Thank you, Dr. Howard, very much for that overview of the Infectious Disease Division. So as many of you know, I'm Walid, and I have a great honor today to-- we all have the great honor today to have Dr. Richard Santen with us from the Division of Endocrinology. So during his very long and illustrious career, he's held several leadership positions, including chief of the Division of Endocrinology and vice chair of medicine at the Penn State School of Medicine, as well as chair of medicine at Wayne State University. Since coming here to UVA, Dr. Santen has been a leader both for our institution and nationally in the field of endocrinology for the past several decades, most notably serving as president of the Endocrine Society pretty recently within the last few years. His NIH funded research has focused on several areas, including the development of aromatase inhibitors for treatment of breast cancer, mechanisms relating to estrogens of breast cancer, and the effects of vaginal estrogens on circulating hormone levels. For his efforts over the years, he has earned national research and leadership awards, which are too numerous for me to list today. And further, given his specific expertise, he has served as the lead author of the Endocrine Society scientific statement on menopausal hormone therapy, and on a review of the management of menopausal symptoms in breast cancer survivors. Dr. Santen continues to manage an active clinical practice while doing all this, as well as focus on mentoring the next generation of endocrinologists, so we're certainly very fortunate to have him here to speak with us today on this very complex topic of menopausal hormone therapy. So without further ado, if you could just please join me in welcoming Dr. Santen. [SIDE CONVERSATION] Thank you very much. I'm going to be talking about the menopause today. How in the world am I going to tell you anything about the menopause? So to try to give you an idea about this, we've asked Janice Spradling, one of my patients that I've taken care of for a number of years, to share with us some of the symptoms of menopause that people experience. Now, my talk-- basically, it's going to be taken from a guideline that we wrote which was meant to really be an international guideline. You can see down below in yellow the various societies that have sponsored this. Cynthia Stuenkel was the key author; JoAnn Pinkerton here, from the Midlife Health Center, was an individual; and myself. So we have a number of disclosures-- my own are three companies. I'll tell you, from some of the work that I've done at Pfizer-- just to be transparent-- we'll comment on that later. So what about a historical background? My wife came to me in 2002, totally distraught. The news said that hormone therapy was terrible for patients, and it was based on this aspect. It was the Women's Health Initiative Study comparing Premarin and Prometrium-- I'm sorry, Premarin and medroxyprogesterone acetate-- with placebo. And what we're seeing is that there was a two-fold increased risk of stroke, of DVT, of heart disease-- a 23% increase-- and a 26% increase in breast cancer. There were very few patients that were benefited from this, because most of these patients were older. So after this, the use of hormone therapy around the world went down about 80%. But then we began to rethink-- the average age of patients in the Women's Health Initiative Study was age 63-- and in fact, women start to make a decision about hormone therapy shortly after menopause, and commonly plan to use this for about five years. So what happens to the younger women that are on hormone therapy? Well, when you go back and do a post hoc analysis, and look at women on estrogen alone-- conjugated equine estrogen or Premarin-- ages 50 to 59, with symptoms. The symptoms are relieved, and there are 12 out of 1000 women over five years that don't develop diabetes, eight that don't have fractures, five that don't die, and two that don't develop breast cancer. So the pendulum has really swung toward benefits of hormone therapy in selected populations of patients. So when we develop these guidelines, we wanted to take a step-to-step approach. Wanted to look at definitions, health considerations, women that could take hormone therapy, women that couldn't take hormone therapy, and then the local use of estrogens. So how do we diagnose the menopause? Well, in women who have a uterus, it's simple-- it's a clinical diagnosis based on the cessation of menses for at least 12 months. Women having undergone a hysterectomy but not a bilateral oophorectomy, it's more difficult. Elevated FSH levels and low estradiol concentrations on several occasions-- and this supports the diagnosis, but it doesn't necessarily make it, because in the menopausal transition there's a start-stop, start-stop. And this is only a guideline, basically, to think that menopause basically is happening. So we have to look at health considerations for all women, and we're talking here about women less than 60 years of age, and women less than 10 years since menopause, because this is really when women choose to be on hormone therapy. So we need to address bone health and smoking and alcohol, cardiovascular risk, cancer screening and prevention, and so on. We had some difficulty in writing the guidelines-- what do you do in a woman that doesn't have any symptoms of the menopause, but has osteoporosis? We know that menopausal hormonal therapy is very effective for those patients, and so we really waffled on this. And the Endocrine Society is now writing guidelines as to when you should choose hormones in these patients. But the bottom line is, if the patient doesn't have contraindications to estrogen, this is certainly an option. So let's talk, then, about women with moderate or severe symptoms of menopause, vasomotor symptoms. They have an interest in taking hormones, and there are no contraindications. So we have to look at the analysis of benefit versus risk in these individuals. So we talked about the usual time to-- start on therapy is right after the menopause. So we want to look at the risks and benefits for those ages 50 to 59, or 10 years after menopause onset, assuming they'll use this for about five years. So we expressed all risks and benefits as attributable, and we used the Women's Health Initiative study in a post hoc analysis, just looking at these younger women. So what's attributable risk? It took me about five years to explain this to my wife. So if a woman has a five out of 100 chance of getting breast cancer over five years, and on hormone therapy she has a seven out of 100 chance, the attributable risk is two. So this is the risk in which the hormone therapy increases the risk of therapy, and this is really the most important parameter. So we can look, then, to see what the risks and benefits are in this younger group of patients. Let's look, first of all, at conjugated equine estrogen plus medroxyprogesterone acetate. So the primary endpoints were coronary heart disease and invasive breast cancer. And so there are about two to three women out of 1,000 taking hormone therapy for five years who will have a heart attack or invasive breast cancer that they would not have had otherwise. Pretty similar for stroke, pulmonary embolism, and deep venous thrombosis. The benefits are a reduction in fractures, a reduction in all cause mortality, and about a five out of 1,000 women will not develop diabetes that would have otherwise. So let's look at conjugated equine estrogen alone during the intervention. Now, paradoxically, there is a reduction in coronary heart disease and invasive breast cancer. Still pulmonary embolism and deep venous thrombosis; an improvement of fractures and all cause mortality; and about 10 out of 1,000 women over five years, a reduction in diabetes. We like to say these risks are relatively small-- two to five out of 1,000-- so I was trying this morning when I was jogging to figure out some other comparison that we can think about in terms of risk and benefit. And what I come up with is-- you drive a car for five years, you have one out of 1,000 chances of dying of a car accident. So we're really talking about risks that are relatively small in this setting-- but nonetheless, they're real. So in doing a clinical guideline, we had two meta-analyses that were done. And the first thing is, is there a difference between oral estrogen and transdermal estrogen? What we found was that the relative risk ratio of oral versus transdermal was 1.63 for veno-thrombotic episodes, 2.09 for deep venous thromboses-- and the conclusion, because these were all observational and not randomized controlled trial data-- that probably transdermal estrogen is much safer than oral estrogen. Well, the logical question then is, is transdermal estrogen causing any more DVT or pulmonary emboli than placebo? And the data available from this 80,000 postmenopausal women randomized trial was that the hazard ratio was 1.1, confidence limits 0.8 to 1.8, which would tend to suggest that transdermal estrogen is not associated with DVT. This has to do with the first-pass effect of estrogen in the liver, which doesn't occur with transdermal. So as in the guideline, we really recommend transdermal estrogen over oral for most patients. So let's go on then-- we have this patient considering MHT. She's symptomatic, she's interested in MHT, and if she's older than that, you consider other options. If not, you would consider this as a possibility. The next thing is, what about contraindications? So you're not going to use it if the patient has contraindications-- you will use it if these are absent. So what are the contraindications? I won't read all of these, and there really are no good scientific articles that talk about all the contraindications. So this is the list that you would find if you look up the FDA about estrogen. And most of these, as you can read, are known sorts of things that can occur. So this is controversial around the world, but we recommend evaluation cardiovascular risk in patients that are going to go on menopausal hormone therapy. And if the risk is high, consider other options; if the risk is it is acceptable, then you can use menopausal hormonal therapy. So Dr. Kerry was involved in some guidelines about risk evaluation. Most of the guidelines include men and women. We chose the Reynolds Risk Calculation Score because this was designed specifically for women. And you can see the factors that are involved in this-- it's online. And this particular patient-- age 50, total cholesterol one in seven, and so on-- had a 10 year risk of 1.14%. So one can do this in thinking about whether you're going to use hormonal therapy for a patient. So in the guidelines-- we adapted this from JoAnn Manson's data in the New England Journal and elsewhere. So if the 10-year cardiovascular risk is low-- less than 5%-- it's appropriate to use menopausal hormonal therapy for less than five years, or for up to 10 years. If the risk is moderate, we recommend choosing transdermal; and if the risk is over 10% chance of having cardiovascular event, you want to choose something else. Also need to evaluate breast cancer risk. So how does one do that if the risk is elevated? You're going to consider other options. If it's acceptable, it's appropriate for the patient to do this. So we recommend this-- it's called the IBIS breast cancer risk evaluation tool. You can find this online-- it's also called the Tyrer-Cuzick model. And basically, I pull this up on my computer in my office-- it takes five minutes. These are all of the parameters that are put into this. It plots a family tree for you, and it will tell you what the risk of breast cancer is over time. It will tell you what are the chances that patients have BRCA1 or BRCA2 and need to be tested for that. So we use this across the medical center now for people that are talking about menopausal hormonal therapy. So we came up then with a similar assessment. If the risk is low, and that's less than 1.67%, menopausal hormone therapy is OK. If the risk is intermediate, I do this with caution. And if the risk is high-- greater than 5%-- in five years, avoid menopausal hormonal therapy. Where do we come up with these numbers? Well, these are the numbers that are used to decide whether a woman should be on tamoxifen to prevent breast cancer. So if a woman should be on tamoxifen to prevent breast cancer, this is probably not a woman that we should be giving menopausal hormonal therapy to. So remember that it takes a long time for a breast cancer to develop. It requires 16 years on average for the tumor to undergo 30 doublings, which makes it large enough to be detected on a mammogram. So in actuality, in the population, about 7% of women have breast cancer-- post-menopausal women-- that's not diagnosed yet because it's too small. So in actuality, the estimation of breast cancer risk with any of these models probably is likely determining that, if a patient already has an occult undetected breast cancer, it's going to grow large enough over time to ultimately be diagnosed. So the next question is, does the patient have a uterus? If no, estrogen alone. If the patient has a uterus, then the common therapy is estrogen plus a progestogen. And this would be a Prem-Pro, or it would be a combination of transdermal estrogen plus Prometrium. I'm going to comment on estrogen combined with bazedoxifene. This is a new therapy-- I call this one the internist's therapy because it doesn't cause any increased vaginal bleeding. And then tibolone is used in 40 countries, but it's not approved in the United States. Now I've got to tell you that we did a lot of work on this, as did JoAnn Pinkerton, funded by Pfizer-- so that's the transparency of my comment here. We call this a TSEC-- tissue selective estrogen complex. It sounds totally paradoxical. You're giving an estrogen plus an anti-estrogen-- bazedoxifene-- but it turns out, when you look at this, it has a totally unique cDNA signature, so it's very different than estrogen or the anti-estrogen. The combination together creates a clinical-like set of symptoms of relief that are very different. The main thing is that it eliminates the need for a progestogen, and because of the bazedoxifene, it reduces vaginal bleeding. And I say that this is ideal for an internist to prescribe, because we're not very used to handling unexplained vaginal bleeding. This is approved in the US and in the European Union-- it's not been approved everywhere around the world at this point. So what if the patient has a contraindication to therapy, or, as many patients, they're fearful of taking hormonal therapy? What basically can you do at that point? Well, the major symptom that we're thinking about is hot flashes. And some recent data have looked at the trajectory of hot flashes over time, which I would say that none of us in the room knew about this. So it turns out that about 25% of patients will have hot flashes that will start as early as eight years before the menopause, and will continue for the next 13 years. So menopausal hot flashes in some individuals can persist over a long period of time. There is another quarter of patients who have very few hot flashes over time; another group that have hot flashes just up until the time of the last menstrual period, and then the hot flashes decline. And there is another group in which the hot flashes really start around the time of menopause. So we need to ask our patients about these four trajectories. And these studies were from the Swann study-- just 500,000 women around the United States, where they were looking carefully at this. So the next question is, what causes a hot flash? Well, this is really due to narrowing of the thermoregulatory neutral zone. What in the heck is that? So heat dissipation is usually triggered with an increase in temperature of 2 degrees Fahrenheit. So if you get hot, you're going to try to prevent yourself from becoming hyperthermic. And this is mediated by vasodilatation, mostly in the face, but all over the body. So this narrowing is, after menopause, you only need an increase in 0.5 degrees of Fahrenheit to trigger this heat dissipation. So when this happens, if a woman gets too warm, she'll have a hot flash, and she can treat herself by basically trying to prevent this. The most recent data is-- this is mediated by neurokinin B neural pathways. So there are now three inhibitors of neurokinin B that are being developed. When this was presented at the Endocrine Society, the stock of one of these companies went up by about $7 million in a day. These are now in phase III trials, and I expect that, probably in a few years, we'll be using the neurokinin B inhibitors for this situation. [VIDEO PLAYBACK] - I have Janice Spradling here today. She's a patient that I saw several years ago who illustrates many of the aspects of hot flashes and the problems that the patients have with that. Janice, at age 44, had breast cancer-- had chemotherapy, and the chemotherapy caused her ovaries to fail, and her menopause really came on with a vengeance at that time. Going to ask her several things about this so that she can tell us what menopausal hot flashes are like. Janice, maybe just tell what you noticed initially. - Well, after the chemotherapy, through the first couple sessions, I would just burn up, get soaking wet, at night, during the day-- and the doctors just kept saying, it's the chemotherapy. Once we get through with this, they'll go away. You'll be fine. But they didn't go away. Went to the-- - Midlife Center. - The Midlife Center. Said they couldn't do anything for me because I couldn't take estrogen. So they said, we're going to send you to Dr. Santen, and we feel like he can treat you and get these hot flashes under control. So that's how I ended up in your office. - OK. So what's a hot flash for you? - Oh gosh. If it's a bad hot flash, my feet get hot first, and then I just feel my whole body turning, getting really, really hot, and it goes all the way to the top of my head. My skin gets wet, my scalp gets wet. It will last probably five minutes when I have a bad one, maybe three when they're not so bad. - What do you feel like right after the hot flash? - Exhausted. - OK. - Really tired, it takes a few minutes for you to start feeling back to your normal self again. You just feel like you've gone-- melted after one. - Do you sort of feel cold, cold and clammy? - Oh yeah. I will turn real cold and clammy, and then the jacket goes back on at work, till the next hot flash comes along, and then I'll take the jacket off at the end. - OK. So one way to deal with this is you take off your jacket or take off your sweater, that sort of thing. So if you have a mild hot flash, where is that affecting you? - That usually starts right around the chest area, just up around the head and scalp. It doesn't really bother the rest of my body that much-- just from the neck up. And there, then you get clammy and hot, and then once it starts wearing off, you cool down back to normal. - So now you're at work while this is happening. What are people saying about you when you're having this? - When I first started these, I froze everybody to death. I controlled the air conditioner in the wintertime down to 68. I had the window over my desk open, sometimes a fan on, and they were sitting around with heaters on, but they were trying to accommodate me because I was burning up so bad at work. - And I'd wear layered clothes where I could take a sleeveless top and a long sleeve shirt where I could take the shirt off at work. And if that didn't work, then I'd run outside and stand in the cold air until I cooled down. - So now you've told me that your boss thought maybe he was doing this to you? - Yeah. Every time he would come and talk to me, I'd have a hot flash most of the time, and my face would turn red, and I would start losing concentration-- and he thought I was getting ready to cry, so he'd bolt out of the office. Finally he went to the supervisor and said, every time I talk to Janice, she looks like she's going to bust out crying. He says, what's wrong? Am I doing something wrong? - And she said-- no, it's a hot flash. She said, just go to talk to your wife. She's a nurse-- she'll explain it to you. So after that, he didn't run away from the office anymore after he talked to his wife. But he thought he was making me upset, and I was going to cry every time we talked about something. - Goodness, yeah. OK. You know, a lot of people have much difficulty at nighttime with hot flashes. Has that been a problem? - Oh, lord-- in the beginning, I never got any sleep. I was up three or four times during the night, and I've even changed pajamas during the night, I'd have them so bad. I go out on the deck at night, or on the front porch, just trying to cool off. And of course, we kept the temperature down low-- [INAUDIBLE] would freeze, but I was comfortable. So if I keep the temperature down in the house, I usually can tolerate them, but I'm still-- it wakes me up, and I have to get up and walk around for a minute or two, then crawl back into bed, go back to sleep. - OK. So a lot of women that have hot flashes noticed that if they get into a warm room, that'll trigger the hot flashes. That happen for you? - Oh yeah-- it happens all the time at work, because they keep the conference rooms so warm, and when I go in there, I can start feeling-- within about 10 minutes I can feel just the mild ones getting ready to happen, so I'm grabbing a piece of paper, trying to fan during the meeting or whatever is going on in these warm rooms. - Right. So what other things trigger your hot flashes? - Spicy food and caffeine. And I cut out all caffeine out of my diet, and no spicy foods, and that seemed to help a lot. When you're having dinner or something, just you say-- I don't want that. And you drink water if they don't have caffeine-free tea or anything like that wherever we're at. - OK. A lot of patients that I see with hot flashes at night time get a little bit depressed the next day, or have trouble with their memory. Have you had that problem? - Oh gosh, yes. Memory was one of the bad things, because I could remember sometimes from day to day, things that I was supposed to do the next day, and I think it was all contributed to no sleep at night. And then I'd be so tired the next morning, I'd catch myself at work at times propping my elbow up on my desk, and the next thing I'd know, I'd kind of dozing off just because I was so tired all the time. - So we often, in thinking about hot flashes, have a scoring system-- and we talk about the number of hot flashes per day and multiply that by the severity. Severity would be mild, moderate, or severe. It sounds to me that your hot flashes are really severe. - Oh, I'd agree with that 100%. - OK. And then the number of hot flashes per day, you said maybe 20? - At least 20 a day, sometimes 30, depending on what was going on with work and in my personal life could make a difference in the number of hot flashes. - OK. Some recent information suggests that there's a group of women where hot flashes continue over a long period of time. Was that true for you? - Yes. Mine's been going on about 20, 21 years now. - OK, OK. Well, I think you've given us a good picture of what hot flashes feel like-- yours are obviously much more severe than most people, but you have most of the elements that we think about. We're going to stop at this point. I'm going to interview you a little bit later to talk about the treatments for hot flashes. Thank you for coming. [END PLAYBACK] So let's talk a little bit about therapy for hot flashes-- [SIDE CONVERSATION] --beyond estrogen. So estrogen works exceedingly well for blocking hot flashes. [SIDE CONVERSATION] Estrogen works exceedingly well, so that would really be the first treatment for a patient that didn't have breast cancer the way Janice did, or that had contraindications. But what other agents do we have? So there are a number of other ones-- paroxetine is really the only one that's been approved by the FDA, but in general, the SSRI, SNRI class of drugs-- venlafaxine, desvelafaxine, citalopram, and so on-- are effective. Now if you read about this in the medical literature, it said that these aren't so effective. But it's quite interesting that, if you do a study of menopausal therapy, about 30% to 50% of patients will have relief of their hot flashes with placebo. We have some idea that patients that are very anxious or have certain circumstances at work and so on, the placebo works. But if you then look in these trials at any of these agents shown in green, there's about a 30% to 40% increase in reduction of hot flashes. Here is shown placebo composite severity and number. And I always tell patients, I don't care if you're responding to the placebo effect of the drug or if you're responding to the pharmacologic effect of the drug-- doesn't matter. So you're going to have about a 50% to 60% to 70% relief of hot flashes, and this is quite helpful in some patients. Gabapentin is an agent that makes you very sleepy during the daytime, so I use gabapentin at nighttime for hot flashes. It's very effective. You get a twofer-- the patient gets put to sleep, and the patient has relief of their hot flashes, and the drug wears off by the time they wake up. So it's been a very effective way of treating some patients. Clonidine is a drug that works based on randomized controlled trials, but it's not very effective, and only works in a very small percentage of patients. I had a CEO who, at her board meetings, had these godawful hot flashes, and the only thing worked was clonidine, and it worked beautifully-- because it seemed that the stress aspect of presenting to her board maybe triggered these off. There's been a lot recently about hypnosis, acupuncture, behavioral modification-- these are not very effective or practical, and I don't really recommend that. And then we have the neurokinin B inhibitors, which I think are going to be quite useful in these patients, and useful because I think it will block a specific pathway mediated by hot flashes. And as I'd mentioned, phase III trials are underway at this point. So how has Janet been treated? [VIDEO PLAYBACK] - So Janice, we initiated some treatment when I saw you some time ago. Why don't you tell me a little bit about what you were put on, and what the effects were? - The first thing I was put on was Effexor, and it helped some, but not enough. It was just like I still had almost the same number of hot flashes a day-- it helped a tiny bit, but wasn't taking care of the whole issue. - OK. So what did we do next? - Next, you put me on the clonidine dermal patch that you change once a week, and then the clonidine tablet that you take once a day. That helped, but it probably helped maybe 50% more. But I was still having them, and still losing sleep. And then the last thing you put me on was gabapentin, and the gabapentin seemed, with the combination of the other three, really worked. I was able to sleep at night, and it toned the hot flashes down a lot. - OK. So if I would say they were 100% controlled or 20% controlled, what would you say? - I'd say probably 80% to 85% under control. - OK. And when you had hot flashes, during that, what triggered them off? - Stress can do it. The spicy foods, caffeine, chocolate, anything like that will just set them off to increase the intensity of the hot flashes. - So the same thing that you had before, just many, many fewer of them? - Yes. - So now how many would you have a day, would you say? - I'd probably have 10 a day, maybe. - And the severity? - I'd say half of them are severe, like a grade of 10, and then the rest of them are just mild hot flashes-- just the minor ones that you just get a little hot from your neck up. - OK. So that sounded to me to be a little less than 85% control, but clearly beneficial. - Oh yeah. Much beneficial. If I go off of one, I can feel them increasing. - OK. A lot of patients on gabapentin, if they take it during the daytime, they get very sleepy. Did you notice that? - Oh gosh, yes. I was on it for three times a day, and if I took it in the morning, I'd find myself wanting to take a nap at work and prop up and close my eyes, and just about go to sleep, so I stopped taking the one of a morning, and then just took two in the evening. And then I would sleep much better during the night, but I just couldn't take it during the day and work. - OK. So when you're on the gabapentin just at nighttime, that seemed to be OK without sleepiness during the daytime. - Right. - OK. Did you ever stop any one of the medicines? - Yes, sir. We stopped the Effexor, and I was off of it for a month. And as the month went on, I could feel the hot flashes increasing again, almost to the point that-- they weren't 20 to 30 a day, but they were increasing more, so I went back on the Effexor, and you could feel it tone down some once I was on all four medications at the same time. - OK. Now I remember recently you came in and you were having some difficulty with more hot flashes. And I think that the dose of gabapentin had been reduced a little bit. - Yes, sir. - And we increased the dose back up to I think 900 milligrams at night? - 600. - 600 milligrams at night. And did that help to reduce the hot flashes? - Yeah, that helped a lot during the night by taking that, because if I had one during the night, it would be just-- wake up, cool down, and you'd go right straight back to sleep. It wouldn't be like they were continuing constantly-- you could cool off, and then get drowsy again, and right on back to sleep. - OK. So with your regimen now that you're on, what side effects are you having? - The biggest side effect I have probably is just dry mouth, so I have to constantly drink water or some kind of liquid to keep my mouth from being so dry, but that's really the only thing that I have, that I can see, is just the dry mouth part. - So your energy is good? Your memory is OK? - Mm-hmm. - OK. So how long has this been going on now? - Probably for about 20, 21 years now. - OK, so you're unusual, but we've learned recently that the hot flashes can last a long period of time in a group of maybe a fourth of women with hot flashes. So thank you very much for sharing your story with us. - Thank you for having me. - You're welcome. [END PLAYBACK] So you're going to have some questions for Janice later on. This has been a very interesting area, the study of hot flashes, because it gets us to focus on these candy neurons. It's neurokinin B, it's kisspeptin. And these are-- it's an area of the brain that controls temperature regulation. It also controls reproduction. So it's an area that is involved in hot flashes. So if you have a hot flash, there is an LH pulse that occurs at the same time. [SIDE CONVERSATION] So it's a very active area of research, and I think ultimately it's going to help quite a lot in trying to help patients with menopausal symptoms. So finally, there are some individuals that only need local therapy. So this is for vulva-vaginal atrophy. There's a new term for this now called the genitourinary symptom syndrome of menopause, and it relates really to vaginal atrophy, vaginal dryness, dyspareunia frequent urinary tract infections, and so on. And this is an estrogen deficiency condition as well. So how do we manage this? Well, we always suggest using vaginal as opposed to systemic estrogen if the vulva-vaginal atrophy is the only indication. So with this, you really don't get an increase in plasma estrogen levels, and one doesn't have to worry so much about breast cancer or any of the other aspects, because the drug is not basically getting absorbed. But there are some other ways of treating this also. One is with the selective estrogen receptor modulator, ospemifene. This is a drug that works quite effectively on the vaginal mucosa. There's a lot we don't know about ospemifene. We don't know if it prevents breast cancer-- it could. We don't know about its effect on heart disease, but it has been approved basically for treatment of vulva-vaginal atrophy. And some women would prefer to do this rather than the local route. And then finally, a year ago, dehydroepiandrosterone-- this is a hormone that you always heard about in medical school. We had no idea what it did. That gets converted into estrogen in the vagina, and it causes relief of vulva-vaginal atrophy symptoms, and it has to be taken once a day, as opposed to the other agents that are taken twice a week. So what are the take home points? Well, first of all, the pendulum is swinging back. So for properly selected patients, the benefits of menopausal hormonal therapy will outweigh the risks-- but one has to select patients that aren't at increased risk for heart disease, and patients that aren't at increased risk for breast cancer. The second thing is, if a woman can't take menopausal hormonal therapy, there are effective relief of menopausal symptoms can be achieved with non-hormonal prescription therapies. And then finally, we know from surveys that vaginal and urinary symptoms are undertreated. Women are not very happy to tell you about that, and you have to ask them about the symptoms. And with that, there is effective therapy, and this would be local estrogen and a systemic SERM is as effective. And then finally, although not everybody agrees with this, I think the data really support the fact that transdermal estrogen-- an estrogen patch, which avoids the first pass effect on the liver-- seems to be associated with less DVT and pulmonary emboli, and is associated with less of the liver proteins that are stimulated by estrogen. And finally, the bottom line is that one needs to individualize the approach to initiation and continuation of menopausal therapy. So with that, thank you very much for your attention. I'm hoping we'll have some questions for Janice. Dr. Marshall. Can I ask you about [INAUDIBLE]? Sure. Some individuals who [INAUDIBLE]. Yeah, this is the $64,000 question. We don't-- Do you have any data? Inpatients, beyond the time that the Women's Health Initiative study was done. So for estrogen alone, five years-- for estrogen plus progesterone, 7.2 years. So we really don't know how safe these agents are over that period of time. So what the guidelines have said-- and we've waffled about this-- if a patient is having effective relief of symptoms, and they would like to stay on the medication, basically tell them what we know about the risks and benefits over that period of time. And it's quite reasonable for a well-informed patient to continue on hormonal therapy if they've been given the risks and benefits, and one we could continue with this. I don't think we'll ever have these data. We have some information from the nurses' health study, where women were followed for 17 years. And under those-- in that study-- which was not a randomized controlled trial, it was an observational study-- after 15 to 20 years of estrogen alone, there was an increased risk of breast cancer, whereas there wasn't in an earlier period of time. And I say that to emphasize that there's a difference between estrogen plus a progestogen, where there's a marked increase in breast cancer risk-- and estrogen alone, which paradoxically reduces it. So we're physicians-- this is the art of medicine, and there are a lot of patients like this-- if you're practicing in New York City, where women want to be young forever, my colleagues there that prescribe menopausal hormonal therapy are confronted with that question all the time, and the approach is discuss it with them. Individualize your therapy, and continue if the patient really wants to have it, provided there are not any major contraindications at that point. Yes. [INAUDIBLE] that was a great talk and wonderful interaction. I want to just ask a couple of questions-- one is about fragmented dosing as compared to [INAUDIBLE]. What's the usual [INAUDIBLE]? Right. So-- there's a little bit of background to this. One wants to use the lowest dose that's effective. When one uses transdermal estrogen-- I usually start with 50 micrograms. And this is not generally agreed upon in the medical community, but I'm an endocrinologist-- I like to measure hormones. And so if the patient has their symptoms relieved with 50 micrograms, that's fine. If they don't, I will dose escalate to 75 and 100, and I would then measure estradiol levels to make sure I'm not getting into super physiologic levels of estrogen. How in the world am I going to determine what's super physiologic? Because in pre-menopausal women, during the-- right at the time of the menstrual period, the levels that are 40; mid cycle peak are 600; and during the luteal phase, 200. So what we've decided to do is to measure estrogen daily during the menstrual period, and find out what the mean level of estradiol across the menstrual cycle-- and that's about 100 picograms per mill. So I will go up to 100 picograms per mill if a patient doesn't have symptoms over that period of time. The second thing then is, what patch is the best patch? John Marshall always says, those darn things always fall off in the shower-- and they do. But if you order the Vivelle-Dot-- it's a little tiny patch, and it sticks much better. It's much more expensive, but that's a good one to use, because it's better tolerated-- there's not as much irritation under it. And you can use Climara, which is cheaper, but that's one that sometimes one has to use. So the second thing is, what do you use for the progesterone or progestogen, and does it make any difference? So we know from the studies in Europe, mainly from France-- the EPIC studies-- that progesterone seems to have no increased risk of breast cancer when combined with estrogen, whereas the progestogens-- medroxyprogesterone acetate, norethindrone, norethisterone, and so on-- are associated with increased risk. Now those are observational studies, and they're not randomized controlled trials, but it would suggest that using Prometrium, which is a capsule that has crystalline progesterone, is beneficial and better to use than Provera or one of the other agents. And then the question is, what dose do you use of that? 100 milligram is safe for five years. After that, there's some increased risk of endometrial hyperplasia. With a 200-milligram dose, it's safe over a long period of time. So I usually use the 100, and then later on, switch. For those of you that don't use progesterone, it makes you very sleepy, and this again is a drug that you have to give an hour before the women go to sleep. And it's wonderful because it's a sleeping pill, and it's gone by the next morning, basically-- the blood levels are gone. So those are kind of the ins and outs of that. And I think all of the experts around the world that I talk to that see a lot of patients with menopause really prefer the transdermal plus progesterone. It's a little bit harder to do it-- sometimes a little more expensive, but I think it does have a good deal of data that suggested that it's safe. Yeah. Thanks. My second question is, it looks like [INAUDIBLE] metaanalysis that [INAUDIBLE] mortality [INAUDIBLE]. And yet heart disease risk is [INAUDIBLE] so heart disease is the biggest killer [INAUDIBLE] America, what is the effective [INAUDIBLE]? Yes, so the all cause mortality issue-- most of the data suggests that that's correct. The data are more robust for estrogen alone than estrogen plus a progestogen. What's actually happening here? So we call this the timing hypothesis, and we know that estrogen, given to a younger woman who doesn't have plaque, it tends to prevent plaque from developing through a number of biochemical events. Once a woman has plaque, then the estrogen causes a turn on of the agents that destabilize plaque and will result in acute coronary syndrome. So this is the timing hypothesis. Early, good-- bad, not as good. And it's led a number of individuals-- and I'm a big believer in this-- that we really should calculate a woman's cardiovascular age. So if she's 50, and has very low risk of having heart disease, she probably has little plaque-- and a 60-year-old who has a cardiovascular age of 50 could probably be on hormone therapy. But it's really based on the fact that plaque increases over time, that there are biochemical effects that prevent it in younger women, and cause destabilization of plaque in older women. But all of this suggests that these risk [INAUDIBLE] gives us some idea of what the underlying risk is, and that's why we use these in determining whether we're going to use this or not Janice, I'm going to ask you-- so are you still having trouble at work with your hot flashes? Off and on, I do. If I get in a real stressed time of day where I'm trying to satisfy four or five people with problems and with the machine run schedules, then yeah-- they'll start. My face will turn red, and everybody's like, are you OK? Yeah, I'm fine. It's just a hot flash getting ready to start. And most of them just laugh about it, they think it's funny. And I just say, well, wait till your wife has them and then you won't think it's so funny anymore. But stress is a big cause of the hot flashes-- real bad. It will make them really bad. So is your job really stressful? Yes, I have a stressful job. I'm responsible for keeping three machines running where I work, and constant jerking schedules around, placing orders in for somebody else, changing, contacting the operators, telling them they've got to change the schedule. So yes, it can be real stressful. And there are days that it's not. OK. Yes. [INAUDIBLE] having breast cancer [INAUDIBLE] by having a high [INAUDIBLE] breast cancer [INAUDIBLE]? This is my favorite question. And it's my favorite question because what you're really doing, by increasing the diagnosis of clinical breast cancer, you're picking it up earlier, because you're putting the patients on hormone therapy. So in general, there is no ultimate effect on mortality, with the exception of estrogen plus a progestogen. So this is conjugated equine estrogen plus medroxyprogesterone acetate. At the 13-year follow up, there was a very small increase in mortality in the women that had been on E plus P for seven years and then stopped, so it's not an absolutely clear answer. But I think the issue about early diagnosis is certainly there, and it's based on a lot of data that we have with respect to that. And that's a reassuring thing with the exception of this long term data on E plus P. [INAUDIBLE] do that [INAUDIBLE] transdermal [INAUDIBLE]. No, you don't mute the positive effect. So what happens if you give Premarin orally, or if you give 17 beta estradiol orally? What happens is, it gets into the liver and gets metabolized, but the active estrogen is predominantly estradiol, and some of the metabolites probably get converted into estradiol in tissue. So when you give it transdermally, you basically replace that same circulating level of estrogen. The only thing that's different is that, when you give oral 17 beta estradiol, and the estradiol levels are about 100, if you give it orally, the estrone levels are 500. If you give it transdermally, the estrogen levels-- estradiol levels-- are 100, and the estrone levels are 100. So the liver basically converts one estrogen into another one, and we tend to think that estrogen gets converted into estradiol in tissue. So if you give oral estrogen, it's very hard to measure what's actually happening, because you have these metabolites. Karen Klein, that I've worked with for a long time, has a bioassay for estrogens, and when you give oral estrogen, and have the same level of estradiol, the bioassay of estrogen effect is about 60% higher because of the estrone and estradiol. So the transdermal works just as well-- it doesn't have the effect on the liver, therefore you don't have all the clotting factors that are altered. And basically, it's effective for bone density, it's effective for hot flashes, it's effective for vulva-vaginal atrophy, and so on. So the transdermal works very, very well. Thank you, Dr. Santen. I think we're just about at time, so I will cut it off there, but thanks again for coming and for a wonderful talk.