Menopausal hormone therapy (HRT): what it is, who it's for and its real risks

Few medical topics have caused as much confusion as menopausal hormone therapy. For almost two decades, many women with disabling hot flushes went without an effective treatment because of a widespread notion that hormones caused cancer. That notion came from a single study published in 2002, and much of what was said at the time was a misreading of its data. Let's set the information out calmly: what this therapy is, why the symptoms appear, what the evidence actually says and where the misunderstanding lay.

What it is and why the symptoms appear

Menopause is not an illness, but the end of reproductive life. It happens because the ovaries run out of follicles and stop producing oestradiol, the main oestrogen, and progesterone. That hormonal decline is directly responsible for the best-known symptoms: hot flushes, night sweats, vaginal dryness. In Spain, the average age at natural menopause is around 51.

Hormone therapy, which you will see abbreviated as HRT or MHT, rests on a simple idea: replacing the oestrogens the body has stopped making. The summaries of product characteristics approved by the AEMPS (the Spanish Agency for Medicines and Medical Devices) put it just as plainly, stating that oestradiol replaces the loss of oestrogen production that occurs during the menopause. When a woman still has her uterus, a progestogen is added to protect the endometrium; if she has had a hysterectomy, that addition is not needed and oestrogen is used on its own. Correcting that deficit is what relieves the symptoms.

How many women have symptoms and how long they last

Hot flushes and sweats, known in the medical literature as vasomotor symptoms, are neither a minor nor a minority complaint. Between 60 and 80 per cent of women experience them during the menopausal transition, and between 25 and 50 per cent describe them as moderate or severe.

And they last longer than was once thought. The SWAN study, which followed a large group of women over the years, found that the median total duration of frequent hot flushes is 7.4 years, and that they persist for a median of 4.5 years after the final period. There is also notable variation by ethnic background: in African American women the duration reached a median of 10.1 years. So we are not talking about a few months of passing discomfort.

What the evidence says about how well it works

There is little argument about its effectiveness. The North American Menopause Society, in its 2022 statement, considers it the most effective treatment for vasomotor symptoms and for what is called the genitourinary syndrome of the menopause, which covers the dryness, the discomfort and the urinary problems linked to atrophy. It also prevents bone loss and reduces fractures: in the very 2002 study that caused so much alarm, the group receiving oestrogen plus a progestogen had a reduction in hip fracture with a relative risk of 0.66, which works out at roughly 5 fewer cases per 10,000 women per year.

An important limit is worth setting out: being effective for symptoms does not mean it is useful for preventing chronic disease. Current guidelines are clear that hormone therapy is not indicated for the sole purpose of preventing cardiovascular problems or dementia. It is not a preventive treatment for those conditions, and using it with that in mind would be a mistake.

Who it makes sense for: the window of opportunity

Here is one of the key points that got lost in the confusion. The evidence points to what is known as the timing hypothesis, or window of opportunity: in healthy women with symptoms, under 60 or within 10 years of menopause, the balance tips in favour, with benefits outweighing risks. Starting hormone therapy in a 52-year-old with intense hot flushes is not the same as starting it in a 65-year-old with no symptoms and years of menopause behind her. Where a woman is in her life changes the equation completely.

The misunderstanding around the 2002 study

In 2002 the results of the WHI study were published, a large trial with 16,608 participants. It was the origin of the alarm. The problem was not its data, but how they were extrapolated. That trial was carried out in older women, with a mean age of 63.3, in other words a long way from the time of menopause. And it used one specific oral formulation: conjugated equine oestrogens combined with a synthetic progestogen, medroxyprogesterone acetate.

The mistake was to apply those results, obtained in older women and with one specific formulation, to young, symptomatic women and to every presentation and route of administration alike. The risks were also communicated in relative terms, which sound striking, without the context of absolute risk, which is what really matters to an individual person.

The real risks, in absolute figures

When the results from that oestrogen-plus-progestogen group are translated into absolute risk, per 10,000 women per year, the scale of things looks very different. These were the figures:

• Coronary heart disease: relative risk 1.29, around 7 additional cases per 10,000 women per year.
• Stroke: relative risk 1.41, around 8 additional cases.
• Venous thromboembolism (clots): relative risk of about 2.1, around 18 additional cases.
• Invasive breast cancer: relative risk 1.26, around 8 additional cases per 10,000 women per year, that is roughly 38 cases versus 30, with a confidence interval that came close to the threshold of non-significance.

And on the same scales there were benefits: colorectal cancer with a relative risk of 0.63, around 6 fewer cases, and the reduction in hip fracture already mentioned. The honest reading is that we are talking about small differences in absolute terms, not a massive danger for any woman who takes hormones.

The decisive nuance about breast cancer

This point deserves a pause. The increase in breast cancer observed is associated above all with the synthetic progestogen added, not with the oestrogen itself. The other arm of the same study demonstrates this: in women who had had a hysterectomy and received oestrogen alone, without a progestogen, there was no increase in breast cancer, and a reduction in risk was even seen, with a relative risk of around 0.77 to 0.79 in the extended follow-up. In other words, the worrying part is not simply taking hormones, but which type of progestogen is combined with them and in what context.

Not all hormone therapies are the same: the route matters

One of the biggest errors in that extrapolation was to lump every formulation together. The route of administration changes the risk profile. Transdermal oestradiol, absorbed through the skin as a patch or gel, is not associated with the increase in clots that does appear with the oral route. The ESTHER study quantified this: with oral oestrogen, the risk of venous thromboembolism had an odds ratio of 4.2, whereas with the transdermal route it was 0.9, essentially no increase. As for the progestogen, in that same study micronised progesterone was not associated with greater thrombotic risk: its odds ratio was 0.7. That is why the British NICE guideline recommends considering the transdermal route rather than the oral route in women at higher risk of venous thrombosis, for example with a body mass index above 30 (recommendation 1.5.28).

Vaginal oestrogens: a case apart

When the main problem is vaginal dryness, discomfort or urinary symptoms, there is an option that acts only where it is applied: low-dose vaginal oestrogens. Because their action is local, they do not require adding a progestogen even if the woman still has her uterus, and they do not carry the systemic risks of oral hormone therapy. It is a different route, with a safety profile of its own.

Common myths, taken apart

• "Hormone therapy causes breast cancer." Put like that, as a blanket statement, it is false. The absolute risk in the group taking a progestogen was small, around 8 additional cases per 10,000 women per year, and with oestrogen alone it did not increase and even fell.
• "The 2002 study proved that hormones are bad." It proved no such thing. It was a misinterpretation: results from older women, on one specific formulation, were extrapolated to young, symptomatic women, and the relative risks were presented without the context of absolute risk.
• "Hormones protect the heart." It should not be presented that way. The trials showed no cardiovascular benefit, and there was even risk in older women or those with established disease. It is not a cardioprotective treatment.
• "Bioidentical hormones compounded at a pharmacy are safer." There is no evidence that compounded preparations are safer or more effective; they are not standardised or backed by trials, and guidelines advise against using them.
• "You must stop it after 5 years or at 60." No such rigid limit exists. Duration is individualised according to symptoms and the benefit-risk balance, with periodic reassessment, using the lowest effective dose for as long as needed.

The situation in Spain

In Spain, hormone therapy is authorised by the AEMPS for menopausal symptoms such as hot flushes, night sweats and vaginal dryness, and for the prevention of osteoporosis in women at high risk of fracture who cannot tolerate other options. Various presentations are marketed here: oestradiol as a transdermal patch and as oral tablets, oral and vaginal micronised progesterone as endometrial protection in women with a uterus, tibolone and low-dose vaginal oestrogens. Since 2008 the AEMPS has maintained an information notice that asks for each case to be individualised and for the continuation of treatment to be reassessed periodically; for symptoms it frames treatment as short-term, giving 2 or 3 years as an example, and does not consider it justified in women without symptoms. It is worth knowing that this notice and the summaries of product characteristics retain conservative safety wording, inherited in part from that 2002 study, which should be read with the nuances of the window of opportunity and of absolute risk in mind.

In short, and what to do with this information

Menopausal hormone therapy is an effective treatment for hot flushes and genitourinary atrophy, and it protects bone. Its risks are real but, properly set in context in absolute figures and at the right point in life, they are small for most healthy, symptomatic women; the route of administration and the type of progestogen change that balance. Whether it makes sense for you, in which formulation and for how long, is a decision to take with a professional who knows your case, not on the basis of a headline.

And that conversation can start today. What does exist in Spain today is menopause treatment with a prior assessment, a prescription where appropriate from a registered doctor and ongoing follow-up. If you want to know whether it fits your case, you can check whether you are eligible.