HRT & Breast Cancer, Heart Disease, and Bones: Separating Fear from Fact

The WHI study claimed HRT raised breast cancer risk by 26%. What it didn't say is that this finding was not statistically significant and that the evidence on heart disease and bone health points firmly in HRT's favour.

Of all the fears that keep women away from HRT, the fear of breast cancer is the most powerful. And of all the statistics cited to justify that fear, the most influential comes from the WHI study's claim that women taking combined hormone therapy had a 26% increased risk of breast cancer compared to those on placebo. That number has echoed through two decades of medical consultations and dinner-table conversations. It is also, on close examination, deeply misleading.

The breast cancer risk that wasn't

A relative risk of 1.26 sounds alarming. But a relative risk only becomes meaningful when the underlying absolute numbers are significant. In the case of the WHI's breast cancer finding, the increased risk was not statistically significant, meaning it could have been due to chance. For context: the relative risk connecting tobacco smoking to lung cancer is 26.07. The WHI finding was not in that category.

"No conclusive evidence, including the WHI trial, proves that HT causes breast cancer - the overwhelming preponderance of data shows estrogen + progestogen therapy has a null effect on breast cancer."- Hodis & Sarrel, Climacteric, 2018

The story grew more complicated and more favourable with subsequent analysis. By 2006, co-principal WHI investigator Garnet Anderson reported no increased risk of breast cancer among women given combined HRT.

The reason? The placebo group had an unusually low rate likely because many of those women had previously been taking hormones before joining the trial and had stopped. The apparent "increase" in the HRT group was partly an artefact of that low baseline.

For women in the WHI study taking estrogen alone, those without a uterus, the story is more striking still. After 18 years of cumulative follow-up, the estrogen-only group showed a 45% statistically significant reduction in breast cancer mortality compared to placebo.

Newer HRT forumulations change the picture further

When researchers looked beyond the CEE (equine urine formulation of HRT) used in WHI and examined the newer isomolecular estradiol (E2), the Nationwide Finnish Comparative Study found that any history of E2-based hormone therapy was associated with up to a 50% reduction in breast cancer mortality risk.

Concerns have been raised about progesterone and breast cancer. But a systematic review by Stute et al. found that estrogens combined with oral or vaginal micronised progesterone (vs. the synthetic MPA progestin used in the WHI) do not increase breast cancer risk for up to five years of treatment.

For women who have already had hormone-sensitive breast cancer, low-dose topical (vulvar and vaginal) estrogens have been shown to be safe.

Heart disease risk

Heart disease is the number one cause of death in women worldwide, killing more women than all types of cancer combined.

The incidence of cardiovascular events rises after menopause, particularly in women with severe vasomotor symptoms. The Study of Women's Health Across the Nation (SWAN) found that women experiencing hot flushes had higher levels of subclinical cardiovascular disease, including greater aortic calcification and poorer vascular function, than women without menopausal symptoms.

The WHI claimed that HRT increased cardiovascular risk. But when researchers isolated younger women in the trial, those aged 50–59 and within ten years of menopause, the opposite was true. After 13 years of follow-up, HRT was found to have a beneficial effect on the cardiovascular system, reducing coronary disease and all-cause mortality.

The Danish Osteoporosis Prevention Study (DOPS), a randomised trial of 1,006 healthy women aged 45–58, showed that after 10 years, women receiving HRT early after menopause had a significantly reduced risk of mortality, heart failure, and myocardial infarction with no apparent increase in cancer, blood clots, or stroke risk.

"This robust scientific data supports a reconsideration of estradiol and micronised progesterone as preventative therapeutics for the reduction of cardiovascular disease." - Gersh et al., Progress in Cardiovascular Diseases, 2024

The ELITE trial, a randomised, double-blind, placebo-controlled study, found a benefit to cardiac health with estradiol specifically. This suggests that the cardiovascular risks found in the WHI may have been particular to oral conjugated equine estrogen, not to the transdermal estradiol now widely used.

Osteoporosis risk

Worldwide, one in three women over 50 will experience an osteoporosis-related fracture. Nearly 75% of hip fractures occur in women, and the consequences are severe: mortality rates up to 20–24% in the first year following a hip fracture, with another 33% left fully dependent for at least a year.

The lifetime risk of death from a hip fracture for a 50-year-old woman is 2.8% - equivalent to her risk of dying from breast cancer.

Clinical studies have consistently shown that HRT in any form can reduce bone loss, decrease bone resorption, enhance bone mineral density, and reduce both vertebral and hip fractures. The positive bone health findings from the WHI received almost no attention in 2002.

The costs of that silence have been measured. One Italian analysis estimated 43,000 extra bone fractures per year in the USA attributable to the decline in HRT use following the WHI. A separate longitudinal study of over 80,000 postmenopausal women found that those who stopped HRT after 2002 faced significantly increased risk of hip fracture and reduced bone mineral density compared with those who continued.

In Part III, we look at brain health, disease prevention, and what women can do to advocate for the care the evidence says they deserve.

→ Continue to Part III: HRT & Brain Health, Prevention, and How to Advocate for Yourself

 → Go back to Part I: The HRT study that left a generation of women to suffer in silence

Sources:

Hodis & Sarrel, Climacteric 2018 Hodis HN, Sarrel PM. Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials? Climacteric. 2018 Dec;21(6):521-528. doi: 10.1080/13697137.2018.1514008. Epub 2018 Oct 9. PMID: 30296850; PMCID: PMC6386596.

Bluming & Tavris, Estrogen Matters Bluming A, Tavris C. Estrogen Matters. New York: Little Brown, 2024.

Mikkola et al., Menopause 2016 (Finnish Study) Mikkola TS, Savolainen-Peltonen H, Tuomikoski P, Hoti F, Vattulainen P, Gissler M, Ylikorkala O. Reduced risk of breast cancer mortality in women using postmenopausal hormone therapy: a Finnish nationwide comparative study. Menopause. 2016 Nov;23(11):1199-1203. doi: 10.1097/GME.0000000000000698. PMID: 27465718.

Stute et al., Climacteric 2018 Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018 Apr;21(2):111-122. doi: 10.1080/13697137.2017.1421925. Epub 2018 Jan 31. PMID: 29384406.

Cold et al., JNCI 2022 Cold S, Cold F, Jensen MB, Cronin-Fenton D, Christiansen P, Ejlertsen B. Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study. Journal of the National Cancer Institute. 2022 Oct 6;114(10):1347-1354. doi: 10.1093/jnci/djac112. PMID: 35854422; PMCID: PMC9552278.

Gersh et al., Progress in Cardiovascular Diseases 2024 Gersh F, O'Keefe JH, Elagizi A, Lavie CJ, Laukkanen JA. Estrogen and cardiovascular disease. Progress in Cardiovascular Diseases. 2024 May-Jun;84:60-67. doi: 10.1016/j.pcad.2024.01.015. Epub 2024 Jan 24. PMID: 38272338.

Schierbeck et al., BMJ 2012 (DOPS) Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Køber L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012 Oct 9;345:e6409. doi: 10.1136/bmj.e6409. PMID: 23048011.

Hodis et al., NEJM 2016 (ELITE) Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. New England Journal of Medicine. 2016 Mar 31;374(13):1221-31. doi: 10.1056/NEJMoa1505241. PMID: 27028912; PMCID: PMC4921205.

El Khoudary et al., Menopause 2019 (SWAN) El Khoudary SR, Greendale G, Crawford SL, Avis NE, Brooks MM, Thurston RC, Karvonen-Gutierrez C, Waetjen LE, Matthews K. The menopause transition and women's health at midlife: a progress report from the Study of Women's Health Across the Nation (SWAN). Menopause. 2019 Oct;26(10):1213-1227. doi: 10.1097/GME.0000000000001424. PMID: 31568098; PMCID: PMC6784846.

Karim et al., Menopause 2011 Karim R, Dell RM, Greene DF, Mack WJ, Gallagher JC, Hodis HN. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization. Menopause. 2011 Nov;18(11):1172-7. doi: 10.1097/gme.0b013e31821b01c7. PMID: 21775911; PMCID: PMC3511047.

Islam et al., Menopause 2009 Islam S, Liu Q, Chines A, Helzner E. Trend in incidence of osteoporosis-related fractures among 40- to 69-year-old women: analysis of a large insurance claims database, 2000-2005. Menopause. 2009 Jan-Feb;16(1):77-83. doi: 10.1097/gme.0b013e31817b816e. PMID: 18703983.

International Osteoporosis Foundation International Osteoporosis Foundation. Epidemiology of osteoporosis and fragility fractures. https://www.osteoporosis.foundation/facts-statistics/epidemiology-of-osteoporosis-and-fragility-fractures