The history of HRT: from enthusiasm to fear, and back to nuance

From enthusiasm to fear

Oestrogen treatment became widely used during the second half of the twentieth century, both to relieve menopause symptoms and, increasingly, in the hope of preventing chronic disease. The importance of protecting the womb lining with a progestogen became clear: systemic oestrogen alone can increase endometrial cancer risk in women who still have a uterus.

Then came the Women’s Health Initiative (WHI). In 2002, its trial of oral conjugated equine oestrogens combined with medroxyprogesterone acetate was stopped early after the overall balance of risks and benefits proved unfavourable. Findings included increased breast cancer and blood clot risk. Headlines travelled far, prescriptions fell sharply, and many women were left afraid of all hormone treatment.

The findings mattered, but they were often applied too broadly. Participants were postmenopausal women aged 50–79, with an average age of about 63; the trial was not a study of every HRT preparation or specifically of women starting treatment for symptoms around the menopause transition.

What newer studies have shown

Long-term follow-up of the WHI, published in 2017, found no increase in overall mortality over 18 years among women who had taken hormone therapy. In the oestrogen-alone arm (women without a uterus), breast cancer risk was in fact slightly lower than with placebo.

The Danish DOPS trial (2012) randomised recently menopausal women, on average 50 years old, and found fewer cardiovascular events after ten years of treatment, without a clear increase in cancer or stroke. The KEEPS and ELITE trials (2014–2016) explored the same question with imaging: ELITE found that oestradiol slowed the progression of arterial thickening when started within six years of menopause, but not when started ten or more years later.

Large observational analyses, including a 2019 Lancet meta-analysis, confirm that combined oestrogen and progestogen therapy is associated with a small increase in breast cancer risk that rises with longer use. Risk depends on the type of progestogen, and micronised progesterone appears to carry a lower risk than older synthetic progestogens, although the data are less certain.

Why age matters: starting at 45 vs. 65

The ‘timing hypothesis’ describes what many studies now point to: the balance of benefit and risk depends on when treatment begins. For healthy women under 60, or within ten years of their last period, benefits for symptoms, bone and quality of life generally outweigh the risks.

For a woman in her forties or early fifties, the absolute risk of serious harm is low — in younger WHI participants, the additional risk amounted to only a few extra events per 10,000 women per year. Blood vessels are still relatively healthy and oestrogen seems to help maintain them.

Starting for the first time at 60–70 or more is different. Arteries may already carry plaque, and the baseline risk of stroke, blood clots and heart disease is higher, so the same treatment adds more absolute risk. That does not mean women over 60 can never use HRT — many continue safely — but the decision requires a more careful individual assessment. Women with early or premature menopause (before 40–45) are generally advised to take hormones at least until the natural age of menopause.

Oral vs. transdermal oestrogen

Oestrogen taken as a tablet passes through the liver first, which increases the production of clotting factors. Oestrogen absorbed through the skin — as a gel, patch or spray — bypasses this ‘first pass’.

Large observational studies, including the French ESTHER study and a 2019 UK analysis in the BMJ, show that oral oestrogen is associated with an increased risk of blood clots, whereas transdermal oestradiol at standard doses does not appear to increase that risk. Transdermal treatment is therefore often preferred for women with a higher risk of clots, migraine, obesity or raised blood pressure.

The history of bioidentical hormones

‘Bioidentical’ means that a hormone has the same molecular structure as the hormones a woman’s own body produces — oestradiol and progesterone. The early hormone products were not: the WHI used conjugated equine oestrogens from pregnant mares’ urine and a synthetic progestin.

In 1980, micronised progesterone was developed, making it possible to take natural progesterone by mouth. Around the same time, transdermal oestradiol patches came on the market. In the 2000s, after the WHI, ‘bioidentical’ became a popular term — partly thanks to celebrity books.

Today, body-identical oestradiol and micronised progesterone are approved medicines in Denmark and the EU: the Danish Medicines Agency (Lægemiddelstyrelsen) and the European Medicines Agency assess them for dose, purity and quality, and the Danish national recommendations and European guidelines support them as first-line treatment.

Where that leaves us

The lesson is neither ‘HRT is dangerous for everyone’ nor ‘HRT is risk-free’. Age, time since menopause, medical history, route, formulation and duration all matter. The goal is to prescribe thoughtfully, for a clear reason, and review regularly.

Bring to your consultation

• A note of your period pattern, symptoms and how they affect everyday life.
• Your medicines, contraception, and personal and family medical history.
• The questions that matter to you: benefits, risks, bleeding, treatment options and follow-up.

References

1. Writing Group for the WHI Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321–333.
2. Manson JE et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the WHI randomized trials. JAMA 2017;318:927–938.
3. Schierbeck LL et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women (DOPS). BMJ 2012;345:e6409.
4. Hodis HN et al. Vascular effects of early versus late postmenopausal treatment with estradiol (ELITE). N Engl J Med 2016;374:1221–1231.
5. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk. Lancet 2019;394:1159–1168.
6. Vinogradova Y et al. Use of hormone replacement therapy and risk of venous thromboembolism. BMJ 2019;364:k4810.
7. Canonico M et al. Hormone therapy and venous thromboembolism among postmenopausal women (ESTHER). Circulation 2007;115:840–845.
8. NIH. Researchers review findings and clinical messages from the Women’s Health Initiative, 2024.
9. The Menopause Society. The 2022 hormone therapy position statement. Menopause 2022;29:767–794.
10. Sundhedsstyrelsen. Hormonbehandling i klimakterie og menopause. Den Nationale Rekommandationsliste, 2021.