was reduced by 30%.

When broken down by years since the menopause, all forms of HRT show a decreased CV risk when used less than 10 years since the menopause, with an increased risk over time.

A recently published WHI analysis of a surrogate measure of atherosclerosis found that younger postmenopausal women taking oestrogen-only HRT had significantly lower coronary artery calcification scores than women on placebo5.

Women taking oestrogen were 42% less likely to have severe coronary artery calcium scores than women on placebo. Those who were particularly compliant with treatment had a 61% lower risk.

These results provide further reassurance that there is no increased cardiovascular risk with short-term use of HRT around the menopause, and there may be a trend towards a cardiovascular benefit in these younger women.

The important warning is that we cannot assume this benefit will continue for HRT use at older ages. Starting HRT above the age of 60 increases their risk of heart disease, strokes and venous thromboembolism and the endothelial response to oestrogen means that HRT cannot be recommended for prevention of chronic disease.

Osteoporosis

The absolute risk of osteoporotic fractures in women in their 50s and 60s is small.

However, half of all women over 50 will have an osteoporotic fracture in their lifetime.

It has now been shown that giving women two to three years of HRT around the menopause offers long-lasting benefits for the prevention of postmenopausal bone loss and osteoporotic fractures up to 15 years later6.

Starting HRT perimenopausally to prevent osteoporosis is not justified except in a younger women with a high risk of osteoporosis, as HRT is the only treatment that has been shown to reduce fractures for women below the age of 70.

Dr Imogen Shaw is a GP in Essex

Breast cancer risk

WHI

  • In the oestrogen-only arm was lower than placebo.
  • In the oestrogen + progestogen arm an increased risk emerged with duration of use, was statistically significant at 3 years and reaching a relative risk of 1.26 by 5 years when the trial stopped. The increased risks were seen mainly in the subgroup of women who had used HRT before the start of the trial (RR=2.21 compared with 1.07 with no prior use).
  • The addition of progestogen increases the breast cancer risk but reduces the risk of endometrial cancer

MWS

  • Increased risk
  • With all routes of administration.
  • Current use of all HRT regimes.
  • Combined HRT showed greatest risk.
  • Effect seen with less than 2 years of use.
  • This contraindicates all other previous clinical trial evidence.

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