Estradiol and micronised progesterone: what modern hormone therapy looks like

When menopausal hormone therapy (HRT or MHT) comes up, many people still have the headlines from twenty years ago in mind. But the clinical conversation has moved on considerably. Doctors no longer prescribe just any combination: the focus now is on estradiol and micronised progesterone, on when in life treatment begins, and on tailoring it to each person. Here we explain what this therapy is, why two hormones are combined and what the current evidence says, with its nuances and without the drama.

What hormone therapy is and why it combines two hormones

Menopausal hormone therapy is a group of medicines authorised in Spain by the AEMPS to treat the symptoms of the menopause: hot flushes, night sweats and vaginal dryness. They contain oestrogens, with or without a progestogen. Oestrogen is what mainly relieves vasomotor symptoms, those flushes and sweats that interfere so much with sleep and daily life.

So why isn't oestrogen enough on its own? Because in women who still have a uterus, oestrogen alone stimulates the endometrium and increases the risk of hyperplasia and endometrial cancer. The product information authorised by the AEMPS puts it plainly: that risk increases when oestrogens are used alone for prolonged periods and depends on the duration of treatment and the dose. Adding a progestogen for at least 12 days of each cycle, or continuously, prevents that increase. That is why the combination makes sense: the progestogen protects the endometrium. In women who have had a hysterectomy, with no uterus, oestrogen alone can be used.

Why estradiol and micronised progesterone are the talk of the moment

Not all progestogens are the same, and this is key to understanding the shift of the past two decades. The regimen studied in the famous WHI combined conjugated equine oestrogens with medroxyprogesterone acetate (MPA). In Spain, clinical guidelines recommend avoiding medroxyprogesterone acetate, which was used in the past and is associated with a higher risk of breast cancer and coronary heart disease, and using micronised progesterone instead.

The figure behind that shift: in a meta-analysis of two cohort studies in postmenopausal women (mean age 59), the risk of breast cancer was lower with micronised progesterone than with other progestogens when combined with oestrogen (RR 0.67; 95% CI 0.55–0.81). That doesn't mean it is harmless, and it is observational data: the British NICE guideline considers that there is not yet enough evidence to establish whether the risk is different with micronised progesterone. But it does suggest that the type of progestogen may matter, and that lumping all regimens together is a mistake. It is precisely what many experts criticised about the WHI: it used a single regimen and its conclusions were stretched to cover every type of hormone therapy.

What the WHI study actually said

The WHI (JAMA, 2002) was the study that brought the use of hormone therapy to a halt. It is worth looking at its numbers calmly. With the oestrogen plus progestogen regimen (CEE+MPA), the excess absolute risks per 10,000 person-years were: 7 more coronary events, 8 more strokes, 8 more pulmonary embolisms and 8 more invasive breast cancers; and at the same time 6 fewer colorectal cancers and 5 fewer hip fractures. The global index of excess was 19 per 10,000 person-years.

Two important nuances tend to be left out of the headlines. First: all-cause mortality was not affected during the trial. Hormone therapy did not increase overall mortality. Second: those numbers relate to one specific regimen and one specific population, which is why extrapolating them wholesale to today's combinations of estradiol and micronised progesterone is now questioned. Even so, in Spain the AEMPS, on the advice of its Committee on Safety of Medicines for Human Use, reviewed the benefit-risk balance in January 2004 and restricted the indications: favourable for climacteric symptoms that affect quality of life, at the lowest effective dose for the shortest possible time, and unfavourable as a long-term first-line treatment to prevent osteoporosis.

The window of opportunity: when timing matters

One of the most useful concepts in the current evidence is what is known as the window of opportunity. According to the 2022 NAMS position statement, for women under 60 or within 10 years of the onset of the menopause and with no contraindications, the benefit-risk balance is favourable for treating vasomotor symptoms and preventing bone loss.

By contrast, for those starting therapy more than 10 years after the menopause or over the age of 60, the balance is less favourable, because of higher risks of coronary heart disease, stroke, venous thromboembolism and dementia. In other words: starting early is not the same as starting late. Timing changes the equation, and that is why the decision cannot be a one-size-fits-all one.

Benefits and risks in perspective

On the benefit side, hormone therapy remains, according to The Menopause Society, the most effective treatment for vasomotor symptoms and for the genitourinary syndrome of the menopause, and it prevents bone loss and fractures. The Cochrane review documented a 75% reduction in hot flushes compared with placebo.

On the risk side, the NICE NG23 guideline explains that the risk of breast cancer increases with combined therapy, grows with years of use, is higher while it is being taken than afterwards and, after stopping, falls but persists for at least 10 years; with oestrogen alone the increase is very small or none. It is also worth being clear that hormone therapy is not a cardiovascular prevention tool: the CEE+MPA regimen should not be started or continued to prevent coronary heart disease, because cardiovascular prevention is not an indication.

The AEMPS summary of product characteristics sums up the general principle well: therapy should be continued only for as long as the benefits outweigh the risks and, for menopausal symptoms, using the lowest effective dose for the shortest possible time. That is not the same as a rigid cut-off in years that applies to everyone; it is an individual assessment that is a matter for a doctor, and one that is reviewed periodically.

What about phytoestrogens and natural supplements?

It is a very common question. The Cochrane review on phytoestrogens found that some trials reported a slight reduction in hot flushes, particularly with extracts high in genistein, but many of those trials were small, short and of low quality, with no indication that other phytoestrogens work better than taking nothing at all. To be honest about it: there is no evidence that phytoestrogen supplements are an equivalent substitute for hormone therapy. They may appeal to some people, but they are not in the same league in terms of evidence.

In short

The takeaway: modern hormone therapy is not the one that caused the scare twenty years ago. The type of hormones matters, the timing of starting matters, and the decision is always an individual one, with clear benefits for hot flushes and bone health and risks worth knowing about without blowing them out of proportion. If you are going through the menopause and these symptoms are affecting your life, what does exist in Spain today is menopause treatment with a prior assessment, prescription when appropriate by a registered doctor, and ongoing follow-up. With AiON you can check whether you are eligible in a few minutes and take the first step with professional support.