#259 - Women's sexual health: Why it matters, what can go wrong, and how to fix it | Sharon Parish, M.D.

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode, I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay. Here's today's episode. My guest this week is Dr. Sharon Parrish. Sharon is a prominent sexual medicine specialist and professor of medicine in in Clinical Psychiatry and Clinical Medicine at Weill Cornell Medicine. Throughout her career, she has become a leading expert in sexual medicine, focusing her work on helping patients overcome sexual dysfunction. She has published numerous articles and book chapters on sexual health and is a sought after speaker and educator on the topic. In this episode, we focus the entire conversation around women's sexual health. So for folks who are curious about men's sexual health, not to worry. Next week we'll be launching the complementary podcast to this that focuses exclusively on men's sexual health. In this episode, we review the female physiology and anatomy in order to better understand some of the potential problems and treatments available to women that we cover. Throughout the interview, we speak about how sexual health and sexual dysfunction can affect a woman's wellbeing and how childbirth and metabolic health can affect women's sexual health. From there, we cover a variety of issues a woman may face throughout her life by looking at three different case studies. Using these case studies, we differentiate and tease apart the differences between desire and arousal. We talk about different classes of drugs that are available for women as it relates to desire and arousal. We talk about the impact of birth control. We talk about treatments for women who are having difficulty achieving orgasm, including testosterone and dhea. And we of course talk about the role of hormone replacement in addition to many other things. One final point I learn something with every podcast I do. In other words, every time I finish interviewing somebody, regardless of how well I know the subject matter beforehand, I always come away learning something. But it might be the case that this episode in particular taught me more that I didn't know relative to any other podcast I can recall. So I think it's safe to say that whether you're a man or a woman. You will learn a lot from this episode that will improve the quality of your life. So without further delay, please enjoy my conversation with Dr. Sharon Parish. Hey, Sharon, thank you so much for making time to meet with me today. This is a topic that is incredibly applicable to more than half our population, because while we're going to be talking about sexual function in women, of course women have partners. And so, by extension, I would argue this is a topic that is applicable to our entire listening population. It's also a topic where there seems to be a lot of misunderstanding, a lot of asymmetry in attention. We're going to talk about a bunch of those things as we get going. Before we do, though, I just kind of want to give people a sense of your background and how you arrived where you did. So you went to medical school, you did your residency in internal medicine and primary care, correct?

That is right. And primary care, meaning with a focus on ambulatory medicine and being sort of a general medical physician with a focus on primary care and academic general medicine.

At what point during that process did you realize that your interest was in sexual health?

I think when I was in med school, really, I was always struggling, it seems like a little bit of a strange union, but always struggling between deciding whether I wanted to be a general internist, a psychiatrist, or a gynecologist. You know, this interface particularly, although as an internist, I do take care of men's sexual health as well. This interface between women's health, the mind and the body, behavioral issues, and comprehensive, or for lack of a better word, holistic care for all sort of was always tugging at me in three different directions. And somehow when I eventually found my way to sexual medicine, it just kind of brought it all together. I did some projects on women's health and then in residency also on various women's health issues and reproductive issues. I worked, for example, in a contraception clinic, an adolescent medicine program, STD program. So I did a lot of work in that area. I did a fellowship afterwards at NYU Bellevue in psychosocial and behavioral medicine in the general medical field. And I worked with then some sexual medicine experts in some projects. And that's when I really moved more deliberately toward the field.

And so how does the field stand today? How many physicians are there in the United States, if you had to estimate that have your degree of training and clinical focus?

The field of men's sexual health is a little more clearly defined. Like, there's many psychiatrists, urologists, and even men's health internists who have Like a clear distinction. I think women's sexual health is less clear. But again, gynecologists, some internists, family medicine physicians, a few psychiatrists, and then there's psychological therapists. It goes across disciplines. It's a little hard to define, but I can say that there's many fewer who clearly identify. I went to the International Society for the Study of Women's Sexual Health annual meeting a couple weeks ago and there were 600 attendees. Five to 600. And that probably represents most people who work in the field. There's sex therapy meetings and pelvic floor physical therapy meetings that have others. But if you're looking at the field of sexual medicine, it's not robust. If you go to the AUA, I think everybody there, 20,000 people, think they could probably handle maled problem. So if that gives you a point.

Of comparison, that's sort of in line with what my expectations were. Let's also just maybe by way of background, perhaps start with what is encompassed in this field. So you've already kind of alluded to it a little bit. There's clearly a supratentorial component to this. There's also an anatomic component to this or physiologic component to this. How does it make sense to maybe walk me and the listeners through the background knowledge of this physiology, anatomy, so that we can better kind of go into what some of the problems are and what some of the treatments are.

With any issue where you're looking at the mind, the body, a genital response, a hormonal response, you know, the integration. I always take people back to the concept of the biopsychosocial model. I guess you're asking, when it comes to sexual response, what are the bio. What is the psycho and what is the social and what's the contextual? Maybe just for sexual health problems. The brain is a really active organ, as I'm sure you can imagine. We have thinking and feeling. And that probably on a biologic or neurophysiological level, translates into neurotransmitters and the interaction with hormones and pathways, brain neural pathways, neural networks. And there's the psychological concepts of conditioning and learning and unlearning reward and disappointment, et cetera, all plays a role. And it's fascinating how that might all interact. There's the general medical state, our vascular system, nervous system, and like systemic medical issues that might impact those. And there's hormones, and they get stimulated by the master glands in the brain, our genitals that make sex steroids and our adrenal glands and thyroid. So there's a collection of hormonal locuses that play a role potentially in sexual health. And then there's the local genital milieu. And that might include the vascular system, the nervous system, small nerves, the mucosa, the surface, and then there are muscles and soft tissue, so all in the genital tract. And then there's a bladder in the rectum, the breasts, which play a role in stimulation. So I think that that's the big picture. How does this all come together in a three dimensional concept where you integrate experience, relational issues, culture and time is really the fascinating part of this field.

So how do these things change during a woman's life? Obviously, puberty is a very important milestone, but I suspect also menopause is an equally important transition that is much more abrupt, at least from an endocrine standpoint, than men would experience at the same age.

Yeah, so I think there are times when hormones, like, play a more master role in sexuality and sexual response. You know, what's tricky about this is, and I guess the body's kind of programmed and smart is that there's a lot of life cycle and life stage things happening, and those are prime times as well. Whether one commands the other or not, it's hard to know. Menopause is kind of a longer process than people think. There's perimenopause, there's menopause, there's postmenopause, and there's a lot of life cycle stuff going on. You know, that's probably the most defining moment for women in that it interfaces with no longer being able to reproduce. There are significant changes in hormone levels like estrogen that affect level of vaginal comfort. And at the same time, androgens decline. That affects desire. And when you're starting up with puberty, that's probably all roaring up and getting going. And you're also developing the cognitive skills of relational issues and sexual relationships. So those are two peak times. I have worked with adolescents. I have more experience with midlife women. That's the focus often in my practice. And those are the people that. This is a good time to mention this point. The data suggests, and my experience with this field suggests, that the time when women are most interested in looking into it is in those perimenopausal, late reproductive, perimenopausal and early postmenopausal years.

When you say looking into it, do you mean looking for it for themselves?

So it might be that they have a problem. It might be they want to understand it better. It might be they want to be proactive and preserve their sexuality. It usually is that something's changing and they weren't expecting it and want to know why or they want it to be better. People have a little trouble sorting out, like, is it the relationship at this point, is it the menopausal changes overall, is it the sexual function? Or is it sort of all of it? And I think that's what makes the midlife sexual medicine challenges the most complex and challenging, but also the most interesting and the most rewarding. I think there's also the most likelihood where women are midlife. Women are youthful, they're young, they're active, they're connected. They're not like, you know, some other time in our universe where they're becoming the wise woman sitting in the tent, you know, retiring from child rearing and everything else. I mean, often women are peaking in their career if they're having, you know, these trends vary a little bit. Children later, you know, they've got teenage children, college children, aging parents, big careers, bodies changing and wanting partners. And there's a lot going on. So they're the most likely to seek attention. Actually, we can say a lot about helping them today.

I also would like to talk a little bit about how the anatomy changes post childbirth and does that have anything to do with sexual function? And I guess I want to kind of also at some point soon define some of the problems. I can think of three off the top of my head, right? One would be low sexual desire or hypoactive sexual desire. One would be inability to have an orgasm and a third would be discomfort or pain. Clearly a big problem for women post menopause due to vaginal atrophy. So those are three things I think we must address today. Do you think there are others that are important enough that to a non expert audience we should also present I.

Never want the forgotten. We'll call her sister. The forgotten sister to desires, arousal and having women understand that when they come to me, they're like, I no longer get turned on. And I mean, is it about wanting? Is it about mental or subjective or cognitive excitement? Is it that bridge between desire, meaning thinking and actually being in the moment and being excited?

Or.

Or is it their genitals are no longer responding and then that sometimes is uniquely or can be tied to orgasmic difficulties.

I see.

And I think it's really in the field. It's an area of discussion and sometimes even controversy. I think for women it's hard to separate what they're asking for. Sometimes Women come to me and they say, like, I no longer want sex, but everything works okay. Sometimes they say, like, I love this person, or I want to have sex with myself. That's not the problem. But nothing's turning on. Like, I'm not feeling anything. And learning about that for one's body and being able to articulate that, and I think it gets commonly tied to orgasmic changes. We could certainly discuss whether they're the same process or different.

Okay.

You know, childbirth. I don't know if you want to talk about that now.

Yeah, let's talk about it. Just because I think we've already established there are these two enormous hormone swings, Right. There's the swing on, which is reasonably quick, and then there's the swing off, which is relatively abrupt. But as you point out, it's occurring over years, not months. It's also worth mentioning it's the estrogen and progesterone that are coming off really quickly. The testosterone is kind of coming off, not as quickly. We can maybe come back to that in a moment. Let's talk about anatomy in a minute, because I'm guessing that women have very different experiences with childbirth. And presumably a vaginal delivery is different from a C section in terms of the impact it has on the pelvic floor. By the way, that's something we should define for people so they understand the anatomy of the pelvic floor. But anyway, yes, let's talk a little bit about how that might impact any of the elements of sexual health in a woman's life.

You know, it's not the time typically, where the sexual problems that people come to me for. I'm also not a gynecologist kick in and stay. They tend to be, for some women, relatively transient postpartum. But it also depends on, like, how many kids and what age and all of that. So let's talk about the pelvic floor for a moment, because that's where that might impact with childbirth. So the pelvic floor is kind of a mysterious concept, but if I had to give it one concept, it's the idea that it's a basket of muscles, and they attach from various parts of the inner pelvis, so, like, onto the pupis ramus, onto the ischial spine, onto the bones around our pelvis, internally and into the walls and then also into the organs, and they create a basket around the uterus, around the urethra. Like, for example, there's a sling around the urethra and the anus that holds it up and also holds up the uterus. And they also provide motion during childbirth. They allow for the childbirth process. They're quite active during sexual activity. They contract and release. They help us with urination, with defecation, and so forth. And it'd be easier if we had, like, the opportunity to show people a diagram. But I think the best way to.

Understand it is we'll include diagrams in the show notes.

That would be wonderful. The best way to understand is it's a basket of muscles that hold things up and, and help things move. And when they're not working properly, they can result in, for example, difficulty with urination or incontinence or sometimes pain during sexual activity or changes in orgasmic function. That's sort of the broadest concept. We can get into the nitty gritty of disorders, but I guess you were asking about childbirth. So with pregnancy, those muscles stretch a lot. Things are expanding. Sometimes women will notice improvements actually in their sexual function because if they've had tight pelvic floor muscles that are causing changes in sexual response or even pain, it sometimes gets better. Sometimes with deliveries, they get stretched, they get irritated, they get torn. It's rare that any of those things I find persist unless there was really a birth trauma. That often gets confused with what happens with other things during childbirth. For example, episiotomies, lacerations, suturing, where there can be scarring, there can be inflammation around a suture line, there can be, et cetera. So I think the general process of muscles stretching during childbirth is one thing. During pregnancy, it's different. And any other related injuries or trauma during the actual birthing process of a vaginal delivery is another. The only other thing about C section versus vaginal delivery, this could be a whole nother topic, but in general, vaginal deliveries are better for women.

Yeah, say more about that. Again, I'm very ignorant of most of these topics.

I think people have this idea that they're going to preserve the size of their vaginal canal or prevent their pelvic floor muscles from stretching, et cetera. And the truth is that most of that goes back. It's not all that unusual for women to just have a transient difficulty for four to six weeks and things improve. But having surgery, an abdominal surgery, you're opening your abdominal wall, there are muscles, there's scarring. It sometimes leads to other kinds of later difficulties that people don't anticipate. And it's also safer for the mother and the baby not to have surgery.

What is the, for lack of a better word, incidence of C section versus vaginal birth today? In the United States. Do you know?

I don't know that number. We could easily find it. I don't have it offhand. I'm not an obstetrician. I don't deliver babies. But the biggest concern that I hear in sexual medicine discussions is that people have this idea that it's better for their sexual health not to deliver babies vaginally. Maybe that's the most important message. And that the number of C sections has been going up and is alarming. And that routine, scheduled C sections to preserve sexual health for a whole number of reasons isn't really better for women. And that might be a myth. I'm not an expert in childbirth or in delivery because I'm not an obstetrician or a gynecologist. But if someone asks my opinion, I say, like, have your baby vaginally. And most people preserve their sexual function. That's not a peak time. The bigger problem actually is postpartum. That comes up in my practice. You know, people are breastfeeding. They're essentially like postmenopausal women. And they may experience because their hormones are dipping way down. They're not. They're still keeping ovulation off by breastfeeding, and they're experiencing vaginal dryness, irritation, sometimes changes in sex drive. And they're not aware of the effects of breastfeeding on sexual function, on a vulvovaginal changes and sexual response. And there's easy things to do for that, especially the vulva and vaginal symptoms.

Can you give me a sense of how high the FSH and LH are during breastfeeding?

You're asking are they organically comparable to a postmenopausal woman? I guess is the question.

Yeah. And is estradiol sufficiently low as well? Like. Yeah. I'm trying to understand how low estradiol is, how high FSH is.

I think there's so much variability. So it depends on, like, if you're completely breastfeeding and completely anovulatory, women can look postmenopausal.

Wow.

That's defined as over an FSH over 35. Most women aren't fully an ovulatory. They're having irregular cycles. They're ovulating intermittently. So I think the numbers are all over the board. But you can have estradiols as low as, like, 20 or 30. Right. Which isn't.

Yeah. Might as well be in menopause.

Yeah. And everybody's like, HPA axis and sensitivity to lactation is a little bit different. And sometimes women aren't breastfeeding completely. And the correlation with how much milk they're making and whether they're ovulating isn't clear cut either. What I would say is if you're breastfeeding and you're not having menses for six months, the likelihood that you're hormonally similar to a postmenopausal woman is higher and that you're completely anovulatory and that if you're having dryness and difficulty and pain and low sexual function, that you should talk to your doctor because they're things that we would do. Some of the same things that we'll probably get into in a little while.

We're going to talk about that because I guess you could make the case that if there's one thing we want listeners to take away from this program, it's that there's really no reason for any woman of any age to be struggling with vaginal dryness, regardless of how far she is into menopause or whatever. We have the technology to solve that problem all day long, right?

There's a number of approaches and that is the most treatable or the most manageable amongst these conditions. And the algorithm or the options for that are the most clear cut. So I'm a general internist by heart. You know, I'm a card carrying general internist, although I've gotten quite specialized in my work. So some of the my colleagues say to me, well, you know, you're not doing procedures, you're not a gynecologist, you know, what's the big deal? You just come, you hand them a lubricant, a moisturizer, maybe some vaginal hormones. What's the complexity of the concept or the consult? And what it comes down to is women really, really don't understand the whole thing. What's happening in their body, the difference between the things that we can offer them and how to put them together and use them and then how to integrate that into their sex life. And that's what I would say. Like the number one concept that I get or referral that I get is to help a woman walk through that.

So one other thing I want to talk about before we leave, the sort of basics and the foundational stuff is the role of metabolic health, slash systemic vascular health. So again, in men this is really clear. So for example, higher incidence of ASCVD, higher incidence of ED, similar concept to endothelial damage, higher incidence of type 2 diabetes, microvascular disease, higher incidence of erectile dysfunction. How clear is that relationship in women? In other words, do the things that drive glycosylation of proteins and microvascular disease in other parts of the body, do they contribute to sexual health in women as they do in men through the ED pathway?

So I'm glad you brought this up because this is really an emerging discussion in the field for those that are not aware in men. There's kind of a really clear literature and guidance that if a man is having ed, it may be a mirror to small vessel cardiovascular cerebrovascular disease. And we can use surrogate markers like looking at Doppler studies in the urologist's office of penile and genital blood flow, and then send them for a coronary calcium score, even a coronary ct. Right. And look and see if we can see those correlations. And there's good evidence supporting that they mirror one another. And so if a man has erectile dysfunction and sexual dysfunction associated, they should have a cardiovascular assessment. That's sort of the emerging. Those are discussions.

Just so folks know, a Doppler study is a study that uses waves to look at blood flow through blood vessels. And it's very helpful when you're looking through these sort of smaller blood vessels that you wouldn't otherwise be able to get a good look into.

And so I think before we got started, I was telling you I just had a two day meeting where this was the depth of the discussion. Where are we with understanding the presentation of erectile dysfunction as a market for cardiovascular disease? And if someone has cardiovascular disease, what kind of recommendations should we make about asking men about sexual function? And then what do you do about it? Do vasodilators to medications that PDE5 inhibitors that dilate the small vessels work? And my participation in this particular conference was about the discussion of do we have similar measures in women. So first of all, if someone comes to me and says, like, I have no genital sensation, does that mean that she has vascular disease? I mean, there's also nerves there, but it's really not as clear cut. Like a man comes in and says, you know, I don't have an erection. Woman's like, I don't feel, you know, I can't be sure that exactly what it is. There's been some research looking at using something called clitoral, Cutler Doppler ultrasound or CDU with assessment of like, the blood flow, which is called the pulsatile index, looking at resistance to blood flow as an objective measure of how to assess arousal in women. So right now it's just at the level of the lab or research. It's not really being used clinically except in a very few selected practices who also research this. If someone comes in and says, I don't feel, can I put a clitoral doppler on and look and see? Yes, that's the explanation. That's one thing. The second thing is how well does this correlate with the risk factors that we have seen in men, Things like metabolic syndrome, hyperlipidemia, diabetes. And if someone has those things, should I then be asking her about clitoral sensation and doing testing both to understand her sexual function and also as a mirror for her systemic blood vascular risk? Again, we're starting to study that, but we don't have clear information. There's this concept called the female genital vascular district. And does that whole area, the larger vessels and the small vessels, does that give us a correlate or a window? Can we use that again as markers for small vessel disease and then vice versa? If someone says to me, I have a patient with metabolic syndrome and a high A1C, obesity, diabetes, hyperlipidemia, et cetera, is that a high risk patient that I should be really counseling and talking to about sexual medicine and then using that as a reason managing those issues to preserve sexual health. And I think we need to define first of all, what is the role of clitoral doppler testing. There's no research on carnary calcium scores or Carney CTs on women and their correlate with sexual function. And can we use these both as mirrors of sexual function and predictors of other issues, other vascular issues for women? I feel like this is the most important growing field that it needs to catch up, you know, that we can't just look at like, oh, she's complaining, she's post menopausal. I think I'll hand her a lubricant because she's not feeling things. That's very crude compared to what we have available for understanding men at this point. So that's a long discussion. But as it's an area of great fascination. But practically speaking, we don't have a lot to offer women in the office yet, but we need to.

But it sounds like we're moving in the same direction, that we kind of have a clear sense of what's going on with men, which is. And by the way, this is something I do see in my practice quite often, which is you have a guy that shows up with a hemoglobin A1C of 5.9, so he doesn't have type 2 diabetes, but he clearly has too much blood glucose and dyslipidemia. A year later, when you've got all those biomarkers improved, he also notices he doesn't need his Cialis anymore. That's a very obvious, clear, repeatable, common story. So I don't think it's a huge stretch to assume that women could experience the same thing.

I like to, when I talk about this with my patients and my colleagues, I like to say there's the motivator and there's the mirror. That's obvious when you're talking about a man. They're like, with these parameters. And then you say, so tell me about your sexual function. How's it going? Any difficulty with erections? They report it. And you say, well, you know that they can sometimes go hand in hand or. And that's a good motivation overall for many men. Right. They want to improve everything. And that might be sometimes even the biggest motivation that's important to them. So that's a reason to lose weight. I think we need to have the same way to think about women. And I think the other thing for all people is that we don't do enough to teach that prevention and lifestyle and disease management is important for sexual health and validate how important that is for quality of life. Like, there's all these reasons you don't want to have heart disease. You know, we should be saying you don't want to have sexual dysfunction. There's not enough education when people before they have issues.

How clear is that, Sharon? Again, empirically, it just makes sense. But what can we say about sexual health and general health? What I mean by that is overall well being as a function of sexual health. We've already established the causality in the other direction. Meaning when your metabolic health is poor and your vascular health is poor, it can impact sexual health. But what I'm saying is, even independent of that, if a person is otherwise healthy physically but still having sexual dysfunction, how does that translate into the rest of their life?

There's a couple ways to look at this. One thing is, most of the research, I guess we're talking about women today.

Yes, yes.

Most of the research is association research. So it's sometimes a little hard to tell. I think you understand the difference between really risk factor and cause and effect. We know which lifestyle and health factors seem to be associated with better sexual function, better satisfaction, better sexual activity. And most of the research is actually in desire when it comes to that. For example, I'll give you a few examples in women there's interesting research that being resilient, having a positive attitude for women, especially as they get older, having a partner, being connected socially, having support, normal bmi. The funny one is Mediterranean diet. Actually it probably has to do with overall health and well being and the other benefits, all those things are associated with good sexual function. And whether people who do those things preserve their sexual function or those things preserve sexual function is still. It's association. I sort of think it doesn't matter, you know, you want, they're both are good. Where it matters as a motivator is that validating the importance of sexual function to quality of life is critical for people feeling that they have permission. Like that's a good reason for me because sometimes it's like an afterthought, like, oh, okay, it's okay, I could prevent heart disease, but do I have to preserve my sexual function? That's a little indulgent. Why should I go to the gym just to have better sexual function? My kids need me to help them with their homework. But if it's like, okay, I can't have heart disease, I have to go to the gym. So I think part of it is validating that for people that probably there's strong association. On the other hand, we know what the heavy hitters are in terms of overall sexual function and biological medical conditions and psychiatric disorders. I'm not sure if this is exactly what you asked me, but it's a point that I think is important to make. We could go back and clarify if you wanted to hear anything different. So the heavy hitters, we could talk about categories. There's what we've already been talking about. There is associative data that metabolic syndrome in women, obesity particularly interestingly, hypertriglyceridemia, which probably makes sense to you, and then coronary artery disease and diabetes. But what's interesting about the last two is that the condition itself isn't as clearly correlated as the psychological adaptation or relationship to the disorder is for women. So for example, if someone had a heart attack or has heart disease and they're female, and it's more about how they see themselves and their interest or enthusiasm in becoming reengaged with activity than clearly the severity of cardiac disease. And that might just be, we don't have good research or it might be different in women. And same thing is true with diabetes. Like in men it's clear, like the higher A1C, the more sexual dysfunction, neurovascular disease, et cetera. But in women it's more about the impact of diabetes so far in the research, are they depressed because they have diabetes, they don't like wearing the monitor so they're embarrassed to have sex or like things like that, or their feet are numb and it just makes them negative rather than their blood sugar control. But I think that part of the problem is that we don't have as good research. And then there's the whole bucket of genital, urinary symptoms, menopausal symptoms and cancer. We haven't even talked about cancer yet. Breast cancer, gynecologic cancer, cervical and urinary cancer, ovarian cancer. So those are the categories, all those things I just mentioned that are associated with lower sexual function and sexual problems in women. And then there's the whole bucket of depression, anxiety and their treatments that also clearly interacts with sexual function in women and can be problematic.

And I'm kind of curious about both of those in both directions. So for example, like if you take two women who are identical in all ways, but one of them is sexually active and sexually healthy, and the other one is having sexual dysfunction for whatever reason, and let's assume it's not a physiologic reason, so let's assume it is a supratentorial reason and as a result of that she's just not sexually active. Do we have a sense of their quality of life, their well being as a result of that? In other words, what I'm really trying to understand is how important is sexual health for overall well being, in particular in this case for women.

There's a kind of a collection of different buckets of research looking at this. Probably the strongest and most consistent research comes out of the desire literature and looking at the impact of hypoactive sexual desire disorder, which is more like a diagnosable condition or distressing low desire, on overall quality of life. And there's, I could quote you studies, but there's a number of well done, both survey studies which are like in the community and population studies, and clinical data studies collected in clinical settings, suggesting that there's a strong correlation with impaired desire and overall quality of life. The problem I think with this research is the dichotomy or distinction you're making that it's purely supratentorial or psychological. Relational lifestyle is sometimes so hard to tease out, I'm sure, because no one person has zero biology impacting sexual function. But I will say something that does support that point of view. Practically speaking, you look at the, if you're a clinician, let's say, or someone comes to you. You look at the biology, you look at the psychological factors. Maybe it's sometimes even past sexual function or sexual trauma or religious upbringing or how they saw themselves as a sexual being from the time they were young. Even as a physician, I asked those questions. Then you look at the relationship, you know, and how that is, or the culture. And then you look at the things that you think are contributing and those that are amenable to intervention. And you do get to the idea sometimes that it is the psychology. You can reach that. But you want to be careful not to assume that you thought about everything in their biology until you have. But that said, you were asking me the condition of someone who has, like, a psychological sexual dysfunction, and what is the level of distress? Like, when people identify it and they want it to be different, it's extremely distressing and quite impairing to quality of life. And it can be a mirror for very distressing feelings. There are studies that look at the level of distress and the qualities, and they show things like, for example, loss of sexual desire, despairing, hopeless, feel old, feel ugly, don't feel connected, feel sad, feel hurt. You know, there's a whole collection of emotions associated with it. And typically in this research, they also look at discrepancy. And when they look at the discrepancy between, for example, a clinician's perspective or perception and the patient's, when they're asked by, like, someone else, like an independent reviewer, usually it's way underestimated how distressing or impairing it is to quality of life. We don't do a great job of understanding this. Part of it is legitimizing this. And that's what we're doing here today is like, really legitimizing. Like, this is a real thing for you. It affects your quality of life. It's okay to tell me. And it's okay to want this to be different. And when women are given that permission, either because they're being interviewed in a study or somewhere in a doctor's office, they embrace it because it is something that they're feeling. They're feeling impaired quality of life. I think that's what you're sort of getting at. This is worth emphasizing, giving this audience permission to understand that you can seek assistance or understanding or even treatment for these things, for different sexual assumptions. And we could get into defining them a little more specifically soon. And that's good. It's not something you should put as like, an afterthought in your life, because, first of all, it's Good for quality of life, it's good for your relationship. And there's also some. I don't know if you quite asked me this, but there is some research supporting the idea that it improves overall health.

That's not a stretch, right? I mean, whether or not that turns out to be true, we would only know with more rigorous study. But there's plausibility to that based on other things that we understand about the relationship between hypercortisolemia, HPA dysfunction, stress, all sorts of things that we know do directly impact physical health. So my way of thinking about these things is they may or may not impact the length of your life, but the quality of your life is at least as important, if not more important. And it's very hard to argue it doesn't impact the quality of life, especially if, as you say, it is being perceived that way. So I'm going to preface my next question with an assertion which is just because evolution didn't care about something doesn't mean we shouldn't. And the example I would use is atherosclerosis. So evolution had no interest in preventing atherosclerosis. If it did, it would have got rid of APOB hundreds of thousands of years ago because we didn't need it. I mean, we would have gotten rid of it in the last thousand years, I think, and we wouldn't have atherosclerosis today. But given that it didn't interfere with our reproductive fitness, it's of no concern to Darwin. That said, now that we can live longer, we have every reason to care about it, and we've taken great pains to reduce our risk of dying from it. Okay, so put that aside for a moment as I ask a very naive potentially question, but one that I've often thought about, which is, do women have it harder when it comes to sexual health because evolution didn't necessarily care about their sexual function post childbearing years, whereas in theory, evolution might care if men could reproduce through the length of their life?

You know, absolutely. This is a really important topic and area for discussion. So let me start with a point that I make often. I mean, women who are perimenopausal, menopausal, and postmenopausal aren't sick. And so sometimes people talk about it. And when you have postmenopausal vulvovaginal atrophy, right? Like, that's a horrible term. Talk about evolutionary terms that make people feel bad.

It needs a whole PR firm to come in to just come up with better terminology here.

As an Aside, I think you heard this terminology is that the North American Menopause Society and International Society for the Study of Women's Sexual Health about, I guess it's almost a decade ago at this point, and I was involved with this process. We got together and had a whole panel on what to do about this name vulvovaginal atrophy, for a whole variety of reasons, and concluded that it is what happens, you know, things atrophy, but it's not what we want women to think about. So we came up with the terminology genital urinary syndrome of menopause. So vulvovaginal artery can lead to genitourinary symptoms during and after menopause and the syndrome of menopause. So it took away the disease state. It's not really an illness, it's a syndrome which could be thought about in many other ways. I mean, happiness is a syndrome. And so we were really trying to neutralize it. I don't know how well it stuck. It does speak to this idea, first of all, a few concepts. One is when people talk about symptoms or treatments, I are we talking about a disease? I guess when we're talking about atherosclerosis and aging, we're talking about a disease. So on the one hand, you could put them as parallels, right? There's hormonal changes, the ovary stops making things, the brain does other things to the sex steroid hormones, testosterone declines in both ovarian adrenal production, et cetera. And we have physiologic changes which lead to aging, lead to decreased sexual function and even complete loss of good sexual function. Pain doesn't allow women to, you know, engage in quality of life, improving sexual activities, relationship building activities. So evolution has not been kind to women in a whole collection of ways. I think that's what you're asking me. And although women aren't sick, our position in the field, and certainly mine, is that we have the skills, the tools and the sophistication to manage it and to reverse it and to have a very different outcome than evolution would command. I'll speak not too personally, but I'm a midlife woman. I'm not ready to turn in the towel. And I can tell you that most of my colleagues and friends and family members have the same attitude. And so the challenge in the area is, first of all, not medicalizing this too much and making someone feel sick or you give them things that make them sicker. And to balance that, for lack of a better word, lethality therapy balanced to the Point where you're optimizing without giving people other problems. Like you give a hormone, you don't want to give breast cancer or endometrial cancer, or you give estrogen, you don't want to cause cardiac disease. And so that's the work that we do in this field is learning how to trick Mother Nature or evolution safely. But optimize all of these things. Sexual function, quality of life, longevity even. We could get into the discussion about whether hormone therapy improves longevity. I know that's an area of interest of yours.

Okay. This has been an excellent foundation for us to now go through some of these various things. So let's start with sexual dysfunction and I'll leave it to you which one you want to start with. So do you want to talk about arousal and desire separately and kind of walk through that sometimes? I find this helpful. Sharon, with other podcast guests where we do actual case studies. So I can make some up, but you can feel free to adjust them and say, okay, so a 35 year old mother of two, married, comes into your office and says, I love my partner, I just don't want to have sex. I'm just not in the mood. So tell me, what's your workup? That's basically all she says on presentation. Let's just pretend that the kids are old enough now that she's not like sleep deprived waking up every 10 minutes. So her kids are, you know, 10 and 12 or something like that.

And let's make her 39. If her kids are 10 and 12.

Okay, perfect. So she's 39, her kids are 10.

And 12 or 41. Right. Where things may be starting to change.

Yeah, yeah, perfect.

So point is, I have reasons for that.

She's premenopausal is the point I'm really just trying to get at.

Right.

And that's it.

And she doesn't have tiny kids waking her up in the middle of the day.

She's out of the difficulties of child rearing. Okay, well, how do you want to work her up and how do we help?

Let me just give you the categories and tell you how I would think about her. Who have you seen Masters of Sex? So the whole concept or how to organize sexual dysfunction was based on the work, really first of Masters and Johnson, that there was a response cycle that had an order. They looked at both men and women. They were actually really quite progressive. And the idea was that people started with getting aroused. And I think in their concept it was all physiologic because they mostly just looked at physiologic parameters, although they understood the psychology of things to some extent, that there was this idea that people get physically and mentally excited, they reach some sort of escalation and maybe even a peak or plateau. And that can be variable. And there's some models that for women there's more variability in plateaus. And then the classic response cycle is it results in an orgasm, climax, peak. Lots of different words get used, but we're just going to use the word orgasm, keep it simple. And that there's different patterns for that too. Right.

Can I ask a question? Different ways to have it that goes before that. So what comes first, desire or arousal? Desire comes first. Does it? Or do you have to have some arousal to then trigger desire?

I'm going to talk about desire in a moment because that's an interesting question. But in their model they kept it simple. You engaged in sex and you got aroused. And so maybe they thought like the interest in having sex was about being turned on or being aroused. They didn't really get distinguished about it. And then you have an orgasm. And for women, like there's different patterns. It could be happen in different ways with clitoral stimulation, vaginal stimulation, et cetera, and sometimes multiple orgasms, which is more characteristic for the variability in women. And then there's this idea of the refractory or resolution phase. And that's kind of for like many decades, since their work in the late 50s, early 60s, that's how people have organized their thinking. A few people came along, notably Helen Singer Kaplan in the 70s and she happened to be a psychologist at Cornell and has a whole discipline and following, some of which are my colleagues still there are a few around and added this idea of wanting or desire and felt that it was really distinct thinking about it, anticipating, willingness to engage and that if you didn't separate it, you were missing something about what could be a problem for someone like. So that 35 year old or that 39 year old we're talking about.

I think she's 41 now, but yeah.

No, we made her fool because her kids were 10. I wasn't letting her have kids at 25, but some do.

Okay, good point.

Her kids, if you said they were 10 and 12. I was just trying to be realistic. The other thing is I feel like it comes up in that if it's not late, reproductive, Postmenopausal, it's like 38 to 41. I don't know why, but I hear that a lot. There's sort of time frames that come up. We can talk about why that one is, but that's why I picked it. But she might say to me, like, you know, I'm exhausted. I have these kids, I have this job. But I agree. And I'm always kind of like, it's still, even to this day, surprised to hear. But I said you get turned on. Well, yeah. I mean, I feels fine. I do have an orgasm. Oh, yeah. And is that satisfying? Yeah. But I don't want sex. If you get rid of the idea that desire is separate, you miss that. You know, there's a lot of variation on that. We could talk about a different patient where they say, like, theoretically, I really want to be with this person, but I know that, like, things aren't going to work. I'm not going to feel anything, I'm not going to get wet, I'm going to have pain. So that I avoid and that I don't want because of that reason. Like, there's variations on that. So it's really helpful to keep these concepts separate. There's some work coming out. I don't know if you want to get into this. It's come out over the last decade, actually, in some sort of lay press books that are smushing them together, saying that they're indistinguishable for women, but I feel they shouldn't be. I feel they need to be separated. And that's based on, first of all, vast clinical experience that you need to walk people through this to understand the problem by separating them. Secondly, that the available treatments target different things and the physiologic plausibility for separation is strong in terms of risk factor and response to treatment, intervention and the opportunity for future direction and improving sexual function. If we keep them together, we're going to lose that. And to get very granular about this, the psychiatric compendiums has now combined them, desire and arousal as one thing called female sexual interest and arousal disorder. Whereas the sexual medicine societies have put out strong position statements as well as nomenclature papers suggesting that we have to have these categories be separate. And the upcoming ICD or the International Classification of Diseases is going to maintain separate coding for desire and arousal for both men and women.

And yet you're saying the DSM combines them?

It's the DSM 5, which came out now. It's almost 10 years ago. Interestingly, they just put out a revision, which I worked on, actually, as a medical reviewer. They insisted on keeping it the same. They told me that at the onset, you can review this, but we're not separating them. And they wanted me to look at sort of the medical piece of this. Again, it's based on the idea, and I think this is fair for the kinds of people that show up in psychological and psychiatric offices, that for women it often is interchangeable, like it can be. It is still separate for men. Do you want to digress for this for a moment? Because it's interesting and I think it resonates for people. And then we'll come back to what we would, how we would evaluate your 39 year old or 41, whatever she is now. So Rosemary Besson is sort of the mother of this model. And there have been others that have written about this, primarily the professional literature, but there's some books out right now, some lay press books about this. And the idea is that instead of this linear response cycle, that a better model for many women or for some women is something more circular. It's called the circular incentive model. And it's the idea that what drives sexual response isn't linear. Women go, I want to have desire, I want sex, I'm going to go find my partner, I'm going to initiate or I'm going to receive and then I'm going to be turned on and then I'm going to have an orgasm that's going to be great. And that when you say that to people, lots of people are going to say that I must be abnormal because I don't feel that way. And that their normal is more something like this. Like they're not particularly feeling spontaneous sexual desire. But the circle starts with the motivation and the incentive to be close to drive toward intimacy. They're mostly neutral, but because they are close to their partner or even we should make sure we understand that sex with oneself fits in here too. They like want to feel the benefits that come from a sexual encounter with either a partner or oneself. And they're receptive or seek the stimuli, but not because they're feeling like sex, hunger, the classic desire, but because of that motivation. And if everything's intact, psychological and biological influences that govern arousability are intact. They're going to have all that arousal, their brain's going to turn on their body. Your heart rate's going to go up, your nipples become erect, you're going to feel the genital sensations and that will trigger engagement or arousal that'll make you feel more invested and then more desire and then more arousal and that will lead to satisfaction and maybe an orgasm.

So that's a chain reaction there, sort of.

Right. It's modeled as a circle but it's the idea that that satisfaction, knowing it's good, knowing you're going to feel close. One of my favorite expressions from one of my long standing patients is the afterglow is what motivates it. How you feel together with how she feels connected, how not just herself good, but in the relationship. And that if you don't normalize that thing where desire and arousal kind of smush together when everything works, you're going to make people think there's something wrong with them, that they don't have spontaneous sexual desire. So there's a book out there. For example, Emily Nagosu wrote a book called Come as yous Are Some of the Work of Lori Brado. These are live press books. Looks at this, that we want to make it okay, that you can be motivated by other reasons. But where this model gets confusing is that it doesn't normalize low sexual desire where you can't make it work. So let's go back now. Let's go back to your example. So if she says to me everything works fine, but I still, even though I have a good experience, I still come back to this and I don't want to have sex, then that model doesn't apply to her and she's not normal. And where that model misses is they forget that we have to make sure that people who don't feel reinforcement, don't feel motivated to re engage, don't have the desire, the willingness or the interest. It isn't normal. Where I do find this idea works the most, where people are kind of neutral, but they engage to be closest in long term relationships because they know what makes the relationship work. So this person comes to you, what I'll do is I'll walk her through. I'll say, you know, do you feel sex, hunger? Do you initiate? Are you receptive? No, no, I avoid it. I finally give in because I know he's grouchy or she, or whatever. How does everything work? Does your brain turn on? Do you get breast sensations? Does your body get general arousal? Do you get genital sensations? Do you feel engorged? Do you get lubricated? The degree to which I ask specific questions is variable. Sometimes I ask more general questions like do your genitals get turned on? And do you peak? Do you climb? I've tried to find the language. Usually I just say, do you have an orgasm? And sometimes that's a whole other discussion. Women aren't sure. So I try to help them understand what it is they're experiencing. And there's a Lot of variability in the female orgasmic response. But women orgasm.

Can we put a pin in that and come back to that? Sure. I want to make sure we cover that. But let's continue with this patient.

And then I always ask, this gets forgotten often is, do they have pain? Now this is a premenopausal woman, right? Likelihood she's no longer breastfeeding. She's probably ovulating regularly, having regular menstrual cycles. So I interweave those of the gynecologic history, like what's the menstrual history? A 39 year old could be having an early menopause. I make sure that I'm not missing that emerging dryness, pain, discomfort. You can't always assume you know someone's age, you know what's happening. So it's regular cycles. Are they having dryness, pain? Are they, in this case, she's no longer ovulating. Are they taking some other medication? Are they on an antidepressant? So then I look at factors. Things like medications can affect multiple different phases. But so I collect that information for a variety of reasons. Someone with low desire, I would collect medication information. Someone with arousal difficulty.

What are some of the worst offenders there? I know that SSRIs certainly wreak havoc in men. Do they also do so in women?

So if you're talking about general sexual dysfunction, that can affect a variety of phases. Antidepressants, but all psychotropics, all categories of psychotropics. And these days people aren't just on antidepressants. The SSRIs and SNRIs are probably most well known to cause multiphase dysfunction. There's differences though. I mean, that's one of the areas that I consult with a lot because I work closely with psychiatry here is that not all drugs are the same. It is a class effect. But there are better drugs. And then there are other categories. Like for example, bupropion, which is more dopaminergic, is a different choice for a variety of reasons.

That's Wellbutrin.

That's the brand name for that is Wellbutrin. The generic is bupropion.

Within that class of drugs, what are the ones that are more likely to reduce desire?

So the classic SSRIs, most of them fit in that and the bundle together or they cluster together somewhere around 35 to 40% of what we call treatment emergent sexual dysfunction. But I want to make a really strong caveat in a moment about this because there's some, actually some new Research kind of debunking some of this a little bit. But that said. So the SSRIs, do you want me to use brand names because people know that better or generics? So Prozac, Fluox, I'll use both, being mindful of this. Prozac, Fluoxetine, Sertraline, Zoloft, Paxil, Paroxetine, Those are the SSRIs. And probably escitalopram, Lexapro and Citalopram, they're probably similar. That said, I have patients who say like I develop low desire on Prozac or I have difficulty with orgasm on Sertralin, on Paxil, but not on Prozac. So we sometimes tried a few. If I think an SSRI is the best choice.

That's definitely been our experience clinically is that yeah, there's a class effect, but at the end of the day it's kind of drug specific. And I always tell patients we're not the ones that are prescribing those, we're not psychiatrists. But if your doctor's prescribing you an SSRI or an snri, I always say the probability that you're going to get it right on the first one in terms of efficacy and side effects is actually not that high. So you have to be willing to switch drugs to find that right combination of efficacy and avoidance of side effects and you'll be able to stay within the same class usually. But it's there seem to be, you know, non trivial effects.

So again we're talking about the condition that you're treating it for. Usually it's depression or anxiety or both. And then there's the side effects, which amongst them is sexual dysfunction. So then there's another category, the snris, the serinergic norepinephrine drugs, which I know you're familiar with. There's more variability in the data on that. So there's Duloxetine, there's Venlafaxine, which is Effexor, which is probably the most commonly used one, and then there's Pristiq, which is Desvenlafaxine. All of them are probably similar to the SSRIs. But venlafaxine is interesting. At a low level, low dose, it functions more like an SSRI. And that as you kick in above, like 75 is up to 75 is probably low, somewhere over 100 to 150 functions more like an SNRI. And so teasing out the sexual dysfunction and the dose dependency is a little Tricky on that one, but just keep that in mind. And then des. Venlafaxine has some data suggesting it's less likely to cause sexual dysfunction and probably has to do with the chemical composition and how it's different than venlafaxine. Then there's some new drugs. I guess they're not so new anymore. Vilazidone and vortioxetine, which have very unique and different mechanisms and they seem to be better. They're complex serotonergic dopaminergic transporters. They're a little complicated in their mechanism, but the bottom line is they work both with serotonergic transporters as well as dopaminergic drugs. So it's the multi receptor factors that when you're looking at the sexual dysfunction component, that's why the theory is that they're better. The best data is actually with vilazidone.

Though I have some best data for fewest sexual side effects, lack of sexual dysfunction.

The problem with the research on the three newest that seem to be the better, that is Desvenenlafaxine, vorodioxetine and velazidone, is that the studies weren't perfect. There was a lot of high pre treatment sexual dysfunction. So when they separate from placebo and not having treatment emergent, it may be the effect of just treating disease, state of depression and improving sexual function. Which speaks to the point that I told you I wanted to make in a minute about what some of the newer research says about this in general. The other drug is mirtazapine, which is kind of an atypical ssri. It is very low in sexual dysfunction compared to the other SSRIs. But it has some other problems with side effects. It can be sedating, which is good for people who don't sleep. And there's some weight gain that people report with that. And why that is a little unclear, but probably the dopaminergic component.

Let's assume that this woman is not taking any of those psychotropic meds. Would her being on an oral contraceptive.

Yes. Thank you.

Okay, so what's the role of oral contraceptives in this?

Yeah, so I was gonna tell you about that in a minute. When we talk about hormones in this age, premenopausal women. Let me make my point though, because I don't wanna forget. So there's some research that's come out both in menopause for menopausal women and in general that the best thing to do for a depressed person for Sexual function is to treat their depression. I still am having trouble teasing this out, that probably the best thing to do is pick the best drug for them for their depression and that it's more important to get them undepressed in terms of sexual function. And that a small percentage, even though the numbers in other studies say 30 to 40%, will get what's called treatment, emergent sexual dysfunction. But one of my colleagues, who I admire greatly, who does a lot of work in this area, said something to me the other day. We're working on a project, a paper that relates to this. She said, look, the bottom line is, here's the simple answer. If you treat their depression, most likely their sexual function is going to get better. If it doesn't, it's due to the drug. And I thought, if they don't want to, it's not because their depression's not better, because depression is associated with sexual dysfunction. And then that's when you start to say, well, if this is important to that person, you switch the drug around. And this is where we can come in, is where we can say, look, this is an important reason to switch meds. But some people say to me, I don't care. Like, I just am so happy I'm feeling good. And I sometimes say great, or sometimes I say, well, you could feel good on something else and still have good sexual dysfunction. Don't dismiss that. So it depends on the patient. So the other big category, so we talked about psychotropics, and they're less commonly prescribed in like ordinary situations. But antipsychotics, anxiety meds, they all have some issues around sexual function. And should that be relevant, we could discuss that. So the other categories, like not so much for this woman, blood pressure meds, there's some discussion about how to think about those. Collection of pain medications are another big bucket. Hormone suppressing drugs, like if someone's on a aromatase inhibitor for cancer, prophylaxis, et cetera. But the thing that we really want to make sure we talk about in this age group and you're bringing this up, is combined hormonal contraception. I'm glad you raised this, Peter. So confusing area also. People are very polar on this and very opinionated. But I think it's important to recognize not just oral contraceptives, it's combine systemic hormonal contraception. So people take birth control pills which have estrogen and progesterone. They also use patches like the orthoeverpatch and the ring like the NuvaRing. Right. And those combine and There's a whole bunch of different types of these. But the idea here, what are you doing when you give hormonal contraception? You're turning off the brain and that feedback loop that makes you ovulate, you know, make a lining, shed it and be able to have a pregnancy and then shed it if you don't. And you're turning that all off by giving super high doses of hormones. So what happens? The short answer is with combined contraception, it's probably most noted in the research is that a small percentage of women get that high level of estrogen, but the vulvovagining mucosa doesn't recognize it. And you can develop a vestibulodynia, a vestibulitis, that the vestibule is that tissue around the entrance to the vagina, not so much inside the vagina, but that surrounding tissue called the vestibule is very sensitive to the drop in these endogenous estradiol and the synthetic estrogen sometimes don't do their trick and they can develop a vestibulodynia, meaning pain and dryness and almost look like a postmenopausal woman when it comes to that. That's one issue with contraception. It's probably that number. You want a number? The work of some of my colleagues in this area who do like sexual pain and vestibular DNA work say it's.

Somewhere around 10%, meaning 10% of women that are receiving systemic users who are receiving systemic growth.

And that it's probably similar with rings and patches, but it's not as well documented. And then there's some variability. Like higher dose oral contraceptives have been more likely low. I'm sorry, the very low dose have been more likely implicated. And people do better if they have like more robust high dose, like sort of more standard 35 microgram pills as opposed to these ultra low, like the 20 micrograms.

Like is low lowestrin considered low?

Yes, that's an example. So the ultra low ones tend to be the biggest culprits. That said, the experts in the field feel this is very important for us to understand. The ordinary gynecologic community thinks it's relatively insignificant. Whether they're under detecting this particular piece of it or not is something that needs more development. The other issue with birth control pills is that it can have an effect on neurotransmitters and sometimes women will develop mood issues with, as you probably know, with like high dose oral contraceptives. And that may have an impact on the neurotransmitter milieu and the mix that leads to sexual dysfunction and low sex drive. Then finally, and this is probably more important as women get a little older and it might lead us into the discussion about testosterone. Is that so? Three things. One is they can have an effect on the local vulvar tissue if we have this issue, particularly the lowest dose estrogen. The other thing is depends on the androgenicity of the birth control pill. That's yet another issue. And there are androgen receptors in the vulvovaginal tissue. So that may change sensitivity or even lead to pain. That piece of it. The second thing is that intersection with brain neurotransmitters and mood. And that effect on sexual function could also be clinically important. And then finally, and this is like a whole nother thing, what do you do when you send all that hormone into someone's body? You increase the production of sh, so.

You'Re binding up more of the hormone as well.

The easiest way to think about it is you need something to carry it around with. And that SHBG goes up in other states like pregnancy. You might ask me like the same with birth control pills in pregnancy or when you take thyroid hormone. There are other things that make that production of that go up. The data across situations is like you could say, okay, it's like around 100 such with this or is not so clear. I think it's best just to say it makes it go up. Now that is 100% of women, like I get asked this question like does it matter? 100% of women have a higher SHBG if they take for example, let's just say high dose birth control pills. Let's just stick to that for now. Everybody who takes it has that and what does that do? So it helps carry it around. But it also fortunately or unfortunately, whatever you want, the fellow travelers, androgens or testosterone gets carried by shbg. So because you're increasing shbg, there's some thinking that you're binding up the circulating testosterone and you may be lowering free testosterone in those women. And that might be another potential contributor, low desire. Now we get into testosterone, we can talk about that. But has testosterone affect desire? Probably at the level of brain receptors and turning on those pathways of desire. And there's some genital changes too in the metabolites of androgens that change sensitivity and that might impact desire. But that's a secondary state state. And we're also going to. When we talk about testosterone, we were talking about how it doesn't like, abruptly change so much like ovarian hormones with menopause that it's more of a gradual decline. So the intersection between contraception and women in their late 30s and early 40s and testosterone is interesting. So if you look at my arm when you're 18 to 24, that's when we start to study reproductive. Your testosterone's like, up here in the 40s for women, right? And then it kind of goes down like, I wish I could do it better, but it declines. And by the time you're in, like, those late 30s, early 40s is about half. Like, if you look at normal ranges, studies that have tried to of what you were when you were 18, and then it levels off at somewhat lower in your 40s and 50s and actually goes up a little bit past 60 and kind of levels off down there. So if you're on birth control pills, that curve is way down. A woman at 40 might be much more sensitive to that effect than she was if she was on a birth control pill at 25. And that difference in her testosterone or free testosterone may be significant in that she'll come and say, I have no sex drive or I have no general sensitivity. That's a kind of an important thing that most people don't tell their patients when they put them on a birth control pill or combined contraception for 20 years. Now, the other thing, and I think it was in. We get some notes in advance. It was one of the questions you asked, what happens, believe it or not, even though people say it doesn't come back. Like, let's say you take a birth control pill from 20 to 40 and then you have, you know, you decide to switch to an IUD after your second baby or your third baby, which happens a lot. What happens to my shbg? There's really only, believe it or not, really one good study that was done by Claudia Panzer in like 2000, something like that. And we need more. There's some other data, but not a good study. And she looked at current users, never users, and stopped users who stopped six months ago. And the bottom line was at six months, the stopped users, the previous users were in the middle of the other two. They hadn't gone down to normal. Now, no one ever studied them out to three or four years. But I can tell you, and my colleagues can say that if that woman walked in and she'd been on birth control pills and I checked her shbg, even if she had stopped it, it's always going to be higher than the person who Never used them. I just see that all the time. So does that mean that her free testosterone at 40 is lower than it would have been if she hadn't used birth control pills for 20 years? Well, that's the theory.

Wouldn't it have to be? Unless her testosterone has gone up? I mean, because SHBG is doing the lion's share of the binding. I mean, albumin is a relatively small contributor to this process. So isn't it about 85% of the androgen binding is coming through SHBG.

It depends a little on how much you have. But that's roughly the idea, to answer your question. Depends a little bit on how much SHBG you have. But most of the binding is through shbg, and a small percentage is through albumin. There's one more point. Point, which, before we go back to talking about binding in a second, is part of the controversy, is it's not clear that free testosterone is the bioactive component to what makes desire happen, both in the cells and in the brain. So the naysayers are saying, well, okay, but that's not necessarily the active component. And, like, looking at SHBG and free T might not be what we need to be doing anyway.

And, sorry, just let's go down that rabbit hole a little bit further because this is something that fascinates me endlessly, is, at least in men, the way I think about this. But I would think that's parallel in women. The one thing that's missing from all biomarkers that we can measure. So let's just make sure people understand the lingo you and I are throwing around. Testosterone is a measurement assay. When you go and measure, when you ask, what's a person's testosterone level, there's an assay that breaks apart and separates testosterone from albumin from shbg. And you actually measure in nanograms per deciliter the concentration of testosterone in that plasma. When people talk about free testosterone, that is not measured. That is calculated. It's estimated based on the measured testosterone, the measured shbg, and the measured albumin. But there's a whole other issue here which I don't think gets enough attention. I do plan to explore this in subsequent podcasts because I find the topic really fascinating, which is androgen receptor saturation. I'll give you a very clear clinical example I see in men, but I know it applies to women, which is you take two guys that both have a total testosterone of 500, and let's just assume that their free testosterone are estimated to be roughly the same, and you give them both testosterone. So now they both have a total testosterone of a thousand. One of them feels significantly better, the other one says, I don't really notice a difference. There's an argument that says that the guy who doesn't feel any different already had his androgen receptors saturated. So yes, you drove up his testosterone and yes, more of it is free, but it doesn't matter because where it matters most in the nucleus at the androgen receptor, you haven't increased it. Whereas the guy who says, oh my God, you've changed my life, my libido is higher, I'm recovering from workouts better, I'm putting on muscle, everything feels better. He was probably undersaturated. So this is something, I mean, to my knowledge, Sharon, we don't have a way to measure this clinically. You know, I know that there are people in the lab who can do this, but.

Right. So this is part of all of that emerging understanding and lack of clarity is now being brought to the question of female testosterone too. And even less is understood about the role of the circulating actual, measurable testosterone. What we think think is free or bioavailable and how that's interacting with the androgen receptor both in non genomic and through genomic mechanisms. And then all of that, what cells do we even mean in a woman? Is it her brain, Is it her genitals, Is it her nipples? Like we don't even know. But the theory is that the most important place that testosterone acts is in the brain. So like, is it, where is that happening at a cellular level in the brain? If you look at like the most general concepts, is that testosterone is the hormone of desire, testosterone and its metabolites, and that it interacts with brain neurotransmitters to turn on pathways of desire. And when it drops, it's sensitive. Like if you look at the early work of Helen Singer Kaplan, who was a psychologist, I love reading her work because she actually talked a lot about this and said the goal, this is like my mantra. I have it in a couple slides, which is to fine tune that just the right amount of giving exogenous testosterone safely to turn the rain back on to where she was when she was satisfied. Meaning like premenopausal satisfied, but not invoking lethality and keeping her safe. And that titration is the work of desire, you know, the desire treatment. Right. When you're using pharmaceuticals. So the argument is, first of all, do we know what's actually happening? And then do we know what we want to fix. Getting back to our original discussion, this woman, let's say she was on birth control pills and it's been 20 years and like, she stopped them on and off for her kids, but she still is taking them and her SHPD is high and her free T measure is low, and then she has low desires. Are we confident enough to say that's why? And then the answer question is, will stopping her birth control pill solve the problem if her SHPG doesn't come down? Or am I going to give her doomsday prognosis? Because women will say to me, well, what if it doesn't come down? Will I be like this forever? And then it gets into this whole question of, like, is she a candidate for exogenous testosterone? She's premenopausal and she's still menstruating. So we could go on and on with where this leads us. I think we want to talk about, like, what do we know, what don't we know, and what are the pragmatic or practical implications of what we do understand and how we counsel patients ultimately?

Well, I think this is as good a time as any to go a little further down the testosterone hole because I think we're making this up as we go along vis a vis this case. I think where we're arriving organically is actually quite a common phenomenon. You know, I've made this point on a previous podcast. I think when I was on Andrew Huberman's podcast a long time ago, I made this point it's worth making again, which is we think of testosterone as the man's hormone, estrogen, progesterone as the women's hormone. Not entirely correct. In fact, one of the challenges is the way the labs report the units of estrogen and testosterone are different. Testosterone is typically reported in nanograms per deciliter, whereas estrogen is reported in picograms per milliliter. So when you convert these to the same units so you can do an apples to apples comparison, you realize that testosterone is much higher in a woman than estrogen is. Let me repeat. That a woman has estrogen.

Yes, absolutely. Thank you for saying that a woman.

Has much more testosterone in her body than she has estrogen. This is a staggering thing that surprises most women and most men alike. And to me at least, the implication is, given that testosterone is the most abundant sex hormone in a woman's body both pre and post menopause. And by the way, post menopause, the gap is even bigger because of the reasons we've Already discussed. It is not a surprise that changes in testosterone, a hormone that is largely responsible for desire, can be just as important in women as they are in men. So this brings me to this asymmetry.

Such an important point is like, really people just have such a hard time wrapping their brain around it. They think that the only hormone they should be talking about is their estrogen. And then there's this idea that estrogen supplementation improves sexual function. And that's like a whole nother discussion. But it's so poorly understood how important testosterone is to the functioning of women, particularly when it comes to sex organs and sexual desire or sexual function.

So this is where I think there are lots of places we can fault the medical system. And we're gonna line those up and stack them here in a minute. But let's start with one of them, which is the double standard and frankly, the lack of scientific rigor around evaluating testosterone replacement for women. So there recently was. There were two trials actually looking at a, if I'm not mistaken, a gel and a transdermal testosterone product for use in women. I believe the gel didn't find a benefit. I can come up with several reasons why not. But the transdermal testosterone, it began with an I. I don't remember the name.

Intrinsa.

Yeah, Intrinza.

There was a Johnson and Johnson Patch, 300 micrograms. So even trickier when you think about these numbers. It was a 300 microgram patch, very low. I was like struggling with the numbers.

But here's the thing. It raised testosterone, it improved sexual function, and the side effect profile was not of concern. This was a drug that should have been approved. Why did the FDA not approve it?

There was more than one trial. There's a wonderful paper. It was in Lancet, I think, in 2019. That's a meta analysis of over like 50 something studies. There are some that are sort of most well known because they resulted in presentations of campaigns toward the fda. But there have been a number of randomized controlled trials using patches. The Intrinsibrand by Johnson Johnson was a particular campaign that was brought to the FDA based on their randomized trial. That study was, I think it was also. I'm using the 2000 a lot. It approximates it. It was actually Jan Shiffrin in the New England Journal, and the first study that she looked at was the equivalent of the 300 microgram patch in oforectomized women, young women who had low desire. They had distressing low desire. And the estimation for the 300 micrograms is that's the physiologic amount. This is also a little complicated, but that's the physiologic amount that approximates what you would get in a mid reproductive or late reproductive age to bring you back to that level. Somewhere around let's say 30ish, 27 to 38, something like that. It's based on like the reference range for normals for women and that when you gave that patch they looked at outcomes. The outcome of interest was hypoactive sexual desire disorder or sex drive or libido and it showed positive improvements. And it was based on both self reports, satisfying sexual events, et cetera, as well as other phase responses, arousal, orgasm, overall satisfaction. It showed really no adverse effects in the short run. But they looked that and other data looking at longer term safety studies and we can talk about some of the other trials and data too. But it looked at intermediate cardiovascular outcomes, cancer outcomes and metabolic outcomes and there were no hits. But it was a 24 week trial, six months. And the main thing in small percentage of women was what's called hirsutism. So it was a little hair growth like on the face along the nipple, it was about 18% and a little acne. But women didn't get virilized like hirsutism is kind of a scary word. They had a little extra hair. I like hair growth, a little hair growth. Easily handled by dipilation strategies that women use anyway. And the acne was relatively mild and women did well and they liked it. And it was brought to the FDA at that time. And the issue wasn't efficacy, it was lack of long term safety data. There was a lot of rancoring. I know some of my colleagues were very, very upset about it at the time. And it did get approved in Europe for some time for that indication O for recognized women with low desire. And it was used off label in other postmenopausal women. It went off the market for reasons other than efficacy or safety. And it's no longer available in Europe as a 300 microgram patch. So no patches available anywhere in the world for women.

So let's just level set for people so they understand something. There's an undercurrent of bad science here which was one of the reasons given for the fear around this use of topical testosterone was extracted from the incorrect and erroneous fear that still lingered from the Women's Health Initiative. So that's kind of problem one here. I think problem two is the double standard which is how many topical injectable transdermal testosterone products are approved for men right now in the United States.

We can say at least two dozen, like depending on how you look at the indication whether it's for, you know, hypogonadism versus sexual dysfunction, you know this. Right. So let's just say two dozen.

Okay, so those products get approved on biochemical efficacy. Do they or do they not raise.

Testosterone and also outcome, like the outcome of, you know, that you're looking for the target outcome of the study.

They don't require the five year safety window because we've already established over decades that exogenous testosterone at physiologic doses is safe. So again, you could make the point. Well, Peter, why do you care about this? I mean, you can prescribe it off label to women, which of course we do.

Oh no, there's a huge reason to care.

So let's talk about why does this matter?

There's been a lot of feeling that the standard just to emphasize this clearly applied to the first drug, the Lipigel. You asked me about that. It never made it to the fda. They withdrew their applications and so forth.

I'll talk about why didn't have efficacy claims. Right.

It was called Lipigel. They looked at the data for out to five years and had like seven years of women patient data research. And it didn't show any hits for being unsafe. And it was loaded for women with cardiovascular risk factors. There was no increased rates above baseline rates of cardiovascular disease, of breast cancer, of intermediate markers for metabolic or Cardiovascular risk like A1C lipids, inflammatory markers, and they reached the therapeutic level in the blood. So they felt that they could clearly state that this represented safety data, but the efficacy hit wasn't met. And so they did not take it further to the fda, unfortunately. And that's been the last effort since then. But just going back, so the problem is that you're saying like, why do they approve these testosterone products? Because the concept has already been proven right, that we know the FDA makes this assumption that it's safe, but when this was taken to the division that looks at this, it's really the hormone and reproductive end. There's no precedent. But the lack of approval doesn't then permit the precedent, the history, the knowing, the expert consensus in the field that it's safe. So you never can get there if you don't approve something at 24 weeks. So this is the conundrum that we face. Like this is the problem. There's only one place in the world that has a government approved product of Testosterone, it's the continent of Australia. They have a product that is now available that you can get. It's called androfem and it's 5 milligrams. This is the dose. You can go up to 10 milligrams of the item, the testosterone that gives you this physiologic amount of testosterone. People get confused because the patch was 300 micrograms, but it is available in Australia, it's government approved, it's based on the same research, the same numbers, the same blood levels, the same outcomes. There's a way for practitioners and from other countries, by sending their licensing information to actually order it for patients, but it's not done very much. So no other place in the entire world has approved a testosterone for women. So you're asking me, like, why does it matter? We just prescribe it off label. The problem is there's no regulation to it. So let me say something else that I think was implied, but you're mentioning the study about the 300 microgram patch that went to the company, that went to the fda. There have been a number of randomized controlled trials looking at similar doses, mostly in patches, looking at women on and off estrogen, pre and postmenopausal, surgical and natural menopause that have shown the same efficacy with the outcome of hsdd, hypo, optic sexual desire being the primary outcome and showing other parameters with improvement like arousal, orgasm, satisfaction, et cetera. And based on that, consensus papers that have come out in the last couple of years really say that this is indicated and probably late reproductive age. There's two different guidances and definitely postmenopausal women based on this efficacy and safety data and these numbers of randomized trials, and this large meta analysis that looked at efficacy and safety of numerous studies demonstrates this. So you can prescribe it. It's off label, but it's supported by all of this data. The problem is it's impossibly hard to prescribe it carefully and with the precision, unless you're in Australia, that we should command for our patients. So, yeah, it's really imprecise and it's a problem.

And let's explain this because I want to talk about it, which is because you have to basically rely on one of three methods. One is using a man, sort of a male topical product, but then their doses are wrong. You're stuck using like Androgel, which, by the way, I think is a suboptimal product, even for men. So you're now you're taking a product that I don't think is very good for men trying to apply it to women. You can cut patches into tiny little areas. So take an FDA approved patch and cut it. You cannot use the FDA approved injectable because the concentration is too high. Those are 200 milligrams per milliliter. And you can't get enough into a needle. Like it's basically you just need what's in the needle, let alone in the syringe. So you're basically left with three options. None of them are an FDA approved product. One is a compounded cream, one is a compounded injection. So they can compound it at 20 milligrams per milliliter of testosterone sipion, which is 1:10.

So just to be clear, we want to give about 1/10 of the male dose.

That's right. And then the third is compounded pellets, which again you can get an FDA certificate for the raw ingredient. But it is not an FDA approved product the way for example, your Vivel dot is FDA approved as top classroom. So therein lies the rub. That's the crux of it as I see it.

I think it's good to explain this to people. So we said earlier that testosterone was the most in a little more depth was the most robust circulating hormone in women. That said there are normal ranges for women. They're sort of broken down by decade and quartile. So like 18 to 25, 25 to 35, 35 to 45 and sort of 45 to 50 and up. And there's been a couple of good studies, particularly by Andrew Gay and Erwin Goldstein was involved with this work looking at creating normal ranges. So the idea is when you treat a woman, you want to go to the physiologic range for mid to late reproductive age women. So therefore you're not overshooting and you're not undershooting and probably that's the time that that's the best range. So somewhere like, for example 28 to 35 or 28 to 37 with a standard direct total testosterone assay. We didn't talk about what you should measure and follow. We can come back to that. And that was what they found was safe and efficacious in these studies was that physiologic range for mid reproductive age women based on normal ranges in studies. By the way, I want to correct myself. The data I just have it in front of me is that it was 46 studies looking at 36 that of these trials were randomized and like 8,500 women close to 8,500 women. There's lots of data, it's not lacking. There's probably even more that didn't get into the Smith didn't meet the criteria. We have lots of data, it's not based on lack of data and we do have decent outcome data, meaning it's extension trial data for up to four to five years and randomized trial data clearly up to 24 weeks, but certainly in some trials up to even two years. So it's not any different than what we have for men. We just have long term use with FDA approved products because they've approved them that you were speaking about.

So it's a little bit of a cart horse problem, which is we're stuck in this paradigm where unless we get some approval, we can't get out of it. To do the longer studies that you'll.

See post market that are carefully done and will satisfy future approvals. Right.

Effectively the phase four trial.

Right. So you need to use one tenth of the male dose because that's probably what gets you to this physiologic range that I was talking about. Now the Australian approved government product does do that. It starts there and then you monitor levels and there's no cut point for saying this. Testosterone is the one. You don't treat a testosterone, you treat a syndrome. That's the first thing you treat hsdd and I usually check baseline levels to make sure they're not high because if someone comes to me and they're 52 and their testosterone's surprisingly high, they're not in that later quartile, I might say to them, I don't think this is the solution to your problem. But if it's low as I expect it to be, they're not abnormal, they're not deficient, they're just normally what they should be, then I shoot to treat them to that reproductive physiologic level. So you want to use one tenth of the male dose. The position papers that I've been involved with state that because it's so hard to get the concentrations consistent, we recommend using transdermal male products at female doses as opposed to compounding. And if you're gonna compound, you're probably better off with transdermal than a pellet or an injection because of the peaks and the difficulty in not getting into the. The key thing is you don't wanna get into that supraphysiologic level which hasn't been demonstrated to be safe in women. And so the trick is really it's so hard to use 1/10 of a male dose. So here's what I tell someone and it's a joke. I prescribe a year 30 day supply, for example, of the tubes, the 1% testosterone tubes. They go to the pharmacy. The pharmacist rejects the prescription. It's not covered by insurance. The pharmacist calls me and says, do you know it's a woman? I'm like, I write it on the prescription. Didn't I say the patient is a woman? Hypo androgenism is the diagnosis hsdd. And yes, she's going to pay for it. I tell them to look at a cost saving app and find the cheapest place. It's usually $200. They buy 30 days. They have to hope it works because they have to waste the $200. Then I say take a tube and waste one. Divide it into 10 little piles and then figure out what you're going to do to get that amount onto your body every day. And then we'll do a blood test in three to four weeks. That is not the kind of medicine I want to practice. So one strategy is to tell them that you can buy them in the pharmacy 5cc syringes and squirt the thing in and use half a cc a day. If it's a tube, it's easier to squirt in than a packet. I have a patient, she's my most brilliant patient, she's a baker. So she discovered that the cooking spoon, somewhere between a pinch and a smidge was a tenth of her packet. And then when her level's a little high, she's like, okay, I'll level the spoon a little differently. This is crazy. There's no better solution.

Yeah, it's total alchemy. Tell me, what's the instruction you give women for how and when to apply? Do you say, I want you to do this right after the shower. I want you to exfoliate your inner thigh. I want maximum absorption. Like, how are you making this as consistent as possible.

A relatively hand hairless area, a buttock, an outer thigh, the back of the calf, just so it gets absorbed. You obviously don't want to wash within a couple of hours. It doesn't matter the time of day. If you want to make sense to do it the same time of day. The other thing to really herald is it can transfer. So if you have children that you're holding or if you have a female partner and it's skin to skin contact, it actually can transfer. And it's not thought to be insignificant. They're too important points for us to all know it can transfer. So you want to put it somewhere it won't transfer if that's going to be an issue. Even though the amounts are much smaller. And everyone knows that about male. Like if you squeeze one of those tubes out on a male shoulder, you know this. It's like a whole big surface area. It's much smaller in women, but still. And if you're going to get a blood test, don't put it where you're going to draw it, or don't try to wait some hours so that you still get a little bit of a peak, even though with daily use of transdermal, it's more of a steady state. The other caveat is if there's a potential for getting pregnant, they really have to be on good contraception. So who might that be? So there is a biological plausibility. And the guidance in the clinical guideline says that you can consider this in later reproductive age women. And so every now and then a menstrual cycle peaks in. And all of us have heard of an unexpected pregnancy in those women. Probably by the time you discover you're pregnant, the testosterone is not going to do much harm to the fetus because it's usually only a few weeks. But we don't want people using testosterone and getting pregnant. That's one of the big reasons. I mean, and we didn't get back to this with the oral contraceptive patient. The solution isn't to leave her on a birth control pill and give her testosterone. First of all, it's not indicated for premenopausal women. Second of all, that's not what you do. Right. You try to correct the hormonal imbalance.

If this is the woman we're talking.

About going back to her. Right?

Going back to our hypothetical case. Yeah. Let's just say that that's the path we're going down. You would remove her from the oc, probably switch to an IUD if SHBG levels were still sufficiently high. And free testosterone, well, let's just say total testosterone was kind of 40th percentile. You'd say, look, we're gonna bring that up higher. Given that your SHBG is so high, it's gonna bring your free testosterone right up to about the 50th percentile. And again, you're using that as a guidepost. But it's ultimately symptoms that you're treating. You're managing symptoms.

And so let's say that's what I decided. I look at the biological psychological and social factors in this woman. And I decide like that's the, the thing that's amenable to intervention. I'm going to change our contraception. So it's not just women who are already on these that I tell I'm a little Birth control pills, combined contraception. I want to make this disclaimer. Patches and rings are extremely effective and most women don't have a problem. So if you ask me what should I take, you have to talk to your doctor. Should I use NIUD to start with? I can tell you how I counsel my own daughter, but that's my college age daughter. But that's different than what I would tell patients in people. They're incredibly effective worldwide. They prevent unwanted pregnancies, they protect against birth fatalities, et cetera. Worldwide, they liberate women all across the world. We don't want to like say nobody should take birth control pills of course, but for this discussion, if somebody has a problem, that's something you can change. And if it's one of the problems we talked about, what you should tell a 20 year old about whether you use birth control pills or put it in an IUD is like a whole nother conversation to be preventive. Again, this is a small percentage of people who develop these issues. Some women aren't sensitive to the everyone gets a change in their shpt. Some women aren't sensitive to it. Some women aren't sensitive to the non endogenous estradiol in their vestibules. Some aren't. So I can't tell you who that's going to happen to. Again, the decision about what to use over time is a discussion with your doctor. I think more gynecologists need to offer informed consent so women can choose more carefully at the onset. And this is an important campaign that gets messed up. There's no informed consent. They just hand people a prescription. At 21 you should give women choice. But anyway, so getting back to testosterone. So I think the challenge is then we weren't going to use it on this patient. But let's go back to this for a minute is that you're going to then have to do that 1/10 of the male dose. But you do have to follow levels because women are all over the place. Like how well they get 1 10, how that 110 of a product that wasn't well.

Also how variable the absorption is. Not all people have the same skin.

These were not designed for women. I can tell you that the data in Australia is very positive. For example, I work very Closely with one of the main researchers there, a woman named Susan Davis, who's done a lot of the work in this field, both in Australia and worldwide, and a first author on a number of really important testosterone consensus papers. She impresses me. But what she tells me about the clinical outcomes and the ability to get kind of steady state good blood levels because it's a controlled product designed for women, regulated and formulated. We need that. That said, you do have to follow levels mainly to make sure that you're achieving safe doses. So, like, if you said to me, well, like let's say someone has a level that it's too low and they're not getting benefit, would you go up? And I'd say, sure, because we haven't achieved the physiologic range and I know it's still safe. So I am like checking it to make sure if they're not having symptoms that are improving, to see that we're giving them enough. But the most important reason for monitoring blood levels and I monitor because of what you explained, the smartest thing is just to mentor a total T. We didn't go through this in elaborate detail. It's not clear that that's the best marker for knowing whether that's the way to tell whether testosterone is helping a patient in their cells and in their brain, their genital cells, their brain and some other body cells too. But that's probably the grossest, best measure we have. Free T is calculated and we don't even know if that's the bioactive component, testosterone. It's a very complex what now is called intrachronology. It hits the cells, it gets converted into metabolites, androgenion, dht. It enters the cell through the androgen receptor and has both genomic and non genomic effects. Non genomic means direct action. Genomic means it causes gene translation, other protein development, which then has trophic effects. And so all of that's happening. Probably the total T is the best measure of both not being too toxic and also probably targeting. Now you ask me what's the best type of total T. So most people have direct assays in their lab. If you send your patient to your hospital lab or Quest or LabCorp, they're imprecise when you use them. For women, they're not the best measure, but they're good enough for what we're doing and what we're talking about. The mass spectrometry testing, which has fancy names, is used in research and in clinical labs.

And I believe you can specifically order that so we do order LC Ms. When we send our patients.

I don't know if people know what that is.

When we order estrogen levels, testosterone levels, we actually request LC M s because we've seen how, believe it or not, supplements that you're taking can dramatically impact the readings. And we noticed this actually first in men. We were getting men who would get estrogen levels back that were, you know, normally a male estrogen level might be 25 to 40. We'd see guys with like 200. I'd be like, that's impossible. Right. First of all, he has no symptoms of having an estrogen of 200. Come to realize he's on some supplement for I don't know what, and that's impacting with the assay. You send him to get an L, C, M S and it comes back normal. So all of this stuff gets very complicated very quickly. Just quickly. I want to talk about one other hormone before we leave this and go to our next topic. And that is the role of dhea. For folks who might not be familiar, DHEA is a precursor to testosterone. DHEA is actually not regulated in the United States. It's a hormone you can buy over the counter, which is odd. I don't really understand why it's unregulated. But that's another story. What is the role of oral or topical DHEA in female sexual health?

Testosterone. Its metabolites and its precursors are also like an area of confusion. The simple version, which is good right now, is the DHEA is a precursor, so why not use that and then make testosterone? So testosterone gets metabolized to things, for example, like 5 Alpha DHT, which is probably the most potent metabolite and aromatase to estradiol. So when we're talking about throwing all these things out, we're talking about, do we want to look at a precursor or a metabolite and then what's actually working in the body or in the cell? So the short answer is there have been some trials looking at oral DHEA for the outcomes of interest that we're talking about here. For example, low sexual desire. And they have not been convincingly positive. Safety has not been really well studied to the extent to which I just told you. There's all these randomized trials of efficacy and safety for testosterone for women using the product, the 300 microgram or gel products. Right. 300 microgram patch. And again, that's different than the blood level, which we're measuring in picograms for ML. Picograms for ML is what we measure for one. We'll come back to the measurement in a second. But the oral dhea, which is administered in milligrams, some outcome studies have been done. They've been small, they've been problematically designed. All the criteria for good randomized trials haven't been met. And there's no good safety data, really looking at this. But the biggest thing is that efficacy has not been demonstrated. So we don't recommend oral DHEA for the indication of hsdd. I know people use it. Whether it helps some patients and whether we're doing anything problematic to the way we're measuring different things is. Is impossible for me to tell you because we don't have good control data on this. That said, there is very good data supporting the use of a vaginal intravaginal dhea. The chemical is called Prosterone. The brand is called Intrarosa. Basically, it's like a little suppository. It's used for vulvovaginal atrophy, resulting in genital urinary symptoms of menopause. And the indication is dysphoria, pain, post menopause. And it has very good efficacy and safety data with very little systemic absorption for that indication. And the rationale for it, instead of using an estrogen local product, and maybe we'll have a few minutes to get into that, is that there are mixed receptors in the genitals that need both estrogen and androgen. So it gets metabolized into both androgens and then eventually to estrogen at the intracellular level. That's the theory of it. Right? Because again, remember, DHA is a precursor.

How do you decide, Sharon, for a woman who's presenting with a pretty common presentation, whether to give estrogen, whether you're going to use an estrogen suppository, or whether you're going to use a DHEA suppository?

The data suggesting differences in efficacy isn't there. So you really could offer. We can get into, like, how do I. Even. Even among the estrogen products, there's a whole bunch of. Of choices. There's creams, there's rings, there's inserts, and then there's tablets. They're all local vaginal estrogen products that help with dryness and pain and sexual activity. And then dhea, the intrarosa product, is an option. And so the standard practitioner will start with an estrogen product and if it doesn't work, switch to intrarosa. I think it works really well. So I offer it as an option. And there are some. I Have some educated patients who that's what they want. The other thing is that it doesn't have a black.

Any distinct pros and cons to.

Yeah, so it doesn't have a black box warning which we'll also have to get into. And so some people like, just like not seeing that warning.

And the black box warning with the estrogen is around breast cancer or clots.

So it has to do with both endometrial and breast cancer and vascular thromboembolism. And there are a few other things thrown in there. The idea is that they're applying the risk factor data primarily from the whi actually for systemic estrogen therapy. It's a class labeling requirement that has to go on these low dose products which haven't demonstrated any of the same negative outcomes. Even the systemic hormone therapy that could be dissected. So some practitioners prefer not having a black box, some patients prefer not having a black box. Sometimes it's someone like my mother had breast cancer, I don't want any hormones, I won't use estrogen, but they'll use this. And there's no real rationale, there's no proof that it's any more or less likely to cause any cancer at all. The other issue is that in cancer survivors it doesn't have the black box. So sometimes oncologists, and again, that's a whole discussion we could have whether they're worried unnecessarily. And I think there's some people where I feel they're quite androgen deficient and it might be a better choice to start with. So for example, like I have a 40 year old had an O4 ectomy and doesn't want to go on systemic hormone therapy. And I know that her testosterone levels and her androgen levels have plummeted overall because over the ovary, about half of the circulating testosterone, even though she lost some of it since she was 25, you've now taken out half of what she has. We didn't talk about this. So in every woman, about half of your androgens are made in your adrenal gland and half in your ovary. And the part that goes down like in later reproductive years and through the menopausal transition, is the ovarian component. The androgen component stays about the same. There is some decline in that. So when you take someone's ovaries out at a young age, you're lopping off, especially the younger, the worse. Those are the people that are the most likely to have what I think is Physiologic or organic sexual desire, difficulties from low testosterone, from testosterone removal or androgen removal, abruptly. So that's someone, I might say. And they're not using systemic hormones. I might say this might be a better direction. That's like not based on any really systematic research. It's just experience.

Okay, let's come back to something you mentioned earlier in the discussion of our first patient as we now talk about our second patient. So our second patient, let's say she is younger. Let's say she's 30, she has no kids, been sexually active for 12 years, and she comes to you complaining of inorgasmia. So she says, I have desire, but. And I do get aroused somewhat, but I have never been able to either alone or with a partner achieve what I think I'm told an orgasm is. I'm really teeing this up so that you can explain what an orgasm is, because in a male it tends to be somewhat more binary. I'm curious as to how you would counsel this woman and if you think that this is a reasonable example to use to explain that.

Sure. What I thought you were going to tell me is that nothing else is going on. She has no sex drive. And are there FDA approved drugs for low desire, which we didn't talk about for women? But that's not the question you're asking me. Let's come back. Let's turn her into someone who has a different problem after that. Because I think we don't want to forget to mention there are two drugs we're talking about. All this testosterone that's not approved. We should make sure before we conclude that we let people know there are two drugs FDA approved for low sexual desire in premenopausal women. But let's go to orgasms. So one of the biggest things, when someone comes to me. This is not an uncommon clinical scenario. You picked a good one, Peter, because a youngish woman, but old enough to start realizing, like, hey, I'm 30 by now, like this should have happened, or is there something wrong with me? Sometimes they don't care, but they think there might be something wrong with them. Sometimes they're like, you know what? It's enough, I want one of these, you know, or there's a lot of reasons why people seek it, but first thing I do is try to figure out if it's primary anorgasmia, meaning they've never had an orgasm, or secondary, meaning they had one and now suddenly it's gone. The scenario I think you're telling me is someone who has really never really felt like they had an orgasm. And now. So one of the first things I ask them is like, why are you now coming here to talk to me about this? What is different?

Well, let's just say it. I'm really with a amazing sexual partner and everything is perfect. And he or she is wondering if there's something wrong with them. And this inability to have an orgasm is actually interfering with our relationship because it's now creating a stress where my partner feels inadequate. I'm making this up, but I would assume that this is a classic presentation.

Yeah, no, it's a common reason. So the most common reason that women suddenly decide to come to me for anorgasmia is that they are now in a relationship. And it may be that they themselves want to have a more satisfying experience or the partner wants to. Sometimes they lose relationships because they. It's not so much the partner isn't willing to work it through, but they feel uncomfortable about having this problem and letting a partner see that they can't solve it. It's usually contextual, but not always. Sometimes women just sort of come to this realization that this is something they want to explore. So you asked me what an orgasm is. I mean, I think the idea that it's a peaking. You become interested. You feel a sense of. We've talked some about arousal. You feel like, mentally excited. Your body feels turned on. There are physical changes that you notice. And then there's sort of a sensation of. That feels. It's throughout you that you're peaking and maximal pleasure. And it's an overall sense of like an escalation to something in the genitals. What's actually happening is first there's what we can talk about. What happens when you get stimulated. There's sensory input. You get a stimulation to the sensation. It causes a response that heads to the spinal cord. It can trigger the autonomic nervous system first, the parasympathetic nervous system, system to cause vasodilatation. Here's where the pelvic muscles sometimes can relax during sexual activity. You get muscle relaxation, vasodilatation, and then it triggers eventually, as you become more and more aroused, interestingly, the sympathetic nervous system gets triggered. And that's what triggers an orgasm. And in women, it can be a sensation of pleasure in the brain. And it's really interesting to talk about what's going on. Like, FMRI studies have actually looked at this. But generally it's pelvic floor. The pelvic floor muscles contract, blood vessels become maximally. Dilated and nerve stimulation results in the local release of some neurotransmitters which cause secretions and lubrication. So it's, for example, vasoactive intestinal polypeptide. There's some involvement with nitric oxide and cmp, like in men, contributing to both phaseal dilatation, secretion and so forth. So you get like, again, you get this stimulation, parasympathetic nervous system, then sympathetic nervous system, then muscle contraction, local hormones, brain chemistry, local hormones, secretions. And people get this sense both of, well, being, pleasure, pelvic floor contraction. They may get secretions and then they feel they have had an orgasm. So there's a lot of variability. That's the full Monty. There's a lot of variability. Some people just feel like intense sensual or mental pleasure. Others feel a warm, intense sensation in their genitals, but don't notice lubrication. Sometimes people will come to me and it's like a part of it isn't there, like, how come I don't squirt? That term comes up sometimes. And that's a whole nother discussion. Like, is that supposed to happen?

So first of all, what proportion of women have that sort of ejaculatory response with an orgasm?

It's hard to say. Some of my colleagues believe that it's part of every sexual response and that it's just not being perceived. I would say about 20% of people are aware of it, and that's sort of what's written. But again, so there's this whole nother theme going on in the sexual medicine literature about whether women have the prostate function in the local genital milieu that results in the squirting of fluid. What I can say is it's controversial. And probably more commonly what I hear in when people are having sort of a more normal orgasmic or arousal and then orgasmic response is that the lubrication from the mucosal surface becomes robust. And that's probably the interaction between vasodilatation, the nervous system, and the local hormones such as VIP and nitric oxide. Where the squirting of fluid and where the female prostate actually resides structurally is an area of controversy. I think that's the simplest answer, and I don't think that's the biggest piece of orgasm. Getting back to that, I don't know if you have other thoughts or no.

I find this to be a totally fascinating topic, as any male would who's seen all extremes of this. It's not consistent either. So you wonder, is that a super orgasm Some women have that every single time.

I mean, it's so, I think, a more interesting question. I mean, I think it's a good one because that's not really what people are bothered by. It's that they don't feel like they're getting that overall, like, sensation and peaking sensation, both in their brain and in their genitals. It's that sensory experience and the intensity and the muscle contraction that they're probably not experiencing. It's not so much they're worried about the lubrication or so to speak, the squirting. That's not like the big. Some are and some aren't. But the biggest issue is your scenario is, like, that thing doesn't seem to be happening to me.

This woman that we're presenting with, this is clearly not the issue that's germane to her.

I'm trying to think where to go with this, but the first thing I would do is make sure I understand whether this was something she used to have or she never did.

Let's assume the answer is no. This is primary.

So the thing about secondary and hesmia to know is that if a woman has the capacity for orgasm and she loses it, one of two things have happened. Like, some kind of significant psychological impact that you need to find out about. Could it be trauma, relationship, struggle? Something happened and you want to understand that. Or there's a physiologic factor, like a medication or a neurologic condition or something. And it could be things like, one of my colleagues is really into, like, the nerve damage from spinning classes. Now, that doesn't mean don't go out and get rid of your peloton. But like, in men, nerve damage can blunt sensation and may interfere. So, like, I look for those things, but we're not talking about that right now. So the first thing I do is find out, like, why? And look at the context and make sure, like, somebody's not pressuring her. Like, you know, there are people who are like, I don't really care, but my partner wants me to have an orgasm, so I just fake it. And he's bugging me. And I'm coming here to see if I can have a real one. You know, I've heard that. And, you know, sometimes I explore it further. I never accept the answer at face value. I'm big on, like, finding out more is, like, have they just given up or they really don't worry about it. And there are some people in the field who feel like saying, well, not having an orgasm can be normal. For some women. So I avoid that. Like, is it not having an orgasm normal? I sort of say, okay, well, like, is this important for you to have this and find out about it? And let's learn techniques or strategies for seeing if you can reach this experience. I don't know what to say. Like, don't worry, it's normal. Go away, someone's come to me. So we look to see, are there strategies they could do to have it. So there are multiple kinds of orgasms. The big buckets are clitoral, vaginal, or both. This is where there's maybe some numbers. About 30% of women, maybe, if you want to go with rough numbers, reach orgasm through piddle stimulation. About 30 through vaginal and 30 have flexibility. Now what Techniques for reaching orgasm vary widely across women? Some women can have orgasms just thinking about it. Some nipple stimulation. Some women report it with even breastfeeding or like the shower water hitting their nipples. Some women need direct clinical stimulation, manual oral. Some women like vibrators. Other women through the thrusting of the intercourse. And there's again the question, where's the D spot fit in? Right. This spot, that's a spongy spot just inside the vaginal canal on the roof. That's an area of sensitivity. The bottom line is there's lots of nerve bundles in lots of places, and a lot of them can be stimulating enough to trigger this whole mechanism. That's what I tell women. And the big thing for you is to figure out whether you've learned where you can be most stimulated to have a more intensified response. That's where I kind of start with. So, like, whether it's clitoral, vaginal, through intercourse or not, it's more about what the stimulation patterns are and how much they've explored for learning about that. That's sort of the short answer.

Do we have a sense of the correlation between the number of women who would present? As this patient has a woman who is young, in her reproductive years, who is anorgasmic, who also does not masturbate. Is that a high correlation, in other words, is part of the problem in this situation? She is unaware of what her sensations are or what her mechanisms are, and therefore a can't reach that threshold on her own, and then secondly isn't able to communicate that with her partner, or is there no association between that?

I mean, I think the data is a little hard to tease out. What I will tell you, first of all is primary anorgasmia versus secondary. It does somewhat correlate with age. So younger Women are more likely to have primary anorgasmia, whereas other sexual dysfunctions get more marked with age, you know, desire and arousal problems due to some of the factors we've been talking about. Primary gasmia tends to get better with age when women can learn more about their orgasmic response. So that's how I'll answer that differently. In large population based studies, it's the least common reported sexual dysfunction, either primary or secondary. But it may be that we just don't know how to ask about it. Like for example, there was this large population based study that many people in the field have heard of called the Preside study. It was like sort of the largest population based study. It was a, of 31,000 women, a 50,000 survey, 31,000 women reported with self report of distressing sexual problems. So overall sexual dysfunction desire was somewhere around 10 to 15% and orgasmic problems were like 3 to 6% of the women reporting those problems.

What was the age range on that survey?

18 to like 100 to like 99.

So all women effectively, but midlife.

All orgasmic disorders, midlife and women the most likely to report it. But primary an orgasmia tends to be the most likely reported in younger women.

In younger women.

So I think once a woman learns. Another point is that once a woman learns about her orgasmic response, she doesn't usually lose it unless an organic or psychological factor, like I mentioned, intervenes.

So let's go back to this woman. How are you going to do the workup?

So it's pretty quick workup wise. Mostly it's the story, tell me about your sexual function. It's a history. I check the other phases, right? I want to make sure she's not in birth control, but it's not having pain and like that is a negative. And so I'll ask her to tell me like her story. Does she have sex with herself? Has she tried masturbating? Does she have a partner? What does she do with her partner? You know, what does she know about being able to stimulate herself? Does she know the structure? Does she know I might show her a picture? Does she know where her labia are? Does she know where her clitoris is? Has she tried nipple stimulation? What have they used as a couple? Has she tried using vibrator? You know, like I'll get into what her knowledge about and what techniques for stimulation. If she, what is her partner tried and what is she able to do in terms of communicating with her partner? So the real question is does she know what stimulates her and can she teach or train or ask her partner to do that for her. If it's in partnered sex, there are two problems. Is one, women don't really know yet. And so the prescription might be learning more about that. And there are a number of ways to do that. The other issue is communication between partners. Like they aren't sure how to teach their partner to do what they know works. This is not this patient. But it's one thing that happens as women get older that we haven't really talked about this, that you do need more stimulation with age, even if you don't have any pathology. So if you don't have diabetes or vascular disease, many women need more stimulation with age because the sensitivity goes down. And so I really normalize the use of vibratory stimulation because it helps a lot. But sometimes it also helps for younger women. This is less the case sometimes for young women because they don't need quite as much stuff stimulation. But I asked them, like, have they tried techniques for improving or enhancing stimulation. The biggest factor is that women kind of don't know their structures. The actual clitoris isn't the most sensitive. It's the sides of the clitoral, the flanks of it, the side, for example, around the vestibule, the size of the clitoral hood, just inside where some people call the G spot. These are where the neurovascular bundles are concentrated. That top of the clitoral hood is actually very easily irritated and not doesn't like being rubbed very much. And like some partners are sitting there rubbing, rubbing, you know, like as an example, I mean, not to be too graphic. And so some education about vaginal, vulvar and clitoral stimulation techniques for stimulation. So I send people to books, there's a number of books and we could talk about those. So that's where bibliotherapy. Looking at some really responsible lay press literature on like a book called Becoming Orgasmic. The Joy of Sex has been republished and published and published. And it's still a great book.

What year was the first version of that book?

I think it was in the. That's a good question. I should have checked that for you. But could it be the 70s? It might even be soon. You know, it was some decades ago. Good question to find out.

Call it 50 years ago. Okay, so the Joy of Sex. So rattle off the names of the books that you would use as reference here.

So these are some books that I like for yourself. Becoming Orgasmic, the Joy of Sex. Sandra Lieblum has a couple of different books She's a sex therapist who's no longer with us. She had an unfortunate accident, but she's written several different books. More of her work is on desire, Laurie Brato on mindfulness. And it talks a lot about learning how to stimulate yourself. So there's books available. There's also a website. I have no commercial investment in any of this. I just want to make sure people know that, that I sometimes send people to. It's called omg. Omg. Yes. Like, oh my God, Yes, I guess so.

Sorry. The website is just www.omgys.com.

I just google it and it pops up. O M G Y E S. Oh, my God. Yes. I mean, we'll just say it. That's what I think it is. And it's a very responsibly produced website that has a lot of education for women. So there's a small amount of money for a subscription. I think the standard program's like around $40. And then there's a larger fee for more involved program. It's not free, but they have some demos on it. And it has a lot of educational videos, including very explicit videos on showing techniques for scleral and other kinds of stimulation and really teaching people to learn how to stimulate themselves and become orgasmic.

Is this a site that is also just as helpful for men to learn about their partners, female partners of other women?

Right. It's designed for female stimulation, but it could be for the partner food be.

For the partner just as much for the.

And sometimes it's easier for someone to sit and watch a video with their partner than to have to show them themselves. So it's not uncommon that I'll say, well, you could start by yourself and figure out which videos you might want to watch with your partner. So that's another example. There are some other resources, but those are some common things that I would do with that patient. You can send the person to a sex therapist too. And I'm not a sex therapist. I counsel. We haven't talked a lot about psychological therapies. There is some data for using mindfulness based therapy and cognitive therapy for an array of sexual disorders. For an orgasmia. The sex therapists use much more explicit techniques. So they use things like directed masturbation. So you could send them to a sex therapist. I make the distinction. I counsel and I give advice. And I'm a medical physician who does kind of a multifaceted analysis and intervention. But if I think they need more work, I might suggest that patient go to a sex therapist. And so the Techniques for learning about orgasm with a sex therapist might be for example directed masturbation. It's kind of some of what we're talking about. But they might instruct them More sex therapists these days, it's not like if you saw again Masters and Johnson, they don't go behind a room with a glass window and like have sex in front of the sex therapist. There are surrogates. That's not what I'm talking about. But they'll discuss very, you know, in more detail about technique and they'll give homework assignments. There may be advice or guidance about positioning. So they might bring the partner in and discuss positioning. They might use something called sensate focus. So a lot of times people, in addition to that, we didn't kind of get into this yet, but people develop a lot of anxiety so and that makes the problem worse. They develop like what's called spectatoring and performance anxiety. So there's a technique that works for any sexual dysfunction but can be used here where you gradually introduce levels of sexual and partner communication and you start with very non threatening things like you sit, you hold hands, you hug and a couple's given gradual especially when people become very anxious that like am I going to have an orgasm? What's going to happen? So the sensate focus prescription can be done by sex therapists and then sometimes more so with distraction and low desire. Mindfulness and cognitive therapy can be introduced by certain people who specialize in this. And then the other thing we didn't mention is sometimes I discover like a really deep seated and important psychological issue that's linked to this. Like an unfortunate scenario would be someone who's sexually traumatized and like every time they get into a, or they develop even a genital aversion. Right. There used to be something called sexual aversion disorder that's been kind of removed from the DSM for a variety of reasons. But every time they enter sexual encounter they'll have an intrusive thought and maybe there's mixed in with PTSD or there was very strong religious prohibition or cultural prohibition. And then if I pick that up I really send them right to a psychological person to work with that because it's something that's now they understand or come to realize may be interfering with their sexual quality of life and their happiness. So we didn't say that, but at the onset that that's much more primary.

Let's go back to the two drugs that we didn't talk about of course, besides testosterone just to make sure we close the loop on that.

Yeah, I think I'm glad you raised the whole point about office counseling. So a lot of what we're talking about before we move to the drugs is that there's office counseling. Like I would do looking and we didn't get into this so explicitly, but I look at like, what's the relationship, what's the timing, what's the lifestyle factor? So I was thinking we were going to go there with that 39 year old or however old we decided she was. I call it the rant. So she'll come in and she'll say, I'll say, well, tell me what's going on. They'll be like, well, I have two kids, there's homework, there's dinner, I work all day, there's the house, there's the laundry. Then I have to answer my email at 12 o' clock and then it's one in the morning and the partner wants to have whatever partner it is, wants to have sex. Like I'm too tired, you know, sometimes they're not helping me, gets thrown in there. And so a lot of what I do is dissect this back. I'm sure you do this too in your work is help people look at how their lifestyle is. So that's that. So when someone comes to me with low desire and I look at these lifestyle factors, we look at some of the other medication factors, we look at whether there's another sexual dysfunction, like contributing to low desire and they have hypoactive meaning, distressing, low desire. That's clinically diagnosed. And I don't see another modifiable factor. That's where in postmenopausal women I might think, okay, do we need to add androgens? We should say like first you do a biopsychosocial assessment before you use a pharmaceutical and you look at these factors, you look for relationship counseling factors, you look at referrals for psychotherapy or sex therapy and you look at modifiable medications, other things you can change. And then if you reach the point where you're like, I want to use something explicitly for sexual desire in postmenopausal women you can use testosterone, like that's an option. We didn't talk about who the candidates are and when you would use that. The biggest hitters are people who've had olfrectomies at a young age, early menopause, post menopausal women with distressing low desire. And then you have to of course, do informed consent when you do that. Now for premenopausal women who we reach the same conclusion. Like there's nothing I can modify or nothing obvious. We do have two FDA approved products for this and strangely they're around and they're available and very few people when I either they know about it and they come to me for a prescription because they've already been through everything else. When I tell them, they're shocked to hear that that's available. Have you heard of these? Like many people have?

I have not, no.

Yeah, Interesting. Right? So the first one, I'll briefly tell you about them and feel free to ask me questions. Would you like me just to explain what they are at this point?

Sure, yes, please.

So there's Flibanserin. The brand name is Addi A D D Y I. And it was like a lot of these drugs. It's a centrally acting drug. It acts on serotonergic and dopaminergic receptors and it has a complicated mechanism which is actually not fully understood. It's mixed serotonergic agonist and antagonist. It's actually 5h2ta and 5h2 1a and 2a one's agonist, one's antagonist. It's mixed agonist antagonist and has activity at D4 which is dopamine receptors with moderate affinity for some other serinergic receptors.2b and 2c. And that region specific effect seems to be pro sexual was studied for depression but discovered to be helpful for low desire.

Kind of like Viagra was studied for blood pressure and found to.

Right. But this is essentially acting drug. So that's not to say that like women who respond to this are getting it because they're depressed. But one wonders, there may be a spectrum of like why people have no libido specifically as a presenting complaint of why a centrally acting drug could be helpful. It's FDA approved. You're supposed to kind of rule out this other stuff and manage all the biopsychosocial factors before you consider it. That said, like you use the same criteria you use for any decision to use a drug. Like it's not so fancy.

Is it a drug that a woman takes every single day or is it one that she takes?

So it's daily on demand, centrally acting. It's a single dose. There's only one dose. There's no titration, 100 milligrams. It's taken at bedtime. It's been FDA approved since 2019. It's been around. There was a long road at the fda. I was part of that. More so than the testosterone. I was There I happened to be the president of during the few years it was approved. So I spent a lot of time at the FDA trying to advocate for its approval. I can tell you more what that struggle was like more personally. It is administered at bedtime. Initially, they did a lot of research looking at hypotension and syncope and its interaction with alcohol. And for some time it had a rems, meaning there was a risk mitigation strategy where doctors had to actually take a test before they could prescribe it. There's other drugs like that around. And patients had a sign of form that they wouldn't drink alcohol at the pharmacy. And pharmacists had a sign that they counseled patients. It was re looked at that it was really no different than any drug in class. Like SSRIs, give hypotension if you take them and drink alcohol or make you feel woozy or sedated. And so it's drug in class advice. Now there is still a black box because the FDA wouldn't go all the way. It's similar in class to SSRIs. The side effects are similar. Anyway, you take it at night and most people, you take it and you go to sleep. It can cause a little sedation. It's sort of like mirtazapine. I tell people, take it and go to sleep. Most people tell me they sleep better and they're not drowsy. You take it, probably you see the maximum effect about four weeks. But usually they say, give it eight to 12 weeks. If it works, you continue it. If it doesn't, you stop. Generally is about as effective as an SSRI is for depression. The measurements in the studies are a little complicated and we can come back to questions about that. But it looked at both desire ratings on a validated scale called the FSFI and satisfying sexual events. And it was found to be moderately effective. But in responders it was quite effective. Again, what we don't know, like when you're depressed, you say take it for six to 12 months and then we stop and we see how they do. If there's been some neuroplasticity and brain rewiring, and you probably know some about this, we don't have that research. It's young about how long we treat for and whether we stop. And I can answer questions about that. Again, the side effects are similar to SSRIs. About 10 to 12% of people get dizzy or tired. But that's fine. If you take it at night. Dry mouth on a handful, it's as safe as any central acting drug that people prescribe routinely. There are some contraindications. It can interact with CYP3A4 inhibitors and can worsen the side effects of SSRIs, although it's not contraindicated to prescribe them to.

Are they contraindicated with.

No. Interestingly, it is being looked at and it is sometimes used as a remedy for SSRI induced side effects. But SRI induced treatment emergent sexual dysfunction. But the issue is that you may have augmented side effects and the patient just has to watch for that. I've used it in a handful of patients. It's not my first strategy actually. That's a whole nother discussion about what to do with treatment emergent sexual dysfunction. We talked a little bit about just changing drugs or switching or adding bupropion. I don't do this first. So that's one drug. I don't know if you want to just make sure we have time to talk about the other or I can answer more questions.

Yeah, let's spend a second on the other one.

So the other drug's completely different. It's brimalanatide is the chemical. The brand is called Vylice. V Y L E E S I. These are both the only drugs available. There's no generics out there. Their websites have good information for patients. This one is a complicated one, but I'll tell you about it. It's a cyclic 7amino acid melanocortin receptor agonist and with a high affinity for what's called the type 4 melanocortin receptors. It's an analog of MSH, which is melanocyte stimulating hormone. And what it does in the end is it acts in brain pathways that stimulate dopaminergic pathways. So it's a direct hit for desire. Right. The other one is a little more complicated. In cooking you're sprinkling a little. This receptor in that receptor, this one hits the dopaminergic pathways. It's given on demand as a self injected treatment.

Injected?

Yeah. So it looks like an epipen a little bit. You have to look at a picture on the website. I wish I could hold one up. I actually should hold a trainer up. And you stab your thigh. It has a fine little needle. When you stab it releases it. It's very painless. I can tell you. I've tried dummies and patients tell me it feels less than like a finger stick and less than a ppd.

And how long does it take to.

So you inject 1.57mg which is 0.3mls of a solution subcutaneously with this autoinjector into like your abdomen or your thigh, like a thick muscle. And it takes about five seconds to go in. So you say 1, 2, 3, 4, you know, and then you pull it out. You can also see that the liquid's gone down. You can look down and see it. It's a little scary for women but you don't feel anything at first.

I'm sorry, you only take this drug when you want to have sex.

So it's done on demand. So what's the theory? So you should take it about 45 minutes before and it's considered on demand one time use self injected and it lasts in your body presumably about 24 hours. That's the theory. What happens is that women will say like after a little while they just feel more like the idea seems more interesting. Their brain, this is where this bridge between desire and arousal comes. They start to feel like hey, you know, I'm feeling kind of interested and turned on. And then when they engage in the activity the arousability is more intensified. So it's supposed to be intra event improvements and overall sense of satisfaction. And that fits into that idea that it fuels the future. Like they know, like hey, I might be neutral or not even interested but if I do this I'm going to feel more turned on and the experience is going to be more pleasurable because I'm going to feel more into it. Both mentally desirous and probably arousal.

How much does this drug cost?

Flibanserin is available everywhere. Brivolanatide has a specialty pharmacy that you can see see on their website. Put it this way, if your insurance doesn't cover it, both of them have guaranteed maxes between $40 and $90 per month for vobanserin. You get a 30 day supply for this, you get a four week supply from the specialty pharmacy. And it depends like many insurance companies don't cover this but they guarantee a maximum.

Does it need to be refrigerated?

No, you keep it on the shelf. I think just in a cool dry place. The outcomes on this, there's one thing to know about this, the outcomes on this have been pretty much there's no head to head studies between the two but pretty good. And they've looked at both improvements in this desire rating scale, the FSFI as well as clinical events like satisfying sexual events and clinical meaningfulness has been good, good, moderate to solid outcomes. I can give you numbers if you want for all of this. But the main thing with this is that the first couple of dose or two people get nauseous. It's about 45% of people. Nausea lasts about two hours, about 40% of people. And that tolerates out. By the second time it's down. The data suggests it's down by about somewhere around 20, 40%. It's up to 40 and then it's down to about 8%. And then most people don't mention that they feel nauseous.

So do you advise that women maybe use it a couple of times without trying to have sex so that they get over the nausea?

Or you can go to sleep because most people, if they're sleeping and then like in the mornings, people notice it does sort of last for at least 12 to 15 hours, maybe even 24 or just lay down. Some people prescribe like a dose of anti nausea pill with it for the first dose or for a couple of doses. I don't find the nausea is that clinically problematic. But if people have it, they're like it's over in a couple hours and it didn't happen the second time.

If you put aside sort of cost insurance or hesitancy with an injectable versus a pill, if you put all those things aside as non issues, how do you decide which of these two drugs might be more appropriate?

So one thing is patient preference. There's no head to head trials, but they're probably equally effective.

Okay.

You know, do they want it on demand? So the other thing about this I want to mention is was a rare occurrence of focal hyperpigmentation about 1% in the clinical trial when they used it more than eight times a month. But we tell people probably to stick to four a month to limit that risk.

And sorry, hypopigmentation at the injection site.

Or just in general no face Gingiva breast like melanocortin, melanoreceptor sensitive tissue. And it was in the clinical trial and it was seen in 1% of people. It's not clear if it goes away if you stop it. But if you don't use it beyond, it's not thought to occur if you don't use it beyond the recommended guidance. He said that backwards. Use it less than eight times a month and it probably isn't going to happen. But we have to tell people that. So the two contraindications for this are uncontrolled hypertension or known cardiovascular disease because there was small increases in blood pressure, about 8 to 10 millimeters of systolic and diastolic. It's probably not. It's probably overkill. It was originally studied as an intranasal and it did raise blood pressure. Intranasal squirt and it did raise blood pressure more. So they switched to the injectable. And there were some trials on this in men and some of my male colleagues like think about how this might be used off label for an array of male sexual dysfunctions. So the other point I want to make is there are a couple of at least one good large RCT in postmenopausal women. You should have asked me why is this not approved for postmenopausal women. So this has to do with the fda. Again, the FDA required that the companies go for indication of a category because this goes to the reproductive group at the FDA and they required that they put in an application for either pre or post. So they started with pre so they didn't have to deal with all the hormonal complications of like hormonal status, hormonal replacement and never went back for post.

Is it typically given or prescribed off label for post?

So here's what I say. There's good RCT data for postmenopausal women that's very strong. That suggests there's no difference both in outcomes and risk and safety. And no RCT data. And that's for fibanserin. I'm sorry, there's no RCTs for ADDI. There's postmenopausal data for ADDI, none for VILICI. So you're in no man's land if you're prescribing this off label for postmenopausal women. But there's no physiologic plausibility for the risk.

But you could give ADDI and testosterone to postmenopausal women without contraindication.

Well, if you're doing off label for both right off label, yes. And I don't usually start with I'm a purist. I start with one thing and either layer or switch. That's clinical skill. Really clinical art. I have multiple. They tend to be younger postmenopausal women who are on addie and understand and I have them clear informed consent understand it's off label that there's research supporting it. I don't have not used Vilesian postmenopausal women. Some of my colleagues have because I just, you know, nervous that there's no data, there's no biological possibility that should be harmful.

Are these Schedule 4? Are they controlled or uncontrolled?

They're not controlled. Testosterone is.

Yes, testosterone is. Yeah.

You have to have a DA number. It's controlled. You can only give a month at a time, which is easy for women because you give them a box of 30. That's no man's land. They get 10 months. So these were, again, they were proved for premenopausal women purely because the FDA in their reproductive group required that they go for one indication. The companies didn't go back. The other thing. How do I pick? So one thing is patient preference, the other one is any contraindications. So the CYP3A4 inhibitor issue is a problem for flibanserin. Someone's on other psychotropic drugs and I'm worried about oversedation. I might not choose that. If they have to be on, like, they're on HIV drugs, for example, like CYP3A4 inhibitors, they're taking a lot of antibiotics or Diflucan. You have to wait. There's guidance about how long to wait in between all the CYP3A4s. And that's a nitty gritty we probably don't want to get into at the moment. Liver disease is another relative or strong contraindication for fibansrin because it's a metabolism. So vilisi would be a good choice in those cases. If someone has high blood pressure or they have like aversion to getting nauseous for the first time. I mean, it's a discussion. Some people are terrified of injecting themselves. And it's really one, like, people do it. They're like, it's no big deal. You do have to know that and tell people that it's not hard to do it. You know, what's interesting to me is I'm known to prescribe these. I don't get a lot of requests. I'm the only person in my institution I'm at Weill Cornell that I know that routinely would offer this to people. I'm a referral source. I work both in medicine and psychiatry. And when I talk about it at meetings, like, people are not writing a lot of prescriptions for these drugs. I don't know whether.

Why I was going to ask you that because I'd never heard of these drugs. You could argue, well, I don't take care of women with respect to sexual health. But what you're just saying seems to suggest that these are potentially underutilized, possibly.

So I'm a little bit. I think it depends a little on setting. Right. I'm based at Weill Cornell. I Have a faculty practice that people refer to me from the institution, from outside, but I see people from the community. I have colleagues who have sexual medicine practices that are purely private and community based who write lots of prescriptions every month for this. So it might be how and what people are seeking in certain settings. I don't know if they're underutilized, but. Well, there's one other point I want to make in a second, but they're certainly under. Not known about or under recognized.

I guess the biggest question I take away from all of this or the biggest sorry, observation I would take away from all of this is I think that there are probably a lot of women out there who don't know what tools are available to them or their doctors with respect to the entire spectrum of sexual dysfunction.

Right. So I think there's a lot of misunderstanding just back to these drugs. There's a lot of confusion, like I was telling you earlier about what is normal. That's where this whole idea of blending desire and rails like if I don't ever want to have sex but I can get an orgasm, why should I take a drug for desire? That's what a doctor might say. But a person might then not feel like legitimized and saying, well, you know what, I want to want. It's not good enough that I'm 39, I can get stimulated, get an orgasm, but that I still don't want to want. Maybe that person, maybe they're not on birth control pills or they stop the birth control pills and six months later they still have no desire. Why not try addi? They need to be validated. Like it's okay to want to want. So that's part of the problem is that there's still a taboo. We could have a whole discussion about a woman wanting to want. That's part of the issue. Like it's, it's okay if I have pain. We didn't have a lot of discussion about treating vulvovaginal atrophy causing gsm. There's the options for, for like lots of things. List them. Lubricants for comfort, moisturizers for moisture, topical hormones for resurfacing. There's a whole range of options. They're safe, they're not systemically absorbed. They're erroneously worried about in terms of like the black box and other. It's easy to treat. And we started, I think, talking about this a little bit. There's low recognition and lack of uptake. At least it's normalized. Like a woman should not have to be in pain, like, that's more normalized. That said, I can't tell you how many women soldier on either avoiding sex or in pain because they don't either know or feel validated to seek treatment for gsm. But take desire. That's like, even lower that where people feel, like, legitimized and validated. Like, I should go to the doctor or to my clinician and get a treatment for my low desire and take a medicine every day. That's an indulgence. I have so many other priorities that people think I should have.

And do you think that that's generational, Sharon, or do you see just as much of that in younger women as you do older women?

This drug is available. People could come get a prescription for me, and they're premenopausal and they're not banging down the door. So I think there's a whole other phenomenon going on in the younger people. To me, it feels like the connection to sexuality and quality of life is sort of delayed. I don't know what's going on.

Yeah, it's funny. I hear Bill Maher talk a lot about this. He's one of my favorite commentators on All Things Right.

This is a whole.

He often talks about the literature and the statistics around sexuality in young people. And he kind of seems to make the same comment. Obviously, this is something you're observing in your practice as well.

My most common age group is midlife women, and for the reasons we've been talking about. And I also do work in menopause, too. So that's probably why they come to me for the mixture of things. Like, my most common patient would be, like, menopausal symptoms, night sweats, sexual function changes, relationship issues, mood. Like, that's my busy day, so it may be my referral source. But I do get young patients. And what I'm seeing, I guess I been around a while. I've been in practice for a While at this point, 30 years, I guess, at this point. And it seems like people like having boyfriends and girlfriends and partners in their 20s and. And like wondering about the quality of the relationship and thinking about the sexual relationship has gone down some and even a lot. And it seems to be where people are seeking help at older ages. And that the concerns of people in their 20s, for example, has more to do with STD prevention or the other thing you'll see in this age group we haven't talked about. It's not exactly a sexual dysfunction. Sometimes they have pain and sexual dysfunction as well. Vulvodynia vestibulodynia. And that tends to be more of a referral issue. Herpes, sort of how to deal with that? Not so much like quality of sex, quality of life, connecting and relating. I'm not seeing that in the 20s. I don't know, it's sort of a little bit ill defined and hard to explain. And certainly the college and young 20 year olds that I know, like, aren't having partners. You know, they're just floating around and they're not engaging in meaningful discovery about sexuality in a way that I think sets them up as well as maybe at other times for future relationships. That's what I wonder about. Yeah, the observations you've heard.

No, I've heard these observations in multiple channels. It begs the question, why? And of course the other question, which is, is there anything pathological about that? Does that produce a state later in life or down the line that in some way diminishes happiness, sense of purpose, quality of interaction? So I guess it's all TBD at this point. Before we wrap everything up, I just want to make sure we address effectively the third patient in this sort of hypothetical visit to Sharon's office, which is the woman who is two years since her last period. There's no ambiguity about the fact that she's in menopause. She hasn't had period in two years.

Or postmenopausal, like vegan menopause. That's such a vague concept.

Yeah, postmenopausal, Right. Biochemically, it's also unambiguous. Her estradiol level is, you know, 10. Her FSH is 75. She is, let's just say for the sake of argument, having some vasomotor symptoms. So she still gets hot flashes and night sweats. She's also starting to experience vaginal dryness and discomfort. And as a result of that, her sexual desire, she has some hesitancy, let's just put it that way. She's saying, this is uncomfortable. I don't really want to do this, but she says, you know, my mom had breast cancer and hormones are obviously the worst thing in the world. So I hate waking up with my sheets soaked at night. Oh, by the way, I also turns out I've got osteopenia. So anyway, take it away.

The first thing I sort of try to do is break it down a little bit. You talked about, I guess there were several buckets. One is what we'll attribute to the menopausal transitional symptoms. So typically those symptoms are a collection of things you mention. Some of them, hot flushes are hot flashes resulting in sometimes sweating and sometimes at night. The reason people call it night sweats is because it wakes people up and it can be bothersome and intrusive both day and night. It can lead to fatigue because people are waking up, have a hot flash, they sweat, they wake up, they worry, they can't get back to sleep. Sleep. And so you can get some difficulty with sleeping. You can get some independent insomnia. People report cognitive fogginess and sometimes a little bit of mood instability. I'm careful to say that like a significant mood disorder shouldn't be attributed to menopause. It's a vulnerable time because of everything else that's also going on. So I watch carefully for mislabeling mental health issues in this time frame, which is. It's also a vulnerable time. And it. It may have to do with the hormonal changes too. Actually, the brain is. The neurotransmitters are sensitive to fluctuations in hormones. So there may be mood changes and there may be concomitant mental disorders that sometimes emerge. That's a caveat. But the stuff we're talking about, it has to do with these. And then as you proceed through menopause, the menopausal transition and become postmenopausal, some of that can still continue for a while. On average, this stuff lasts three to five years. Up to five to seven worse. One to two. Typically worse, like right before and right after the years that you cessate your menses. It wouldn't be unusual for her to be going on like for a year or two. The sum of the teaching is she'll probably on the other side of it. And some of this might get better, the flashing and the symptoms. But you also mentioned there were some hormonally related potential disease progression. Things like bone density, which is systemic levels, and then the effect on the vulvovaginal tissue and the of part, possibly discomfort with sexual activity. And then on top of it, you mentioned changes in sexual enthusiasm or interest, which could be due to the discomfort, or it could be due to this whole other phenomenon we were talking about, about declines in androgens that sort of parallel this timeframe. So I kind of help people break it down and say, okay, let's figure out which things we want to start with. We want to do it all at once. And what can we address with a single intervention of addressing multiple things? Like, I think that's what you're kind of getting at. So it depends, like who they are and how much I want to do at once with them and what else is going on. I know you heard me repeatedly say this. I'm really looking at this is like a prime lifestyle time. So the reporting of distress around this is probably to some extent influenced by any of this, particularly like the menopausal symptoms in the context of everything else going on for these people. People. So let's take, like, people that are heavier body weight, exercise less, have already have sleep difficulties, have other medical problems, may be more likely to have symptoms, lower body weight, exercising. People that have relationship stress may be more likely to be sensitive to the changes in, like, their partner being upset that there's decreased frequency because they're more tired. Or maybe they can't communicate with their partner and can't teach them to use a lubricant because they're afraid to ask. Like, so you have to get some of this too. Like, tell me about your relationship. Tell me what's going on. Are you working? Do you have kids? Do you have older parents? And then that frames how I see or what is their health status in terms of metabolic disease and other factors, how I look at what to do and how much to do at once and where to start. So there is lifestyle stuff and there's counseling and relationship stuff. Let's take that out for now. I think you want to go to the question of hormones. So the single best treatment for disruptive vasomotor and collection of symptoms is combined estrogen progesterone therapy and no progesterone. If someone doesn't have a uterus to treat those symptoms, for example, you can decrease hot flashes by 80%, 75 to 80%, even more, at least 50%. And so if someone tells me, like, I'm having a hot flash every two hour, two, I'm waking up, I can't get any sleep, and they're opening the window and using a fan and taking a bag of frozen peas on the back of their neck and wearing the most expensive, like, menopausal pajamas they could find on the Internet. And nothing is helping. I'm like, you need to go on hormones. I can't. My mother had breast cancer. Okay, let's look at whether that's really true. So using hormones for a period of time, the lowest dose that treats the symptoms the most effectively is not going to give you breast cancer. Most likely. I can't promise that you won't get breast cancer because 1 in 8 or 9 women get it anyway. And you might be genetically more likely, but not from a Short term use of the lowest dose possible to suppress your symptoms.

That's the important distinction there, right? Of course, you have no idea if a woman's going to get breast cancer, given that it's so prevalent. But what we can say with an absurdly high degree of certainty is even under the worst conditions possible, which was the conditions of the Women's Health Initiative, where for all reasons I'm not going to go into now, because I'll have a dedicated podcast that will focus exactly on all the issues around the whi.

Yes, we should.

You should even saw in that situation only an absolute increase in risk of 0.1%. And that was only in the incidence of breast cancer in the women receiving conjugated equine estrogen and mpa, both products that we are not using today. Secondly, there was no increase in breast cancer mortality, which, by the way, that effect lasted till today. We still follow those women and we can see that no more of them have died of breast cancer than their counterparts.

So glad to hear that you're gonna dedicate a full podcast to this cause. There's a lot of layers to this, but the short version is the WHO used oral synthetic estrogens and oral progesterones, which you could use them, but nobody does. There are oral therapies available, they're bioidentical and usually people are using oral estradiol and oral progesterone that are bioidentical. The doses are different and lower. There's also now transdermal products available. The problem is that there's never been as large an RCT for the length of time. So the shortage from data showing that there's other ways to have even better outcomes and maybe even no outcomes. And there's also been extensive reanalyses of both the actual data and subgroups. So, first of all, women 50 to 59 are very different than people who started hormones. The WH wasn't for symptoms, it was for disease prevention. It was osteoporosis and cardiovascular disease.

The women were actually asymptomatic, right?

They were older when they started and it doesn't apply to this patient at all.

And the data also, I think, are unambiguously clear that if there's any negative effect of the combined hormone therapy in the whi, it had to be due to the mpa because the conjugated equine estrogen group alone got better.

They had no more breasts.

Not only that, they almost achieved statistical significance by 0.2 of a P value for a reduction in the Incidence of breast cancer, an effect that also has persisted for over 20 years. This is looked at in every subanalysis.

So I think you're making the strong point that the reanalysis of subgroup by age and they were never looked at by symptom indication, and then teasing out the effects of each of the computer components have even debunked the things that people think are scary or risky. And that said, we also have similarly researched, but not as large groups and not as long, other types of products that are both orobioidentical and transdermal. So what I would say to this patient then is like I mentioned in a sort of a slew, some of the lifestyle things and there are also some over the counter stuff like black cohosh and there's using soy. None of that works as well as systemic estrogen and potentially with progestin therapy. And the reason for the progestin is it protects the uterus against endometrial hyperplasia. And I think you need to use it, even maybe very short term you don't, but for this indication you do. So the venous thromboembolism risk is probably, no matter what you do, it's probably a little higher, probably better with transdermal. And I tend to almost never put people on oral, although there's oral products available and there's actually a combined oral product. You can probably obviate that to some extent, but it's a low risk issue. And I haven't seen it happen with transdermal clinically, although it's not proven that it doesn't. So these are like patches or gels that are available for these products for both estrogen and there's an estrogen progestin patch. And then you can use an estrogel with an oral progesterone. And it comes in different types of gels. And there's also a ring that you can use called a fem ring.

In women who struggle with systemic progesterone, do you find yourself sometimes using systemic estrogen with progesterone coded IUD to provide.

Sorry, I didn't mean to interrupt you. I was just so enthusiastic that you reminded me of that. So it's not a labeled indication, but you can use a progestin IUD for endometrial protection. Clinically, there's some prevalence studies or risk studies looking at this, I should say their perspective is the best word I could use for them. And they're really looking at the outcomes of the number of people have the adverse outcomes when they use the iud and they don't point to a signal, although it hasn't been randomized. So there are many clinicians feeling like there's good data to justify using an IUD for endometrial protection. Usually it's the higher dose, the Mirena, and it's good for five to seven years, although some feel that you could leave it in longer and still get the protection because the levels stay present for some time. And that's a strategy used by many, whether you put it in before they don't tolerate the progesterone or you just decide that. And the theory is that also that it's an alternative. It also might provide overall less progestin exposure, although the oral progestin is bioidentical, levonorgestrel isn't. So there's back and forth about it, but that's a strategy. Now, remember, this is for hot, for all these symptoms. Now, the decision to continue or treat it's also a very good treatment for osteoporosis, but that's a different conversation. So beyond this, if you were just going to do symptoms you tried for a year or two, then taper, see how they did, if you want to continue for bone protection, it's a very good drug. So it's bone protective. It's not considered a treatment for osteoporosis. It's a preventative measure, but it probably also prevents further fracture. We can get into that data too.

But I've done the back of the envelope math just to get on my soapbox here. And first of all, prevention is everything when it comes to bone loss. We don't really want to wait until someone has osteoporosis to whip out the bisphosphonates, which frankly don't necessarily have an enormous impact on fracture risk because while they're increasing bone mineral density, it doesn't necessarily come with some of the torsional qualities of bone that we might want to see in a healthy bone that hasn't gone through that period of degradation. But let's put that aside for a moment and just acknowledge that if you do the math, far more women will die as a result of of fractures of femur, hip, pelvic bones later in life that could be ameliorated by the use of judicious hormone replacement therapy to prevent them from getting there than will ever die from breast cancer as a result of hormones. And by the way, it's not even close. We're talking orders of magnitude difference. And this is what I find most frustrating in the hrt Discussion, frankly, is even if you discount symptoms, and I don't know how you can. I mean, symptoms is everything in medicine. But even if you didn't care about symptoms simply on the basis of bone health, it's a real tragedy to me that there is an entire generation of women for the past 20 years that have been largely deprived this therapy on the basis of very bad science and far worse reporting and interpretation of said science.

I couldn't agree with you more that there's a lot of misconceptions about the importance of preventing bone loss and probably we're also treating osteoporosis when it becomes established and that the other options, although there are good ones, have limitations and you don't get the added benefit of some of the things that combined hormone therapy has. So there's a few conversations. One is what to do for her now. Like at this point, I'd probably say it's going to help your symptoms. Let's say nothing else has helped her. She's tried the over the counter stuff. Maybe she even tried, tried black Coho. She ate some soy. You have to eat a lot of soy every day to make it work. Let's get all that. Say she tried all that. And then I'm like, look, this is going to help you. Let's use the safest, lowest dose. You're certainly not going to get cancer from this. You might get it. The other thing is that people don't know that other things they do are riskier for breast cancer than their hormone. We don't probably have time to get into the comparative data, but drinking.

Well, yeah, having insulin resistance. Drinking alcohol. Exactly.

Drinking alcohol. More than one drink a day. Not exercising, being overweight. That goes along with having metabolic dyslipidemias, high blood sugar, metabolic syndrome, being overweight. Those are probably more important for breast cancer risk than small doses of transdermal hormones for a couple of years for symptoms. Now when you get into continuing at least past a few years or even through 60, the first 10 years, whatever, that's a different conversation. But like you're already getting at the point point that there's a lot of data and a lot of reasons to keep going. And we've all heard some famous friend quote, when do you stop your hormones? Some variation of like three days before you die or. I've heard that in a few different ways from a few different experts, including those that used to worry about the whi. For example, Joanne Manson speak in a number of meetings. She was the original PI on this.

Joanne's really. She seems to be the one who has reversed most of the initial sort of fear around the whi. And I'll be sitting down with Joanne to talk about this so she can.

Speak about it and really analyzing carefully the subgroups, the follow up data. It's not to say she's refuting what was published, that's accurate, it's just that.

It, it's the interpretation.

Right. She's not the one that said three days before you die, by the way. I don't want to misquote her. I just put her in the same paragraph. The one thing that's very clear is that it's the best treatment for symptoms. And the North American Menopause Society and some of the other formal experts say the shortest dose for the period of time that you need to manage their symptoms. At a minimum, we need to turn around anybody who doesn't understand that. There's also other pharmaceuticals you can use. SSRIs actually for hot flashes, but we already explained they have some issues and they don't work as well. You can use clonidine, which has low rates of success and a lot of side effects, but or gabapentin, same thing.

Which again, all of those seem so backwards to me because there's no ambiguity about what is causing those vasomotor symptoms.

I don't go there unless I'm stuck. And I have to for a variety of reasons. We don't want to forget to remember that there's other things she's complaining about. And I'm guessing we don't have too much time left. But she's also telling you that she has dryness and discomfort. So does that estrogen you're sending in her system. Let's say she agrees to take that transder. Does it get to the vulvovaginal tissue? You know, I have some patients who say, yeah, that's fine, my lubrication is fine, I'm not dry. Others need more locally delivered and it is not contraindicated to give both and in fact indicated. So there are two main symptoms, three I see with gsf, vulvovaginal atrophy and general urinary syndrome or symptoms of menopause, vaginal dryness, pain with sexual activity and a collection of genital urinary symptoms, even independent of sex. So you can try lubricants with sexual activity for comfort. You can give vatril remoisturizing agents which are given multiple times a week. They're available in gels, suppositories, lotions There's a number of good products out there. Some have hyaluronic acid, for example. Some have other chemicals. You're recommended to use those. They help these polymers and other products help draw out some of the moisture and resurface a little bit, but they don't change the mucosa. And then sometimes I throw in some dilators if people have been sexually inactive for a while and the tissue is tight and guide them on that. And then sometimes for sexual function, as an aside, I remind them that they might need more stimulation. So lubricants can be help with comfortable stimulation. Silicone particularly, although it's slippery, adding vibrators. So that's all for like. And there is some with sexual function, the use it or lose it phenomenon. So promoting regular sexual activity, even sex with one's sexual to help with keeping regular lubrication occurring in combination potentially with lubricants with activity even with oneself. Use of vibratory stimulation to enhance the response. And then vaginal moisturizers for any symptoms independent of sexual activity regularly. That's like the formula. And a lot of women don't even know that. And the algorithms say do all that and if they're still having pain, add a low dose vaginal hormone. And we talked about that. There are estrogen products, there's rings, there's tablets, there's cream, there's inserts and then there's intrarosa. There's also an oral serum that's indicated just for vulvovaginal atrophy. Somebody wants to take an oral pill, which is a whole nother category. It's called osphena, the chemicals osphenipine and it has some of the serum issues. But it is indicated. One of the main benefits is some argue it may be good for breast protection in people at risk.

But I'm sorry, it does or does not provide systemic levels of estradiol.

It's not an estradiol, it's a serum. It's a serotonin estrogen receptor modulator. It's a little unusual. A lot of people don't know that it's FDA approved, it's not very commonly prescribed and not that one may choose it. It's indicated. It's an oral serum indicated for GS vulvovaginal atrophy causing dyspareunia. It's called Asphena at 60 milligrams a day and it may be theoretic. It's not indicated for this, but it may be theoretically useful for people who need breast protection. You know if they have like a family history, because it's a serum. Sometimes Roxifene is used for breast prophylaxis, but it's not indicated for that. It might have positive effects on bone, but again, not indicated for that. I don't use it very often.

Do you find that the time that a woman was, you know, deficient of hormones, the longer that period of time, the greater the likelihood she will need additional treatments beyond the systemic estrogen?

Thank you for asking. Well, so the tissue changes are progressive. So the truth is that it depends when you catch someone. So the answer is a little nuanced. So if you catch someone three to five years out, they're going to have more tissue changes than someone one to two years out. So if you decide that that woman doesn't need it yet, I could just educate her a lot on lubricants, moisturizers, using vibrators for stimulation, regular sexual activity, improve that. But by the time she's three to five years out, she might be the same as someone that you, you're not going to prevent the tissue changes five years later. So that's kind of the nuanced answer. It tends to be more likely to be sometimes early on, they're just dry. And some of the other things that I mentioned, the non pharmacologics work fine, but as time progresses, either the systemic hormone, if they're on it, is going to be enough because it's just enough to leak into that tissue and not have the tissue changes be. Or they're going to start to need it because five to 10, 15 years out. And when you get someone who comes to me, it's not unusual, 65 or 70, they've reached a threshold then like lubricants were working. The other thing is to avoid things that have a lot of chemicals in them because that tissue is sensitive. You know, like warming liquids, scented things, you know, use things that are like a little less filled with stuff. But then someone will come to me at 65 and 70 and they may be at that threshold. Somebody might be 60. I have patients who are like 80 who just need a lubricant. Even though everyone gets the changes, the severity of tissue changes, mucosal loss of cushioning, decreased lubrication, tightness and shortening. That varies. It's not 100%. Atrophy is 100% of people, but the degree and the severity varies. There's some endogenous hormone factors. Whether they've had an oophorectomy. The use of systemic hormones probably figures into that because some probably leaks down there. Management of this is yet a whole other area that I love to talk about too, but very, very low hanging fruit in a sense, because you can do a lot and it's easier for people to accept and understand once you teach. There are some barriers. Like people are kind of like disconnected, so it's not unusual. Like somebody's 30, they have sex, they get satisfaction, they have an orgasm, not paying much attention to their vulva, their vagina, their vestibule, their urethra. And now you're asking them to like put this there, put that there, use this dilator. People don't want to mess with this. Like, you'd be surprised. Feels like a lot. Like I didn't have to do anything for my vulva and vagina when I was 25 or 30. Now I'm 60 and I got to do all these things for my vulva and vagina. So I'm kind of like, well, you put Botox in your forehead, you put cream on your face, you know that you didn't do that neither. It's just the way it is.

That's a fair point. Well, listen, Sharon, this has been a really interesting discussion. As I said at the outset, I think it's a discussion that's beneficial to both sexes. I guess there are several takeaways here. So one is there are probably a lot of women who are unnecessarily experiencing some form of sexual dysfunction because they don't maybe realize what's available to them in terms of systemic tools, local tools, therapeutic tools, medications, therapy, et cetera. And I think the other thing that you've just alluded to at the end is that this is kind of a journey over time. And in the case of women, I think the changes are more dramatic from ages, you know, whatever, 15 to 95 than even in a man. And they probably require a little bit more willingness to be attentive to oneself and be a little bit more proactive potentially during that aging cycle. Again, the obvious ones that we talk about are hormones, but some of these anatomic changes are obviously just as important. Not to mention the health related changes that may be feeding into this, the metabolic stuff. Interesting to know that that's as important as it is in men, where it's a little bit more obvious structurally.

Yeah, no, I think those are all really important takeaways. And you hit on some of the, I think the most critical key points. You know, in healthcare it doesn't always happen, but I've been hearing about like pulling out all this education about menstruation in school schools in certain states really worries me because that's even the most basic. But in the community, in healthcare, education about sexual health and sexual function across the life cycle is really a need. So it worries me that as we pull back on the more even basic education about menstruation or STD prevention, we have to be very proactive to make sure this doesn't go in the wrong direction. Learning about how to choose contraception and sexual function in your late teens and early twenties and know what your choices might be and why. Learning about the impact of childbirth, learning in your later reproductive years why you're still menstruating but your sexual desire might be dwindling. You know, like, how to integrate my brain and my body. If I'm, like, under a lot of stress and anxious and depressed, like, should I take a medication? What are the implications for my overall quality of life as I enter menopause? What do I do about my system? One thing, like with hot flashes, if you're not sleeping and you're exhausted and you're feeling poorly, you're not going to be enthusiastic. But you're also noticing changes in your vagina, your vulva, your genitals. How do I address those? Don't just lump it all together like, oh, it's menopause. That's supposed to happen to me, because that's what the clock says. And then we didn't get a lot into much older women, but there is a whole sexual understanding for the sexuality of older yet women. You know, 70s, 80s, 90s. I get women coming to me with some of the same, but also different questions. People in some of these studies were up to 100. People can be sexual well into their long years. And there's a lot of ageism. I want to end with that talk about menopausal sexual health. Ageism and menopause ageism. As you get into even older Women past like 70, 75, there's a lot of ageism. And in a man coming to a doctor at 80 for a drug for erectile dysfunction wouldn't be surprising, right? But a woman showing up with question would be so, like, that's the last thing I'll say is, like, there's a long lifespan. There's a lot of different issues. And we need to work on clinical skills, resources, treatments, as well as, like, education in every forum for teaching women how to think about this. We could do a course, Peter. You know, I mean, it's this huge area.

Look, I hope that this podcast, which covers a lot more content than you're typically given in a conference to speak about, you know, gets some circulation and provides the public health message that we want to get out there. And if nothing else, at least gets people speaking to their doctors a bit more and finding their way to people like you. Again, there aren't nearly as many of you as maybe there should be, but if there were 600 people of your qualification at a recent conference, my hope is that people will know where to do it. So I guess let's close on that. If a person wants to find a doctor like you, what are they searching for? What's the qualification? How do they ask their primary care physician for a referral to someone of your skill?

We're sort of talking about, like, sexual medicine. There are sexual medicine physicians, some of the sexual medicine societies. I was talking a little bit about the International Society for the Study of Women's Sexual Health. There's the Sexual Medicine Society of North America. And you might hear that from some of your speakers on mao. They all have find the provider websites. You know, you might want to say to your clinician like, can I have a referral to someone who does sexual medicine or deals with sexual health? They may not know? So you can go to the society websites. When you're talking about menopausal medicine, I should say, like, the North American Menopause Society has a bigger meeting. There's several thousand, but they also have a finder provider website. If you think you want a kind of a subgroup, like, for example, a sex therapist, there are websites. For example, Asect A S S E C T has a website with Find the provider, the physical therapy. There's a national physical therapy website. I could send you these websites.

Let's do that. And we'll link to them all in the show notes so that there's a very clear reference trail.

I think that's faster. Right. But the point is that each of these kinds of subgroups that I mentioned have find the provider websites. But remember, like sexual medicine specialist, menopause specialist, pelvic floor, physical therapist, sex therapist.

Those are the buckets.

Those are the kinds of keywords. Yeah.

Well, Sharon, thank you very much for the generosity with your time and your insight. Like I said, a lot I've learned and I suspect a lot that everyone have learned. So thank you very much.

Well, thank you very much. Great questions.

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