Therapy for the effects of menopause 

The British Medical Journal (BMJ) recently held a webinar as part of their Known unknowns – exploring uncertainty in medicine series looking at therapy for the effects of menopause.

The first speaker was Martha Hickey, Professor of Obstetrics and Gynaecology at the University of Melbourne, who looked at key issues surrounding menopause.

She began by saying that there are many definitions of menopause, but no consensus about whether it begins with the final menstrual period or a year after the final menstrual period.

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Although 25 million women will transition to menopause each year and the biology is ubiquitous, the experience between woman can vary considerably.

So why does menopause happen in the first place? No one really knows, she said. It is thought to be due to the loss of ovarian primordial follicles. The human ovary contains a fixed number of non-growing follicles established before birth that decline with increasing age culminating in the menopause. She says it would be fantastic to understand what regulates the size of that primordial follicle pool during intrauterine life.

Another area of huge uncertainty, she added, is why some women experience menopause that is premature or early. It is estimated that about 10% of women will have premature early menopause. Some of it is iatrogenic due to chemoradiotherapy normally for cancer treatment, or sometimes due to surgical removal of the ovaries as in oophorectomy. But in most cases, the cause is unknown. It could relate to the size of the primordial follicle pool, but again this is not certain.

Another issue is the variation in menopausal symptoms. Professor Hickey said that between 10 and 40% of women will no symptoms at all, apart from changing their menstrual cycle. Then there are estimates that 25% of women will have more severe symptoms but there are no reliable predictors.

She said that there is no way of establishing which women are going to have distressing or prolonged menopausal symptoms and which women are going to have no symptoms. There is, however, huge variation by race and by geography.

Current treatment options for menopause

Professor Hickey went on to say that hormone replacement therapy (HRT) is a big area of controversy at the moment. It is a very effective treatment for vasomotor symptoms (hot flashes) and reduces these by about 80%, but she says that when the treatment is stopped about half the women who take it will have resurgence symptoms.

There are also effective alternatives to HRT, such as non-drug methods like cognitive behavior therapy. There is also non-hormonal prescription medication such as fezolinetant (Veozah), which was recently approved in the US for the treatment of moderate to severe vasomotor symptoms caused by the menopause.

She said it was concerning that a number of women might start HRT because of hot flushes during the perimenopause or menopause transition, yet there is actually no data on the efficacy or safety of HRT until they reach post-menopause.

It is commonly stated, she added, that HRT has all kinds of preventive properties in terms of chronic disease and long-term health. The best data available on this comes from the United States Preventive Task Force on menopause in 2022, yet it did not recommend HRT to prevent any chronic diseases.

In the UK last year, about 14% of women were thought to be taking HRT, with indications that this is increasing. It is therefore interesting, she said, to know why since 80% of women are symptomatic, why don’t they all take HRT? That is another unknown. Is it because they can’t get it or that they don’t want it?

What about other hormones such as testosterone? She said that endogenous testosterone, produced by the ovaries, does not fall over the menopause transition so it’s not like oestrogen and progesterone. If you take testosterone, it does improve libido, but the effect is actually quite modest. It is only recommended in women who’ve got a psychiatric condition called hypoactive sexual desire disorder, and it has no other clinical role.

So how can we support women better through the menopause transition? She said she thinks we should take a different approach and consider how we can empower women to manage this normal life stage. Professor Hickley said this includes giving women realistic and balanced information, giving them tools to help them choose the right treatment, access to a clinician who will listen with empathy, joined up care for chronic disease, as well as practical support in the workplace.

Menopause and the workplace

She said that as over 40% of our workforce are women over 50 years, we have to think about what can we change in the workplace to accommodate menopausal women?

At the moment coping at work is one of the main reasons why women take HRT. Another approach would be to change the workforce, so they don’t need to take hormones just to be able to do their job. We can also challenge the narrative of menopause as a hormone deficiency disease, like diabetes or thyroid disorder, which has been very widely promoted.

She ended her talk by saying she thought it was important that if menopause was going to be framed as a catastrophe, we need to think hard about the message we’re sending to younger women who will inevitably face their own menopause.

Summary of the evidence on drug treatment

The second speaker of the session was Gillian Reeves, director of the Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, who looked at the main evidence for drug treatment, as well as the risks and benefits of HRT.

Although menopause is currently a hot topic, she said, there are areas where there is consistent strong evidence, and other areas where there is a lack of consensus or even just a lack of data full stop.

She added that breast cancer is one of the endpoints that has the most information. A recent analysis of the worldwide evidence from observational studies showed that the relative breast cancer risk in women who are taking oestrogen-only or combined HRT increased with duration. This is similar for users of combined therapies.  Once women stop taking HRT, she said, although this risk decreases somewhat, there is some excess risk which persists for many years.

It is not clear whether that is due to just chance, or whether that’s driven by something else. Overall, she says that the data is quite compelling for an adverse effect of HRT on breast cancer risk.

The estimates suggest that in women who are taking oestrogen-only HRT there might be about one extra breast cancer per 100 users. But for women taking continuous combined preparations where progestogens are added each day, this goes up to about one in 25 users. She added that the consensus, therefore, is that there is an increased risk of breast cancer associated with HRT.

Reeves also said that HRT can increase the risk of other female cancers, particularly endometrial cancer for oestrogen-only therapy and ovarian cancer with both types of therapy. As these cancers are a lot rarer, the excess risks associated with HRT for them are somewhat lower. The greatest excess of endometrial cancer is in users of oestrogen-only HRT, but the greatest overall excess for total female cancers is in users of combined preparations.

Benefits of HRT

What about the benefits of HRT? She said that this is only clear for fracture risk. In fact, HRT was a first-line therapy for osteoporosis until the adverse effects on breast cancer risk became apparent.

Women taking HRT can have a 40% reduction in fracture risk overall, but unfortunately, once they stop taking it this benefit disappears quite quickly. The data also suggests that even within a year of stopping use, the risk goes back to that of someone who had never taken HRT.

She said that you could conclude that HRT does protect against fractures, but the effect is very transient. What people overlook is that if women take HRT in their 50s for 5-10 years, they are not going to get lasting benefits to protect them in their 70s unless they carry on taking HRT, which of course would incur additional breast cancer and possibly other risks.

What about cardiovascular disease? This is a more contentious area, she said. It was the outcome that the Women’s Health Initiative trials were set up to address. In this trial, there was a clear and significant increased risk of stroke, and this is why the oestrogen-only trial was eventually stopped.

For coronary heart disease, which was thought to be prevented by HRT, there was no evidence for risk or a benefit. If no more analysis had been done on this data, the conclusion would be that HRT increases stroke and VTE but doesn’t really have an effect on coronary heart disease.

However, a subgroup analyses that received a lot of attention looked at oestrogen-only use and coronary heart disease by age randomisation. It found a borderline significant reduction in risk in women who had been randomised in their 50s.

She said that some people saw this as evidence for a critical window of opportunity hypothesis, where to get the benefits for coronary heart disease, you really have to start taking HRT almost as soon as the menopause hits. And taking it later would have no beneficial effect and actually might increase risk. However, when the trialists looked at this question specifically, they found no evidence of any difference in effect.

Some observational data does show a small to 20% reduction in coronary heart disease in users of HRT. But of course, it’s very difficult to assess how those results have been impacted by confounding factors, she said.

Lastly, Reeves addressed dementia risk. She said that there is a sense that HRT reduces your risk of cognitive decline, but the main randomised clinical trials suggest a somewhat opposite effect.

Data from the WHI memory arm found that there is a non-significant increase for oestrogen-only users, but a significant two-fold increasing risk for combined HRT users, but this is based on small numbers. She said if you look at the observational data for the association of HRT and dementia, it is very inconsistent.

One of the best studies, she added, used a primary care database and looked at prescription records. It then followed women up to see what their risk of all dementia and Alzheimer’s disease was. It found no increased risks of developing dementia overall but did find a slightly increased risk of developing Alzheimer’s disease among long-term users of oestrogen-progestogen therapies.

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• Further talks were given by Margaret McCartney, GP, Glasgow, and Claire Hardy, senior lecturer in organisational health and wellbeing, at Lancaster University.

• The webinar can be viewed here.

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