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BackTable / OBGYN / Article
Challenging the Black Box Warning on Estrogen to Improve Menopause Management
Mackenzie Sweeney • Updated Jul 28, 2025 • 118 hits
With nearly 75 million individuals in perimenopause, menopause, or postmenopause in the United States alone, it is essential that evidence-based medicine guides the management of genitourinary syndrome of menopause (GSM). Historical data from the 2002 Women’s Health Initiative (WHI) studies sparked widespread concern regarding estrogen therapy and led the FDA to issue a black box warning on estrogen-containing products. Emerging evidence supports the safety and efficacy of low-dose vaginal estrogen for the treatment of GSM, yet efforts to revise or remove the black box warning on estrogen have remained largely unsuccessful.
In this article, urologists Dr. Yahir Santiago-Lastra and Dr. Suzette Sutherland explain the origins of the FDA’s black box warning on estrogen, review current evidence supporting low-dose vaginal estrogen as a safe and effective therapy for GSM, and report ongoing efforts to align regulatory policy with contemporary data to ensure patients with GSM receive optimal, evidence-based care.
This article features excerpts from the BackTable OBGYN Podcast. We’ve provided the highlight reel in this article, but you can listen to the full podcast below.
The BackTable OBGYN Brief
• The black box warning is the FDA’s most severe safety-related warning, indicating a medication poses a significant risk of serious or life-threatening adverse effects.
• The FDA issued a black box warning on estrogen in 2003 based on Women’s Health Initiative (WHI) findings that linked estrogen therapy to increased cardiovascular and breast cancer risk – without differentiating between systemic and low-dose topical estrogen therapies.
• Recent studies have shown no increased breast cancer risk with estrogen therapy; however, a 2018 citizen’s petition to remove the black box warning was denied by the FDA.
• Advocacy groups such as Let’s Talk Menopause have lobbied to increase federal funding for menopause-related research and launched the Unboxing Menopause campaign to support the removal of the black box warning on low-dose vaginal estrogen.
Table of Contents
(1) What is an FDA Black Box Warning?
(2) History of the Black Box Warning on Estrogen
(3) How Clinical Research Removed the Black Box Warning on Testosterone
(4) Continued Efforts to Challenge the Black Box Warning on Estrogen
What is an FDA Black Box Warning?
A black box warning is the strongest safety-related warning issued by the FDA, indicating that a medication carries a significant risk of serious or life-threatening adverse effects. Improper use of some medications with black box warnings can lead to death or permanent disability–for example, isotretinoin (Accutane) can result in severe birth defects if taken during pregnancy. Other medications with black box warnings may lead to non-fatal adverse effects that are difficult to manage–such as Clozapine, which can cause severe neutropenia. Despite these risks, providers may prescribe medications with black box warnings when the therapeutic benefit to the patient outweighs the potential harms. The FDA may remove a black box warning if substantial evidence demonstrates that the warning is no longer warranted.
[Dr. Yahir Santiago-Lastra]
Going into what the black box warning is, let's really go into it, so you leave this episode knowing exactly what it is. The black box warning is the strongest safety warning that's issued by the FDA. It's intended to highlight serious risks, but it's sometimes been misapplied and there are some historical medications that have undergone a label change. There is possibility to change it.
Then the other issue there is to understand why this is applied to certain medications. Number one, it could be because the medication confers life threatening or fatal risk, so the medication has been shown to cause severe adverse effects that can lead to death or permanent disability. An example of that is isotretinoin or Accutane. It can cause severe birth defects if it's taken during pregnancy. There can also be a lower risk, but still really concerning severe or irreversible adverse effects like fluoroquinolones, which can cause tendon rupture or permanent nerve damage.
It can also be issued because the adverse effects perhaps are not fatal, but they're not easily managed. For example, Clozapine causes a risk of severe neutropenia and that requires frequent blood monitoring. Because that's not easy to manage, there's also a black box warning there. Then the warning usually arises from clinical trials, large scale observational studies or post-marketing reports showing that there are one of those significant risks. An example of that is Vereniclein, which is Chantix, used to have a black box warning, no longer has one. That was based on psychiatric risks, based on case reports and post-marketing data, and it was later removed after further more robust research showed that the warning was not applicable. What's important to consider here is the disproportionate risk. The reason I'm emphasizing these things is because when we put this towards vaginal estrogen, it really doesn't add up, but it has to have disproportionate risk compared to benefits.
The drug may still be useful, but only in select patients where the benefit outweighs the risks, and a great example of that are opioids. They have a black box warning for addiction, abuse, and overdose risks, but we know that we still use them in some patients because the benefit outweighs the risk.
[Dr. Suzette Sutherland]
The crux here really is for the patient is this medicine, it might help you. We think that there's benefit to this medicine, but there are significant risks and you need to take a pause and see what those risks are, and are you willing to take those risks? That's what the black box warning is really saying.
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History of the Black Box Warning on Estrogen
The FDA issued the current black box warning on estradiol affecting all estrogen-containing products – in 2003, following the Women’s Health Initiative (WHI) study that linked estrogen and progestin therapy to elevated risk of cardiovascular events and breast cancer. After emerging data contradicted these findings, the North American Menopause Society filed a citizen’s petition for the FDA to remove the black box warning on estrogen in 2016. The FDA denied this petition in 2018, citing insufficient data from well-controlled studies. Efforts to further challenge the black box warning on estrogen are complicated by the FDA’s standard of reviewing one citizen’s petition per issue and by the warning’s lack of distinction between systemic estrogen therapies–initially associated with adverse effects–and low-dose, topical estrogen therapies.
[Dr. Suzette Sutherland]
Dr. Santiago-Lastra has done a lot of work in this area looking at what we call the black box warning for estrogen. I just set the stage there. Why don't you take a little bit from here and explain to us, "What is this issue with this black box warning?" There's a lot of media around that right now and people don't really understand. What is a black box warning? How is it supposed to be utilized?
[Dr. Yahir Santiago-Lastra]
Absolutely…To better give that context, I think quickly going through the history of what I call the estrogen wars or battling the FDA for women's health. That was coined by one of our colleagues, Dr. Rachel Rubin, and I think it's really true. It all starts in 2002. We can definitely refer to Kelly Casperson's episode on the Women's Health Initiative study, but that's when first estrogen and progestin were linked to increased cardiovascular and breast cancer risk.
Then in 2003, right away, the FDA issues a black box warning on all estrogen products. Now if we look back at that data, we can see how the data was confounded and really obscured the reality, which is that estrogen is very beneficial. In 2004, they started to notice that there was an estrogen only study that found a small stroke risk, but no excess breast cancer risk. Then in 2016, after some burgeoning data, the North American Menopause Society put in a citizen's petition to the FDA to remove the black box warning.
Then in 2018, the petition was rejected and this is where we are. The FDA at that point cited that there was a lack of well-controlled studies and it snowballs into the issue for access that we have as a result of the black box warning today. We can go over a little bit more about what a black box warning is and how it pertains to estrogen specifically, but I wanted to put that context out there so we know what the status of the problem is and why we're here today discussing it.
[Dr. Suzette Sutherland]
Yes. What we're talking about too is the black box warning specifically here for the use of vaginal estrogen, very local, small dose vaginal estrogen, which is different from using larger dose systemic estrogen, although I would argue the data isn't there either to show that that's harmful, but rather beneficial, which we talked about in the other episode a little bit more.
In any case, this black box warning at the first step is to try and get the FDA to separate this idea of local low-dose vaginal estrogen. What are the risks and benefits associated with that versus the systemic, and should it be part of this black box warning? With that, let's look into again, we're all physicians here and providers here are mostly that are our listeners, but I don't know that people really understand exactly what a black box warning is and what it's trickle down is.
[Dr. Yahir Santiago-Lastra]
...I want to underscore something that you just mentioned that I think is incredibly important because it is the crux at which this problem arises and it is estradiol. Estradiol has the black box warning. We cannot parse out vaginal topical low-dose estrogen from systemic estradiol as far as the FDA is concerned. That's where we are running into this issue where low-dose topically applied vaginal estrogen is incredibly safe and has had none of these adverse events attributed to it, but the black box warning is for estrogen in general, and that creates the problem that we have.
...
Let's talk a little bit about what a citizen's petition is and why it's important. Before that, I did want to highlight what the black box warning for estrogen was highlighting in and of itself. The black box warning for vaginal estrogen, if you look at, for example, the lowest possible dose Vagifem, twice a week, the black box warning for vaginal estrogen seems alarmist when you look at it.
It warns of endometrial cancer, cardiovascular disorders, probable dementia, and breast cancer, but these risks have really not been shown in these large-scale studies that we now have available. Even in 2025, we've had a recent meta-analysis that looked at tens of thousands of women and showed no increased breast cancer risk in those patients, which is excellent, but this label really hasn't changed since 2002. That one time when they tried to change the label, it was through something called a citizen's petition.
A citizen's petition is a process in which, either through advocacy or through professional societies, whatever organism decides to put in that formal request to the FDA. It could be an individual, it could be an organization, it could be a stakeholder requesting that they amend these regulations and amend these warnings. It could be about updating the drug labeling, which would be excellent for vaginal estrogen to just have that underscoring that vaginal estrogen in its recommended dosing are actually very safe. All of those formulations are actually very safe.
It could be any other regulatory action based on new evidence. For example, just removing the black box warning altogether, because what has been shown over time is that systemic estrogen is also a lot safer than the Women's Health Initiative initially led people to believe. The citizen's petition process is a key tool for advocating changes to outdated safety warnings, so that seems to be the best process.
Then there's another little hiccup there, another obstacle, which is that the FDA typically considers only one citizen petition per issue. Again, it's already been addressed in 2016. It's already been filed. That means that any new petition has to be coordinated with existing efforts or pursued through alternative advocacy strategies like pairing with industry who hasn't really requested any label changes for vaginal estrogen since this citizen petition was filed.
[Dr. Suzette Sutherland]
Can you give us some insight into why that petition was then denied? When we do have updated data that shows even the pharmacokinetics of vaginal estrogen does not increase systemic estrogen levels. All of these risks that are touted to be associated with systemic shouldn't apply to the vaginal. Even that, again, I said is debatable. Why was it then denied?
[Dr. Yahir Santiago-Lastra]
It was denied in 2018, actually, but the citizen petition was filed 2016, 2018, it is denied. I think the main reason that it was denied is because there weren't these large scale studies of tens of thousands of patients showing no increased conferred risk with systemic or vaginal estrogen. They felt that at that time in 2016, the evidence was really lacking to reverse the label change.
How Clinical Research Removed the Black Box Warning on Testosterone
Following the 2023 TRAVERSE trial, another randomized control study involving 5,000 participants that found no increased cardiovascular risk associated with testosterone therapy, causing the FDA to remove the black box warning on testosterone. In contrast, multiple studies involving tens of thousands of participants have shown no increased risk of breast cancer with estrogen therapy, yet the black box warning on estrogen remains in place. While acknowledging the disparity in regulatory responses to male vs female hormone therapies, Dr. Yahir Santiago-Lastra underscores that the TRAVERSE trial offers a model for pursuing similar regulatory change regarding estrogen.
[Dr. Yahir Santiago-Lastra]
Here's when another history lesson is a little bit beneficial, and it is if we look at what was accomplished with testosterone. Many urologists may be really excited to hear that in 2025, in February, the FDA actually removed the black box warning for testosterone, and that was removed following strong clinical evidence of cardiovascular safety through the TRAVERSE trial.
Really quickly, the TRAVERSE trial was published in 2023. It confirmed that there was no increased cardiovascular risk with testosterone therapy, and that actually those super therapeutic levels that we are often worried about are actually don't pair out in the literature when people are safely treated by their providers. This was a trial of about 5,000-plus men.
If we look at the studies in women published out of Denmark, if we look at the recent 2025 ASCO study through the University of Arizona, we are talking about tens of thousands of women showing no increase in breast cancer recurrence or mortality, improved survival. There was a 2025 meta-analysis that looked at six studies covering over 24,000 patients showing no increased risk. I think if we look at the great news that we received with testosterone, and we look at the data that we have for estrogen, it's really no better time than now with the data that we have to request those label changes.
[Dr. Suzette Sutherland]
Yes, I'm glad you brought that up. I want to touch on that a little bit, and especially with respect to gender issues and advocacy here. We have a bit of a paternalistic, I think, attitude still in medicine. We see it all the time. Although we want to deny it, but we still see it. There's this idea that we tolerate more suffering in women. Women have problems with their menstrual cycles, then they have pain at delivery. They have babies, and then afterwards they have more pain. Then in menopause, we have issues during menopause, and we allow that suffering to some degree.
That's really what the WHI study, the fallout of it was, is that, "We know we could give you this estrogen and maybe progesterone if you need it as well, so on and so forth. We could give you the hormones, but there's such a risk associated with it that we think for you to suffer is better, or to use non-hormonal options, which we know aren't as good, but they can be beneficial."
If we look at the men's side of things, when men go through, I'm going to say men-o-pause, and end up aging and lower testosterone levels, and men start screaming about having erectile dysfunction and low libido, then men suddenly get heard. When we made a point here, when we look at this TRAVERSE study, it was a great thing that it happened, but it happened really quite quickly. Pharmaceutical industry jumped in to pay for this study. It did have 5,000 men. It was a randomized control trial against a placebo. My understanding is the primary efficacy, trying to look at cardiovascular risk with use of testosterone. By the way, they used men who already had a cardiovascular risk or lots of risk factors for cardiovascular disease, so that's interesting.
They were able to make their decisions based on only about, almost 400 patients in that primary endpoint. Although we look at and say it was a large study, 5,000 patients, they had a lot of fallout. For different reasons, this isn't the place to get into all of that, but the determinations were made on really a small number of patients, if you want to think about it, if you're looking at population-based patients, or studies, and then also over three to five years.
In comparison to that, my understanding also is one of the denials that's happening today is we don't have enough data. We don't have enough data concerning the use of vaginal estrogen. Dr. Santiago last time mentioned four concerns, but the biggest one that everyone's always afraid of is the breast cancer. They said, "You have some of these wider population registries, population studies that you've looked at."
You mentioned already the meta-analysis, that's 100,000 patients, tens of thousands of patients, but they didn't go out long enough. They need to go out 10 years to make sure there's no risk of breast cancer. Why is five years okay for men, but women we need a study for 10 years? Here's the inequity here, right?.
...
[Dr. Yahir Santiago-Lastra]
…I think that when I look at the success with the TRAVERSE trial, my first instinct is to be happy, I'm a urologist. I'm really happy. There's always a part that gets a little annoyed that women didn't have the same benefit, but when you think historically, one really important tidbit of history is Ruth Bader Ginsburg and her first sex discrimination case. That was Moritz v. Commissioner, and that client was a man. The man she represented had been caring for his mother. She was able to show that he needed the same benefits as a woman, and that a man could also be a caregiver. I think that is something we can utilize for the TRAVERSE trial as well.
Yes, men got testosterone approved before estrogen did. Now we can argue, "Hey, testosterone is a hormone. The cardiovascular risks that we're concerning were similar with a similar pathophysiology," so that's one step in to say, "We got to readdress this for estrogen." Then the other risk, the data is actually strongest for the breast cancer risk. There is robust data showcasing that there is no increased risk of breast cancer recurrence with low-dose vaginal estrogen. To me, that makes it easier.
[Dr. Suzette Sutherland]
Just to point out what you said too, because the discussion has been about the incidence of breast cancer usually. Even in breast cancer survivors, you use the word recurrence. There's no risk of recurrence, breast cancer or increased mortality associated with it. We have that data today. Thanks for pointing that out.
Continued Efforts to Challenge the Black Box Warning on Estrogen
Professional organizations continue to advocate for the reassessment of the black box warning on estrogen, emphasizing the safety and efficacy of low-dose estrogen therapies. Recent legislative efforts have increased federal funding for menopause-related research and directed the FDA to revise hormone therapy safety labeling using recent research. Advocacy groups such Let’s Talk Menopause raise public and professional awareness about the safety of estrogen therapies. Dr. Suzette Sutherland emphasizes the audience can contact FDA officials to support the removal of the black box warning on low-dose, vaginal estrogen through Let’s Talk Menopause’s Unboxing Menopause online campaign.
[Dr. Yahir Santiago-Lastra]
The process is nebulous and obscure because there's already been a citizen's petition and it's been denied. I think the work that's being done right now is to continue to get the word out, as we are doing. This episode is a really great example of that. The webinars that you've seen me give for different professional societies. The AUA has been generous to get all of the stakeholders aligned through the Bladder Health Alliance, which you may be familiar with through your work with the Urology Care Foundation. There's a lot of patient advocacy groups and professional societies in that Bladder Health Alliance.
We've had a few stakeholder meetings to talk about what this next step forward are and underscoring that we need to have our legislators on board, which many of them are. There have, in particular, been two bills that were put into discussion recently to show bipartisan menopause support. Representative Yvette Clarke from New York and Mike Kelly from Pennsylvania put a bill through to improve research and access to menopause-related care. Vaginal estrogen is like, boom, straight in the middle of that.
Then there's a Menopause Research and Equity Act, which is a Senate bill. Lead sponsors were Senator Baldwin, I believe, and Lisa Murkowski. That also allocates millions of dollars for menopause-related research and directs the FDA to revisit hormone therapy labeling using up-to-date safety data. That's where the legislative advocacy has come into play. Professional societies, including the AUA, have been pivotal in getting those things to be at the top of the list for many of the legislators.
Then, secondly, we have getting the citizens interested, and by citizens, I mean patients, patient advocacy groups, all of these people, the ones that are directly affected by this problem, getting them to know and request that this occur. A lead organization there is Let's Talk Menopause. Rachel Rubin, again, mentioning her name, is a key figure there, but there are a lot of other really key figures in industry and Capitol Hill, as well as clinicians who are part of that group who really push and lobby for anything related to menopause, the label change included there. Then you have the providers. The providers are best represented through their society. The AUA put vaginal estrogen and the black box warning at the forefront of its most recent advocacy summit. We had some time to talk about the barriers that exist to the label change. Then we also had all of the urologists that were there, all of the patient advocates that were there sign the current petition in place through Let's Talk Menopause to get further support.
Then the last part is industry. I know that Pfizer is in the works for updating some of their safety data and presenting that for possible label changing. That has been the hardest nut to crack as far as industry is concerned. You can think about they have to be in compliance with their risk management. They have to weigh these things, importantly, because whenever you request these label changes, there is that risk.
Whether it's related to bias against women, because we see that they moved so much quicker and faster with testosterone, that is certainly possibly a part of it, but I think that the process is usually at play when there are equity problems. We let the process get in the way of progress.
[Dr. Suzette Sutherland]
Hopefully this allows what happened with testosterone, and on the heels of that, we're able to move a little more quickly for ourselves, in the female arena, because it is amazing how quickly that went. You've described nicely the process, all the pieces of the puzzle that have to come together to make this happen, yet it happened pretty quickly for testosterone, and yet we've been battling this for how long?
Really, one of the main requests, for the FDA with this black box warning is just to request an update, looking at the most recent data. To weigh in on this black box warning, because remember, the data that's being used for this black box warning is from 2002, 2003, from the WHI study, which wasn't even a study to look at vaginal estrogen whatsoever. It's very misguided in that sense. Hopefully, just bringing this more to the forefront and to light that we can make some headway.
I did want to mention really quickly, you already mentioned the Let's Talk Menopause campaign. I wanted to make sure to mention because that's something that every individual can do. If you want to get online, look up Let's Talk Menopause. They have a major campaign going on right now that you can sign the petition about Unboxing Menopause, that's what it's called. You can get your name on the petition, you can write general stories about maybe patients you've taken care of, or maybe if you have personal stories yourself, you can add to that. Any little piece that you can add to that is helpful. That's what our listeners are able to do even today to help the process.
Podcast Contributors
Cite This Podcast
BackTable, LLC (Producer). (2025, July 1). Ep. 87 – Evaluating Hormone Therapy in Menopause Management [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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