Female Sexual Health: Barriers and Roadmap to Optimal Outcomes and Treatments

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Dr. Daniel Simon (Host): Hello, everyone. My name is Dr. Daniel Simon. I am your host of the Science at UH podcast, sponsored by the University Hospitals Research and Education Institute. This podcast series features University Hospitals’ cutting-edge research and innovations. Thank you for listening to another episode.

Today, I am happy to be joined by our guest, Dr. Sheryl Kingsberg, Division Chief of Behavioral Medicine in the Department of OB-GYN at University Hospitals Cleveland Medical Center and Professor in the Departments of Reproductive Biology, Psychiatry, and Urology at the Case Western Reserve University School of Medicine. Her areas of clinical specialization include female sexual disorders, menopause, pregnancy, and postpartum mood disorders, and psychological aspects of infertility. Dr. Kingsberg is a past president of the Menopause Society and the International Society for the Study of Women's Sexual Health. She currently serves as the Advocacy Chair for both of these organizations.

Welcome, Sheryl.

Dr. Sheryl Kingsberg: Thank you, Dr. Simon. It's a pleasure to be here, and I am honored to be one of your guests.

Dr. Daniel Simon: Well, thank you so much for coming. So, University Hospitals is known for its innovation, but what may not be known is that the Department of Obstetrics and Gynecology was way ahead of its time and, for over 40 years, has integrated behavioral health right into their department with a Division of Behavioral Medicine. Tell us a little bit more about the history of this division and how research evolved by integrating behavioral medicine with obstetrics care.

Dr. Sheryl Kingsberg: Sure. Well, the division was started, again, before I was born, over 40 years ago, and really was so unique. And, you know, while nowadays we understand that behavioral health is important to medical health and it is becoming more integrated, there was no such thing back then. But the Chair of OB-GYN, Brian Little, and psychiatrist, Mim Rosenthal, and Dr. Smith, who had come over from Metro Hospital, really put together this unique idea that if you could put behavioral medicine within the department, you would be able to reach women who are having all kinds of psychological problems that were of course going to be related to women's health, whether it's pregnancy loss or postpartum depression. Menopause wasn't a thing then, even though women were going through menopause, but all of those areas became sort of integrated and nobody had thought of this across the country.

Dr. Daniel Simon: Well, that's obviously incredibly important to know because now, of course, we wouldn't think of having a department without that function. And so, I'm so glad to know that we've had experience over now four decades. So, you have been an integral clinical researcher in the subspecialty of female sexual medicine and have been involved in the clinical development and randomized trials for several pharmacologic agents for female sexual dysfunction, with University Hospitals being a clinical trial site for most of them. And your work obviously started many years ago with Procter & Gamble related to a testosterone patch for the treatment of hypoactive sexual disorder in postmenopausal women. Tell us a little bit more about your work and how it's evolved. I know that I've heard a recent talk that you've given where you list all the medications for men that takes up a page and only a handful for women. So, tell us about that journey and how you've been such an important part of it.

Dr. Sheryl Kingsberg: Sure. Not even a handful, I could hold up two fingers. Now, I have to say that one of the reasons why University Hospitals has been such a wonderful site for these clinical trials is because behavioral medicine has been integrated within OB-GYN. We are the perfect site to have a sexual medicine expert mixed in with OB-GYNs, because most of these treatments have involved using women's health and gynecologic exams. And so, this has been perfect for clinical trials and for UH. So, the very first trial that was done for a product for women's sexual health was the testosterone patch, which Procter & Gamble developed. And in fact, it worked, and it worked very well. And it was a patch of 300 micrograms of testosterone, which essentially puts women, postmenopausal women, and this was a drug for postmenopausal women into their pre-menopausal range. So, all you were doing is essentially restoring the testosterone that they had lost, thank you to menopause, back to their premenopausal level. And we saw that about 60% of women had a response. If they had lost their sexual desire, it was restored. And it was, unfortunately, it was about 20 years ago, which was shortly after the Women's Health Initiative initial reports came out, which scared everybody, including the FDA, away from hormones. And right after sort of the Vioxx scare, that the FDA was not so thrilled about approving drugs for women.

So, they wanted a very large safety trial that Procter & Gamble said, "Nah, we're not going to do it." It got approved in Europe and was effective in Europe. And now, what we use are off-label testosterone gels, the male versions, which are FDA approved, we titrate down to that same dosing level. And we use it, unfortunately, off-label for postmenopausal women. So, we have done the trials, we know what works, we know what doesn't. There are no FDA approved products.

So, that was the first thing, and it was for postmenopausal women. Now, the FDA actually thinks about women as two different species. They think about women as premenopausal or postmenopausal. The two drugs that we at UH worked on and developed and got approved are for premenopausal women. They are both non-hormonal agents. One is called flibanserin, its brand name is Addyi. And that is essentially a mixed serotonin agonist/antagonist that works to restore sexual desire in women who have hypoactive sexual desire disorder. And the second one, the first one was approved in 2015, and brimelanotide is the second one that was approved in 2019. And I have to say, I'm very honored to have been the first author on the publication of the clinical trials of those treatments, and we were a site for those. And brimelanotide, brand name is Vyleesi, which is an on-demand injectable. So, it's with an auto-injector, like an EpiPen. And it works on-demand within about 45 minutes, both non-hormonal. This is a melanocortin receptor agonist, so very novel idea. And they are effective in premenopausal women, although they are often used off-label for postmenopausal women because we have data, particularly for flibanserin, which is approved in Canada for postmenopausal women up to the age of 60. So, they're used off-label. We just don't have any approved treatments for postmenopausal women yet.

Now, moving forward to other conditions. So, that's hypoactive sexual desire disorder, and that is the most prevalent sexual problem for women of all ages. But there are other conditions that cause sexual problems. One is female sexual arousal disorder, and that really is the loss of genital sensation that allows for experiencing pleasure. So, if you have desire, but you can't feel enough sensation to feel sexually aroused, that would be FSAD. Now, Dare Bioscience is developing a topical sildenafil, which is Viagra, as everybody knows, a topical version in a cream, and we were, again, one of the sites for their phase II trial. And I have worked with them to develop the trials and have gone to the FDA. This has shown promise to treat premenopausal women with loss of sexual arousal. And Mithra has an E4 product that is a different form of estrogen that is from actually pregnant women, in the fetus. And E4 has been studied as a treatment for vasomotor symptoms in menopausal women. And now, they're also looking at it, and I have designed this sort of pilot trial to see whether or not it would actually be helpful to treat arousal disorder in postmenopausal women. So, that trial is up and coming.

Dr. Daniel Simon: So, let me step back just for a sec and give us a sense of how effective are these therapies? So, just to get our listeners on the same page, what were the top line results of these FDA trials that gained approval for these drugs?

Dr. Sheryl Kingsberg: Early on, the FDA had required sponsors who were developing these trials to kind of model their clinical endpoints after the old male studies, right? Because when you're looking at, say, a PDE5 inhibitor like sildenafil or Viagra, what would be a good result? Somebody who could have a satisfactory sexual event, right? If you can get an erection that is usable for intercourse, then that would be a satisfactory or a satisfying sexual event. So, they carry that over to say, "Okay. In these trials for desire, we want you to show increased satisfying sexual events." Well, that's all well and good, except women with low desire were already having sex. They're having duty sex. They're having sex with their partners, right? So, counting the number of events is not really a good way to look at desire for women. It doesn't even talk about desire. What we want are to show patient-reported outcome changes that show an increase in desire. And both of these drugs that got approved, and including the patch, showed increases in patient-reported outcomes in desire, going from no desire to some desire because, trust me, the FDA would never approve a drug that made women want sex all the time, right? So, you go from no desire to some desire, which is very meaningful for women who've lost their desire. And despite the fact that it's a terrible endpoint, there was an increase in satisfying sexual events. So even women who are already having sex, even though they weren't really all that interested, now we're having more sex and showing a change there, too.

With arousal, though, you're looking at something different. So, you want to look at desire and wanting for the desire trials. And by the way, the definition and the criteria for having a disorder means you also have to have personal distress. So, all of these trials include an endpoint about distress. So, not only do you need to show an increase in desire, and sometimes even number of events, but you also have to show a significant decrease in personal distress. And so, the drugs that got approved do all of that. With arousal, it's now looking at changes in lubrication and sensation, not necessarily wanting, because you should have desire and now have lost your ability to feel sensation, and a change in distress. So, those are the endpoints that we look for arousal.

Dr. Daniel Simon: So, let me ask you a question. You talked about a topical sildenafil, Viagra-like compound and also an injectable. Tell me why didn't you try just Viagra and Cialis orally for this condition as opposed to a topical?

Dr. Sheryl Kingsberg: Well, the developer was able to find a way to put the sildenafil into a cream, which made much more sense, instead of making somebody take something orally and systemically, that really we're focusing on working locally, to be able to put it into a cream made way more sense, and women really appreciated that. So, just like we use vaginal estrogen creams or inserts for a vaginal atrophy or genitourinary syndrome of menopause, this too can also work for arousal. Now, the E4 product is an oral, right? Because that will hopefully have a twofer effect. You'll be able to use it for vasomotor symptoms related to hot flashes. And if you have an arousal disorder, which is not uncommon in women at menopause because they lose estrogen in their urogenital area, and so that they could have a twofer effect there.

Dr. Daniel Simon: So, I understand that the topical sildenafil went through a phase II trial. What were those results?

Dr. Sheryl Kingsberg: Well they showed, well, now, this is an exploratory study. So, the phase II trial was an exploratory study that the FDA really wanted to see what kind of endpoints were appropriate. And so, in this trial, we used a lot of endpoints. We looked at various different outcome measures. And so, while with this study, there were not robust efficacy points, the whole point was not as much to show the efficacy, because we know it does work. But to show what endpoints would be the best, because nobody has gotten a drug approved for female sexual arousal disorder. This is a first and the FDA knows that. So, everybody was sort of in line with, "Well, let's look in this exploratory study to see what actually would be a good endpoint and how do we best assess and measure this."

In fact, prior to even doing the study, we did a content validity study because the FDA didn't even know whether women could respond to what arousal disorder looked like to them. And so, I'm an author on that publication, which just came out this past year evaluating many women on how they perceived the idea of arousal disorder and what content made sense for them. And then, we used that for the phase II trial. So, the phase III trial, which hopefully is coming soon and will hopefully be done at UH as well, will now take those endpoints, have them much more focused and be able to show efficacy along with safety. But really, in this case, it's a little sildenafil cream, 3.6 milligrams, and it should show efficacy across hopefully 12 weeks, maybe 24.

Dr. Daniel Simon: Wow. That's really exciting. And we look forward to having you back to discuss those results. So my final question to you relates to your work that you do in perinatal and postpartum mood disorders. Obviously, depression post-pregnancy is a problem. It's the same in my field of Cardiology. We have depression post-MI in 25-30% of patients. Tell us a little bit about your exciting work with Reunion Neuroscience about a synthetic psychedelic and how that may be helpful in postpartum depression.

Dr. Sheryl Kingsberg: Well, thanks for asking about that, Dr. Simon. I don't know that many of your listeners are aware that postpartum depression is the most common consequence of pregnancy. People think about other physical conditions, but postpartum depression is the leading cause of maternal death. So, if you don't think it's important, it really is. Postpartum depression affects up to 15% of all women who have a child. There are certainly other risk factors, if you have a history of premenstrual dysphoric disorder, if you've had a loss, if you have a history of depression, but across the board, 15%.

Now, we have been using cognitive behavior therapy, I do that for a living, and that works very well. We have a selective serotonin reuptake inhibitors and SNRIs that are effective for treating postpartum depression. But guess what? They don't have an indication for postpartum depression, but we use them. And more recently, there have been two drugs approved that that are specifically indicated for postpartum depression. That's brexanolone and zuranolone, which is the oral version of brexanolone, which is an allopregnanolone. And those have been shown to be effective in treating postpartum depression. But it's not a one-size-fits-all and treating postpartum depression still remains an unmet need.

So, what we're now looking at, and I have been so excited to be involved from the ground floor with Reunion is looking at psychedelic medicine. So, that is really the wave of the future in so many areas in Psychiatry, including treatment-resistant depression in end-of-life care, right? But now, we're looking at it for postpartum depression. Why? Because it would be a one treatment and done. So, women can have one treatment, have maybe four-hour trip, so to speak, they can pump and dump for, say, 24, 48 hours. Then if they're breastfeeding, they can continue on with breastfeeding and their depression, hopefully, will be resolved. I think it's hugely exciting.

Dr. Daniel Simon: So, these are serotonergic compounds. I mean, what is the basis of how they work?

Dr. Sheryl Kingsberg: Well, we assume that they are serotonergic compounds. You know, mechanism is not completely understood, but that they should not only affect the reuptake inhibitors, but they should also, by virtue of taking somebody through that trip, it helps them with shifting neurochemistry that has been off thanks to those hormonal shifts, but also gives them a new perspective on the depression that they're experiencing. So, we don't particularly know exactly the mechanism of action, but we certainly know that psychedelics are here to stay. They are not the psychedelics of the '60s. They are now well studied. And this one is interesting because it's a synthetic, it has a shorter half-life than psilocybin. And so, that's going to be really beneficial to women who don't want it in their system very long.

Dr. Daniel Simon: Well, you know, I always like spending time with you and learning from you. We were just together at our American Heart Association Go Red. Your breakout session was, you know, standing room-only as we always expect. Of course, I love the title of your talk, The Heart: The Most Important Sexual Organ.

So, it's great to see you again, Sheryl. Thank you for taking the time to speak with us today and to learn more about research at University Hospitals, please visit uhhospitals.org/uhresearch. Thanks again for listening.