HRT: Scientific Data, Patient Safety And Concerns Of The Press

HRT – What’s the latest?
Hormone replacement therapy continues to be surrounded by confusion and controversy with newspaper headlines about HRT appearing on a regular basis. Over the last decade it has changed from being used by millions of women, often long term and seen as being good for flushes, good for bones and good for heart, in fact good for almost anything, to being used only for “severe” symptoms at the lowest effective dose for the shortest possible time. The correct path probably lies somewhere in between these two extremes.

So what has caused this dramatic turn around? The publication of results of large trials and studies, particularly the Womens’ Health Initiative trial and the Million Women study, with the associated media interest has led to many women and health professionals losing confidence in HRT, yet menopausal symptoms have not gone away and as yet, no other treatment has been shown to be as effective as HRT in controlling menopausal symptoms. It is unfortunate that sensational headlines are what are most remembered, even though the reports have often provided a balanced view, keeping risks in perspective. It is also unfortunate that initial results of risks of HRT from the WHI trial received so much publicity whereas further analysis of the results which has shown a much more reassuring picture, received little media attention. Further, the Million Women study has been hugely criticised in relation to the study design and many experts feel that it is difficult to draw accurate conclusions from the results, yet it is often quoted as showing definite associations of increased risks of cancer with HRT.

Venous thromboembolism
From the WHI trial, venous thromboembolism occurred in 1.7 per 1000 women aged over the age of 50, not taking HRT and this was doubled in those taking HRT, the risk still being small. Reassuringly, for women aged 50-59 who were of normal weight, the incidence of VTE in the HRT group was the same as in those on placebo. The greatest risk is within the first year of use and is most relevant to women who have other risk factors, including previous or family history of blood clot, obesity, immobility or underlying blood clotting problem. It is possible that transdermal estrogen and lower doses of oral estrogen may not carry the same risk.

Breast Cancer
Long term HRT use (>5 years after the age of 50) is thought to confer a small increased risk of breast cancer. From both the WHI trial and Million Women study, estrogen only HRT carries less risk than estrogen combined with progestogen, the WHI trial demonstrating no increased risk with estrogen only taken for up to 7 years, in fact a decreased risk was shown. From the WHI trial, overall, combined HRT probably accounted for 3-4 extra cases of breast cancer per 1000 women who took combined HRT from the age of 50 for 5 years, but the increased risk in the combined HRT group in fact only occurred in the women who had taken HRT before the trial and then taken it for the duration of the trial. By 5 years after stopping HRT, the risk returns to baseline. It is possible that women who develop breast cancer while taking HRT may have a lower mortality rate than those who develop breast cancer when not taking HRT. To keep this concern about breast cancer in perspective, postmenopausal obesity or 2 units of alcohol per day confer a greater increased risk of breast cancer than 5 years of HRT but understandably, breast cancer risk is one of the commonest concerns of women.

Endometrial Cancer
Estrogen only given to women with an intact uterus increases the risk of cancer of the endometrium. Estrogen combined with cyclical progestogen (sequential HRT) reduces this risk but does not eliminate it. Sequential HRT given for >5 years does confer a small increased risk of endometrial cancer but no increased risk applies to estrogen combined with continuous progestogen (continuous combined or period free therapy). In practice, women who have increased or irregular bleeding when taking sequential HRT for >5years should be offered investigation as a matter of urgency. Women who bleed after the first 6 months of continuous combined therapy should also be offered investigation but significant pathology is less likely to be found.

Ovarian cancer
The WHI trial showed no increased risk of ovarian cancer with HRT, but the Million Women study recently reported an increased risk of 20% in users of HRT for 5 years. In fact the actual risk was said to be 1 extra case per 2,500 women using HRT for 5 years. Even if conclusions can be drawn from this controversial study, the risk is small and it is unlikely that this information would significantly influence use of HRT.

Stroke
Both estrogen only and combined HRT were associated with a small increased risk of stroke in the WHI trial. In women aged 50 to 59 not taking HRT, stroke occurred in 3 per 1000 women over 5 years. 5 years of HRT was associated with 1 additional case. A more recent study reported from Sweden of almost 17,000 women aged 45 to 73 years, showed no significant association between hormone use and risk of stroke. Of the HRT users who did have a stroke, the risk was associated with advancing age, smoking, obesity and hypertension. Therefore in the absence of other risk factors, the risk of stroke from HRT is extremely small and in fact there is some evidence that lower doses of estrogen than were used in the WHI trial can reduce the risk of stroke compared to placebo.

Heart disease
For many years, HRT was thought to reduce risk of coronary artery disease. However, the WHI trial has shown early, small increased risks in cardiovascular events, but this increase was only significant in the women who were 20 or more years post menopause and women who were less than 10 years postmenopausal when starting combined HRT, and women taking estrogen only, showed no increased risk with a likelihood of reduced risk. The dose, type and route of HRT used are important in cardiovascular effect, as is the timing of commencement of therapy; HRT started early in the menopause has no harmful effects on the risk of heart disease but once disease of the arteries has developed, commencing HRT may promote further damage. It is therefore very unlikely that HRT used for women in the early menopause for control of menopausal symptoms will be harmful for the heart and may still yet be shown to be beneficial if started early enough.

Alzheimer’s disease
Some studies show a reduction in risk in HRT users but the WHI showed an increased risk, though only in the older women. Recent analysis from the Women’s Health Initiative Memory Study in fact showed for women who took HRT before the age of 65, there was a reduced risk of all-cause dementia of 46% and a reduced risk of Alzheimer’s disease of 64%.

A major difference between trials such as the WHI trial and the observational studies which have often shown a reduced risk of both heart disease and dementia with HRT, is that in the WHI trial, women commenced HRT some time after the menopause, (only 10% were in the early menopausal years and on average, the women were 12 years post menopause with the age range being 50 to 79 years), whereas in observational studies, HRT has generally been commenced early in the menopausal years to control menopausal symptoms. It has been proposed that there is a “window of opportunity” whereby, if HRT is commenced early enough, it may be beneficial not only for control of symptoms and prevention of osteoporosis, but also for prevention of heart disease and dementia; the debate continues!

Benefits of HRT
The main reason for using HRT continues to be for control of menopausal symptoms for which it has been shown to be effective in placebo controlled trials. Symptoms are likely to affect about 70% of menopausal women and for many, no other currently available products, either prescribed or “over the counter” will be as effective.

HRT is beneficial for preventing osteoporosis by its effect on bone resorption, bowel calcium absorption and renal calcium re-absorption. Although it is not currently recommended as first line treatment of osteoporosis, it still has an important role for women with premature menopause and those with risk factors for osteoporosis who also have menopausal symptoms.

It seems likely that when used within the first 10 years of the menopause, HRT is beneficial for the cardiovascular system but currently it should not be used with this as the primary indication; further trial results are awaited.

Other possible benefits include reduced risk of colon cancer, improved dentition, improved skin healing and reduced wrinkles, reduced macular degeneration and reduced cataract formation but these are all controversial.

The benefits and risks of HRT are influenced by age, duration of therapy, medical history, family history and severity of symptoms. These factors vary between women, and even for each woman will change with time and with development of other medical problems. Treatment has to be individualised and has to be reviewed annually.

Generally, for women with menopause age <50 years, the benefits of HRT for both symptom control and long term health, far outweigh the risks. For symptomatic women aged between 50 and 60 years, the benefits of HRT outweigh the risks. For women aged 60 to 70 years, the benefits roughly equal risks and management should be individualised, and for women aged >70 years, the risks are likely to outweigh the benefits. Even with the older women, if symptoms are significant and unresponsive to other therapies, HRT can still be considered as long as an informed choice is made.

Overall, HRT still has an important role in menopause management and when used appropriately and reviewed, the benefits outweigh the risks for by far the majority of users.

Websites:
Menopause Matters: www.menopausematters.co.uk
British Menopause society: www.thebms.org.uk

Further reading:
Menopause: Answers at your fingertips by Dr Heather Currie. Class publishing www.class.co.uk
Management of the Menopause, The Handbook 4th edition–handbook of the British Menopause Society. Available from www.thebms.org.uk

*Dr Currie is also the founder of menopausematters.co.uk, an award winning website for patients and health professionals (Editor).

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