The FDA is seeking your comments on black box warning for women's hormone therapy

The FDA is seeking comments on black box warning for women's hormone therapy

The FDA is currently seeking public comments regarding the black box warning on women’s hormone therapy products for menopause. Here’s what you need to know:

Background: Since the early 2000s, all estrogen-containing menopause hormone therapies in the U.S. have carried a black box warning about increased risks of breast cancer, cardiovascular events, stroke, and dementia—based on findings from the Women’s Health Initiative (WHI). However, a growing body of experts, including original WHI researchers, now argue these risks were overstated, particularly for younger women and those using low-dose or non-oral formulations. They assert the warning discourages many who could benefit, especially from local (vaginal) estrogen therapy, which is not thought to increase these systemic risks in the same way[1][2][3][4][5].

Recent Action: On July 17, 2025, the FDA convened a panel of menopause and women’s health experts to review whether these warnings are still appropriate. The panel discussed updated data highlighting differences in risk based on age, therapy type, formulation, and timing of initiation. Panelists generally favored revising or removing the black box warning, especially for low-dose, vaginal estrogen used for localized symptoms.

Public Comment Period: Following the meeting, the FDA formally opened a public comment period inviting submissions from clinicians, researchers, patients, and the general public. The agency is particularly interested in updated evidence on the risks and benefits of hormone therapy—including differences due to age, formulation, timing, and route of administration—and wants to hear about patient experiences and perspectives.

· SHORT SUMMARY PODCAST:

How to Submit a Comment

· Deadline: 11:59 p.m. Eastern Time (ET), September 24, 2025.

· Where: Submit comments through Regulations.gov under docket number FDA-2025-N-2589. Click here: Comment Now

· What to Include: You may provide evidence, opinions, or experiences regarding the risks and benefits of menopause hormone therapy (especially as relates to cancer, cardiovascular disease, bone health, cognition, or genitourinary symptoms), and whether the black box warning is justified for all types of treatments.

For professionals submitting evidence, references to published studies or experiences with different formulations/routes (oral/systemic vs. vaginal/local) are encouraged. The FDA will consider all comments received by the deadline in deciding whether to revise the warning label but will not respond individually.

This is a significant opportunity for those in the clinical and research community—as well as patients and advocates—to influence FDA labeling and access to hormone therapies for menopause.

References:

1. Kritz, F. (2025, July 25). Why some experts want the FDA to rethink menopause hormone therapy guidance. NPR. https://www.npr.org/sections/shots-...-5477644/menopause-hormone-therapy-fda-health
2. Howard, J. (2025, July 24). Experts call for updated guidance on menopause hormone treatment. CNN. https://www.cnn.com/2025/07/24/health/menopause-hormone-treatment-wellness
3. Owens, C. (2025, July 18). FDA under pressure to revisit menopause hormone therapy warnings. Axios. https://www.axios.com/2025/07/18/fda-menopause-hormone-therapy
4. Urology Times staff. (2025, July 16). Experts urge FDA to remove black box warning on low-dose vaginal estrogen. Urology Times. https://www.urologytimes.com/view/e...lack-box-warning-on-low-dose-vaginal-estrogen
5. Contemporary OB/GYN staff. (2025, July 15). Experts urge FDA to revise boxed warnings on hormone therapies for menopause. Contemporary OB/GYN. https://www.contemporaryobgyn.net/v...d-warnings-on-hormone-therapies-for-menopause
6. U.S. Food and Drug Administration. (2025, July 17). FDA expert panel on menopause and hormone replacement therapy in women. FDA. https://www.fda.gov/patients/fda-ex...nd-hormone-replacement-therapy-women-07172025
7. NPR. (2025, July 25). Transcript: Menopause hormone therapy and FDA health policy [Radio broadcast transcript]. NPR. https://www.npr.org/transcripts/nx-s1-5477644
8. U.S. Food and Drug Administration. (2025, July 21). FDA request for comments: Menopause hormone therapies (Docket No. FDA-2025-N-2589-0001). Regulations.gov. https://www.regulations.gov/document/FDA-2025-N-2589-0001
9. U.S. Food and Drug Administration. (2025, July 21). FDA statement on hormone therapies for menopause [Press release]. GovDelivery. https://content.govdelivery.com/accounts/USFDA/bulletins/3eb6f75

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FDA Black Box Warning on Menopause Hormone Therapy (HRT)​

1. Why the Black Box Warning Exists​

In 2003, the FDA required a black box warning on all estrogen-containing menopause hormone therapy (HRT) products. This happened after the Women’s Health Initiative (WHI) study reported increased risks of breast cancer, heart disease, stroke, and dementia in women who were given oral estrogen, with or without progestin. The women in this study were on average 63 years old.

The problem is that later studies showed these risks depend on age, timing, dose, and route of use. For women under 60 or within 10 years of menopause, benefits often outweigh risks. Low-dose vaginal estrogen has little to no systemic effect.

2. What the Evidence Now Shows​

• Breast Cancer (Estrogen Alone): No increase in risk, and possibly lower risk for women under 60.
• Heart Disease: When started early (before age 60 or soon after menopause), HRT reduces the risk of fatal heart attacks by 25–50%.
• Stroke and Blood Clots: Lower risks with transdermal (patch) or low-dose oral forms compared to older oral drugs.
• Vaginal Estrogen: Safe, with no link to breast cancer, stroke, dementia, or blood clots. Blood estrogen levels stay in the post-menopausal range.

3. What Professional Groups Say​

• North American Menopause Society (NAMS): The benefits outweigh the risks for most women under 60 with symptoms. They strongly recommend removing the boxed warning for vaginal estrogen.
• ACOG and Other Societies: Support labeling that is specific to age, dose, and route of treatment, and encourage shared decision-making.

4. FDA Expert Panel (July 17, 2025)​

The FDA held a public expert panel meeting with 12 leading doctors and researchers. They reviewed new evidence and debated whether the black box warning should stay.

Key Takeaways:​

• Vaginal Estrogen: Safe for all women. Experts unanimously recommended removing the boxed warning.
• Systemic HRT (under 60): Benefits outweigh risks, especially for heart health and bone protection.
• Labeling: Needs to reflect differences in age, dose, and route instead of a one-size-fits-all warning.
• Impact of the Warning: It creates fear and confusion, leading to undertreatment of menopause symptoms.

5. Criticisms​

Some health policy experts worry the panel was biased toward industry and relied too much on observational studies. They want the FDA to keep clear language on potential harms.

6. Next Steps​

• Public Comments: The FDA opened docket FDA-2025-N-2589 on July 28, 2025. Comments are accepted until September 24, 2025.
• FDA Review: The agency will consider comments, new data, and expert input before making any labeling changes in late 2025 or 2026.

7. What Happens if the Black Box is Removed?​

• For Women: More doctors may prescribe low-dose vaginal estrogen and systemic HRT earlier, improving access to treatment.
• Health Outcomes: Could lower rates of painful menopause symptoms, urinary infections, bone fractures, and possibly early heart disease deaths.
• Insurance and Access: Insurers may expand coverage once the highest-level safety warning is gone.
• Research: More studies are needed on transdermal vs oral estrogen, dementia outcomes, and safety for women with a history of breast cancer.

Bottom Line​

The 2003 black box warning painted all hormone therapy with the same broad brush. Two decades of research show the risks are lower, especially for younger women and low-dose vaginal estrogen. Many experts, including the FDA’s 2025 panel, support removing or revising the warning to better reflect modern evidence.

 

Thread 'Ashley Winter, MD, calls for label update on low-dose vaginal estrogen'

Jul 26, 2025

Ashley Winter, MD, calls for label update on low-dose vaginal estrogen

"We are not offering patients comprehensive management unless we consider hormone therapies," says Ashley G. Winter, MD.

www.urologytimes.com

"We are not offering patients comprehensive management unless we consider hormone therapies," says Ashley G. Winter, MD.

On July 17, 2025, a panel of experts convened by the FDA outlined the growing consensus that the boxed warning label on menopausal hormone therapies, particularly low-dose vaginal estrogen, is an outdated or inappropriate representation of the risks. This discussion came on the heels of a landmark development in urology—the...

• madman
• menopause/gsm; vaginal estrogen; hrt; fda
• Replies: 4
• Forum: HRT in Women

 

Review of the FDA meeting: What Really Happened at the FDA Menopause Panel - Excel Male TRT Forum

 

What is the black box warning that the FDA assigned to women's HRT? What are the implications if the black box warning comes off?

The FDA’s black box warning for women’s hormone replacement therapy (HRT)—covering both estrogen-alone and estrogen plus progestin products—highlights increased risks of several serious conditions. This boxed warning is the strongest level of caution the FDA can assign and is mandated for all systemic estrogen and estrogen-progestin products commonly used for menopausal symptoms and prevention of postmenopausal osteoporosis.

FDA Black Box Warning – Core Elements

For Estrogen-Alone Therapy:

· Endometrial Cancer: Increased risk in women with a uterus who use unopposed estrogens.
· Cardiovascular Disorders: Estrogen-alone therapy should NOT be used to prevent cardiovascular disease. There is an increased risk of stroke and deep vein thrombosis (DVT).
· Probable Dementia: Increased risk when used in women 65 and older.

For Estrogen Plus Progestin Therapy:
· Cardiovascular Disorders: Should NOT be used for prevention of cardiovascular disease. There are increased risks of stroke, DVT, pulmonary embolism (PE), and myocardial infarction (heart attack).
· Probable Dementia: Increased risk of probable dementia in women 65 and older.
· Breast Cancer: Increased risk of invasive breast cancer.
· Endometrial Cancer/Ovarian Cancer: Persistent warning about endometrial risk with unopposed estrogens (mitigated by addition of progestin) and data on possible increased ovarian cancer risk.

Prescribers are directed to use the lowest effective dose for the shortest duration consistent with treatment goals and risks for the individual woman. The boxed warning comes from findings of the Women’s Health Initiative (WHI) trial and is present on all U.S.-approved products containing estrogen (alone or with progestin), regardless of route or dose, though most expert criticism centers on its application to low-dose, local (vaginal) products.

Example of Official Black Box Warning (from the estradiol patch label):

WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA AND BREAST CANCER
Specific Risks Listed:
· Stroke
· Deep vein thrombosis (blood clots)
· Pulmonary embolism
· Heart attack
· Breast cancer
· Endometrial cancer (mainly for estrogen use without progestin and with an intact uterus)
· Probable dementia (when started in women 65 and older)

These warnings have been fiercely debated in recent years; many experts argue that the WHI findings don’t apply to most modern HRT regimens or younger, recently menopausal women, and that the boxed warning overstates risk for low-dose, especially non-systemic (vaginal) products. Nevertheless, as of August 2025, this box warning remains the FDA standard.[1][2][3]

1. Why the black-box warning exists

• Origin (2003): After the Women’s Health Initiative (WHI) reported higher breast-cancer, cardiovascular, stroke, and dementia rates in women (mean age = 63) given oral conjugated equine estrogen ± medroxyprogesterone, FDA applied its strongest “boxed” warning to all systemic and local estrogen products.
• Problem: subsequent re-analyses show those risks depend heavily on age, timing, dose, and route. WHI follow-up and other trials now indicate net benefit when therapy starts <60 yrs or within 10 yrs of menopause, while low-dose vaginal preparations show negligible systemic exposure. The Washington Post JAMA Network

2. What updated evidence says

Question	Current best-evidence answer	Key sources
Breast-cancer risk with systemic estrogen alone	No increase; may even fall slightly in <60 yrs cohort	WHI 20-yr follow-up, Manson et al. 2024 JAMA JAMA Network
CV events when therapy starts early	25-50 % ↓ in fatal MI—similar to or better than statins	Panel testimony (Hodis, Makary) Urology Times
Stroke/VTE with transdermal or low-dose oral	Markedly lower than with oral CEE; data approach baseline risk	Observational timing-hypothesis studies Axios
Low-dose vaginal estrogen (GSM)	No signal for breast CA, VTE, stroke, dementia; estradiol levels remain post-menopausal	NAMS 2020 commentary; FDA pharmacokinetic reviews The Menopause Society

3. Professional-society positions

• North American Menopause Society (NAMS) 2022 statement: benefits outweigh risks for most symptomatic women <60; urges removal of boxed warning from local vaginal products.
• ACOG & Menopause Society 2024-25 updates echo route-, dose- and age-specific labeling, emphasizing shared decision-making. The Menopause Society

4. July 17 2025 FDA Expert Panel—who, what, why

• Format: non-statutory “FDA Expert Panel on Menopause & HRT,” 1–3 p.m. ET, livestreamed; 12 invited clinicians/researchers (e.g., Brinton, Hirsch, Hodis, Levy, Manson, Pinkerton, Rubin). U.S. Food and Drug Administration
• Mandate: examine post-WHI evidence and advise whether the black-box remains appropriate, with special focus on formulation, route, dose, age at initiation, and duration.

5. Key discussion points & consensus signals

Theme	Panel take-away	Sample quote
Local (vaginal) estrogen	“Categorically safe for all women” → unanimous call to remove boxed warning	- Heather Hirsch, MD Urology Times
Systemic HT started <60 yrs	Risks “overstated”; CV & fracture benefits predominate	- Howard Hodis, MD Urology Times
Label nuance	Need route-, dose-, and timing-specific language rather than blanket caution	- JoAnn Manson, MD Axios
Education gap	Warning fuels clinician & patient fear → undertreatment of GSM & vasomotor sx	- Rachel Rubin, MD Urology Times

6. Critiques and minority viewpoints
Health-policy analysts (e.g., Adriane Fugh-Berman) argued the roster was “one-sided,” relied on observational data, and some members had financial ties to HT manufacturers. They urged FDA to maintain clear language on potential harms. Axios

7. Regulatory next steps

• Public docket FDA-2025-N-2589 opened 28 July 2025; comments accepted until 23:59 ET September 24 2025.
• FDA will review submissions, internal analyses, and potentially propose label revisions or a formal advisory-committee vote later in 2025-26. U.S. Food and Drug Administration

8. Implications if the black box comes off

1. Clinical practice: Increased prescribing of low-dose vaginal estrogen and earlier systemic HT for eligible women.
2. Patient outcomes: Expected reductions in GSM-related UTIs, osteoporotic fractures, and possibly CV mortality among early initiators.
3. Industry & payors: Generic manufacturers may expand supply; insurers could revisit coverage criteria once the highest-level safety label is lifted.
4. Research gaps: Need RCTs comparing transdermal vs oral in diverse populations; long-term dementia outcomes for early initiation; safety in breast-CA survivors on aromatase inhibitors.

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Bottom line: Two decades of data now show the 2003 black-box warning paints menopause hormone therapy with too broad a brush. The July 17 FDA panel strongly favored route- and age-specific labeling—especially removing the warning from low-dose vaginal estrogen—while critics cautioned against over-correction. The agency’s decision, shaped in part by public comments due this fall, could finally bring U.S. labeling in line with contemporary evidence and international practice.

 

What really happened at the FDA Menopause Panel Meeting? : What Really Happened at the FDA Menopause Panel - Excel Male TRT Forum