The Black Box Warning on Vaginal Estrogen Might Be Wrong — and the Science Still Isn’t Complete

The FDA’s open docket is a rare chance to fix both, and here’s how you can contribute

The Food and Drug Administration has opened a docket on Menopause Hormone Therapy (MHT), finally getting the name correct (small steps, I know). This means there is an open call for feedback. Here is the main part of the request:

On July 17, 2025, the FDA hosted the FDA Expert Panel on Menopause and Hormone Replacement Therapy for Women. The panel focused on the risks and benefits of menopause hormone therapy, and in particular, the risks of breast cancer, uterine cancer, and certain cardiovascular risks versus potential benefits on bone, genitourinary, cardiovascular, and cognitive health. Discussions focused on data regarding differential risks and benefits depending upon the age of hormone initiation, formulation, and dose since the original publication of the Women’s Health Initiative (WHI) Study.

As a follow-up to this meeting that included invited expert panelists who spoke in a public forum, the FDA is opening a docket to allow for submission of broad, public comments on the risks and benefits related to menopause hormone therapy, including data that could support updates to the labeling of such products. The agency is specifically interested in perspectives on risks and benefits concerning breast cancer, cardiovascular disease, genitourinary systems, bone health, and dementia. As well as being interested in how such risks and benefits might differ based on timing of hormone initiation, including age, duration of use, type of estrogen and progestogen used and dosage forms, including route of administration. This request is part of the FDA’s effort to understand various perspectives on these safety considerations and the use of hormone therapy for menopause-related conditions in clinical practice.

You can read more about my thoughts on the FDA panel on MHT here and here.

Comments for the FDA must be received by 11:59 pm, September 24, 2025, and the place to comment is here.

This is what I posted; feel free to copy and post some or all of the 11 bullet points below:

• The FDA must follow the appropriate pathway regarding evaluation of the black box warning for vaginal estrogen and convene an advisory committee with recognized experts in the relevant fields. This should include a representative from the Menopause Society and the American College of OB/GYN, as well as a gynecologic oncologist, an epidemiologist familiar with the studies on vaginal estrogen, an expert on drug safety, and an expert on estradiol levels. Public commentary must also be allowed.

• The FDA must consider vaginal estrogen separately from MHT. These are not the same therapies, as they have different risk profiles, indications, and benefits. What some of the experts said about vaginal estrogen at the July panel has already been misconstrued to be about systemic (blood stream) estrogen, but these are different therapies and should be treated as such.

• A warning of some kind on vaginal estrogen products is indicated for persons with breast cancer, endometrial cancer, and any other estrogen-sensitive cancer.

• The package insert for vaginal estrogens should include the lack of long-term safety data for endometrial cancer and a warning about reporting any bleeding after menopause.

• The FDA should require endometrial safety studies as part of post-marketing surveillance and/or fund studies to eliminate the knowledge gap about the long-term safety of vaginal estrogens for the endometrium.

• The FDA should commission a study to evaluate estradiol levels with vaginal estradiol cream.

• The advisory committee should consider whether safety labeling for endometrial cancer should differ based on dose, considering some doses of vaginal estrogen have been shown to positively affect bone, suggesting some absorption.

• Any panels and advisory committees going forward regarding systemic MHT should include a representative from The Menopause Society and the American College of Obstetrics and Gynecology, an expert on osteoporosis representing the Endocrine Society, a representative from the Society for Preventive Cardiology, an oncologist who specializes in breast cancer, and an epidemiologist with relevant expertise.

• The FDA should not make recommendations about MHT being cardioprotective or preventive against dementia without randomized trials designed for these outcomes.

• All financial disclosures from participants on panels and advisory committees must be appropriately noted, including advertising revenue from social media partnerships, as this did not happen at the panel for MHT.

• The financial associations for any patient organizations that are involved must be disclosed, as patient organizations are a known avenue for Pharma to exert influence.

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I want to be clear, I do not believe the medical literature supports the current black box warning for vaginal estrogen. The purpose of a black box warning is to call attention to serious or life-threatening risks, and as I’ll discuss below, many of the risks on the label do not reflect the literature. I also believe that we don’t have sufficient data about vaginal estrogen, although whether what we don’t know meets the threshold of a black box warning is a decision that requires thoughtful review by appropriate experts.

It’s vital that we insist on a process with an appropriate advisory committee and robust discussion of the data about benefits and safety from those who have done the research. This means appropriate experts discussing the studies scientifically and transparently. People with agendas can easily corrupt this process, which can open the door for dismissing science over what gets attention on Instagram and Podcasts. Another risk with not following the appropriate process is pharmaceutical companies essentially paying for outcomes via patient advocacy groups, physician payments, and influencer campaigns. And without due process, another huge concern is Dr. Makary, the head of the FDA, could make unilateral decisions about medications.

Let’s review what we know and what is less clear.

The Black Box Warning on Vaginal Estrogen

Regarding Cardiovascular and Other Risks

The black box warning about these risks is related to WHI data, but the risk of breast cancer was seen only in the combined arm, not the estrogen-only arm, so its inclusion here isn’t even supported by the data presented. Stroke was the only statistically significant increased risk during the the estrogen only arm.

Since the WHI, there has been observational data published about the safety of vaginal estrogen. Three of the more recent and compelling publications:

• The WHI observational study (2018, WHI-OS) has an average of 6.4 years of follow-up data.¹ The investigators looked at breast cancer, coronary heart disease, stroke, endometrial cancer, and several other outcome measures in relation to reported use of vaginal estrogen, and women were followed over time. Vaginal estrogen was not associated with an increased risk of any of the adverse outcomes mentioned in the black box warning. Although this is not a randomized study and is based on observational data, it represents a large group of women, with data collected prospectively, and the results are reassuring.

• A database study from Denmark (2024) identified women with breast cancer and matched controls, then looked at the national registry of medicinal products to compare the use of vaginal estradiol.² There was no association with breast cancer, even for use up to nine years. This observational study had specifics on the dose of estrogen, which is helpful.

• The Nurse’s Health Study (NHS, 2018) followed women over 18 years, and found no increased risk of any health outcomes listed on the current black box warning.³ One issue is that the dose or type of vaginal estrogen was not recorded.

I believe there should be a warning on vaginal estrogen for people with a history of breast, endometrial, or other potentially estrogen-sensitive cancers. This does not mean that they should not use the medications, but it means more care and discussion are needed. It’s common for medications to list concerns about specific medical conditions. For example, in the United States, the box for ibuprofen warns about several groups of people who may be at higher risk for complications.

Vaginal Estrogen and Endometrial Cancer

This is the first part of the black box warning, and merits a separate discussion. Estrogen can cause endometrial cancer when it is not paired with an appropriate dose of a progestogen, also known as unopposed estrogen.

What has been glossed over somewhat in the discussion about vaginal estrogen and the black box warning regarding endometrial cancer is the fact that we have no peer-reviewed, clinical trials with safety data for vaginal estrogen that are longer than a year, meaning where women have been followed and evaluated by ultrasound and/or endometrial biopsies, which is the best way to identify potentially concerning changes, precancer, or cancer. In fact, many of the studies are shorter than a year. It’s also important to note that we lack thirty years of safety data for many medications. This is why post-marketing surveillance exists, and why studies continue after drugs are approved and in use. We should therefore try to obtain this data about vaginal estrogen and the endometrium, especially as many women may use this medication for decades.

Part of the problem with many of the observational studies is that the doses and how the women used vaginal estrogen, meaning did they place the product high in the vagina or lower down towards the vaginal opening, are missing. In addition, the endpoint is usually the diagnosis of endometrial cancer from medical records, but we also need data about precancer.

Another point that is rarely discussed is that there are a couple studies that have linked vaginal estrogen (the ring and 25 mcg vaginal estradiol tablets) with improved bone health/reduced fracture risk.^1,4 While one possibility is that there was a confounder that was missed, perhaps women with arthritis, a risk factor for osteoporosis, were less able to be sexually active due to hip or back pain, so less likely to use vaginal estrogen, so there is a “healthy user” bias for vaginal estrogen. But it's also possible that some estrogen was absorbed as bone is exquisitely sensitive to estrogen. If estrogen is bring absorbed, what does this mean for the lining of the uterus?

While the WHI-OS and the NHS studies do not show an increased risk of endometrial cancer, an observational study from Denmark showed almost double the risk of endometrial cancer with vaginal estrogen.⁵ This study did allow women who were using MHT, whereas in the publications from the WHI-OS and NHS, women who were using systemic MHT were excluded from analysis. Also, the doses of vaginal estrogen in the Danish study tended to be higher, 25 mcg of estradiol twice a week, which can result in elevated levels. However, we must also remember that women using vaginal estradiol cream are getting more than this dose of estrogen.

The FDA considers low-dose vaginal estradiol to be products with < 37.5 mcg of estradiol or < 0.625 mg of Premarin (0.625 mg Premarin is 1 gram), although some experts consider low-dose vaginal estrogen to extend to products with ≤ 50 mcg estradiol (estradiol cream in the United States is 0.01% or 100 mcg of estradiol per one gram of cream).⁶

A more accurate representation of what we know about vaginal estrogen and the risk of endometrial cancer given all of the above is, “To the best of our knowledge, appropriately dosed vaginal estrogen is not associated with endometrial cancer, although the longest safety study for endometrial cancer is 52 weeks, and so that opinion is largely based on observational studies and clinical experience.”

To me, this means we can and should do better.

Can We Use Surrogate Markers for Safety?

Blood levels of estradiol are one proxy, with the caveat that this information doesn’t tell us about estrogen which may get from the vagina to the uterus in other ways. We have studies examining levels of estradiol, although some of these are older and utilized radioimmunoassays, which are less accurate at the low levels required. With mass spectrometry (the better test to detect low levels of estrogen), the consensus is that an estradiol level of < 10.7 pg/ml is considered menopausal.⁷ The hypothesis is that if estradiol does not go above this level, the product is safe for the endometrium.

Here are the estradiol levels with low dose preparations:^8-14

What about the vaginal creams?

In one study, seven days of Premarin 1 g of cream (0.625 mg of drug), increased estradiol levels five fold, far above the menopausal range, although estradiol levels with 0.312 mg of Premarin (0.5 g of the cream) were 12.8 pg/mL, still elevated over menopause, but much less so.^15,16 One issue with Premarin is that it contains many estrogens, one of which is more potent than estradiol, and others that can act like anti-estrogens, so the full implications of estradiol levels are just not known.

The estradiol 0.01% cream is not well studied with mass spectrometry. In fact, I can only find studies using radioimmunoassays, and so these results may not be accurate:

• ½ gram of cream (50 mcg of estradiol) nightly for 8 weeks applied just inside the vagina with a finger resulted in no increase in estradiol levels (9.7 pg/ml at 8 weeks vs. 7.7 pg/ml at baseline).¹⁷

• 2 g of cream (200 mcg of estradiol), estradiol levels were tested at baseline, and then for several hours over the subsequent 24 hours. The estradiol level went from 14 pg/ml at baseline to 80 mcg/ml at 4 hours and was 35 pg/ml at 24 hours.¹⁸

• 10 mcg of vaginal estrogen given by cream (this required diluting Estrace with more vehicle cream, so not commercially available) increased levels by 2 pg/ml over baseline, only 3.3% of the dose was absorbed.¹⁹

For people using estrogen creams in the lower doses, the general consensus is ½ g of Premarin or ½ -1 g of estradiol cream twice a week is safe, but the caveat is this is based on the observational studies that show use of vaginal estrogen is not associated with endometrial cancer. I think this explains my bullet point above that calls for more data with the vaginal creams.

Estradiol Levels Don’t Tell the Whole Story

Estradiol levels in the menopause range do not guarantee the uterus is not being exposed to estrogen from a vaginal product. Estrogen can theoretically diffuse directly into the uterus and can enter the blood vessels or lymphatics at the top of the vagina. Studies show that when vaginal estrogen is placed in the top 1/3 of the vagina (so high up), there is more absorption into the blood than when it is placed in the lowest 1/3.²⁰ Because of a uterus “first pass” effect, the uterus may receive a much higher level of estrogen than reflected in blood levels. Estrogen can also concentrate in the endometrium, resulting in levels many times higher than what is in the blood.⁶

There is also evidence that even a small amount of estrogen can change the sensitivity of the estrogen receptors in the endometrium.⁶ And despite that fact has been inadequately studied for safety, companies are marketing and many women are currently using compounded estrogen face cream. It’s also possible that the combination of vaginal estrogen cream and estrogen cream on the face and/or body could result in higher than desirable levels, and without data, we can’t know.

We Have Some Good Information, But We Need More

While medical professional societies support that vaginal estrogen in appropriate doses is safe from an endometrial cancer perspective, we must be honest that this is based on observational data and short term safety studies (one year or less) and some observational studies don’t include dose. As dose may affect risk, this leaves us with a knowledge gap.

It’s clear that our understanding of estradiol levels has changed since the use of mass spectrometry; and so we need information on blood levels with all vaginal estrogens using this technology.

What does it mean that some vaginal estrogens are linked with a lower fracture rate? Could it be that there are enough excursions, where estradiol levels are rising above the menopause range, and if so, what does that mean for the endometrium?

If a 25 mcg tablet can push estradiol levels over the menopause range, what does that mean for the estradiol cream with 50 mcg in ½ gram?

What about women using vaginal estrogen in addition to systemic hormones (MHT) or with unregulated topical compounded estrogen products for their face and/or body? We have almost no data here. In many of the observational studies women using systemic hormones were likely using progestins, which offer more protection for the uterus than progesterone, the more common choice today.

What are the estrogen levels in the endometrium with different doses of vaginal estrogen?

Should the lower dose vaginal estrogen products, the 10 mcg or less tablets and softgels, have different warning labels than the higher doses?

I’m not being picky. These are important, unanswered questions, and it would be great if this renewed interest at the FDA generated the impetus and funds to get the answers.

This is why we need a robust discussion about vaginal estrogen products and the endometrium by experts in the relevant fields, so we can make sure the labeling of the products reflects what we actually do know as well as the uncertainty, and to push for the resources to close the gaps that exist.

I know there are doctors and influencers on social media, who claim that “nothing is ever good enough for Gunter.” It’s not just me raising these issues, many of the papers I have referenced have raised similar concerns. We should be pushing for more research on the specific areas in question, not acting as if observational data is good enough and cherry picking our way over these gaps in our knowledge.

What is deeply hypocritical is that I hear some of those same doctors and influencers who have criticized me talk about how “we need more studies” for women in menopause. What do they think I am asking for? I’m not asking to ban vaginal estrogen, I am sure I write 4 or 5 prescriptions for it a day, if not more. I’m asking that we not lose sight of some important questions about absorption with different doses and the endometrium, because I actually want the answers and I think it’s offensive that we don’t have them. We can do better than observational studies, it just takes funding and interest.

It’s important that we remember that two things can be true.

1. To the best of our knowledge appropriately dosed vaginal estrogen is safe (people should not be panicking).

2. Our knowledge has gaps that should be fixed, especially considering this is a medication women may take for decades.

And I’m here for both truths.

References

1. Crandall CJ, Hovey KM, Andrews CA, Chlebowski RT, Stefanick ML, Lane DS, Shifren J, Chen C, Kaunitz AM, Cauley JA, Manson JE. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study. Menopause. 2018 Jan;25(1):11-20. doi: 10.1097/GME.0000000000000956. PMID: 28816933; PMCID: PMC5734988.

2. Meaidi A, Pourhadi N, Løkkegaard EC, Torp-Pedersen C, Mørch LS. Association of vaginal oestradiol and the rate of breast cancer in Denmark: registry based, case-control study, nested in a nationwide cohort. BMJ Med. 2024 Feb 13;3(1):e000753. doi: 10.1136/bmjmed-2023-000753. PMID: 38361664; PMCID: PMC10868295.

3. Bhupathiraju SN, Grodstein F, Stampfer MJ, Willett WC, Crandall CJ, Shifren JL, Manson JE. Vaginal estrogen use and chronic disease risk in the Nurses' Health Study. Menopause. 2018 Dec 17;26(6):603-610. doi: 10.1097/GME.0000000000001284. PMID: 30562320; PMCID: PMC6538478.

4. Helena S. Salminen, Maria E. Sääf, Sven-Erik Johansson, Hans Ringertz, Lars-Erik Strender. The effect of transvaginal estradiol on bone in aged women: A randomised controlled trial. Maturitas. Volume 57;2007: 370-381,

5. Mørch, L.S., Kjær, S.K., Keiding, N., Løkkegaard, E. and Lidegaard, Ø. (2016), The influence of hormone therapies on type I and II endometrial cancer: A nationwide cohort study. Int. J. Cancer, 138: 1506-1515. https://doi.org/10.1002/ijc.29878

6. Stanczyk FZ, Mandelbaum RS, Matharu H, Dancz CE, Sherman ME. Endometrial safety of low-dose vaginal estrogens. Menopause. 2023 Jun 1;30(6):650-658. doi: 10.1097/GME.0000000000002177. Epub 2023 Apr 4. PMID: 37022294.

7. Santen RJ, Pinkerton JV, Liu JH, et al.Workshop on normal reference ranges for estradiol in postmenopausal women, September 2019, Chicago, Illinois. Menopause 2020;27:614-624. doi: 10.1097/GME.0000000000001556

8. Pickar JH, Amadio JM, Bernick BA, Mirkin S. Pharmacokinetic studies of solubilized estradiol given vaginally in a novel softgel capsule. Climacteric. 2016 Apr;19(2):181-7.

9. Archer DF, Constantine GD, Simon JA, Kushner H, Mayer P, Bernick B, Graham S, Mirkin S; REJOICE Study Group. TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol. Menopause. 2017 May;24(5):510-516. doi: 10.1097/GME.0000000000000790. PMID: 28002201; PMCID: PMC5404400.

10. Eugster-Hausmann M, Waitzinger J, Lehnick D. Minimized estradiol absorption with ultra-low-dose 10 microg 17beta-estradiol vaginal tablets. Climacteric. 2010 Jun;13(3):219-27. doi: 10.3109/13697137.2010.483297. PMID: 20423242.

11. Mitchell CM, Larson JC, Crandall CJ, Bhasin S, LaCroix AZ, Ensrud KE, Guthrie KA, Reed SD. Association of Vaginal Estradiol Tablet With Serum Estrogen Levels in Women Who Are Postmenopausal: Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2022 Nov 1;5(11):e2241743. doi: 10.1001/jamanetworkopen.2022.41743.

12. Santen RJ, Markin S, Bernick B, Constantine GD. Systemic estradiol levels with low-dose vaginal estrogens. Menopause 2020;27:361-370.

13. Santen RJ. Vaginal administration of estradiol: effects of dose, preparation and timing on plasma estradiol levels. Climacteric 2015;18:121–134.

14. Crandall CJ, Diamant A, Santoro N. Safety of vaginal estrogens: a systematic review. Menopause. 2020 Mar;27(3):339-360.

15. Dorr MB, Nelson AL,Mayer PR, et al. Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis. Fertil Steril 2010;94:2365-2368. doi: 10.1016/j.fertnstert.2010.03.076

16. Labrie F, Cusan L, Gomez JL, Côté I, Bérubé R, Bélanger P, Martel C, Labrie C. Effect of one-week treatment with vaginal estrogen preparations on serum estrogen levels in postmenopausal women. Menopause. 2009 Jan-Feb;16(1):30-6. doi: 10.1097/gme.0b013e31817b6132. PMID: 18820592.

17. Illston JD, Wheeler TL, Parker CR, Conner MG, Burgio KL, Goode PS, Richter HE. Low-dose 17-β-estradiol cream for vaginal atrophy in a cohort without prolapse: Serum levels and vaginal response including tissue biomarkers associated with tissue remodeling. Maturitas. 2015 Aug;81(4):475-9. doi: 10.1016/j.maturitas.2015.05.010. Epub 2015 Jun 5.

18. Rigg LA, Hermann H, Yen SS. Absorption of estrogens from vaginal creams. N Engl J Med. 1978 Jan 26;298(4):195-7. doi: 10.1056/NEJM197801262980406. PMID: 201842.

19. Santen RJ, Pinkerton JV, Conaway M, Ropka M, Wisniewski L, Demers L, Klein KO. Treatment of urogenital atrophy with low-dose estradiol: preliminary results. Menopause. 2002 May-Jun;9(3):179-87. doi: 10.1097/00042192-200205000-00006. PMID: 11973441.

20. Cicinelli E, De Ziegler D, Morgese S, Bulletti C, Luisi D, Schonauer LM. "First uterine pass effect" is observed when estradiol is placed in the upper but not lower third of the vagina. Fertil Steril. 2004 May;81(5):1414-6.