HRT: “26% more breast cancer” means 8 cases per 10,000

What the WHI actually measured

Two trials, two populations, two different results, constantly conflated. The first tested conjugated equine oestrogens combined with medroxyprogesterone acetate in 16,608 women. The second tested oestrogen alone in 10,739 women who had had a hysterectomy. In both, the mean age was about 63. Oestrogen plus progestin arm, rates per 10,000 woman-years:

The composite global index came to 19 extra events per 10,000 woman-years, roughly 2 per 1,000 women per year. That is real, and it is not what the public retained. Oestrogen-only arm, rates per 10,000 woman-years:

The public message that hormone therapy causes breast cancer rests entirely on the oestrogen plus progestin arm. In the oestrogen-only arm there were fewer breast cancers on treatment, and the global index was neutral.

Age changes everything, except for stroke

The reanalysis by age band (JAMA, 2007) covers the 27,347 women of both trials.

Expressed on the global index of adverse events (JAMA, 2013) the gap is starker still. On oestrogen plus progestin it runs from 12 excess cases per 10,000 women per year among those aged 50 to 59, to 38 among those aged 70 to 79. On oestrogen alone it runs from 19 fewer cases among those aged 50 to 59 to 51 in excess among those aged 70 to 79. One honest caveat is rarely made: the window of opportunity applies to coronary risk, not to stroke. Stroke risk stays elevated at every age, with a hazard ratio of 1.32 (95% CI 1.12 to 1.56).

Eighteen years on, mortality

The longest follow-up (JAMA, 2017) covers 18 cumulative years, 7,489 deaths, and follow-up coverage above 98%.

Over eighteen years, no difference in mortality, in either arm. And the long-term breast cancer follow-up (JAMA, 2020) delivers a result almost nobody knows: on oestrogen alone, breast cancer incidence was reduced, hazard ratio 0.78, and so was breast cancer mortality, hazard ratio 0.60. On oestrogen plus progestin, incidence rose, hazard ratio 1.28, but breast cancer mortality did not rise significantly, 1.35 with an interval of 0.94 to 1.95.

Breast cancer risk, in absolute terms

The individual participant data meta-analysis in The Lancet (2019) pooled 108,647 women with breast cancer from 58 studies. Here are its figures as absolute risk, for a woman starting treatment at 50, on incidence between 50 and 69.

Three findings from that meta-analysis are worth holding on to. The excess risk is about twice as large for ten years of use as for five. Less than a year of use carries a minimal excess. And roughly half of the excess occurs during use, the other half persisting for more than a decade after stopping.

The route of administration cancels the clotting risk

This is the most directly actionable result in the whole file, and the WHI did not test it: it studied the oral route only. The British case-control study (BMJ, 2019) compared 80,396 women who had had a venous thromboembolism with 391,494 controls.

In absolute terms the oral route corresponds to 9 extra venous thromboembolisms per 10,000 woman-years, and the conjugated oestrogens with medroxyprogesterone combination to 18, rising to 37 in women aged 65 to 79. The contrast between 1.58 and 0.93 means that the route of administration, on its own, cancels the excess risk. It is also why the progestagen chosen matters: the molecule tested in the WHI is neither micronised progesterone nor dydrogesterone.

Efficacy, and the figure nobody quotes

The Cochrane review (2004), across 24 randomised double-blind trials and 3,329 participants, measures a 75% reduction in hot flush frequency (95% CI 64.3 to 82.3) against placebo, and an odds ratio of 0.13 on severity. But the same review gives a second figure, decisive and rarely cited: among the women randomised to placebo, the reduction in hot flushes between enrolment and the end of the study was 57.7% (95% CI 45.1 to 67.7). That means a therapy which has never been compared against a placebo can claim 50% to 60% efficacy while doing nothing at all. It is the single most useful test to apply to any proposition on this subject.

Non-hormonal alternatives, what works and what does not

Neurokinin 3 antagonists are the genuine new arrival. The phase 3 SKYLIGHT 1 and 2 trials, in women with at least seven moderate to severe hot flushes a day, give an additional reduction over placebo of 2.39 to 2.55 episodes per day at twelve weeks, depending on dose and trial. That is real, statistically solid, and needs placing honestly: about two and a half fewer flushes a day on a baseline of seven or more. It is not the order of magnitude of the 75% obtained with hormone therapy, and presenting it as an equivalent would be false.

At the other end, the Cochrane review of phytoestrogens (2013), 43 trials and 4,364 participants, finds no conclusive evidence. For red clover the difference in daily frequency is 0.93 episodes, with an interval from -1.95 to +0.10 that crosses zero. And the placebo effect in those same trials ranged from 1% to 59%, which is precisely the range within which an uncontrolled claim can be made to look convincing.

How long this lasts

The SWAN study (JAMA Internal Medicine, 2015) followed 3,302 women for seventeen years.

The received idea of two or three years to get through is wrong by a factor of three, and that matters for the decision: a treatment question framed over two years is not the same question framed over seven.

What the studies do not allow us to claim

The figure of 75% to 80% of women said to have hot flushes has no primary source we have been able to trace. The only verifiable ratio we have is SWAN: 43.9% of women with frequent vasomotor symptoms, in the strict sense of at least six days out of the previous fourteen. That is not the same thing as any hot flush, which is more common.

The estimate of excess deaths attributed to oestrogen avoidance is contested. A 2013 modelling exercise puts US premature deaths over ten years at between 18,601 and 91,610. That is an extrapolation, not a measurement, it drew five published critical commentaries, and the fivefold gap between its own two bounds is enough to signal how fragile the exercise is. We cite it as a contested estimate, never as a fact.

And what the WHI tested is not what is prescribed today. Oral route only, conjugated equine oestrogens, medroxyprogesterone acetate. Neither the transdermal route nor micronised progesterone nor dydrogesterone appeared in it, and the 2019 thrombosis data show that those choices change the order of magnitude of the risk.

What the learned societies say

The numerical threshold set by the North American learned society (2022) is this: for women under 60, or within ten years of the onset of menopause, and without contraindication, the benefit-risk balance is favourable for treating bothersome vasomotor symptoms and for preventing bone loss. Beyond that it becomes less favourable. The WHI investigators themselves, in a review published in 2024, confirm that their results do not support hormone therapy for preventing chronic disease, but do support starting it before 60 in symptomatic women without contraindication.

In practice, if this concerns you

Three questions structure the discussion. What is the gap between your age and the onset of your menopause, since that is what moves the benefit-risk balance most. Do you still have your uterus, since that determines whether a progestagen is needed and the progestagen carries most of the breast signal. And which route has been proposed, since transdermal and oral do not carry the same clotting risk.

Noria Health arranges a full gynaecological work-up in Brussels within 24 to 48 hours: symptom assessment, hormonal profile, cardiovascular and thrombotic risk factors, bone density where indicated, and a review of personal and family history. The report is issued within 24 hours, follow-up is structured at D14, D30 and D90.

What Noria Health does not do: prescribe or advise against hormone therapy at a distance. That is an individual decision, dependent on your age, your personal and family history, and what the symptoms actually cost you. What we can do is give you the figures in the unit that lets you decide.

Further reading

• Fibroids: 1 woman in 2 has them without knowing
• PCOS: 7.9% or 12.7% of women, depending on the criterion
• Endometriosis: 190 million women, up to 12 years to diagnosis

Sources

1. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women, principal results from the Women’s Health Initiative randomized controlled trial. JAMA, 2002;288:321-333. https://jamanetwork.com/journals/jama/fullarticle/195120
2. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA, 2004;291:1701-1712. https://jamanetwork.com/journals/jama/fullarticle/198540
3. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA, 2007;297:1465-1477. https://pubmed.ncbi.nlm.nih.gov/17405972/
4. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA, 2013;310:1353-1368. https://pubmed.ncbi.nlm.nih.gov/24084921/
5. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality. JAMA, 2017;318:927-938. https://jamanetwork.com/journals/jama/fullarticle/2653735
6. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up. JAMA, 2020;324:369-380. https://pubmed.ncbi.nlm.nih.gov/32721007/
7. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk. The Lancet, 2019;394:1159-1168. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31709-X/fulltext
8. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism. BMJ, 2019;364:k4810. https://www.bmj.com/content/364/bmj.k4810
9. MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen or progestogen therapy versus placebo for hot flushes. Cochrane Database of Systematic Reviews, 2004, CD002978. https://pubmed.ncbi.nlm.nih.gov/15495039/
10. Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause, SKYLIGHT 1. The Lancet, 2023;401:1091-1102. https://pubmed.ncbi.nlm.nih.gov/36924778/
11. Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant, SKYLIGHT 2. Journal of Clinical Endocrinology and Metabolism, 2023;108:1981-1997. https://pubmed.ncbi.nlm.nih.gov/36734148/
12. Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, Eden J, Brown J. Phytoestrogens for menopausal vasomotor symptoms. Cochrane Database of Systematic Reviews, 2013, CD001395. https://pubmed.ncbi.nlm.nih.gov/24323914/
13. The Menopause Society. The 2023 nonhormone therapy position statement. Menopause, 2023;30:573-590. https://pubmed.ncbi.nlm.nih.gov/37252752/
14. The Menopause Society. The 2022 hormone therapy position statement. Menopause, 2022;29:767-794. https://pubmed.ncbi.nlm.nih.gov/35797481/
15. Avis NE, Crawford SL, Greendale G, et al. Duration of menopausal vasomotor symptoms over the menopause transition, SWAN. JAMA Internal Medicine, 2015;175:531-539. https://pubmed.ncbi.nlm.nih.gov/25686030/
16. Manson JE, Crandall CJ, Rossouw JE, et al. The Women’s Health Initiative randomized trials and clinical practice, a review. JAMA, 2024;331:1748-1760. https://pubmed.ncbi.nlm.nih.gov/38691368/
17. National Institute for Health and Care Excellence. Menopause: identification and management, NG23, updated November 2024. https://www.nice.org.uk/guidance/ng23

See also: all our articles on gynaecology.

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