Three months of bothersome hot flashes and night sweats, sleep disturbances, irritability, and brain fog, and her last menstrual cycle was 14 months ago. Her past medical history, we're going to make her real. She has high blood pressure. Can someone help with that? Diabetes, medications. She's on Lusartan and Metformin. Her father had a heart attack at the age of 55. Her brother has hypertension. She has no history of breast cancer. She has a BMI of 34. Her LDL cholesterol is 138, and her estimated 10-year risk for heart disease is 5.7%. So which of the following, I know we don't have audience response system here, but I want you to think about this. Which would you use for her as the most appropriate treatment? Would it be a selective serotonin reuptake inhibitor? Would it be gabapentin? Would it be menopausal hormone therapy? Or would it be acupuncture? What do you guys think? Menopause hormone therapy. So I'm going to suggest to you that we would be using hormone therapy for her, and we'll talk about why. So let's just level set here a bit about the basics. Menopause is defined as no menstrual cycle for 12 consecutive months. The mean, at least in the United States, is 52 years of age. It's younger in some countries. I saw a recent study in India, the mean age of menopause is 42 years of age. In the United States, anything over 45 is considered normal, and about 5% of women go through between 40 and 45, and about 3% are going to go through under the age of 40. So it's not insignificant. We still have about 8% of women going through menopause under the age of 45. Now, perimenopause is that time leading up to the last menstrual period. Women can start to have symptoms during this time frame, and we're learning more and more that symptoms are quite common during this time frame, and in fact, that can be a full six to 10 years before a woman has a last menstrual period. So we know menopause symptoms are common. About 75% of women are going to have hot flashes and night sweats, and these start to occur even before there's a significant difference in menstrual cycle length. So these can occur when you're having a 26-day cycle one month and a 32-day cycle the next month, less than seven days difference. These women have the same exact symptoms as women going through menopause, hot flashes, night sweats, sleep disturbance, mood disturbance, et cetera. We used to tell them that wasn't possible, but we now know that it is, and it is actually quite common. We know there are racial and ethnic differences in hot flashes, and about 75 to 80% of women experience these, but we know that women of color tend to have more severe symptoms. They start earlier, and they last longer, a mean duration of 10 years. Ability seems to be a really common symptom. Anxiety is common, and depressed mood. So let's talk a little bit about testing. Do you need to test a woman? Should she test herself? I don't know if you've seen this, but just like the over-the-counter pregnancy test, there's now an over-the-counter menopause test that's out there. I did some investigation a couple of months ago, and I looked into it, and in the United States, you can get home tests for anywhere from $20 to $99. You can either, I'm sorry, I'm not sure why it's advancing by itself. You can test FSH, estradiol levels. They typically are urine, saliva, blood. They ask you about your period history, and they come out and they say menopause, no menopause. The problem here is that FSH is so highly variable in perimenopause. Is there any reason that a woman should do this? Why would she do this? Well, if she's had irregular menses or no menses, and she's on a progestin-containing IUD, you can't tell. All bets are off. She may or may not be having menopausal symptoms. So maybe it would be worthwhile for that woman because you can't go by the menstrual cycle in her. Women who have periods that have stopped earlier than expected, so say a woman stops her period, she's in her 30s. Of course, you need to rule out pregnancy, but then a woman might test then. Or if she has something like PCOS, it's hard to tell. What about in the office? Do you typically need to test a woman to see if she's menopausal? And I would submit that most of the time when she's 45 or older and having typical symptoms of menopause, no tests are really needed here. But again, maybe if she's younger than 45 or she's having atypical symptoms and it's just unclear what the issue is. So if there's uncertainty and you can't use the menstrual cycle as a signal for the perimenopause or the menopause transition, for example, she has a progestin-containing IUD in place or she's had an endometrial ablation or she had a hysterectomy and has her ovaries. Or if she has PCOS or functional hypothalamic amenorrhea. If you're going to test, what test would you use? The FSH is the test we typically use, but again, keep in mind that FSH levels can vary literally by the day and they're not always that helpful. A concentration of 25 IU per L or higher is a marker of the late menopause transition. But for a woman who's truly in menopause, the levels are going to be 70 to 100. You could consider repeating an FSH in four to six weeks to confirm the diagnosis. If a woman has had a pelvic surgery, all bets are off. You can't use the FSH within three months. And we typically do not use estradiol levels. They're just not that helpful. They're typically under 10 in a woman after menopause. They are not useful for defining menopause. And AMH levels similarly are not helpful for menopause definition, but they are used for fertility. Special considerations. A woman using an oral contraceptive pill, you can't use the bleeding pattern. I have women coming in to me saying, well, I'm not having a period, I must be menopausal. If she's on the oral contraceptive pill, it doesn't help you. Similarly, if she's having bleeding monthly with the oral contraceptive pill, it doesn't tell you that she's still pre-menopausal. And the FSH is not a reliable marker for women in this stage. I'm sorry, I'm not sure why it's auto-advancing. So keep in mind, given that 50% of women will not be menopausal at the mean age of 52, they still need contraception until menopause can be confirmed either by the bleeding pattern or discontinue the oral contraceptive pill until the age of 55. This is commonly done now. About 90% of women will be menopausal at this stage. Again, sorry. Consider a progestin-only pill or leave an adjustable containing IUD after 51 and 52. You can use a post-menopausal estrogen regimen and if with the IUD or a progestin-only pill to manage symptoms. And this is often a nice way to handle that. All right, let's talk about vasomotor symptoms in the menopause transition. What are they? Even a couple of years ago, when people asked what is a hot flash, where does it come from? We had no idea. It wasn't until Naomi Rance did some really elegant work around 2013 to discover where hot flashes actually came from. And through her work, we found that the candy neurons, cispeptin, neurokinab and dynorphin, that's the neural plexus that's responsible for the hot flashes. That becomes hypertrophied when there's a loss of feedback of estrogen from the ovary. We know that vasomotor symptoms are triggered when these neurons are hypertrophied and that neurokinab receptor blockade reduces hot flashes. This is really a nice pictorial from the SWAN study. This shows us that not all women experience hot flashes in the same way. So this is divided roughly into quarters and I want you to look at the x-axis down at the bottom. It goes from minus 11, that's 11 years before the last menstrual period, to plus 14. That's a long time for hot flashes. You see the red line at the top, those we call the super flashers. They start early, they flash often, they flash for many, many years. Those women hot flashes are linked with a higher risk of heart disease. We have the late onset flashers, the green line, and we have the ones at the bottom, I call the blue line, it's like my mom. I asked my mom what her experience was because she said when we wrote the first menopause book in 2016, she goes, why are you writing a menopause book? And I said, well mom, what was your experience? I never really asked you. And she said, I may have had a hot flash once when I had a glass of wine. So this is not the usual experience for most women. Most women have a lot more difficulty. There are some women that actually hot flash more before the last menstrual period, and that is the yellow line, and then really have a rapid drop off after that. But the point here is that women experience menopause differently. Let's talk about sleep disturbances in the menopause transition. We know that sleep disturbance is a key symptom of menopause. About 50% of women in the menopause transition report difficulty sleeping. There's a longer sleep latency, so it takes women longer to fall asleep, and there's less deep sleep during menopause. What is this? What's going on here? We know that hot flashes, which also occur at night, can disturb sleep. We know that the loss of ovarian hormones, estrogen and progesterone specifically are associated, the levels are associated with sleep disturbance. We know that mood disturbances can disturb sleep. So we know that if women have irritability, anxiety, they can wake up at night with panic attacks. Depression is associated with sleep disturbance. We also know weight gain in and of itself is associated with sleep disturbance. And then this is a time when women are at increased risk for getting primary sleep disorders like obstructive sleep apnea. More common after menopause for a few reasons. Women tend to gain weight during menopause, but also the loss of estrogen results in a floppier, less supported airway. So women tend to get more sleep apnea when they lose estrogen. Restless leg syndrome is also more common after menopause. But think about what else is going on. There's family and work demands. This is often when women are at the peak of their careers. They have aging parents. They're in the sandwich generation. They're taking care of aging parents. They're also taking care of children who may or may not have lunched. And think about things like aging pets that need to go outside to go to the bathroom. You also have partners or spouses who may have treated sleep apnea and are using CPAP or even worse, have untreated sleep apnea and are snoring all night. So there are many things that can disturb sleep during this time. What about cognitive functioning in the menopause transition? Brain fog. This is something that women come in complaining about. What is brain fog exactly? It's a cognitive symptom that women tend to report around menopause. It impacts memory. So there's difficulty in coding, recalling words, names, stories, numbers. Women, think about being in the office or working and women are having trouble remembering things in the menopause transition. Very difficult to maintain concentration. Also, distractibility, difficulty with multitasking, forgetting intentions. Like you walk into a room and say, why am I here? I forgot what I was going to do. Is it real? The SWAN study has shown that it is real. So women do have documented verbal learning and memory deficits when they complain of brain fog. The good news is that higher level executive functioning appears to be preserved and doesn't change across the menopause transition. Most women's cognition remains in the normal range, but a small percentage of women, and this was Pauline Matthews, and this was Pauline Mackey's work, showed that about 11 to 13% of low-income women, many of them also had HIV, actually tested in the range of cognitive impairment during this time. The timing of onset, it starts to happen when women are in perimenopause and the periods are irregular or are skipped. What causes it? We don't know, but the loss of ovarian hormones suggests that it's the problem. It doesn't seem to be a marker of Alzheimer's disease or a predictor of who will eventually develop Alzheimer's dementia, so that's the good news. But links have been found and are associated with estradiol levels, with hot flashes and night sweats, with sleep issues, with mood disorders, and we think that treating these symptoms specifically is going to be helpful with cognition, but nobody's ever done that study, so we don't know for sure. Mood in the menopause transition. It seems that perimenopause is a window of vulnerability for development of depressed mood and for major depressive episodes. So we know that women in particular are more likely to develop a mood disorder during that time, especially if they've had one in the past, but even if they've never had a mood disorder, they are more at risk to have one during this time. We know that it's more likely if women had a hormonally driven mood disorder in the past, for example, they have premenstrual mood issues or they've had a postpartum baby blues or a postpartum depression, they are more likely to have problems at this time. Most women who have had one, though, have had an issue before. So if you can identify women who have had a major depressive episode in the past, they're at higher risk during this time and you should screen them. How do you treat mood disorders during this time? Well, first line therapies are just like you would use for a mood disorder any other time. We use cognitive behavioral therapy with antidepressants and see what worked for them in the past. If they've used an antidepressant before and it worked before, that's likely what you should use now. But pay attention to side effects. Weight gain is a particular issue and women are also already struggling with weight gain during this time. So be sure to choose a medication that does not cause sexual side effects or weight gain. Consider treating the co-occurring hot flashes and sleep disturbances part of management of depression. If they're having a significant problem with hot flashes, management of that will also help. We also know there's a window of opportunity for the use of estrogen therapy specifically for the management of depressive symptoms during this time. There's been a really nice study that showed that estrogen has a benefit that's similar in magnitude to antidepressants when given to depressed perimenopausal women with or without hot flashes. Estrogen is not effective as a treatment for depressive disorders in postmenopause. So in other words, if that woman is more than about a couple of years into the menopause timeframe and has a mood disorder, hormone therapy is unlikely to help. So what are the indications for the use of hormone therapy? Hot flash management, it's actually first-line therapy for relief of menopause symptoms and inappropriate candidness, and we'll talk about who that is. Genitourinary symptoms, we know it works very well for management of genitourinary symptoms, so vaginal dryness, but also urinary symptoms, urinary frequency, urinary urgency, urinary urge leak, urinary tract infections. Prevention of bone loss, there's level one evidence that helps prevent bone loss. And then for treatment of premature hypoestrogenism, that's premature ovarian insufficiency or bilateral oophorectomy before the natural age of menopause. Who's the best candidate for hormone therapy? It's a woman who's under age 60 or, this is not an and, it's an or, less than 10 years past the final menstrual cycle. So in other words, if a woman menstruates until the age of 58, and she's 61, she's still a candidate for hormone therapy. Bothersome symptoms. Again, it's important to keep in mind that it's not just about the hot flashes. Women often have more than one symptom of menopause. So it's the hot flashes, the night sweats, the sleep disturbance, the mood disturbance, the joint aches. It's all of those. And particularly, the hot flashes, the mood issues, and the sleep tend to respond to hormone therapy. Bone density concerns. Again, hormone therapy can be used and is very effective for reducing the risk of fracture and preventing bone loss. We lose about 12% of our bone density across the menopause transition in the few years around it. We use 30% of our bone loss between the ages of 50 and 80. So this is a risk factor for losing bone. Personal preference to use hormone therapy. No excess cardiovascular risk or breast cancer risk, and we'll talk about that in a minute. And no contraindications. What are the contraindications to hormone therapy use? Unexplained vaginal bleeding. And I always say, this should not be unexplained for very long. If a woman has vaginal bleeding, that's easy to work up and rule out anything significant. A prior history of estrogen sensitive cancer, like breast or endometrial. History of stroke or heart attack. History of an inherited high risk or prior VTE. And then severe active liver disease. So the list is relatively short for who can't use hormone therapy. This is how we think about this in the office. So the first thing at the top is, is she less than 10 years from her last menstrual period? Or less than 60 years of age? And does she have bothersome symptoms that need treatment? Look at the ASCVD risk factors. There's an online calculator. If she's low risk, and if she doesn't have any contraindications to the use of estrogen, she can use estrogen therapy. And she can use any form that she wants, oral or transdermal. If she's intermediate risk for cardiovascular disease, so in other words, think about the woman with obesity, with diabetes, with hypertension, you might want to consider a transdermal preparation. So hormone therapy is not contraindicated in those folks, but you should use a transdermal preparation to avoid first past hepatic metabolism. And then don't forget the follow-up piece. We never start women on hormone therapy and say, bye, have a nice life. See you later. You can take it forever. We're following up with these women on a regular basis, at least annually, if not more often. All right, who should not be using hormone therapy? So the red category is if the cardiovascular risk, their 10-year risk is over 10%. Definitely consider an alternative, and we can talk about what those are. Or someone at very high risk for breast cancer or history of breast cancer. All right, how do you think about breast cancer risk with hormone therapy? This has been, I would say, it's probably my patient's major concern about why they would not use hormone therapy. It's important to note that estrogen plus progesterone therapy is associated with a modest relative risk of breast cancer that's similar in magnitude to lifestyle factors such as alcohol use or postmenopausal obesity. So the relative risk is about 1.3. Putting this in perspective, it's about the same as being overweight or obese. It's about the same as drinking between one and two glasses of wine per night. It's about the same as being sedentary or inactive. It's the same as many lifestyle factors. In contrast, if you look at increased breast density, that is about a four to six-fold increased risk of breast cancer. So hormone therapy is down on the list compared to many other risk factors for breast cancer. I will also, I just added this slide yesterday because this study just came out about a month ago. There was a recent meta-analysis looking at 10 randomized control trials that involved about 14,000 women and almost 600 incident breast cancers. And what they found was the risk of incident breast cancer was decreased in women using estrogen alone hormone therapy compared to placebo. So the results were similar. You know this was weighted by the WHI, which used conjugated equine estrogens. But they also did a sub-analysis and found that this reduced incidence of breast cancer was also associated with the use of estradiol alone. So their conclusion, and by the way, this was written by the authors of the WHI study, their conclusion was that the totality of randomized clinical trial evidence supports that estrogen alone use statistically significantly reduces breast cancer incidence. So this is very different from what we've been taught over the last few years and probably is practice changing. The Menopause Society Guidelines on Non-Hormonal Management of Hot Flashes. There are several things that are effective. You'll see in this list and you have it in your slides. The antidepressants, typically low doses of the antidepressants, not the same as those used for depression, work for hot flashes. But I will tell you they're far less effective than hormone therapy. Hormone therapy reduces hot flashes by about 90 to 95%. SSRIs reduce hot flashes by about 40 to 50%. Placebo is 30% reduction. So in any hot flash trial, there's about a 30% placebo response rate. So again, antidepressants are just barely above that. The gabapentin, the gabapentinoids like gabapentin or pregabalin, they're a little bit more effective, maybe reduce hot flashes by about 50% can be used as well. We did a study on oxybutynin in our group. Found that that reduced hot flashes by about 75% or so. There are concerns because it's an anticholinergic and you don't want to use long term for risk of dementia. But for short term use, it's really, really effective. And then there's a few others. We don't use clonidine so much anymore. It has so many side effects and there's so many other things to use. Let's talk about Fezolinatant. This medication came on the market in the US just in May of 2023. The Skylight phase three trials investigated it and found it reduced hot flashes in terms of frequency and severity at week four and week 12 versus placebo. It achieved FDA approval in 23. It's 45 milligrams once a day. Adverse effects, headache was the most common. Others, there was some abdominal pain. Really, the rest were pretty marginal. They just came out with real world experience. This was published in about September of this year. There was one case of hepatotoxicity in about 86,000 use cases, so one case. But that prompted the FDA to say, hey, you need to do liver tests at baseline. And monthly for the first three months, and then every three months for the first year to confirm that this is not a problem. I think this is out of an overabundance of caution. This is the first in class medication for the NK3 inhibitors. And we're just making sure that there is long term safety. Elanzanatant is a new product that is not yet FDA approved. It's been submitted for FDA approval and is pending right now. It's an NK1 and NK3 receptor antagonist. Phase two studies show that both the 120 milligram and the 160 milligram dose achieved reductions in hot flash frequency from week one through week 12 versus placebo. It's clinically meaningful. There were improvements in sleep and quality of life as well. So there's some interest in this, that there may be an impact of the NK1 receptor in sleep. So what do we get out of this NK3 and NK1? NK3 reduces hot flashes. We know that from Fezolinatant. NK1 promotes sleep and also assists in vasodilatation or helps combat it. So it's probably effective against hot flashes as well. So there may be some synergy between NK1 and NK3 receptor antagonism to improve both. Incidentally, I dug through the literature a little bit on this. And Naomi Rance, who first discovered this pathway, also found that the NK1 receptor antagonism was shown in animal models to reduce visceral fat accumulation. So wouldn't it be great to have a drug that did hot flashes, sleep disturbance, and weight management too? We'll see. So we've just published this a couple of months ago, non-hormone options and two-fers. So it's really great if you think about all the symptoms a woman is experiencing and try to have your medication choice do double duty. And just for comparison, hormone therapy is at the top. It manages hot flashes and night sweats. It helps with bone. It helps with sleep. It helps with genitourinary symptoms and mood. So if you go down to peroxetine, meselate, there's a low dose that's been FDA approved specifically for hot flash management in the United States. But it's available elsewhere in the 10 milligram dose. It might help with hot flashes, but also with sleep and with mood. If you go to the new drug, Fasolinatant, the NK3 inhibitor, we don't know if it helps with anything other than hot flashes yet. Hopefully, Elanzanatant will help with sleep as well. We'll see. All the other SSRIs are in the same category as peroxetine. Gabapentin helps with sleep as well. So it's got a side effect of making you sleepy. So it also helps with pain. So if you have a woman who has difficulty with pain for whatever reason, can't use hormone therapy, it might be great to help. We dose it at night. That way, we take advantage of the sleep effect. Oxybutynin, keep in mind that it's an overactive bladder drug, actually. So it helps with those symptoms as well. Let's talk about weight loss and hot flashes for a minute. Women with obesity are more likely to have severe and frequent hot flashes. Weight loss is associated with a decrease in hot flashes. We know that from the observational WHI study. We did a study at Mayo looking at lorcasarin, which showed a reduction in hot flashes. Lorcasarin is an old weight loss drug which was pulled off the market, probably unnecessarily. But it did show that we had a meaningful benefit for hot flashes after 12 weeks. Those hot flashes came right back when the women came off the drug. There's also been a recent study looking at a specific diet. Neil Bernard did a really nice study looking at a low-fat vegan diet that was rich in soy. And it showed a reduction in moderate to severe hot flashes versus controls. And this correlated with weight loss. So it was hard to say if it was a specific dietary component, like the soy or the whole food plant-based diet, or if it was really the weight loss that helped with the hot flashes. But it's hard to say that a whole food plant-based diet is a bad thing. Is there a role for the GLP-1s or the GIP-GLP drugs? Unclear, but I will say that we have just received some funding to study terzapatide for hot flashes specifically. So more to come on this. I suspect it will work. The Menopause Society guidelines, as I mentioned, do recommend CBT or cognitive behavioral therapy and clinical hypnosis for management of hot flashes. There's level one evidence to support both of those. The reason is that you can work on your framing of this experience. You can work on monitoring of your symptoms, et cetera. But it's been proven that CBT works for these symptoms. It probably is going to help with a number of things. So the physical symptoms, like the vasomotor symptoms, the mood symptoms, negative thoughts, sleep and sleep disturbances as well. So multiple impacts from CBT. So we actually are initiating a trial right now for virtual reality and menopause symptom management. We are creating a program that is specifically designed for menopause symptoms and to help with multiple symptoms, hot flashes, depressed mood, anxiety, insomnia, and also the sexual health concerns. All of these things have been shown in the past to respond to CBT. So currently in development, we hope to have something out and available in testing by next summer. So in summary, menopause is a common thing. It happens to 100% of over 50% of the global population. There's a significant burden associated with untreated symptoms. And we know that many options are available for treatment. Hormone therapy remains first line and is likely to address hot flashes, sleep, mood, and anxiety, and potentially brain fog. Use of non-hormone options in women who have contraindications or choose not to use hormone therapy. Try to go for the two first. So go for something that does double duty in terms of symptoms and choose weight-neutral options. So with that, I look forward to your questions. Thank you.

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non-hormonal treatments