Gynaecologist Perth | Specialised in menopause

There is an interesting and sobering story regarding the science and scientific method around our current understanding of the risk of hormone replacement therapy.

Hormone replacement therapy (HRT) has been used since soon after the second world war. The first negative noted was the need to protect the lining of the uterus with progesterone. Then, for decades, there were a lot of very positive studies emphasising the benefit and safety of HRT. One feature that emerged was a suggestion that it reduced the risk of heart disease, a leading cause of death in both women and men. There was some suggestion that it increased the risk of breast cancer.

Most of the studies were either small or poorly constructed. Around the turn of the century, the Women's Health Initiative Study (WHI) was set up to formally test the role of hormone replacement therapy in reducing the risk of heart disease.

The WHI was a randomised controlled trial, which is the best type of study method we have. To provide definitive proof that HRT reduced heart disease, the population recruited were women at higher risk of heart disease: older women, smokers, women with existing heart disease. They were not women going through menopause. Some women enrolled in the study were in their seventies.

It was a large study that planned to run for five years. There were two groups in the study, those on oestrogen and progesterone, and those on oestrogen-only therapy. Since progesterone is only required to protect the uterus, women who have had a hysterectomy do not need progesterone.

The investigators unmasked the results of the study early at two years. They unexpectedly found an increased risk of heart disease in the treatment group on oestrogen and progesterone. It was not a statistically significant change, but they responded by stopping that limb of the trial. They took the unusual step of going straight to the media and scaring an entire generation of women off taking hormone replacement therapy.

Part of developing our body of knowledge is accommodating new information. When we are suddenly told that black is white, we need to consider that information very carefully, as black is still likely to be black, and the new information likely to be incorrect.

So two decades after this little bombshell, where are we?

Firstly, this type of study can only answer the question that it is designed to test. Oestrogen is not the answer to heart disease. Not surprising. The answer to heart disease is everything else, not a single magic bullet. Don’t smoke, do exercise, watch your weight, control your cholesterol and blood pressure. These are the factors that matter, and oestrogen is marginal at best.

The second limb of the study, with women on oestrogen-only therapy, was continued for the planned time of five years and showed a statistically insignificant reduction in the risk of heart disease. So it weakly confirmed the original view, but again, it is not the magic bullet. You need to manage other risk factors for heart disease.

The area of greatest interest is the effect on breast cancer. This was not the end point it was designed to study, but one of the important observations included in the design.

There was a non-statistically significant increase in the risk of breast cancer in the women taking oestrogen and progesterone, consistent with our understanding before this study was done.

The new information that it did show was a reduction in the chance of breast cancer in women on oestrogen-only therapy. This is not entirely surprising.

The effect of oestrogen and progesterone is the opposite in the uterus and breast. Oestrogen stimulates the uterus and inhibits the breast. Progesterone inhibits the uterus and stimulates the breast.

The inference is that progesterone is the “bad” part of hormone replacement therapy, important to protect the uterus but possibly bad for the breast. That is why the Mirena is probably the best way to use progesterone therapy. It minimises the amount of progesterone in the main circulation.

Again, the people in the study were not women going through menopause but a high heart-risk group. If the analysis of the group is restricted to women close to menopause, especially women on oestrogen-only therapy, there is nothing but positive information confirming the safety of hormone replacement therapy.

There is another large source of data on hormone replacement coming from the Nurses Health Study, a long-running population-based study looking at risk factors for all major chronic diseases in women. It started in 1976 and is still running.

Population-based studies are a poorer study structure than a randomised controlled trial but the size and length of the study gives this study some merit. What it does show is that there almost certainly is an increased risk of breast cancer in long-term users of hormone replacement therapy.

Current recommendations are that hormone replacement therapy should be used for no more than five years after menopause. That is often an achievable goal. Symptoms are worse immediately after menopause and diminish over time. When you stop therapy, symptoms will come back but they are usually milder and therefore more easily managed and will gradually diminish over time.

This recommendation is based on the breast cancer risk. It is very important to put this recommendation in perspective. It is probably less important for women on oestrogen-only therapy, though this will remain difficult to prove. Likewise, women using the Mirena are likely at less risk, also difficult to prove.

Of much greater significance, it is important to look at the level of the risk. From the Nurses Health study, the risk is increased by about 50% after 20 years of treatment. Less than double the risk. Smoking increases your risk of lung cancer by a 30-fold effect, a dramatically greater risk.

I respect a woman’s choice, being aware of the modest risk involved, to stay on HRT for a longer period of time if she finds that she is symptomatic when stopping therapy.

Beware of alternative therapies. Just because we have found that mainstream therapy is not as good as we thought in the late last century, this is not a reason to embark on untested therapy.

There are two main options promoted in the alternative therapy range, one outside of our profession and one in. The oestrogen receptor on the cells of our body is the method by which oestrogen works. Oestrogen, the key, turns the lock, the receptor, and stimulates the cell to turn on and off systems within itself to produce its effect.

Stimulating the receptor produces the effect, no matter how it is stimulated. The oestrogen receptor is easily tricked. For example, the “oestrogen” in the pill is very different from natural oestrogen but works the same.

There are many naturally occurring substances that have oestrogenic action, and will “naturally” stimulate the oestrogen receptor. So-called phytoestrogens, soy products, are an example. Many herbal products contain phytoestrogens. These phytoestrogens have a fairly weak effect, but it is still oestrogen therapy. No matter how the receptor is stimulated, this is still hormone replacement therapy. Less effective and less studied, but it still carries the same potential risk.

Troche therapy has become fashionable within the profession by practitioners trying to capture those who are frightened by mainstream therapy. Rather than tablets or patches, a variety of hormones are delivered under the tongue or in the cheek, dissolving over around thirty minutes.

The selling point is the method of delivery but, realistically, this is just expensive therapy with no proven benefit over traditional therapy. There is possibly greater risk as there are no large scale trials to show that it is in any way better than traditional therapy.

In my experience of seeing such women, they are often being given very large doses of hormones, as witnessed by the effect on their body. This cannot easily be measured by hormone levels, as the hormones disappear quickly from the circulation, but none-the-less, they have had an effect