06/02/2026
KASIM 2025'DE ÖNCEDEN KURGULANMIŞ YENİ FDA KURULU MENOPOZAL HORMON TEDAVİSİNDE KULLANILAN ESTROJEN VE PROJESTİN İÇİN İLAÇLARIN KARA KUTUSUNDAKİ UYARILARI BİLİMSELLİKTEN UZAK BİR GÖSTERİ HAVASINDA KALDIRMIŞLARDI. BUNUN SİYASİ BİR GİRİŞİM OLDUĞUNU, BİLİMSEL GERÇEKLERİN DEĞİŞTİRİLEMEYECEĞİNİ, BU KARARIN SEKTÖRÜN BASKISIYLA ALINMIŞ OLDUĞUNU BELİRTEN BİR YORUM DA BEN KALEME ALMIŞ VE YAYIMLAMIŞTIM. AN İTİBARİYLE YAYIMLANMIŞ OLAN AŞAĞIDAKİ GÖRÜŞ BİLİMSEL VERİLERİN POLİTİK KAYGILARLA NASIL ÇARPITILDIĞINI BİR KERE DAHA VURGULUYOR. OKUNMAYA DEĞER BİR MANİFESTO....
BAŞLIK ŞÖYLE : MENOPOZAL HORMON PROSPEKTÜSLERİ KİŞİSEL GÖRÜŞE DEĞİL BİLİMSEL VERİLERE DAYANMALIDIR. JAMA Published online February 6, 2026
WOMEN'S HEALTH
Menopausal Hormone Labels Should Rely on Evidence, Not Opinion
Janet Wittes, PhD; Eugene Braunwald, MD; Margaret A. Chesney, PhD; Harvey Jay Cohen, MD; David DeMets, PhD; Johanna Dwyer, DSc; Victor Vogel, MD, MHS; LeRoy Walters, PhD; Salim Yusuf, MBBS, DPhil
In November 2025, the US Food and Drug Administration (FDA) an-
nounced its intention to remove most box warnings from the pack-
age inserts of approved estrogen and hormone replacement therapy.
We are the 9 living former members of the Women’s Health Ini-
tiative (WHI) data and safety monitoring board (DSMB). Although
we support a reassessment of box warnings for estrogen products,
we are concerned about the process the FDA used to make its rec-
ommendations and worried that many women will not be aware that some of the products may lead to adverse clinical outcomes.
Box warnings, the most serious safety alert for a prescription
drug, were introduced by the FDA for these products 20 years ago
after the early termination of the 2 randomized, double-blind, pla-
cebo-controlled hormone therapy WHI trials. Both trials random-
ized healthy postmenopausal women 1:1 to receive hormone therapy or placebo. One trial studied the effect of estrogen-progesterone replacement therapy in 16 608 women with a uterus; the other studied the effect of unopposed estrogen replacement therapy in 10 739 women without a uterus.
In 2002, the DSMB recommended stopping the estrogen-
progesterone replacement therapy trial early because of an unfa-
vorable balance of risks to benefits1 (hazard ratios: coronary heart
disease, 1.29; invasive breast cancer, 1.26; stroke, 1.41; pulmonary
embolism, 2.13; colorectal cancer, 0.63; hip fracture, 0.66). 2 Two
years later, the National Institutes of Health stopped the estrogen
replacement therapy trial earlier than its planned end. In response
to the WHI’s findings, the FDA placed a box warning on all estrogen
replacement therapy and estrogen-progesterone replacement
therapy products, reporting increased risk of endometrial cancer, cardiovascular disorders, breast cancer, and, in women older than 65 years, probable dementia. Over the 2 decades since the first warning, the FDA has altered the language somewhat, but the list of risks has remained unchanged.
For decades before the WHI, the popular press and the manu-
facturers of oral estrogen products strongly urged postmeno-
pausal women to take estrogens, not only to reduce the often-
debilitating symptoms associated with perimenopause, but also so
that women would remain healthy and “forever feminine.” 3 When
the WHI was designed in the 1990s, observational studies had re-
ported that the risk of coronary heart disease in postmenopausal
women taking estrogens was 25% to 50% lower than the risk in
women not taking estrogens. 4 A central goal of the WHI was to ex-
amine whether estrogens actually caused the observed reduction
in heart disease or whether confounding factors explained the dif-
ference. An important additional aim was to provide a comprehen-
sive evaluation of the risks and benefits of estrogen therapy.
In July 2025, more than 20 years after the termination of these
seminal trials, the new administration at the FDA held a special expert panel on hormone therapy to discuss whether to change or eliminate the box warnings. As seen in the publicly available proceedings, the process used was quite unusual (Table). A standard FDA advisory committee comprises a diverse group of physicians, statisticians, epidemiologists, patient advocates, and others familiar with the topic at hand. Members receive materials from the sponsor reviewing the evidence submitted in support of the product application and materials from the FDA with its own analyses, along with questions from the FDA to the committee. The FDA instructs members of the committee not to discuss the issues among themselves before the meeting or during meeting breaks. At the meeting, which is open to the public, the sponsor and the FDA present oral summaries of the topics to be addressed. Discussion ensues among the members, the sponsor, and the FDA. Members of the public may give reasons for or against approving the product. Each committee member responds to specific questions from the FDA. Many meetings include questions requiring a vote.
By contrast, the July 2025 expert panel discussing hormone
therapy was a group of people the FDA appears to have known supported removing the box warnings. Each panelist had 5 minutes to speak. No panelist expressed an opposing view, as all argued for removal of the box warnings. Some panelists stated they had dis-
cussed their views with other members before the meeting. There
was no open public hearing, and no material from the sponsors or
the FDA was circulated to the public before the meeting.
A Viewpoint by Makary and colleagues justifying the removal of
the boxed warnings mixes post hoc subgroup analyses of the 2 WHI hormone trials, observational data, and conjecture about mecha-
nism of action. The Viewpoint states, “The evidence basis for the la-
beling changes included a comprehensive FDA evaluation of WHI and post-WHI publications, with particular attention to evidence related to timing, duration, and risks associated with hormone therapy use during the earlier postmenopausal years,”5 citing 3 articles.6-8 These articles, while raising potentially interesting hypotheses, do not provide confirmatory analysis of net benefit of hormone therapy. Two of them6,7 discuss health outcomes from the randomized period of the WHI and the period after the trials ended. Because many participants in the trials discontinued hormone therapy after the trials stopped, these articles cannot provide adequate data on duration of use. The third article, 8 in examining the association of hormone therapy and outcomes in a meta-analysis of 26 randomized clinical trials and 47 observational studies, warns, “Although still unexplained in the current literature, differential clinical effects according to regimen type, timing of initiation, underlying disease, and route of administration were identified in subgroup analyses.” Not cited by Makary et al, nor, to our knowledge, available publicly, is the FDA’s purported comprehensive evaluation of the data.
Some members of the expert panel argued that estrogen admin-
istered as a patch confers less risk than oral estrogen. A systematic
review of randomized and observational studies has questioned that opinion, saying, “[A]vailable evidence comparing the transdermal and oral administration routes for HRT is limited…[L]iterature comparing the oral and transdermal administration routes for HRT provides clear evidence only for the [venous thromboembolism] risk, which is higher with the oral administration route.”9 Only a well-designed randomized clinical trial can reliably compare the risks and benefits of oral estrogen with estrogen delivered by patch.
A thorough assessment would distinguish systemic estrogens
(eg, patches and oral formulations) from nonsystemic products
(eg, vaginal estrogen). Such a study would deal with dosing, tim-
ing, age at starting estrogen, and length of time taking estrogen. It
would carefully weigh the balance of risks and benefits, with a fo-
cus on the benefits in the perimenopausal period. In the current state of evidence, we support the position of Manson and colleagues, “Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.” 6 By removing box warnings without definitive study, the FDA has promulgated opinions that, taken at face value, could hurt postmenopausal women. Although definitive studies would be difficult to perform, in the absence of randomized clinical trials comparing estrogen with placebo starting in perimenopause and comparing oral with patch formulations, we urge the FDA to convene a true advisory panel, with unconflicted members, to weigh the evidence for benefits and risks of various estrogen products.
REFERENCES
1. Wittes J, Barrett-Connor E, Braunwald E, et al.
Monitoring the randomized trials of the Women’s
Health Initiative. Clin Trials. 2007;4(3):218-234. doi:
10.1177/1740774507079439
2. Writing Group for the Women’s Health Initiative
Investigators. Risks and benefits of estrogen and
progestin in healthy postmenopausal women. JAMA.
2002;288(3):321-333. doi:10.1001/jama.288.3.321
3. Wilson RE. Feminine Forever. M. Evans and Co;
1966.
4. Barrett-Connor E, Bush TL. Estrogen and
coronary heart disease in women. JAMA. 1991:265
(14):1861-1867. doi:10.1001/jama.1991.
03460140089033
5. Makary MA, Nguyen CP, Høeg TB, et al. Updated
labeling for menopausal hormone therapy. JAMA.
2026;335(2):117-118. doi:10.1001/jama.2025.22259
6. 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(13):
1353-1368. doi:10.1001/jama.2013.278040
7. Chlebowski RT, Anderson GL, Aragaki AK, et al.
Association of menopausal hormone therapy with
breast cancer incidence and mortality during
long-term follow-up of the Women’s Health
Initiative randomized clinical trials. JAMA. 2020;
324(4):369-380. doi:10.1001/jama.2020.9482
8. Kim JE, Chang JH, Jeong MJ, et al. A systematic
review and meta-analysis of effects of menopausal
hormone therapy on cardiovascular diseases. Sci Rep.
2020;10(1):20631. doi:10.1038/s41598-020-
77534-9
9. Goldštajn MŠ, Mikuš M, Ferrari FA, et al. Effects
of transdermal versus oral hormone replacement
therapy in postmenopause. Arch Gynecol Obstet.
2023;307(6):1727-1745. doi:10.1007/s00404-022-
06647-5
