Testosterone Use in Menopausal Women transcript

So, let's go ahead and get started. Good morning again and welcome to the FDA public workshop on testosterone use in menopausal women. Thank you to everyone joining us here in the room at the FDA campus as well as to our thousands of attendees joining us virtually. This workshop is co-hosted by the FDA Office of Women's Health and the Center for Drug Evaluation and Research. I'm Lakshmi Kanan, senior adviser with the Office of Women's Health in the Office of Commissioner at the FDA, and I'll be your workshop moderator for today.

A few quick housekeeping items before we begin. Please ensure your mobile devices are silent. In the event of an emergency, please exit through the designated doors at the back of the auditorium. Please use the QR code displayed on the screen and at the top of your printed agenda to access the workshop web page with resources including the full meeting agenda, the speaker bios, and to submit questions for our speakers.

We have a highly regarded group of experts serving as speakers and panelists today. Given the time limitation, the speakers will be briefly introduced, but we encourage you to learn about each of the speakers by visiting the workshop web page. Please note the speakers comments do not necessarily reflect the views of and are not endorsed by FDA. To participate in today's Q&A, submit your questions as each speaker concludes their presentation.

Scan the QR code to visit the FDA event page and click the link on the page to submit your questions digitally. Please note, a public docket is also open until October 19th, providing an opportunity for the public to share your comments and feedback. The meeting recording will be available on the event page within two weeks after the meeting concludes. As a reminder, we ask all attendees to please be respectful and courteous to speakers and fellow attendees throughout the meeting.

This is a public scientific forum and we respect all participants to maintain a professional decorum. I'm now pleased to introduce our two opening speakers. First, Dr. Dr. Kavita Vasich. Dr. Vasich serves as the associate commissioner for women's health and the director of the office of women's health at the FDA where she leads a broad portfolio spanning research, policy, scientific initiatives, education and outreach to advance women's health.

She has shaped the AY's approach to studying of sex differences in evaluation of medical products, guided international harmonization efforts and advanced women's health research at FDA. Dr. Vasisht is a double board certified in internal medicine and adult endocrinology, diabetes and metabolism and also holds a doctor of pharmacy degree. Following Dr. Vish we will hear from Dr. Christina Chang. Dr. Chang is a divi director of the division of urology obstetrics and gynecology in the office of new drugs in center for drug evaluation and research at FDA.

She is a boardcertified obstitrician and gynecologist. Her division oversees a a diverse group of drugs and therapeutic biologics for the management of benign urologic and gynecologic conditions as well as products intended to treat conditions and obstitrics. She has led the facilitation and assessment of development programs in these areas. So I first welcome Dr. Vas to the podium and after that I welcome Dr. Chang to give your opening remarks.

Thank you, Lakshmi, and good morning. On behalf of the FDA, welcome to this public workshop. Whether you are joining us in person here today or virtually, your presence underscores the importance of today's discussion and we are glad you are here with us. The FDA's Office of Women's Health plays an important role in collaborating across disciplines within and outside the agency to bridge critical knowledge and scientific gaps in women's health.

At the heart of this work is a fundamental principle. FDA regulated products should reflect the unique biology and needs of women and clinicians and patients deserve the best available science to guide their healthcare decisions. This workshop on testosterone use in menopausal women is squarely within that mission. Consider the scale of what we are discussing today. Each year over 1 million women in the United States enter the life stage of menopause.

And at any given moment, millions more are navigating the physical and often emotional changes that accompany this transition, making it critical to advance the development of safe and effective therapies for menopausal symptoms. We know this issue resonates deeply with many of you. In 2025, FDA opened two dockets for public comments on hormone therapy. While the dockets did not specifically focus on testosterone use in women, this is exactly what you wanted to talk about.

Many commenters requested an FDA approved testosterone formulation for women and described testosterone's role in managing their perry and post-menopausal symptoms. Today's meeting aims to continue this very important conversation. Over the years, off label use of testosterone in women has grown substantially. Since there is not an FDA approved formulation for menopausal women, important questions remain such as long-term safety, optimal dosing, appropriate biomarkers, and endpoints for different indications.

Our meeting bridges together researchers, clinicians, patients, and FDA scientists to discuss testosterone physiology in women and the clinical practice, patient, and regulatory perspectives. By the close of this workshop, we hope to leave with a sharper and shared understanding of what the current science tells us about testosterone's role in women's health, what clinical practice and guideline recommendations reflect, where the evidence gaps exist to inform future research, and efficacy and safety considerations for testosterone products for menopausal women.

Before we begin, before we begin, I want to express my sincere gratitude to our distinguished keynote speakers, Dr. Christine and Dr. Frink, our distinguished presenters and panelists for generously contributing your time and expertise. We are very much looking forward to hearing from you. I want to also recognize our colleagues in the FDA Center for Drug Evaluation and Research, particularly Dr. Christine Wen and Christina Chang and her team.

This has been an incredible partnership and of course our dedicated team in the office of women's health. This effort was led by Dr. Lush Lakshmi Kanan who you just met. So I invite us all to use this meeting to learn from one another. This is exactly the kind of collaboration that enables progress and moves the science forward. Thank you all again for coming today. [applause] It looks like I just lost my ID badge, but here I am.

Um, good morning. My name is Christina Cheng and um, as Dr. Pan mentioned I am the division director uh of the division of urology, obstetrics and gynecology in the center for drug evaluation and research. It is my great privilege to today to welcome so many um both attending in person and virtually to this important scientific workshop. I would like to take this opportunity to thank Dr. and Dr. Frink for being here.

Um and uh I would also um like to to thank our clinical experts for discussing the current scientific landscape related to testosterone use in menopausal women and my deep gratitude goes to the patient representative uh Miss Susan Lake for the willingness to share her personal experience um with her health challenges. And on behalf of Cedar, I would like to thank our colleagues in the office of women's health for their collaboration and support. um to make this workshop possible.

So this morning we will have presentations that examine the physiologic roles of testosterone throughout the woman's life including age related decline, the menopausal transition, challenges that are associated with measuring and interpreting testosterone blood levels and how these levels correlate with clinical symptoms and conditions. We will also hear the review of current and potential clinical uses of testosterone in menopausal women and then examine the strength and limitations um of the data available to support these uses in the afternoon.

Importantly, we will discuss the regulatory considerations including obtaining data to support uh efficacy and safety package to support a marketing application for testosterone use in menopausal women to treat various clinical conditions. And for those who may not know, my division oversees the uh drugs that treat benign urologic, obstetric, and gynecological conditions. Although we have approved many products that contain estrogen and progesterrogens to treat menopausal symptoms, there are no FDA approved uses for a testosterone therapy for menopausal women.

In 2004, a testosterone patch product was reviewed, but ultimately not approved. And fast forward to 2025, FDA held two panel discussions on hormone therapies. First on menopausal hormone therapy in women and the other on testosterone replacement therapy in men. Um and uh the public comments that were submitted in response to these panel discussions included um a large number of comments that supported the use and FDA approval of testosterone products for women.

And our review of these comments led us to recognize that this is an opportune time to continue that public discussion in light of significant interest from clinicians and patients regarding the use of testosterone um to to manage menopausal symptoms. We're also aware that there's been an increasing off label use of testosterone in women who are nearing or in menopause. Despite the white usage, however, knowledge gaps remain, including the context of use, the appropriate dosage and dosing regimen, and safety considerations.

So, the aim of today's workshop is to narrow those gaps and to signal to our stakeholders that we're open and ready to engage to support product development. FDA at the FDA, we're committed to protecting advancing public health. As an OBGYn, it is very heartening for me to see that the health of women, including for menopausal women, is receiving greater attention. FDS mission is to ensure that our patients have access to effective, safe, and quality medications.

So, it's in incumbent upon us to ensure that when we approve medical products, we can present the most accurate, balanced, and evidence-based data to clinicians and patients to help them make informed treatment decisions. Today's workshop is one step towards meeting those goals. Um, thank you for coming to this workshop and for your support. With that, I'll turn it back to Dr. Kan. Thank you. Thank you, Dr. Vas and Dr.

Chang. Next, we are truly honored to have two distinguished keynote speakers with us this morning to set the stage for today's conversation. Our first keynote speaker is Admiral Bri Brian Christine who serves as the 18th assistant secretary for health at the US Department of Health and Human Services where he provides leadership on the nation's public health priorities including chronic disease prevention and strengthening overall health.

He also leads the US Public Health Service Commission Corps, one of the nation's eight eight uniform services composed of more than 5,000 public health professionals dedicated to protecting, promoting, and advancing the health and safety of the nation. Assistant Secretary for Health, Admiral Christine is focused on restoring trust and public health, radical transparency, putting patients first, and ensuring that every American has the opportunity to live a healthier and more fulfilling life.

Admiral Christine has published peer-reviewed research, lectured extensively, and trained surgeons around the world. As a mainstream physician treating the men, women, and children of our republic, Admiral Christine has demonstrated a deep commitment to service, innovation, and improving the health and well-being of all Americans. Um, Admiral Christine, thank you for taking the time to be with us in person today. And and now I welcome you to the podium.

[applause] Well, welcome everyone and thank you so much for being here. It is a privilege to serve as the president's assistant secretary for health. It is a privilege to work with Secretary of HHS Robert F. Kennedy Jr. and it's a privilege to be with you here today. Yesterday, I had the pleasure of attending the Senate confirmation hearing for the nominee for surgeon general, Dr. Nicole Sapphire. Dr. Sapphire did great, and I'm hopeful that we will soon have our surgeon general in place, and I think she'll she will be an advocate for the health of all Americans, and I feel confident she'll be an advocate for the health of women.

This past year has been an incredible year for women's health. In November of 2025, the FDA announced that it would remove a broad blackbox warning from hormone replacement therapy products used to treat menopause. A truly remarkable day when that happened. Understand that in this administration, the Department of Health and Human Services is listening to women and addressing hormonal health across the lifespan. women are being heard and finally being heard when it comes to menopause related symptoms.

[clears throat] But today we are here to uh address another hormone issue in women which is hormone replacement therapy specifically testosterone in women. Now as a urologist my I practiced as a urologist for about three and a half decades. The [clears throat] final 25 years were spent exclusively on treating men. So, my practice was geared toward men, but I have seen the importance of testosterone replacement in men, and I've seen the importance of testosterone replacement in women, including my own wife.

And she doesn't mind me saying that. Uh, and while my practice was focused on men, understand that my passion for advancing women's health is true. It is strong, and it will never change. The Office of Women's Health exists under the assistant secretary for health. And while we're talking about the Office of Women's Health, let me say thank you so much to Dr. Frink for all the work you have done as directing the Office of Women's Health in your new role at the NIH.

I know you will be equally as effective, but what you have done for women's health, thank you so much. And as those reigns get handed off, Dorothy, what I can say is uh you've been a bit of a role model to me in teaching me how to advance for health in this country. Thank you for that. [applause] I look forward to the day when we have the same kinds of offices for men's health as we do for women. What we do for women in this country is so important and we will never never never back away from that.

But I am an unapologetic and unrepentant advocate for men's health and I hope that we can follow the lead of women who have shown us how we advocate for health in this country. And I hope we can do the same for men and I know we will. And I know together advocating for women's health and men's health is two sides of that same coin. And even though my practice was focused primarily exclusively on men, I'm here today to tell a different story.

One of the reasons we're here today is because many urologists, including some of the amazing urologists in this room, uh have taken leading roles in speaking up for women and advocating for women to have access to appropriate hormone therapy. And of course, this includes testosterone. I am grateful to my colleagues for their leadership and my message to all women here today is very simple. Under President Trump and Under Secretary Robert F.

Kennedy Jr., we hear you. We are grateful that you have taken the time to join us today to discuss this very important topic. We continue to face an important challenge because in the United States, we do not currently have a testosterone formulation that is specifically approved for women. And you have to ask ourselves, how can it be that in a place like Australia, and nothing negative to Australia? By the way, I have I have actually had the privilege of having three separate surgical education trips to Australia, operating around the country, educating residents, meeting patients.

I've told my wife who is from the UK, this gives her a bit of heartburn that if we had to live outside the United States, it would be in Australia because I love that place and I'm tremendously respectful for the health care system there. But how is it that women there have access to an approved testosterone formulation specifically for women while women here in the United States find themselves using formulations that were developed for men.

Something's wrong with that. Women in the United States deserve to understand their options when it comes to testosterone. They deserve treatments that were thoughtfully formulated and appropriately dosed for women. They deserve to have their voices and their experiences and their needs reflected in the development of these treatments. And that's why we are so pleased to have all of you here today. Your experiences matter.

Your voices matter. This conversation matters. And as we work together to advance the future for women's health, this conversation is so incredibly important. And I was also grateful and I have to say surprised last December, December of 2025, uh we had the privilege here at FDA of hosting the first ever expert panel on testosterone therapy in men. And I was amazed to see in the public responses, the overwhelming majority of the responses came from women who were sharing their experiences and their perspectives uh talking about the panel that we did here at FDA and saying, "Yes, yes, we support men, but hey, listen, listen to us women as well when it comes to testosterone." That was eyeopening.

Uh now, there is currently a public comment period open through October 19th related to this. I encourage women and everyone who has a stake, has an interest to make their voices heard. The FDA does listen to the voices of individuals. So, thank you for being here today. Thank you for the clinicians who are here, some of whom are dear friends, who I respect tremendously. Thank you for the patients who are here who are going to talk about your experiences because that's critically important.

Thank you for helping us to continue this important conversation about women's health. My message to the FDA, hear me. I am the assistant secretary for health. Listen to these clinicians. They are the best of the best. Listen to the women who need an approved testosterone product. Move boldly. Move with purpose. Always backed by gold standard science and get this done. Thank you very much. [applause] Thank you, Admiral Christine.

We'll now hear from our second keynote speaker, Dr. Dorothy Frink. Dr. Frink is the deputy director of the Ununis Kennedy Shiver National Institute of Child Health and Human Development in the National Institutes of Health. Previously, Dr. Frink served as principal deputy assistant secretary for health in the office of the assistant secretary for health and as the director of the office of women's health at the US department of health and human services.

In these roles she has led initiatives focused on improving health outcomes including efforts related to maternal and infant health, reproductive health and menopause. Dr. Frink is board certified in endocrinology, internal medicine, and pediatrics, and is a nationally certified menopause practitioner. She has published peer-reviewed research on maternal and infant health, diabetes, osteoporosis, and other conditions affecting women across the lifespan.

We welcome you to the podium, Dr. Fank. [applause] Um, thank you all so much for being here today. Um, it is truly an honor. I am grateful to our women's health colleagues at the FDA for developing such an incredible workshop focusing on testosterone for women. It truly has been a remarkable year for women's health and women's hormonal health. I am grateful to be able to share my experiences and as an endocrinologist with you today.

My own medical training took place shortly after the women's health initiative study abruptly ended hormone replacement therapy for women across the United States. In my endocrinology training, I was grateful to learn so much about menopause. However, it was extremely um challenging and hard to effectively care for women with those blackbox warnings. All those years I remember so many women would come back to me with the package insert in hand and say I I can't take this medication and I I would go over with them and in obviously in specific cases go going through the benefits and risks and even when the benefits outweigh the risks they would see that package insert and would be really scared to take hormones.

Last year, HHS and the administration took decisive action to update these blackbox warnings. This is an extraordinary step in how we think about women's health and an important recognition that women deserve accurate, up-to-date, and evidence-based information about their treatment options and about every aspect of their health. Really, there is another important part of this story that has already been addressed this morning, but I'd like to include it as well in my remarks.

Just two years after the Women's Health Initiative changed the landscape of hormone therapy, a testosterone patch specifically designed for women was reviewed by the FDA in 2004 for the treatment of hypoactive sexual desire disorder. The product was ultimately not approved in the United States in 2006 with additional long-term safety data among the concerns noted. At the beginning of the 2000s, when testosterone was actually considered for women or the conversation we're here to have today, we were entering an era of tremendous caution around hormone therapy.

It is important to note that testosterone for women was being considered within that broader environment. Now, more than 20 years have passed. We have more research. We have more clinical experience. And we have more women willing to tell us their experiences. And that is why we are here today. For decades, women have told us that they were not being heard. They told us that their symptoms were being dismissed and that important questions about their health were going unanswered.

Today, we are seeing a change. At HHS, we are listening and we are committed to addressing hormone health across the lifespan. For many physicians, our training teaches us to think about testosterone in women primarily when we are concerned that the level may be too high. We learn about conditions such as polyandocrine metabolic ovarian syndrome, formerly known as PCOS, where androgen levels can be elevated. But it is much more common for us to be but is much less common for us to be as um taught to ask a different question.

What happens when a woman's testosterone level is too low? One patient story that I will share with you today is a woman who I cared for who had an undetectable testosterone level. She had a demanding and stressful job. She was tired, had very little energy and no libido. She had taken medications over the years that can affect testosterone levels. Um, she was in pmenopause and she had been recommended an SSRI. She came to me with a simple but important question.

Could her hormones be causing her symptoms? This is not a a new story for many of you today in this room and listening. It is a story about a woman looking for answers. And it is a reminder that when a woman tells us that something is not right, we must listen, investigate, and continue asking questions. Women deserve answers about their hormonal health. And today we are having a broader conversation about what those answers must look like.

There really is a bright future ahead for women's health and hormonal health is really at the center of that. And of course as an endocrinologist I couldn't be more excited. Realizing that future requires us to continue asking difficult questions, pursuing rigorous research and making sure that women are represented in that research. The NIH, the Office of Research on Women's Health, has led incredible work in sex as a biological variable to ensure that women are appropriately represented and studied in biomedical research.

[clears throat] We need that same commitment when it comes to developing appropriate testosterone options for women. Women deserve to have testosterone options that are formulated and dosed specifically for them. I look forward to the conversations today and to the opportunities that lie ahead. The future of women's health truly is bright and together we have an opportunity um today to make it even brighter. Thank you so much.

[applause] Thank you Dr. Frink and thank you again Admiral Christine for those remarks. We will now transition to begin session one of today's workshop which is on the role of testosterone and female biology. And we ask the audience that you can start participating in today's Q&A by scanning the QR code. So our first speaker today is Dr. Margaret Weman. She's a professor of medicine in the integrative physiology and OBGYn at the University of Colorado School of Medicine where she is a translational clinical scientist specializing in reproductive endocrinology, sex hormone action in women and men and the molecular mechanisms of pituitary tumors and adrenal cancer.

Dr. Virman has been a leading voice in national and international guidelines having led the endocrine society's clinical guidelines on androgens in women and participated in the international guidelines on testosterone in women and she served as past past president of the international society of endocrinology. Dr. Weman will discuss the physiological roles of testosterone throughout a women's life, what we know and what we don't.

Welcome Dr. Weman. [applause] Thank you um Latchmi and thanks to the organizers for inviting me to um start you off on the biology of testosterone. I can advance it. [clears throat] So I'm an endocrinologist and I'm a hormone detective. So when I am studying what testosterone is and how it works, I'm bringing that lens and I'm going to overview what we know about testosterone physiology in women, the changes across the menstrual cycle and then across menopause and then across ages.

And then we're going to identify what we don't know, what has not been studied and what should be studied in the future. So this is a slide that all medical students hate to see and it's a slide of where steroid hormones come from and they all come from cholesterol and we are don't have a pointer here but you'll see that there's this complex diagram but look at the bottom right all these hormones going through from cholesterol come down to testosterone and then in different cell types or with different production from the ovary or the testice or peripheral conversion.

They're converted either in to the testosterone binding to the androgen receptor mostly in men or conversion to DHT by a five alpha reductase enzyme or in women very active aromatase activity in most of the cells in your body your brain your fat your liver. Why is that important? Well, androgens are testosterone and DHT, and they bind to the androgen receptor. Estrogen binds to the estrogen receptor. And dione, and I can't point uh above the bar, and DHEA, an adrenal hormone we're going to talk about, are pro hormones.

They can't bind to the androgen or the estrogen receptor. they have to be converted into testosterone and then DHT or into estradiol to have their effects. We studied for many years the role of estrogens in women and we know the changes that occur across the cycle. But what do we know about androgens? So, oh this slide doesn't have the picture. Well, anyway, this is a slide from a recent article in JCI. And if you look on the very left, it tries to compare the relative amount of testosterone and estradiol in men, premenopausal women, and post-menopausal women.

So, on the left, you can't see the body, but men make testosterone from the testice. And in peripheral tissues, it can be aromatized into small amounts of estrogen. The testice makes a tiny amount 20% of estradile. In contrast, in premenopausal women, both the adrenal gland and the ovary make pro hormones. Some testosterone and dione or DHEA. And you see that the circulating testosterone levels before menopause come from the ovary, the adrenal gland and a lot of peripheral conversion of those pro hormones in target tissues and the estrogen comes from the ovary and peripheral conversion.

Now in contrast after menopause you have very little hormones coming from the ovary. It's and dione again, but they're very small amounts and there's very little estradiol coming as we know in post-menopausal women. And so the amount of testosterone will show you doesn't change, but the amount of estrogens or estradiol drops by more than 10fold. So when we think about androgens and measuring them and you're going to hear about the difficulties in understanding measurement of androgens te testosterone and estradile circulate bound to this proteins SHBG and album and that means that diseases across lifespan that change SHBG obesity visceral ataposity etc are going to change your total measurement that's something to think about.

We're going to hear about the testosterone assays that were always developed for men and only recently have we had sensitive assays to measure the levels in post-menopausal women. Also, DHEA, the adrenal hormone, has intermittently got a lot of press. It's a again a pro hormone. It can't bind to the androgen receptor, but it can get converted both into tea, DHT, and estradile. And again the take-home message to begin with is in females most of the testosterone and the pro hormones are converted into estrogens.

So the first question is do androgens testosterone change across the menstrual cycle and I wish I had a pointer but if you look at this slide that's from uh Sue Davis's group you see in the top two that's estradile and estrone and you see the stars above it. We know that testosterone in that estradile increases across the menstrual cycle and then in testosterone and dione and DHEA testosterone increases across the menstrual cycle and it's probably very important for follicularis and dione a little bit again that pro hormone and no change about DHEA the adrenal gland doesn't change across the menstrual cycle now here's a more detailed look at this across in in in every three days.

And again in the box that you see in yellow, the total testosterone in the first bar, you can see it peaks midcycle. And if we look at the free tea, it peaks right after midcycle. So there's an important role of testosterone across the menstrual cycle. Down below, when they tried to measure DHT, it's sort of scattered across. DHT is not an assay that we have as much data about or sensitivity. So takehome testosterone just like estradile levels change across the menstrual cycle.

We don't exactly know all the roles of the testosterone but we know it's important because we know too much testosterone in the menstrual cycle such as POS can screw up follicularis and cause infertility. We don't know as much about too little. Now the other big question that investigators started now more than 20 years ago. Well, what do testosterone levels do across life? And here is again a very large series um from the Davis group.

And what it shows if we go across it one by one a decline in androgens from ages 18 to 40 before menopause not related to menopause. Okay. And in the top bar you see testosterone and in the bottom you can see 18 to 25 to 30 up to 40. So there is a gradual decline in testosterone levels across the premenopausal ages that and dione drop down also and DHEA also declines with age. The other two um measurements are the 11 keto steroids which we're not going to talk about today but they don't change very much.

So the big shocker as for all of us because we grew up learning about what estrogen does at menopause is what about testosterone? Doesn't testosterone drop abruptly like estrogen does? And the answer is no. Testosterone levels do not drop at menopause. So here's a study of premenopausal, permenopausal, and post-menopausal. And of course in premenopausal that testosterone is going to go up and down. permenopausal and post-menopausal and they controlled it very well with the new assays, the mass spec assays that you're going to hear about.

So this is sort of a shocker for us as endocrinologists thinking about it. We think too low, too high, and just right. But menopause is not a time when testosterone levels drop. Now they do drop and then rise with age. So in this older study before we had even massspec assays you can see this is from on the bottom of the slide 65 to 90 you can see they sort of go down and come up again a lot of scatter in the absolute and then if you look on the left side this is in nanograms per deciliter that we're used to in the United States they're all over the place.

Oh I hope this slide comes in. It does. So, in this new data that's about to be published u that's going to be presented next week uh by Sue Davis, she now has a group of over 5,000 women in Australia that they've studied and now they're going even older 70 to 94 and they've measured testosterone by LCMS and you can see that the effect size is quite small. This is in now in nanom moles per liter but after age 70 there's a slight increase.

So decline across and then slight increase. What does that mean? We don't know. And oops this was the median level. Oh, so just to show the change in a premenopausal woman it would be 35 and the median testosterone in this older group of women was 38. So it comes back up into the premenopausal levels. So what the take-home is is that testosterone levels fall and rise with age independent of menopause. They fall about 50% across life. and then come back up.

Now compare that to the changes of estradiol at menopause which is tenfold. So it's a huge big change in estrogen levels at menopause and very modest changes across life of testosterone. DHEA that adrenal preorm DHEAS drop in older women and older men. And here again in the older group of uh women that's going to come out of over 5,000 women now measured by LCMS you can see that in contrast to testosterone the adrenal pause happens the levels keep dropping.

Okay. And here you can see the median level is 2.6 compared to a premenopausal DHEA level DHS level of or DHEA level excuse me of 5.5. Okay. So, is there a clinical androgen deficiency syndrome in midlife women? The answer right now is no. We have no data to suggest there's a level that if we replete to treat symptoms. So, we need to be discussing as it relates to sexual dysfunction. We'll talk they're going to hear about that as testosterone is a therapy not a hormone replacement.

Okay, at least with the data we have today. So where would we think about testosterone having an action? I told you about its role in normal fertility and people are studying whether or not testosterone in different IVF uh regimens makes a difference. The sexual dysfunction you're going to hear it just shocked us all that it effects were independent of your testosterone level. How could that be a hormone action? but cognition, mood, bone, cardiovascular function, body composition, muscle strength and function and potential negative effects on the breast.

Where are we? Well, most of the studies to date are correlations. We haven't had a product to study. So, what we have now that we have assay measurements is just a measurement and does it correlate? So, does it correlate with low mood or depression? No. Does it correlate with cognition? No. Does it correlate with muscle strength? The answer is no. Testosterone levels were not correlated to muscle mass, strength, or performance in women in a recent meta analysis.

Now, that's not the same thing as saying would testosterone help in any of these issues. Does it affect bone loss? We know bone loss on the left slide in BMI over 30 on the right BMI less than 30 abruptly changes in the late permenopause as women lose bone. And now we're thinking more about giving estrogen for early bone loss in women. But it there's no change in testosterone. Then testosterone is not to correlate with osteoporosis risk or in very small studies improve bone density.

So, where are we? Where are the sites of testosterone action? Either dependent on conversion to estrogen or independent the brain. We're going to mostly focus today on what we know or don't know about sexual drive. The bone men have bigger bones than women. And so, there's some effect of androgens on the tbecular bone. But, as I said, there's no effect in treatment. The ovary on the bottom, we know the follicularis. There's exciting data now about the role of androgens in partuation.

There's new data about the role of androgens in insulin secretion. And there's also cardiovascular data looks very good so far. The big issue that's under active investigation is androgens in breast cancer. And historically androgens were thought to suppress estrogens in ER positive breast cancer. And that data looks pretty strong. However, if you have an ER negative breast cancer or a triple negative breast cancer, the androgen receptor stain may affect either aggressiveness of the tumor or response or resistance to treatment.

So stay tuned for that. So where could we assess low testosterone and that targets premenopausal levels? Well, orctomy if you have it early, not if you're at 70, there's a drop in T. Premature ovarian insufficiency, there's lower E and lower T. Hypopituitism, if you had a pituitary tumor and it was rected, all your hormones don't work. Lower TN adrenal insufficiency, it has a lower DHEA, that pro hormone, and hasn't been studied enough about the effects of TN.

So, additional research is needed. Additional research is needed to know the role of testosterone and these pro hormones versus estrogen on sexual dysfunction, cognition, mood, bone, cardiovascular function, body composition, muscle strength and function. Importantly, as scientists, we have to sort of ask ourselves, do we expect any action of testosterone to have a dose response like we do for estrogen or other hormones and be dependent on levels or is it going to be independent of levels?

And just like we use a birth control pill, we don't measure levels, but it's a contraceptive agent. Right? So, can we provide a testosterone in a medication that's safe to study further? And with that, I'll stop and thank you. [applause] >> Thank you, Dr. Weman. Our next speaker brings important clinical expertise in measuring and assessing testosterone levels in women, a significant and ongoing challenge in this field.

Dr. James A. Simon is a clinical professor of OBGYn at George Washington University and founder of interim medicine specialists. A certified menopause specialist, se sex sexuality counselor and clinical densidometrist. He is the only physician to have served as president of the menopause society and an award-winning educator researcher. He has led over 450 clinical trials and authored over 850 publications including more than 40 publications on women's testo testosterone.

He recently received the lifetime achievement award from the Androgen Society. So let's all welcome Dr. Simon to the podium. [applause] Ladies and gentlemen, [clears throat] members of the FDA and guests, the last time I appeared before the FDA to discuss testosterone in women was at the Proctor and Gamble Intrinsa Testosterone Patch Advisory Committee on December 2nd, 2004, nearly 22 years ago. My involvement began even further back in my first publication on testosterone and women was September 2000 in the New England Journal of Medicine.

Since then, as you heard, I've investigated and co-authored many other papers on this subject. Over this time period, our understanding of androgens in women has advanced substantially. We have accumulated evidence from randomized trials, systemic systematic reviews, consensus documents, decades of clinical experience supporting the use of physiologic testosterone levels for appropriately selected women. Yet, despite this progress, there remains no FDA approved product in the US.

What makes test this meeting today especially noteworthy especially for me is the extraordinary engagement of patients, clinicians and advocates. Their comments highlight unmet needs including the absence of female specific products, reliance on off label and compounded therapies, cost concerns, and the need for additional research. As Dr. Wearman just mentioned. Most importantly, this meeting reminds us of the real impact these symptoms have on women's lives and their relationships.

Science advances through better evidence. Medicine advances when patients help define meaningful outcomes. and regulation is strongest when scientific rigor, clinical experience, and patient voices are considered together. Today, I'm optimistic for an old guy. Optimistic because the evidence is stronger than ever. Optimistic because patients are engaged in unprecedented numbers. and optimistic because this workshop this workshop allows us to evaluate the science today rather than 22 years ago.

So thank you to the organizers for this opportunity to present at this history making event. I'd like to t turn now to my assigned topic clinical testosterone measurement. These are my disclosures. There are a lot of them as you heard. I do a lot of clinical trials still doing them. None of them affect my comments today for you. And um I hope that more and more of corporate America will continue their interest in women's health and women's sexual health.

So if you fall asleep after this slide, it'll be fine. Female testosterone concentrations challenge routine imuninoassays. The standard up to this point or reasonably up to this point. sensitive liquid chromatography with tandem mess spectrometry which has been mentioned a couple of times and we'll abbreviate because it's a mouthful as LCMS remains the reference approach although one new immunoassay recently um got certification for the CDC and approaches in fact the sensitivity and specificity of LCMS with regard to testosterone women.

A reference [snorts] standard or reference range or reference interval is method population age specific along with other method related issues. It's not synonymous with biological normality. not synonymous with biological normality, a specific diagnostic cutoff or a treatment target. I cannot say those words more strongly and they've been introduced in different forms just by Dr. Weirman. We need to contextualize age, ovarian status, sex hormone binding globulin, estrogen route of administration, timing, underlying illness, exogenous testosterone exposure among other many variables which are all materially important to the results of these assays.

So the key takeaways for my talk are use total testosterone by a validated sensitive LCMS method because low female concentrations matter but are difficult to measure require method units lower limits of quantification calibration traceability and a method specific reference range or reference intervent interval and use equally equilibrium dialysis. this when necessary to measure free testosterone, a subject I won't go into in great detail.

And don't transfer reproductive age ranges or intervals to natural or surgically menopausal without quantification and calibration. And again, there's no serum testosterone thresh threshold that diagnoses HSDD or a universal female androgen, i.e. testosterone deficiency syndrome. um repeating what Dr. Weman just mentioned. So why testosterone measurements is so difficult? Well, basically it's because women have low concentrations of testosterone.

In fact, low enough to make iminoassay unreliable. structurally related steroids, other androgens, metabolites of those androgens, degradation products of those androgens, other interfering substances, drugs, etc., etc., all interfere with imuninoassay. And so it's very important to quantify using a reliable method including the time of day measure is important. How often do we assay testosterone or blood in patients where we require the actual same time of day for sampling?

Go get your testosterone measured. He said we don't say at 0800 tomorrow on the second day of your menstrual cycle get your testosterone measured. These are all important. Historically, we've changed from bioassays. I did millions of them. Cutting up rats to find how big or little how much their prostates weighed or their prostates didn't weigh in response to some treatment is neither safe, efficacious, coste effective, etc.

Amunoasses evolved with extraction and chromatography. And I did a lot of that, too. Packing columns. Any of you who have packed columns love that event. In fact, they closed a room where I did my fellowship because it was radioactive and we had to lock it up with bricks of lead and it could never be used again. So we've come to gas chromatography or liquid chromatography coupled with mass spectrometry as the best methods for measuring testosterone in women.

And I should say parenthetically, Proctor and Gamble anticipating that their patch would be approved spent a lot of money seeding assays by LCMS in the various laboratories anticipated to be measuring testosterone in women once their patch was approved. This summarizes very briefly the advantages and pitfalls of immuninoassays, but they're very well demonstrated here as to why they shouldn't be used in post-menopausal women.

Post-menopausal women illustrated here in the open circles at the [clears throat] low end of the range as compared to men with the dark circles. You can see that the men are very uniform in their measurements across a wide spectrum of measured concentrations. And at the lower end of normal, the women's assays are all over the damn place. You can't make any judgments when used with the statement all over the damn place.

So LCMS is the workflow standard. It is not easy to do. And this picture of a [clears throat] machine that measures it illustrates one of the disadvantages and that is cost and throughput. So here are the cost and throughput issues comparing LCMS in the right hand column and automated imuninoassay in the lefth hand column. I'll leave you to read these yourselves, but basically it's quick and dirty to do iminoassay. It's more expensive and slower to do LCMS.

These were uh some costs for comparison. This is what was told to me. We let's call these the retail costs. I never buy retail and neither does your insurance company. And so these would be expected to be dramatically lower in a realworld setting where insurance was paying for uh these assays. Something that would come along with an FDA approved product presumably. So testosterone is the preferred firstline analyte measurement.

It's what Ishwish put in their consensus agreement, worldwide consensus agreement on how to use testosterone measurements. Uh free testosterone is available, can only be done in women by equilibrium dialysis. It too is highly variable and quite expensive. Let's talk about ranges. Here's where we get into real thin ice or quicksand. A reference range or reference interval is a statistical interval that specifies a range encompassing about 95% of the population from the upper 95th to the lower fifth of a healthy range in a particular set of individuals.

Remember that set is chosen for a particular endpoint. can't just lump a bunch of people together and say it's normal. So, we need more precise measurements on specific populations in order to define anything approaching a normal not reference range. They must be constructed deliberately including a lot of variables. I've mentioned them but you can read them again here. Presumably for this development of a testosterone product for women, we want normal women of a particular age with particular set of underlying medications etc to get what's normal in that range.

And a different set of data was shown to you, but this is the same kind of information that Dr. Dr. Weirman just showed that testosterone assays go down with age, but across the menopause and with aging, they're relatively stable. And that increase that Dr. Wearman mentioned, I don't think anybody understands that really. Maybe that's the old lady menopausal zest for sex. I don't know. Here are some ranges of testosterone done by different individuals under different circumstances using different cohorts etc.

And you can see that they are different but largely overlapping. The one that I like is the second row and that's women 20 to 80. and it shows quite a large range of what's normal for this large cohort of individuals. Dr. Weman set me up perfectly to note that naturally menopausal women are hormonally very different from surgically menopausal women. And the data in the literature on the efficacy of testosterone for sex is much more easily demonstrated in those surgically menopausal women. probably because the delta of effect given a diff a specific um application is much greater than in those normal women those u normally naturally menopausal women.

So I'm going to conclude here very briefly by showing that this range is highly variable and changes with age and time of day. I had two discuss two discussion questions that I was posed. Are we doing them now? No. Okay. So, um, I'll skip over those and wait until we have a chime to do them, but conclude with measure well, if you measure at all. Female range measurements require validated low-end performance, both precision and accuracy.

LCMS remains the benchmark. CDcertified amuninoassays must be judged individually and we may have opportunity to see some come to market that approach the safety the efficacy um both precision and accuracy of LCMS. Compare correctly. Reference intervals reference ranges describe assay specific populations. They're not universal. They are not normal ranges. They are not diagnostic thresholds. And they are not therapeutic targets.

And we need to respect the context in an individual in an individual a person as her own control as it relates to her age, ovarian status, SHPG, estradile exposure, including route of administration, specimen timing and exogenous testosterone. These all can mess with how we interpret a specific laboratory level. Thank you. [applause] Thank you Dr. Simon. We will now move into session two on clinical guidelines, practice and perspectives for testosterone use in menopausal women.

Our first speaker in this session is Dr. Rajita Patil, a board-certified OBGYn, associate clinical professor and complex family planning subsp specialist. She's the founder and director of UCLA's comprehensive menopause program. She leads clinical, educational and system level innovation to advance sca to advance scalable, evidence-based and whole person menopause care. And we welcome Dr. Patel to the stage. [applause] >> All right.

Well, good morning. [snorts] Thank you for giving me the opportunity to speak today. I will be reviewing the clinical guidelines for testosterone therapy in menopausal women. [clears throat] I have no disclosures. So today I will be reviewing the global consensus position statement of 2019 on testosterone therapy for women including those including who developed the recommendations how the evidence was systematically evaluated and what conclusions were reached regarding safety and efficacy.

I will then review the International Society for the Study of Women's Sexual Health or IShwISH clinical practice guideline which provides practical recommendations for the use of systemic testosterone therapy in women with hypoactive sexual desire disorder or HSDD. And finally, I will discuss the critical evidence gaps that remain, particularly areas that may inform future clinical trials, product development, and future regulatory considerations.

Interest in testosterone therapy for women continues to grow. Many patients seek testosterone treatment hoping to improve sexual desire, energy, mood, cognitive function, muscle strength, and overall well-being. At the same time, an increasing number of clinicians are prescribing testosterone off label because there is no FDA approved product for women in the US. For many years, clinicians have been prescribing testosterone using lower dosages of FDA approved male products or compounded formulations despite uncertainty regarding benefits, risks, and appropriate indications.

The 2019 consensus global consensus guideline position statement was developed in response to this clinical reality. The writing panel included internationally recognized experts, some of which are here today in menopause, endocrinology, sexual medicine, gynecology, with authors represented from major professional organizations all around the world, including North America, Europe, Australia, and Latin America. The goal was to establish evidence-based guidance regarding which women would benefit from testosterone therapy, which indications were not supported by the evidence, where the uncertainty remains, and which prescribing practices might carry potential risks.

Importantly, the final document was not simply the opinion of a small group of experts. It was endorsed by numerous leading organizations all over the world including the international menopause society, the endocrine society, Ishwish, international society for sexual medicine, the menopause society, the European menopause and anthropos society, American college of obgyn and several additional international societies um endorse this guideline.

As a result, the 2019 global consensus position statement has become the most comprehensive and broadly endorsed evidence-based guidance on testosterone therapy for women and effectively supersedes previous guidance statements. So, how was this evidence reviewed? The task force first identified key clinical questions that needed to be addressed and commissioned a systematic review and metaanalyses of testosterone therapy in women.

The meta analyses focus on blinded placeboc controlled or comparator controlled randomized control trials of at least 12 weeks duration and included over 8,000 patients. This ensured that recommendations were grounded in the highest available evidence. Multiple domains were systematically evaluated including sexual function, mood, cognition, overall well-being, muscularkeeletal outcomes, cardiovascular outcomes, breast health, and adverse events.

The resulting evidence was evaluated using formal levels of evidence and grades of recommendation. Level one evidence reflected findings derived from RCT data and meta analyses while recommendation grades reflected the strength at which clinicians should act on this evidence with grade A being the strongest recommendation. Importantly, consens consensus expert opinion was used when evidence was limited or when interpretation of this available evidence was necessary.

So we will go over the recommendations and results from this task force. This first slide really is much of what was just covered by Dr. Simon and Dr. Wearman. So I'm going to breeze through this a bit, but the evidence found that testosterone concentrations decline across the reproductive years. However, there is no abrupt decline in these concentrations during the menopause transition itself. Rather, that the levels gradually decline with age and generally remain detectable and may increase in older age.

The panel also concluded that testosterone measurement in women is challenging and that the expert opinion was that direct assays can be used although massspec is the gold standard and that total testosterone rather than free testosterone is the preferred biioarker for assessing testosterone exposure. There was an expert opinion that testo testosterone measurements should be primarily used to exclude women with unexpectedly elevated baseline levels and to ensure treatment doses do not result in superphysiologic concentrations.

Importantly, the available evidence demonstrated only weak and inconsistent associations between circulating testosterone levels and measures of sexual function. The consensus panel also concluded that there was no testosterone cutoff value that differentiated women with and without sexual dysfunction and that there was no biochemical criteria for diagnosing androgen deficiency in women. A low serum testosterone level does not establish a diagnosis of sexual dysfunction, nor does it predict the severity of the sexual symptoms.

Ultimately, the diagnosis of sexual dysfunction remains a clinical diagnosis and not a laboratory one. After reviewing all the available RCT trial data, I'm sorry, I'm going to go back one. Um, after reviewing all the available RCT evidence, the panel reached one major conclusion. [snorts] HSDD, hypoactive sexual desire disorder, was the only current evidence-based indication for testosterone therapy in women. This indication received the highest level of support in the entire guideline with level one evidence and gradea recommendation.

These conclusions were based on RCT data and a large meta analyses of over 8,000 naturally and surgically menopausal women. Across the studies, testosterone was associated with improvements in sexual desire with an average increase of approximately one additional satisfying sexual month event a month. And in addition, there was they were found to have an increased um arousal, orgasmic function, pleasure, responsiveness, and satisfying sexual experiences while also reducing sexual distress and sexual concerns.

The panel emphasized that fe female sexual dysfunction is not one single condition or entity. These findings should not be automatically generalized to other forms of female sexual dysfunction because the majority of the studies specifically enrolled women with HSDD and that HSDD is distinct from other sexual dysfunction types like female sexual arousal disorder, orgasmic disorders and genital urinary pelvic pain disorders.

And because of that distinction, accurate diagnosis is essential before considering testosterone therapy. Also, these findings should not automatically be generalized beyond post-menopausal women. Evidence in premenopausal women remains insufficient and while data in pmenopausal women and women in the late reproductive stage are limited. And finally, primary ovarian insufficiency or early menopause deserve a special consideration because HSDD is more prevalent in this population particularly after surgical menopause with abrupt loss of ovarian androgen production.

However, recommendations for this population was is really extrapolated from the post-menopausal HSD literature rather than dedicated clinical trials in this population. If the testosterone is prescribed, the goal of the therapy is not to maximize testosterone levels, but rather to restore testosterone exposure to the physiologic premenopausal female range, which is then found to result in improvement in sexual desire, sexual function, and associated distress.

The panel emphasized that testosterone should not be viewed as a standalone treatment. HSDD is fundamentally a biocschosocial condition and treatment should occur within a multimodal framework that addresses these factors. Importantly, identification of these factors should occur before the treatment is isol is initiated and the management of these of these modifiable contributors should really occur alongside testosterone therapy when used.

The next section addresses testosterone preparations. One of the major challenges in this field is that there is no FDA approved version for women. As a result, the panel identified an un a significant unmet need for female specific formulations capable of delivering physiologic testosterone concentrations. In the absence of such products, the consensus panel concluded that approximately appropriately dosed male transermal formulations that are FDA approved may be used off label provided that the serum concentrations remain within the physiologic range of a woman.

The next section highlights the recommendations that this does not apply to. So the panel specifically advised against preparations that result in superphysiologic testosterone exposure including injectables and pellets. These products were generally not represented in the clinical trial data and did not support efficacy and may expose women to unnecessarily high levels of androgens. Similarly, compounded testosterone formulations were not recommended because of the concerns regarding consistency, quality control, and dosing reliability.

The exception would be in situations in which there was no approved alternative and that the compounded product can meet the appropriate quality and manufacturing standards. While the global consensus statement established the post-menopausal HSDD is the only evidence-based indication for testosterone therapy, the Ishwish clinical practice guidelines really provide practical recommendations for how clinicians should diagnose, prescribe, counsel, and monitor treatment.

Oh, I'm sorry. Okay. [cough] [clears throat] The guideline recommends considering testosterone therapy for post-menopausal women with HSD. Importantly, HSDD is not simply just low libido. The diagnosis results with persistent low sexual desire associated with clinically meaningful personal distress. And next is the what treatment should actually look like. Because no FDA approved product exists for women in the US, the guideline recommends using the off label men's version, but at approximately onetenth of the male dose with the goal of maintaining testosterone concentrations within the physiologic female range, premenopausal female range.

The guideline also strongly emphasizes informed consent. Patients should understand that treatment is being prescribed off label and that there is limited long-term data. The counseling section highlights several practical considerations. Transermal preparations are preferred because they most closely mimic physiologic testosterone exposure and avoid many concerns associated with oral therapy. Patients should also be counseledled regard regarding the appropriate application and the risk of transference to others.

The next section addresses monitoring. Total testosterone is measured before t before treatment to establish the baseline exposure and the repeated after initiation three to six weeks later to ensure that concentrations remain within the physiologic female range. The primary assessment of efficacy is clinical and not based on a specific lab value. Efficacy is proven when patients subjective experience results in improvement in sexual function and a reduction in sexual distress.

Clinical improvement often begins uh 4 to 8 weeks within 4 to 8 weeks with the maximum effect typically noted at 12 weeks. If meaningful clinical benefit has not occurred after 6 months, the guideline recommends discontinuing therapy and reassessing for other causes of symptoms. Conversely, women who experience benefit may continue therapy with ongoing monitoring and periodic assessment. So outside of sexual dysfunction, I will now review the evidence around the other domains as it relates to testosterone use.

Starting with general well-being and mood, the evidence reviewed did not demonstrate meaningful benefit. For general well-being, the randomized control trials showed no consistent improvement leading to a level one evidence gradea conclusion that testosterone should not be prescribed for this purpose. Similarly, placebo control trials evaluating depressive symptoms failed to demonstrate benefit. And these findings were reinforced in the meta analysis.

As a result, the panel concluded that testosterone should not be used for treatment of depressed mood. Moving to cognition, the evidence was consist considerably more limited. Few small studies have suggested possible improvements in specific cognitive measures while others showed no effect. Overall, the data was just judged to be insufficient and inconclusive. Therefore, testosterone cannot be currently recommended to enhance cognitive performance, prevent cognitive decline, or prevent dementia.

For cardiovascular outcomes, one clear finding was that oral testosterone is associated with unfavorable lipid effects and therefore not recommended. In contrast, physiologic transdermal formulations did not demonstrate significant adverse effects on lipid parameters, blood pressure, glucose, hemogloins, A1C in the available RCT data. However, it is critical to interpret these findings with the within the limitations of the evidence base.

Most RCT data was relatively short in duration, excluded women at high or elevated cardiovascular risk, and frequently included women receiving concurrent estrogen therapy. As a result, these findings cannot be generalized to the higher risk populations or for long-term treatment. Additionally, while no statistically significant increase in veno venus thrombolic events was observed, there was a non-significant trend towards increased risk and the contribution of concurrent estrogen use remains uncertain.

And finally, for major cardiovascular outcomes, including heart attack, MI, stroke, cardiovascular mortality, the panel concluded that the available data was just insufficient to draw meaningful conclusions. Continuing across organ systems, the consensus panel also evaluated whether testosterone provides benefits for muscoskeleletal health. Looking first at bone health, the available RCT data did not demonstrate improvements in bone mineral density at the spine, hip, or femoral neck.

This conclusion received a level one evidence designation with a gradea recommendation. There was no studies specifically evaluating women with osteoporosis and there's no evidence supporting the use of testosterone for fracture prevention. Similarly, despite common claims regarding improvements in muscle mass, strength, body composition, and physical performance, the overall evidence was not supportive. A few studies reported favorable changes in lean body mass and muscle strength.

However, these studies were generally small. Many included women receiving concurrent estrogen therapy, and findings were not consistently reproduced across the broader evidence base. Importantly, the global consensus statement found no consistent improvement in lean body mass, body fat or muscle function. So, as a result, the panel concluded that testosterone should not be prescribed with the expectation of improving muscularkeeletal health.

The second half of this slide addresses breast outcomes and cancer risk. The available RCT data did not demonstrate an increase in mamographic breast density, which is reassuring because increased breast density is associated with breast cancer risk. Similarly, short-term RCT data has not demonstrated an increased risk in breast cancer with physiologic testosterone therapy. However, the panel emphasized that long-term data remains insufficient and therefore we cannot make any long-term definitive conclusions around breast cancer risk.

The evidence does not support the use of testosterone to prevent breast cancer. And finally, women with a prior history of hormone sensitive breast cancer deserve special attention and consideration. Most RCT data excluded these women, meaning that that there is very limited direct evidence regarding efficacy and safety in this population. For that reason, both the global consensus statement and the issuish clinical guidelines remend recommend caution when considering testosterone therapy in women with hormone sensitive breast cancer histories.

The panel also evaluated safety data supporting testosterone therapy in women, looking first at androgenic adverse effects. Physiologic testosterone therapy was associated with modest increase in acne and facial and body hair growth. Importantly, the RCT data did not demonstrate increased rates of alopecia, clitoromegaly, or voice deepening when testosterone was maintained in the physiologic range. And then across the RCT data and the meta analyses, no significant increase in serious adverse events was observed during the study follow-up among women receiving physiologic therapy.

The finding, this finding received a level a sorry, a level one evidence designation. There is a 4-year open level extension study involving 10,00 women treated with transermal testosterone patch that did not identify a signal for increased serious adverse outcomes. Of course, the same limitations discussed previously apply to the overall safety literature, short short trial durations, and under representation of high-risisk populations.

Because DHEA is a precursor to testosterone, the panel also evaluated DHEA therapy. And although early studies suggested possible benefits, larger trials and subsequent meta analysis failed to demonstrate any meaningful improvement in sexual desire and overall sexual function. Therefore, a systemic DHEA is not recommended for the treatment of HSDD. This is distinguished and separate from vaginal DHEA. Vaginal DHEA is an approved treatment for genital urinary syndrome of menopause, but not recommended for the treatment of HSDD.

So after reviewing the global consensus guidelines, several important evidence gaps remain. But perhaps the most important is the continued absence of an FDA approved testosterone formulation specifically designed for women. Clinicians who prescribe must adapt male products or rely on compounded formulations. And there's this brings in a lot of variability and also an inability to really maintain that physiologic concentration.

And as a result, there's a issue with prescribing and patients receiving proper dosed therapy. And in many ways, this issue sits at the center of the several evidence gaps that are on this slide. The variability of the formulations and the dosing makes it really difficult to define optimal treatment, compare outcomes across studies, and generate robust long-term safety data. Although short-term safety data are generally reassuring, we need more long-term data, particularly around cardiovascular outcomes, thrombomolic events, breast health, our future studies need to also include broader populations that better reflect real world practice.

Additional research is needed in pmenopausal women, early premature menopause, and non-sexual outcomes where current evidence remains limited or inconclusive. And for sexual function research, we need more research on improved outcome measures focused on decreasing distress levels and improving quality of life rather than focusing on satisfying sexual events. So in conclusion, I want to leave you with this. The major unmet need is not just simply about testosterone prescribing and more of it, but access to regulated female specific formulations capable of delivering physiologic exposure and generating the evidence necessary to fully and more comprehensively characterize the benefit and the risk short-term, long-term, and across body systems.

Thank you. [applause] Thank you, Dr. Patel. Next, Dr. Pelen Bau will take us through the benefit, risk, and dosing considerations for testosterone therapy. Dr. Bau is the center director of the women's comprehensive health and research center and professor of obgyn and reproductive biology. She has been at the Cleveland Clinic since 1998. Her practice is a referral resource for the hormonal needs of women with complex medical histories.

Her areas of expertise include menopause, medically complex contraception, osteoporosis, and sexual health. Let's welcome Dr. Bur to the podium. [applause] So, I hope your eyes are able to separate me from the background. Note to self, different suit color next time, but I come bearing gifts. I have showand tell items. All right. Um, so I was asked to talk about real world dosing and the implications of that for risk benefit conversations.

I have no conflicts of interest or financial disclosures. So, as you all heard, we do not have an approved product yet, but a lot of women are getting their hands on testosterone. Okay? And this is really old data. This is uh an estimate from 2009. So, we know that the testosterone prescribing has increased and especially in the last 5 years, there's almost a tripling of prescriptions. So, patients are getting their hands on it.

How are they getting on it? And what are they getting? Right? So the typical patient scenario in the clinic, 55-year-old woman distressing sexual desire. She's failed the typical behavioral interventions that we would start with. She understands the risks and benefits and desires treatment. And the science says she may be an appropriate candidate. So how do we actually prescribe it? So in my caveman mind, I think of things in three logistical hurdles.

Okay. The first is if I'm following the rules and doing what the guidelines say, use the FDA approved treatment, it's a prescriber problem because I am essentially giving a 10 to 20 month uh prescription to that patient of testosterone. If that patient forgets to follow up, I I just feel uneasy uh about that, you know, without having that touchpoint followup. If I go rogue and decide to go compounding, well, then I just can't always be sure about the purity of the product.

Okay? And then and when I say go rogue, do I compound? Yes, I do. Despite the fact that the guidelines say don't do it. Um so if I decide to write the prescription, I also have legal issues because it's a controlled substance. So I'm going to break all three of these down separately. So the first dilemma, following the rules, the FDA approved treatment. What we are being asked to do is take a prescription that's suited for somebody with testicles and somehow adapt it to somebody with ovaries.

Okay. Um, and so if we're thinking about the key differences between a female versus a male formula. So obviously we have none approved in the US, but there was a lot of studies showing efficacy and safety of the 300 microgram patch that was approved in Europe for surg but unfortunately it was a very narrow indication surgical menopause even though we knew it could be used in natural menopause. So you know didn't get widespread use subsequently withdrawn and you've heard a lot about Australia today.

Um they do have a cream in Australia and several other countries and it's because Australia has been doing some leading research uh for multiple decades in this arena. So they have a 1% cream and the male products we have uh in the US at least 12 brand names and six delivery routes. So that's what we need to use and most of the time we're using the 1% gel because it's the easiest to work with. So the math wasn't mathing okay for a while I was when I first started doing this I said okay a 300 microgram patch is what we always see in the literature you know I'm using one/10enth of a tube a tube looks like this packet looks like this this volume amount um so that's 50 milligrams in here so one/10enth is 5 milligrams that's 5,000 micrograms how does that even make sense well it's typically of these trans ddermals roughly one/tenth is being absorbed it varies but roughly one/10enth.

So that makes this about 500 micrograms. Then typical a little bit more than the patch. The one thing to know about the male formulations is that they have these enhancement um absorption enhancers or boosters which does change how well it's being absorbed. Um and in fact in the UK there's been some reports of you know people the math is tough. So sometimes it's misdosing and overshooting it. So how do we do this? How do we do this safely?

And I highlight 120th because updated guidelines will come out suggesting that maybe 120th is a better starting dose. All right. So, if we're going to purchase a box of these, because most pharmacists will not break these down, you have to box buy the whole box. So, it's about 30 tubes. So, each of these uh tubes should last 10 days or 20 days. Okay. Um and then often times we're using it in a syringe. So, I don't have a pointer, but that uh black cap there, patients do have to cap it when they're using the syringe because it's alcohol- based.

And if it um evaporates, it's the volume is going to change, the concentration is going to change. So, some of the challenges uh if you you have to make sure that the pharmacist is giving the what looks like a toothpaste tube, not what looks like a ketchup packet. It is very hard to get this into this without getting it everywhere. Okay. Um but pharmacists I've gotten multiple calls back from the pharmacist saying I don't know if it's a tube or a packet and I'm not willing to open the box.

Um the cost, you know, when you're asking the patient for pay all of this out of pocket, that is a lot of cost upfront u might not be easy. And then um air bubbles, you know, very very high-tech, but really if you have when you're measuring in this 5 cc syringe, right? So if you're going to fill this up and you're going to have a 10day supply, you're going to do, you know, half a milliliter each day. If you have a gi if you're going to do uh 20 120th, it's going a quarter of the way between those big numbers.

It is hard to do. And if you have a air bubble, it's patients get frustrated. They're like, um, I'm not sure that I'm doing it right. Um, and then in general, most patients are going to want it in a p area that's not going to grow hair. So, oftentimes we're just for ease, we're using it on the thigh or the calf, so it's an area that they can shave it. So to make it easy, a lot of clinicians will say just use a P-sized amount.

And a P-sized amount actually is about 0.25 milliliters, which is about, you know, 250 micrograms. It's not for of testosterone absorption. It sounds about right. Um but not every, you know, people get hurried and they start with measuring P size and it, you know, they start doing big globs later and then you sometimes get some variability. Um, we can go back to our syringe. But as I mentioned, if you're if a patient is needing 120th, it's really hard to work with this.

So, people will say, "Why don't you just fill up this tiny little 1 cc syringe so you can do a quarter each day?" Good luck. I mean, I know I'm in menopause and my eyes are going, but it's like hard to get this into this little thing. Okay. Um, and so of something that works well is measuring spoons. Now, when I went to medical school in the 1990s, I didn't think I would be doing cutting edge medical care with measuring spoon units.

But it turns out they are pretty standardized. In a pinch is about 1/16th of a teaspoon, which is roughly 3 milligrams of testosterone. And people can adjust down to a smidgen or adjust up to a dash. Okay. Um I think we can do better though, right? Um so adding to the complexity, that's the amount that you're going to give. you know, the patches that have been studied, skin irritation is a little bit more likely with testosterone patches, but the advantage is that you're not transferring to others.

With the creams, the female creams in Australia and other places do not have skin boosters, which is good. It's going to be a little bit more um reliable in terms of um female dosing. So when we think about the formulations, the 5 mg of approved cream in Australia or the UK is roughly 2.5 milligrams of the male gel for us. Um but this is for the approved products where we understand the absorption uh criteria. So this does not apply to compounding which we'll talk about which can be a lot of variation.

And then just remember that these absorption characteristics are studied in different body parts. For men, it's in often times the upper limb, the axilla or the armpits. And you know, most women aren't going to want to put uh you know, testosterone here hair here where they can grow hair. Um and also noting that under the armpit, you can have double the absorption. And even the absorption between the male FDA products is not bioequivalent.

And I think this is a good graph to decide to do a menopause test because if you're having a hard time seeing the gray lines, you're probably at menopause. Um, but what this shows basically this is they took a male testosterone gel used in 24 post-menopausal women and they got every two-hour blood draws. And what they were trying to understand is what is the max concentration? When can we check levels? Um, how are people absorbing this?

Right? And when you look at the median number, so the middle of the road range in that purple distinct line there, you say, "Oh, that's pretty good. Nice and steady." But the real answer is when you look at those faint gray lines, those are every individual in the study. And as you can see, uh, you know, I mean, I don't have the pointer, but what some people are peing really high within two hours and then it's coming down.

Other people are peaking at 10 hours. Other people are not peaking at all. So, how do we measure this? I mean, we need a reliable way that we can study and measure and follow. So, if I'm going to summarize doing the right thing with the FDA approved product, the dilemmas, we have formulation variability, different absorption rates, we're using it in unstudied body locations for absorption. There's boosters versus not.

Um, and then it's hard to dispense. So FDA approval in my opinion would help standardize delivery methods to allow best study of body locations, minimizing chance of transfer to your pet or uh partner, how to follow the levels, and anytime you take the math out of it, you take the chance of error out of it, okay? Because nobody likes math, let's be honest. All right, so dilemma number two, compounded prescription. So it's compounding of hormones has been discouraged by every medical society since 2011.

That's fact. Okay, what is the concern? Because, you know, you're introducing an extra layer of human error. So, I mentioned I do compounds sometimes. It's not what I like to go to. I want to stick to FDA approved products whenever possible, but I only work with one compounder um because it's somebody I can call I have on speed dial, you know, and so you run the risk of super physiologic dosing, not getting enough. Um the problems are related to compounding practice, not to the testosterone product and that we don't really understand the full risks and benefits because most uh adverse events are never reported.

And the reason the guidelines say uh avoid injections and pellets is because you know if you screw up something with a trans ddermal, it's easy. It's not that big of a deal. Your level goes up a little bit. You just pull back on the cream. Um if you have a pellet that's going to last 9 months and you were you hit super physiologic level and you're feeling miserable with roid rage and other concerns then it's hard to undo and we just have to support them while they stick it out.

So this lack of standardization makes it hard to the patients are coming in saying what's the long-term pros and cons for this and it's hard to give them reliable evidence if there's no standardization. All right. So, if you do compounding right though, you can get an idea of how much people are taking. So, if a prescription says it's 1% cream, apply two clicks, that tells me that they're getting roughly 5 milligrams a day.

So, if you hate the math, this is your um slide to go ahead and daydream about something else. But I'll tell you, none of us in medical school, nursing school are taught these pharmacy basics. So, if you want to do this prescribing, you have to go learn the stuff on your own. And a lot of times we will use a meter dose dispenser. And one click is about a quarter gram. And some interesting things like if you've been traveling it'll explode.

Okay. Um so you got to clean it off. And then you got to tap tap to get the air bubbles out. And one click got to tap to make sure you get it. But that's about a quarter of a gram. That's what we're talking about. Okay. And if you do this four clicks, two three four that's 10 milligrams of testosterone. Okay. Um, so what does that mean? So when something is 1% that means there's 10 milligram of actual testosterone product in one gram of the cream vehicle.

Okay? And so four clicks of that would be um 10 milligrams. What I see in practice, people come to me for a second opinion or something and they say the prescription has written as testosterone cream fingertip unit as directed. I have no idea what that patient is getting and oftentimes that's prescribed directly from a pharmacist without even a clinician. I don't know if that's legal or not. Must be people are doing it but I do see it.

So um the vehicle also matters because when it's an FDA approved product we have an understanding of how the skin is functioning as a reservoir, how it's absorbing. You know depending on what you're compounding it can make a difference. And actually some products it'll layer out where you have you know nothing nothing for a few weeks and then a high concentration at the end. Okay. Um and then we know that compounding has been fraught with error because it's hard.

It's expensive to do things right. Right. So there can be significant dose variability anywhere between batch testing has showed between no testosterone up or between nothing up to fivefold. The labeled potency recalls um due to mold insects and then also industrial-grade products that has actually one patient with a hyper sensitivity reaction that was um deadly. So does that happen? Typically no but that's why we need standardization.

So the clinical challenges if I have to summarize them significant formulation variability lack of quality standards if you're uh compounding and it's you're overshooting it and you inject it that's going to be a problem uh for the patient and um we need to be able to report better on the side effects and there's huge variation in cost so compounding practices I mean I can compound with my compounder for 15 bucks I know people that are paying $3,000 every time they get there.

So the FDA approval would I at least level the playing field and set clear cost expectations too and standardize delivery methods and then the legality of it. So this is a controlled substance which means that if a patient if a clinician doesn't feel comfortable because it's not FDA approved and now it's a controlled substance understandably they are going to be nervous about it which creates huge backlogs for the small percentage of clinicians that feel comfortable doing this and this backlog is not an exaggeration this is much smaller number than most of most of the people here their weight list right and it's very stressful for patient for clinicians and very frustrating for patients so what we do is we try to take care of people beyond our neighborhoods virtually.

But that's a problem because a controlled substance even if it's an established patients you've seen in the office once they go back to their home state unless I'm licensed in that state I am not allowed to send a controlled substance there. Okay? And pharmacists technically they're not really supposed to prescribe more than a six-month supply. So, some will give push back because if you're doing following the rules and doing the guidelines stated FDA approved mail product, again, it's a 10 to 20 month supply depending on how you're dosing it.

Um, so I would ask the FDA to consider lifting the controlled uh status on testosterone. I think it will really help. [applause] Thank you. Yes, thank you. And we're not covering today, but we often times compound it to a much lower concentration to the 0.1% which is for volvar use for volvar pain syndromes works beautifully and that's controlled substance too. Um and that doesn't even absorb. So in summary ahead of time too.

So in summary uh testosterone is a safe and effective option for many women. Without FDA approval the prescribing does get complicated. a lot of clicks, a lot of math, and then the lack of approval leads to delays and errors in care. And most importantly, I would like to thank the FDA for caring about this to bring us all together today. [applause] Thank you, Dr. Bau. We'll now hear from another expert clinician working directly with patients in the field of sexual medicine to provide a clinician perspective.

Dr. Rachel Rubin is a board-certified urologist with fellowship training in sexual medicine and founder of the patient centered sexual health practices in Washington DC and Los Angeles where she provides comprehensive care for conditions including arousal, libido, pelvic pain um and menopause. She [snorts] serves as an assistant clinical professor of urology at Georgetown University and has held leadership roles with Ishwish, a contributing advocate for the 2025 AUA guidelines for um GSM and founded the uh sexual medicine research team to advance sexual health research.

Now, let's welcome um Dr. Rubin to the podium. [applause] >> Thank you. Thank you so much. Good morning everybody. Thank you for having me at this historic meeting. I'm Dr. Rachel Rubin. Testosterone was first isolated in 1935, and we learned quickly that ovaries produce estrogen, progesterone, and testosterone. It took less than a decade for the FDA to approve its first male testosterone product. Nine decades later, we have a global consensus on testosterone use in women.

We are here today to get a priority review pathway for a female dose testosterone product. Early in my career as a urologist, soon after I finished my fellowship training in sexual medicine, a 52-year-old woman came to see me. I'll never forget her. She came to see me because she was having severe pain with sex. And even though that was the reason she came, our conversation revealed that she had hot flashes, poor sleep, osteopenia, low libido, and many other common symptoms that come with the hormonal castration of menopause.

Step by step, I recommended evidence-based treatments to her. She used vaginal hormones, in this case vaginal DHEA, to cure her painful sex and also prevent urinary tract infections. We prescribe systemic estrogen patches and micronized progesterone to treat her hot flashes and also prevent bone fractures and help her sleep. All FDA approved products that are so effective and so helpful at improving quality of life that they are currently in short supply because of increasing demand. and that demand is not going away.

She was feeling much better, but something was still missing. So, we talked more and made a shared decision to add off label testosterone therapy, a product FDA approved for men, but at doses appropriate for her. Estrogen, progesterone, and testosterone. All hormones her ovary once made plenty of, but only one that isn't FDA approved for her. And while her story was similar to the ones I have heard from patients thousands of times, what she said has stuck with me to this day.

After she had been using the testosterone for about four to five months, she sat across from me with a giant smile on her face and she said, "Dr. Ruben, I came to see you for pain with sex." And yeah, yeah, it doesn't hurt anymore, but I didn't think I would like it again. I didn't think I would want it again. I didn't ask you for that. She didn't ask me for that because she didn't know she could. This is not just about sex or sexual medicine.

It's about the dignity of realizing that your quality of life matters and should matter to your medical team that's caring for you. I am often asked why I became a urologist. I typically crack a joke and say, "Isn't it every girl's dream to be a penis doctor?" [laughter] While women urologists make up the doctors with the best sense of humor, we actually are only 11% of practicing urologists. But women make up 50% of our nation's urinary tracts and sexual partners.

When I teach my colleagues, I like to remind them that all urologists are board certified to take care of men and women. It's just that our research, education, and training seem to treat women like a rare disease. So why are we here today at all? It's actually a funny story. It's because of my amazing mentors and colleagues in the men's urology space that we have the joy of being here with you today for this historic meeting.

You see, the FDA had a roundt all about men's testosterone in December of 2025. This panel was important and they had significant asks for FDA, including take away the controlled substance designation for testosterone. Please make secondary hypogonatism a preer an approved indication and change the label to reflect new safety data. But when the public was asked to comment, guess what happened? More than 82% of the comments were about female testosterone. 82%.

Men weren't the ones doing most of the advocating. Why? Because look how many FDA approved products we already have just for men. Pumps, packets, long acting injectables, gels, pills. The next slide. Short acting injectables, pellets. I might have even forgotten a few. And that's not counting the many non-approved compounded products being used by the masses. Most people don't realize that the vast majority of male low tea prescribing is for off label purposes, just like I do every single day for my female patients.

Low libido, sexual complaints, fatigue, depression, mood changes combined with low testosterone. The difference, well, isn't it obvious? Legitimacy. FDA approved products take this topic from the fringe snake oil back alleys to the respected scientific rigor it rightly deserves and already has. This is not an unstudied new molecule with unknown biologic effects. Testosterone is a naturally occurring substance in all bodies.

Inside the human body, you need testosterone to form estrogen. Yet, it is regulated by the DEA and it is only approved for men. It is time for regulations to catch up to the science. Today I was asked to give my clinical experience and talk about some of the emerging research in this space. But without an FDA approved product, there are several areas where we have extreme challenges providing this care as well as educating our colleagues.

I tell my patients this every day. This feels overwhelming. So many logistical hurdles. But it doesn't have to be this hard. Let's start with legitimacy. You need to know what I see every day in my office. When we add testosterone, often after starting patients first on estrogen, progesterone, and vaginal hormones to some degree when appropriate for them, we hear them say the magic words. I finally feel like myself. It doesn't always happen right away.

Sometimes it takes a few months, but eventually something just clicks and their quality of life improves. It isn't just their libido. Some women tell me their mood is better, some have more energy, some feel stronger, and yes, we hear a lot about improved arousal and orgasm, just like the research shows. I had a patient who started hormone therapy in her mid-50s. At first, she objected to trying hormones because she read in the news and it scared she what she read in the news scared her.

After multiple long discussions about the evidence, the benefits, the side effects, she decided to try it. Now, she loudly credits the energy that she felt from testosterone as to why she decided to enroll in law school. Every quarter, she would send me her gradepoint average with a note that said, "Thanks to the hormones, I have the energy to keep up with my 22-year-old classmates. She graduated at the top of her law school class and is now practicing law in her early 60s.

But so many women aren't getting the chance to feel that way because the legitimacy afforded by an FDA stamp of approval matters in medicine. A fasttracked FDA pathway to a product helps us legitimize and give dignity to our patients. Beyond legitimacy, let's talk about how an FDA approved testosterone for women also makes it easier for doctors to prescribe it. In March, I was teaching testosterone prescribing at Harvard's week-long menopause course.

This lovely doctor came up to me after my hour-long lecture, and she thanked me. She said, "I loved your lecture last year, and I loved your lecture this year again, and I think I'm finally ready to write my first testosterone prescription." My heart sank. This doctor has taken two weeks of continuing menopause education, and only now did she feel ready to write her first evidence-based prescription. Clinicians are afraid.

They're afraid of controlled substance prescribing and of navigating the logistical nightmare of non-FDA approved treatments. An FDA approved product would remove most of these barriers and get her patients the care they are asking for daily. It would allow for a standard easy to administer dose and increase the likelihood that insurance will cover it and pharmacies will stock and dispense what we ask for. Here's how I write for a testosterone prescription in my private practice.

Here's the prescription. Take a picture. It's also a similar prescription we use at the work that I do at the Veterans Administration Hospital in Washington DC. It took us years of advocacy, but I'm so proud to report that in 2025, the VA agreed to standardize the approval for testosterone for perry menopause and menopausal women with symptoms. Now, if only we could get insurers to join us. I tell my patients that the logistics are the most challenging part of starting testosterone, all because it's not FDA approved.

After I write that prescription, I put in their zip code. That's ridiculous. I put in their zip code into this website that gives a coupon code so that we can find the cheapest price for cash pay testosterone because their insurance will not cover it no matter how much I yell. But they will cover it for their partners who I also give testosterone to even though it's off label for them too. If you look at this slide, you can actually see that CVS has the cheapest price, although they also have the worst shortages of estrogen prescriptions.

Now, so we often need to use multiplearmacies to get everything we prescribe for patients. The prescription should cost our patients about $100, and that's for a box of 30 of these tubes when they use the coupon. Otherwise, if you don't have the coupon, it's close to $500 for 30 of these tubes. The tubes will last you about 10 months, which equates to about $10 a month. So, while it's much more challenging than a compounded product, it is significantly cheaper.

Now, my male patients, they squirt the entire tube out and rub it all over their chest every single day. Sometimes, you know, doing this as well, but they they actually don't like doing gels. And so, we often use other products because gels can be messy. As Dr. Bore said, "Our female patients do just about anything. Five mls, 5 milligrams, a blob, a chickpea size, you know, whatever. They can do a smidge and the tube should last about 10 days.

It's not that serious. I can do a little tiny bit amount. I rub it in and I'm on with my day." That was my morning dose, by the way. Sadly, sadly, when you go to the pharmacy, you may find other obstacles. We write for tubes on our prescription, but one of the generics comes in sachets, which is another term for ketchup packet. Imagine trying to dispense onetenth of a ketchup packet every day without wasting any. Challenging, right?

But not impossible. Our patients figure it out. And oh, by the way, as you heard, testosterone is a controlled substance. So, I need a DEA license to prescribe it, and it's like I'm giving you a narcotic. We've had pharmacists deny prescriptions to patients, deny coupons. Amazon Pharmacy just recently decided to stop approving tubes altogether. Thanks. Thanks for that. Because it's not FDA approved for women, the pharmacists are inconsistent in authorizing and dispensing our prescriptions.

Authorizing and dispensing our prescriptions. 48 hours ago, a pharmacist told my patient, "You know, testosterone is only for men." Only for men. They don't seem to know that there's global consensus that it's safe or that it's approved for women in Australia, the UK, South Africa, and New Zealand. An FDA approved product would make all of these issues vanish. And finally, let's discuss how it helps our research. The last century has seen remarkable advances in health care, thanks in a large part to an investment in research by academia, government, and pharma.

But at times, the system fails us. In the case of female testosterone, we actually have research dating back to the 1940s and goes beyond just studying libido. And yes, like all research, different people with different biases reach different conclusions. But what we do know, what I see in my clinic, what the global consensus said says is that female testosterone is fabulous for sexual health and quality of life. And research shows it's more than just libido.

Arousal, orgasm, quality of life, self-image. It's safe and the benefits outweigh the risk. And we have randomized trials and FDA studies to back that up. Yet, it's still not approved and people demand more research. But no one wants to fund the research because it's still not approved. And when researchers find a way to conduct small studies, the doses aren't standardized because, wait for it, there's no FDA approved dose.

Do you see the problem here? There's a reason most of the advanced data comes from our friends in Australia. They get funding from both the government and a ton of industry support and they have an approved product. But it's also how people market the data and who has the microphone. As with any study, we can all look at it from different lenses. I see the Women's Health Initiative as showing us how safe and beneficial hormone therapy can be.

And yet the media's interpretation of the conclusion caused mass panic, FDA warning labels, and 20 years of misinformation for women. I love looking at this study as an example. This is an NIH funded randomized control trial com that compared two non-FDA approved testosterone formulations against placebo for joint pain in women with breast cancer. That means the oncologists were convinced enough with the safety data that they wanted to study it.

And if you're like most busy doctors, you have never heard of this study. And if you did, you just saw the conclusion that you see here at the bottom. Testosterone didn't help with joint pain. But look, when you look when you look with me more, I see a safe therapy that signals that it helps with so much more than libido. The study found no difference in deepening of voice. unwanted weight gain, acne, or undesirable hair growth.

And patients on testosterone reported improvements in strength, hot flashes, fatigue, mood swings, and stress urinary incontinents. I think our breast cancer patients would want to discuss these quality of life measures with their doctors. But these studies rarely make the news, and the conclusions are all anyone sees. And people keep saying we have no data. An area that has gotten almost no attention but absolutely needs it is something I see every day in my clinic.

Testosterone is important for the pelvis. It's important for the clitoris, the vulva, the pelvic floor, and even the bladder. There's no way this is just about libido. There are estrogen and testosterone receptors like you see here in vulvar tissue. And we know then when we that when we add DHEA and androgen or compounded estrogen plus testosterone at lower doses to the vulvar tissue, you can see here how it miraculously heals and helps with pain as well as urinary symptoms.

This is well known to my medical colleagues in the sexual medicine world, but it is not well known by the majority of clinicians. The pelvic floor has androgen receptors and is being looked at for prolapse research and incontinence. And one of my favorite recent studies is a randomized control trial looking at testosterone eye drops for dry eye. Brilliant. Please researchers watching today do more research and let's advocate for a whole lot more funding.

Thankfully we are seeing a lot more emerging real world data being published. Women are using tons of testosterone, even off label, even though there's no FDA approved products. And they are refilling their prescriptions like crazy and paying lots of money for them. Why? Because it helps them. These studies show us important signals of how to design better studies and find more sources of funding for those studies. Are we asking the right questions?

Are we looking long enough? Are we taking long enough to look for the answers? Are we messaging the results as well as we could? Data from a massive menopause clinic in England has studied their patients and looked at approved testosterone formulations. They have treated over 40,000 female patients with approved testosterone formulation. They have published on improvements in multiple domains like mood, genital, urinary tract, cognition, energy, increased ability to exercise, and sexual health even beyond the standard estrogen and progesterone therapies.

They have also seen signals in their clinic and presented data that menopause hormones plus testosterone decreases opioid use, SSRI prescriptions and even suicidal thoughts that surely must be looked at. Now the explosion of tellaalth has also given us different a different angle to look at patients. This is data from a US-based online tele medicine platform that actually only uses compounded products. And they found very similar results to those in England.

Different products, different countries, similar observations. That's important. And what this slide shows is what I see every day in my clinic, that the benefits of testosterone take time, but are often worth the wait. What brings me so much joy today is that we have hope. This is an incredibly fixable problem and women are women are showing up in big numbers with their comments and in their attendance today. We are on the verge of historic numbers for FDA public comments.

So all of you here today and those of you watching on YouTube, please submit comments by October 19th. I see you and I'm so proud to be here alongside of you. FDA, we are asking you to open a priority review pathway for female dose testosterone. One that takes to account that this drug is already approved for men, approved for women in Australia, and used by millions of women already in the United States. An FDA approved product would bring legitimacy, ease of prescribing, insurance coverage, and better research for women.

Most importantly, it will solidify what that patient taught me all those years ago, that it's about the dignity of realizing your quality of life matters and should matter to your medical team. Thank you. [applause] Thank you, Dr. Reuben, science and clinical practice are most meaningful when grounded in the lived experiences of patients. We are honored to now hear directly from someone who has navigated this landscape personally.

Miss Susan Lake will share the patient perspective on testosterone use in menopausal women. She is a married 61-year-old HRT patient of Dr. Ruben since early 2021. She started using testosterone as a part of her HRT after menopause. After menopause changed her life in numerous ways. Today she shares her story to help other women navigate the realities of menopause and HRT. Because in her words, no women should ever have to suffer like that.

Miss Lake, thank you for being with us today. Let's welcome Miss Lake to the podium. [applause] Thank you all. Um, I can start off telling you about how healthy and happy I am, how strong I am to the point that I just moved a little funny one day and there went my knee. So, it has nothing to do with hormones. That's in check right now. Um, I am so honored to be asked to be here today. um to be in front of the FDA and all these wonderful doctors who are doing something to help us.

It is just a blessing and I want to share my journey. Um I'm happy now but it was very very difficult. In 2015 uh at age 50 I started having hot flashes. Now, I worked in the construction industry, construction and design uh for government renovations. And usually it was just one or two of us women in a in a conference room filled with men. And I'd come in and I'd be about five layers of clothing, but by the end of that meeting, I'd be down to a tank top and I was drenched head to toe with sweat.

And it was starting to become such an issue and such an embarrassment and talking to older generations, they're like, "Oh, well that happens, you know, that that type of thing is going to come up." Well, I wasn't really happy about things like that along with like joint pain in the morning that all of a sudden just appeared like my hands could hardly move and it it was just so bizarre to me. Um, then there came the brain fog and the insomnia.

Um, I I had the feeling that I must have been starting to have dementia or maybe even Alzheimer's. It really concerned me and it was starting to truly derail my life. Then I witnessed the worst and that was when my very healthy libido tanked to a negative three and I was a newlywood at that time. So that was very disconcerting. I went to my GP, wonderful individual, just said, "Oh, your blood work is fabulous. You're great.

Everything looks good. Your physical coming out." I said, "I've never felt so horrible in my life. How can everything be normal?" Then I went to my OB/GYN. I told her, I said, "You know, everything from my joints, my sleeping, uh, sex, lack of interest, um, something is very, very wrong. Is there anything you can do to help me?" And she said, "You know, well, you are at that age and things are getting a little rougher for you. um I don't really have anything at this time.

And that was that for that 15minute um appointment. Well, so I went on to a arthritis specialist and said, you know, this this sudden joint pain, you know, feeling like I can hardly move my hands and um starting to have ankle issues. Um, again it's like well everything has come back just fine. Your levels are good. I I see that you you've got your mobility. Um, you are getting older and [laughter] thanks for stating the obvious.

Well, I'm not one to really take no for an answer or no response for an answer. So, I kept on looking. By this time, it's almost been five years of keeping on looking, keeping on thinking that there's got to be something. This can't be right. This can't be my new normal. And just to hear, sorry you're going through that. That's hard to hear. Well, I wasn't going to suffer through that anymore. Um, and just to point out, I never heard the words hormone or menopause mentioned at any of those appointments.

I was just told I was getting older. So, you know, by this time I I'm even asking my mother, "Mom, can you tell me something about menopause because I guess I'm in the full throws of it." Oh, honey, it was nothing. It was just fine. everything was great. And I said, "Well, that's just wonderful." And all I could think back was into high school and junior high and just being flooded with all this information about becoming an adolescent, becoming a sexual individual.

And I'm like, "Well, they're not going to tell us about not being a sexual individual. I'm stumped with this." Well, um, everything came back through all these these appointments saying normal, normal, normal. But by 2020, at age 55, I no longer recognize my body. I I didn't recognize my mind. Um, the things that used to come so naturally to me, I just didn't have those those powerful skills anymore. And I went to a neurologist.

I said, "Clearly, I must be having some type of dementia or Alzheimer's. Is there anything you can do?" Had MRIs done. I go back in. He says, "Oh, you have a beautiful brain for a woman your age." I just walked out in tears. It was just so so defacing. By this point, I was severely depressed. Anti-depressants weren't really doing it for me. Um, it was 2020, so that had been a hard year working from home, trying to deal with that new normal.

And I got to the point around December that I'm like, I don't want to live like this anymore. I love my husband. I love him so much. He's just the most wonderful man I've ever met. And I have zero desire whatsoever to be with him. And after us having so many fun years together before that and to go to a negative three after a healthy 10, there was nothing left of me anymore. So I talked to a therapist who put me in touch with a sexual therapist. that sexual therapist wasn't taking any in-person u appointments cuz it was nearing the end of 2020.

But she said, "Well, tell me just a little bit about what's going on." And I told her mental, physical desire, lack of the whole thing. She said, "Well, I know someone who's getting into this and who's really making some strides, and I think she'd be the perfect person for you." And that's when I got to meet Dr. Rubin. To say that woman saved my life is an understatement because after learning all the education from her and going through my whole process of hormone therapy, I now am an educator.

I now help my friends and my family so they don't have to suffer like I did cuz we don't have to suffer anymore. So when I started with Dr. Rubin, we had this wonderful conversation over the phone. Uh she set me up with hormone um testing so we get a good baseline. Um the next time I met with her was an hourong appointment. I'd never had an hour-ong appointment with a doctor in my life. She wanted to know it all. She wanted to know the whole thing.

And then for us to discuss what the lab work looked like, what the hormones level work. I even had an an anatomical review. It was so enlightening. It was fabulous. I came back and told my husband and and he was just like, "She did what? And you're going to do what?" And I said, "Honey, just believe me, you're gonna like the end results." So, she started me off on estrogen. Um, I do a fem ring, which is very easy to do, but we started at sort of the basics.

We started with lotions and gels and all that and and then I was like, "No, don't want to do that. This is this is another way to deal with it." And then we gradually went into testosterone. You know, we don't start both off at the same time, but then we go go gradually into testosterone. Fabulous. There's no other word. It did take about two months. On top of the two months, then my insurance company stifled everything which had to make me ask Dr.

Rubin, can you write me a note? The insurance company wants a note to say why you are prescribing testosterone to a woman. So she wrote that I did I was clinically diagnosed with HSDD. She wrote the note. I sent it to them. They called me back. They clearly did not understand. But eventually they said, "Um, I'm sorry, but we're just not going to be able to help you with that." Well, Dr. Ruben doesn't take no for an answer either.

And she's like, "Well, we have something called Good RX." And sure enough, at that time, that box of testosterone gel was $500. And I could not believe that Good RX was able to make it very, you know, able to afford finally. So, here I am starting to feel like a woman again. I'm finally on the testosterone. I'm starting to feel that gradual uh increase in clarity like a film had been cleared from my eyes and my brain was starting to function again.

I was starting to have a little better sleep. Um, and then I was actually starting to want to have sex again. It was just wonderful. I was feeling that inner goddess come back. I'm still a woman. I can still be a woman. And it was just so hard to see so many of my friends going through the whole the same thing and realizing they didn't have to suffer through that. So getting all this and going through those appointments and getting a full education on my hormone lab results, hormone testing and coming full circle.

I had actually been told by Dr. Reuben at that first appointment when she looked at those hormone results