The HRT study that left a generation of women to suffer in silence

For decades, a 2002 headline stopped women and their doctors in their tracks. Here's what that headline got wrong and why it matters so much now.

Imagine a treatment that relieves debilitating hot flushes, improves sleep, reduces joint pain, alleviates vaginal dryness, and supports your cardiovascular and bone health. Then imagine being told it will give you cancer.

That was the experience of millions of women in the summer of 2002, when the Women's Health Initiative (WHI) study announced results so alarming that the trial was stopped early and physicians around the world began pulling prescriptions almost overnight.

The impact was immediate and lasting. A large US cross-sectional study tracking 13,048 postmenopausal women found that hormone replacement therapy use collapsed from 26.9% of women in 1999, before the WHI findings, to just 4.7% by 2020. This was a worldwide trend. Women who had found relief from crippling menopause symptoms stopped treatment. Doctors, already poorly trained on HRT, stopped prescribing it. And a generation of women has since suffered in silence.

But here's what the headlines didn't tell you: the women studied were not representative of perimenopausal women seeking HRT. They were, on average, 63 years old, which is more than a decade past menopause. They were not the healthy, recently menopausal women for whom HRT is typically prescribed. As subsequent analysis showed, these older women already had a higher baseline risk of stroke, heart disease, and breast cancer simply because of their age.

"The WHI's preliminary data release changed physician practice patterns and professionals' menopause education for the ensuing decades." — Levy et al., Obstetrics & Gynecology, 2024

The type of estrogen used in the study is not the current gold standard of HRT.

The study also used a specific type of hormone that is no longer considered the gold standard. The estrogen used was conjugated equine estrogen (CEE), derived from horse urine. The progestin used was medroxyprogesterone acetate (MPA), a synthetic compound that, according to subsequent research, "may have contributed to an increased risk for breast cancer and other potentially adverse metabolic effects."

Since 2002, safer formulations have transformed the landscape. Isomolecular estradiol, a form of estrogen with the same molecular structure as that produced by the human body, is now available as tablets, transdermal patches, and gels. Bioidentical micronised progesterone, structurally identical to what the body itself produces, is considered the safest and most effective progesterone replacement. These formulations have substantially different risk profiles, as we will explore in Part II.

Before the WHI

It is worth remembering what came before 2002. Estrogen was first identified in the early 1900s, and by the 1940s the FDA had approved it to treat menopausal symptoms. By 1975, estrogen was the fifth most prescribed drug in the United States. Through the 1980s and 1990s, evidence mounted that HRT reduced cardiovascular disease, and in 1988 the FDA approved it as protective against osteoporosis. The American College of Physicians developed guidelines recommending HRT as a preventative therapy for the chronic diseases of postmenopausal women. Multiple studies showed no link between HRT use and increased breast cancer risk.

The WHI, in short, reversed decades of positive findings, based on a study population that was older and less healthy than the women for whom HRT was intended.

What current menopause societies say

Today, leading menopause organisations across Europe, North America, the UK, and Australia are unequivocal. The European Menopause and Andropause Society states that for most symptomatic women under 60, or within ten years of menopause, the benefits of hormone therapy outweigh the risks. The British Menopause Society holds that decisions about HRT, including dose and duration, should be made individually, weighing symptom control, quality of life, and bone and cardiovascular benefits.

Why timing matters:

• Health benefits are greater and risks lower when HRT is begun closer to the start of menopause

• Current guidelines recommend starting HRT within ten years of menopause or before age 60

• Re-analysis of WHI data showed younger women in the study (ages 50–59) had better outcomes than older participants

• The British Menopause Society states that arbitrary limits should not be placed on duration of use if symptoms persist

• The North American Menopause Society found no data to support routine discontinuation in women over 65 

  
  

Cutting through the HRT noise

As authors Bluming and Tavris observed in their thorough examination of the evidence, women seeking answers about HRT are now confronted with "a cacophony of voices," from the internet and books to podcasts and products. capitalising on fear. This series aims to cut through that noise and return to what the evidence actually shows.

In Part II, we examine the risks most associated with HRT in the public mind: breast cancer, bone health and cardiovascular disease. The findings may surprise you.

→ Continue to Part II: HRT & Breast Cancer, Heart Disease, and Bones: Separating Fear from Fact

Sources:

Levy & Simon, Obstetrics & Gynecology 2024 Levy B, Simon JA. A Contemporary View of Menopausal Hormone Therapy. Obstetrics & Gynecology. 2024 Jul 1;144(1):12-23. doi: 10.1097/AOG.0000000000005553. Epub 2024 Mar 14. PMID: 38484309.

Yang & Toriola, JAMA Health Forum 2024 Yang L, Toriola AT. Menopausal Hormone Therapy Use Among Postmenopausal Women. JAMA Health Forum. 2024;5(9):e243128. doi:10.1001/jamahealthforum.2024.3128.

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.

Bluming & Tavris, Estrogen Matters Avrum Bluming and Carol Tavris. Estrogen Matters. New York: Little Brown, 2024.

British Menopause Society Consensus Statement 2023 British Menopause Society. BMS Consensus Statement: BMS-WHC 2020 Recommendations on HRT in Menopausal Women. Updated September 2023. Available at: https://thebms.org.uk/wp-content/uploads/2023/10/02-BMS-ConsensusStatement-BMS-WHC-2020-Recommendations-on-HRT-in-menopausal-women-SEPT2023-A.pdf

EMAS Guidelines www.emas-online.org.

NAMS 2017 Position Statement The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017 Jul;24(7):728-753. doi: 10.1097/GME.0000000000000921. PMID: 28650869.

Cagnacci & Venier, Medicina 2019 Cagnacci A, Venier M. The Controversial History of Hormone Replacement Therapy. Medicina (Kaunas). 2019 Sep 18;55(9):602. doi: 10.3390/medicina55090602. PMID: 31540401; PMCID: PMC6780820.

Kohn et al., Sexual Medicine Reviews 2019 Kohn GE, Rodriguez KM, Hotaling J, Pastuszak AW. The History of Estrogen Therapy. Sexual Medicine Reviews. 2019 Jul;7(3):416-421. doi: 10.1016/j.sxmr.2019.03.006. Epub 2019 May 27. PMID: 31147294; PMCID: PMC7334883.