This transcript was automatically generated from the video recording and may contain inaccuracies, including errors or typographical mistakes.

Missed Opportunities In Menopause Management: Advancing Relief for VMS and Sleep

Dr. Jewel Kling (Mayo Clinic Alix School of Medicine): We are going to be starting by talking about identifying and treating the whole patient in menopause care, hot flashes and beyond.

Patient Case Introduction: Athena, 56-Yr-Old Black Woman

To do that, I want to ground this in a patient many of us would recognize. This is Athena. She is 56 years old, about two years postmenopausal with diabetes, hypertension, and obesity. What she wants to talk to you about includes hot flashes, fatigue, mood changes, and weight gain. Have any of you seen Athena in your practices? I certainly have. Maybe Athena is sitting in the room with us tonight. This is where menopause care lives in the middle of everything else we are already doing managing her other chronic medical conditions, but then also talking about these important quality of life symptoms that she is talking to us about.

Patient Case Introduction: Visit Summary

As we think about the case, the observations, and discussion points for us to consider is talking about the possible contributions of elevated glucose and weight to her fatigue. Talking about diet and physical activity she noticed that fatigue interferes with her diet management and physical activity, so we can work collaboratively with her to figure out some smart goals around that. Discuss sleep hygiene, and when we do, we find out that Athena, like maybe many of us, is using our cell phone or watching TV until she falls asleep. Guilty.

Dr. Hugh S. Taylor (Yale School of Medicine): Who does not do that?

Dr. Kling: Then discuss hot flashes. She said she would like to see if working on diet and physical activity and weight loss and sleep hygiene helps with her symptoms. What we are proposing for Athena, and I wonder if you are on board with this is a plan where she is going to commit to walking daily. She gets about 180 minutes per week of exercise and then add a GLP-1 for her glucose and her weight management.

Poll 3

Now back to you. Which menopause related symptoms do you ask about during office visits? We would love for you to select all that apply to what you are asking in your visits.

A. Vasomotor symptoms, which are those hot flashes and night sweats;

B. Sleep problems, fatigue;

C. Mood changes;

D. Multiple symptoms, do you use a questionnaire or an open ended question; and

E. I let the patient initiate discussion of menopausal symptoms;

Look at that all over the board.

Dr. Taylor: Everybody. Lots of ways to approach this. That is good.

Dr. Kling: That is fantastic.

Primary Care Roles: Caring for Patients Across Menopause Stages

Let us start here with primary care, which is a wonderful opportunity to have conversations about menopause care and support women going through midlife. One of the key points here is that primary care is the front line for menopause care. We have that foundation of trust. We have the opportunity to build education. With that, we can really launch into a treatment plan with our patients.

Essential Competencies for Managing Menopause Symptoms

The essential competencies for managing menopause symptoms are similar to what we use for many different disease states or things that we are supporting our patients with. First, start with discussing vasomotor symptoms with appropriately aged female patients. That may look like you are 45 to 60 year old patients, although I am sure all of you can think about those younger than 45 and older than 60 year old patients that may also have those symptoms to talk about.

We will conduct appropriate diagnostic tests, including labs, to make sure there is not something else that may be causing her symptoms, like hypothyroidism or hyperthyroidism. Then discuss all the treatment options with the patients. We are hoping to prepare you with more information about those treatment options tonight, so you can take that back to your clinical practice. Then the very popular and important shared decision making that we will do with our patients choosing a plan that makes sense for them and then following up with them appropriately.

VMS: Hallmark Symptoms of Menopause

The hallmark symptoms of menopause are vast. The cardinal symptom, and one that we will talk about a lot tonight, are vasomotor symptoms, which are hot flashes, those crummy flushes during the day, and then night sweats, the things that can interfere with night time symptoms. Anybody that has gone through menopause or as you are caring for menopause, women, you know that there is many other symptoms that also occur. Changes in the menstrual cycle are often that first symptom we see during perimenopause, but that is not the only thing we can see. Sleep problems, mood changes, memory issues. I wonder if you hear this too, the brain fog.

Dr. Taylor: All the time.

Dr. Kling: Talk about.

Dr. Taylor: Very common.

Dr. Kling: Vaginal health and sexuality, bladder control or lack rather of bladder control, weight gain, muscle loss, joint pain, and headaches. That sounds terrible.

Dr. Taylor: All common and very disturbing, and those hot flushes can be more than just a warm fuzzy feeling for us men who have never had a hot flush. It is not a pleasant feeling, like sitting beside a warm fire at night. They are those flushing and palpitations and heart racing and sweating and anxiety. It can be really quite disruptive.

Dr. Kling: Probably links with many of these other symptoms too. Contributes to those too.

Menopausal Symptoms and Burden of VMS

This next slide shows you both the reported frequency of these symptoms, so you can see based on this report that those hot flashes are reported most. Certainly women are reporting a lot of symptoms, and when we narrow in on the vasomotor symptoms or the hot flashes, we can see that they are impacting so many things in a woman's life sleep, self-care, work, mood, relationships. All the important things that matter to us during our life.

Characteristics of VMS

Here is some of the kickers and why I suspect many of you are here tonight is the majority of women experience these symptoms. More than 80% report vasomotor symptoms. Of those, 80%, about 30% report severe vasomotor symptoms. We see that those episodes peak about one year after the final period, but although what I learned in menopause or in menopause, I am still learning in menopause. What I learned in medical school was probably menopause lasted maybe a couple of years. Most recent data shows that is not the case.

On average, those symptoms last for 7.4 years, and for some women can persist greater than 15 years. Seven to 15 years with those symptoms. That is why we are here talking about treatment for those symptoms. Average are about four to five per day, but women can have more than that. Like I was mentioning 10% to 20%, but really up to 30% can find them unbearable. We do see impacts varying by race and ethnicity, where indigenous and Black women experience the most frequent and bothersome vasomotor symptoms, whereas Chinese and Japanese women experienced the fewest.

SWAN: Sleep Disturbances During the Menopausal Transition

Dr. Kling: This is probably not a surprise to any of us that if you are having night sweats, you are going to have sleep disturbances during the menopausal transition. It is extremely common. We see this from probably most women that are going through menopause. There is some data that physical activity can help with the sleep disturbances during menopausal transition. Of course, if she is having night sweats all night, we are going to need to address those symptoms.

Sleep Disturbances in Women With and Without VMS

We can see sleep disturbances in women with vasomotor symptoms, which makes sense. Even outside of that, women that are not having vasomotor symptoms are reporting increases in sleep disturbance. That group of women may be the women that you are really focusing on those healthy lifestyle choices, the good sleep hygiene, the other tools that we often lean into when we are treating people with sleep issues.

Effects of VMS and Sleep Disturbance on QoL and Mental Health

Again, reinforcing these concepts that the menopause symptoms impact quality of life. This data really supports that, showing that vasomotor symptoms and sleep disturbance have negative impacts on quality of life. Beyond that, it also impacts mental health. Those things are compounded and why we are seeing this constellation of symptoms in our midlife patients.

Factors Associated With Worse Menopausal Symptoms

Now outside of the symptoms that women are experiencing, those symptoms are associated with other things. There is certain women that have more symptoms because of underlying characteristics, including their race and ethnicity, obesity, smoking, a history of childhood abuse, chronic psychosocial stress, and all the other things that are listed here. I will highlight the last point here because I think this is a really important thing for us to call out premature surgical menopause, but probably this should be just listed as premature menopause, right?

Dr. Taylor: Yeah. Premature menopause in any way is really much more detrimental, but I think when it is surgical, it is much more abrupt and sudden so often the symptoms are far worse.

Premature Menopause

Dr. Kling: It is like you knew what was on this next slide, which shows this data that women that undergo surgical menopause have an abrupt increase in all of these symptoms, more severe vasomotor symptoms, higher rates of sleep disturbances, all these things that we are talking about, those women tend to experience them more dramatically. One of the reasons to highlight this is because premature menopause rather is a little bit different than just general or natural menopause.

Importantly, premature menopause is defined as anything that is under age 40. Early menopause is anything under age 45. Why it is different is because studies show that premature menopause or women rather, that have gone through premature menopause, have higher risk of all of these long term health consequences. Increased all-cause mortality, coronary heart disease, dementia, parkinsonism, osteoporosis, and mood disorders. While we will cover hormone therapy and the safety of hormone therapy for symptomatic treatment, these women need hormone replacement therapy until the average age of menopause, which is around 51 years of age, to help mitigate these long term health consequences.

Framingham Study: 2x Higher CVD Incidence in Postmenopausal vs Premenopausal Women

Another really important thing that we think about a lot in medicine, especially as internists, is cardiovascular disease risk. We know at midlife, women's risk starts to go up around that menopause transition. This data demonstrates that clearly. You can see in the blue bars, the postmenopausal women that clearly have higher incidence of cardiovascular disease.

SWAN: VMS and Increased CVD Risk

Really interestingly, mostly led by Dr. Thurston and her team. We found these connections between vasomotor symptoms and increasing cardiovascular disease risk, whereas women that have more vasomotor symptoms have more risk.

Mechanisms Linking VMS and Increased CVD Risk Are Unclear

What is the mechanism? We do not truly know, but think that there might be a few things that could explain that connection, including adverse cardiovascular disease risk factor profiles, likely the influence of endogenous estrogen, or perhaps the lack of endogenous estrogen, and then inflammatory factors that are more likely to increase around the time of menopause. There are some pathways that are being evaluated, including the HPA axis, and some really interesting possibilities. Wondering if there is some underlying connection there, meaning women that are having more vasomotor symptoms that might be a symptom of their underlying cardiovascular disease risk. Is it potentially related to the autonomic nervous system, or one other would be is it connected to these vasomotor symptoms associated sleep disruption?

SWAN: Sleep Trajectories and Increased CVD Risk

Dr. Thurston and her team looked at that in a little bit more detail. Two, finding that sleep, poor sleep rather is associated with increased cardiovascular disease risk where you can see that documented. I believe it is the purple bar here that demonstrates that connection.

Tools for Assessing Menopause Symptoms

Because we want to move forward and give you some helpful tools, let us talk about ways that you can assess your menopausal patients. Many of you did indicate that you are asking these questions in your clinical encounters. I wonder if any of you are using questionnaires. It is not a question on your tablet there, but just something to ponder. These are all different scales that you could consider using. In our clinical practice, we use the menopause rating scale. All of our patients that come in for menopause consult gets that scale. It both informs how we approach them clinically, goes into our note in epic, but then also goes into a database where we are trying to evaluate different associations. Any of these could be considered to help guide that treatment.

Patient Case Introduction: Athena, 56-Yr-Old Black Woman

We are going to get back to Athena now that we are anchoring this back into our clinical case. Remember, she is our 56 year old that has hot flashes, fatigue, weight gain, pain, obesity, hypertension, and diabetes.

Patient Case Introduction: Visit Summary

We have discussed all of these things with her, and as she is leaving, we have decided that she is going to commit to walking daily and adding that GLP. We want to take the opportunity to brainstorm together or discuss either with us, or we are happy to take any of your questions. Please make sure you are providing questions on your tablet. How can patient conversations be improved to better identify and address menopausal symptoms? We can see if there is questions as you are doing that if you have thoughts.

I think one of the obvious ones was on the few slides back, is considering a questionnaire to prompt patients to even start to think about those things even before you see them if it is something they can do on a tablet or in their portal before they see you. They start thinking about those menopause symptoms, and you can start collating them as you are precharting on your patients.

Dr. Taylor: There is always lots of options prioritizing, which comes first I think is a shared decision making with your patient as well. Some of them may want to treat one aspect of their care more, give it a higher priority than another. We have some questions coming in. Does checking hormone levels make a difference in menopause treatment? I have an almost weekly request for hormone levels. Do you check hormone levels? I do not.

Dr. Kling: Very rarely. It is not necessary for the diagnosis or even for the treatment of menopause. If she is around that average age of menopause and has symptoms, I will evaluate for other causes, make sure she is up to date on her testing and her health care maintenance, but especially during the perimenopause period where hormones can be all over the place. If I check them and they are suggestive of pre-menopause and she is having symptoms, I am still going to treat her the same way.

Dr. Taylor: I treat them for symptom relief rather than to a particular level. I know sometimes patients get the idea that checking a hormone level or if there is an appropriate level. I think as long as they feel better, the level does not matter. Some of these places that offer compounded hormone solutions will recommend titrating to levels, but I think that is misguided.

Dr. Kling: It is misguided. There is not data that suggests a certain level that we are targeting. It is much more precise to target to her symptoms. That is what I tell people, because I think some of the messaging from the clinics that you are talking about tries to say it is more precise with the levels, but the good news is, is that you do not need those.

Dr. Taylor: Often that is done just to charge them a large amount for the levels and for a special compounding formulations that are designed to match their blood levels, but no evidence that is better. It certainly does cost a lot more.

Dr. Kling: That is the thing. I will talk to patients, the financial toxicity with many of those things. If we can minimize one of those barriers of financial toxicity, then that is wonderful. It is not just Hugh and I that do not check levels. That is consistent with guidelines the Menopause Society, the Endocrine Society, the International Menopause Society. If you looked at their guidelines or position statements, they would encourage you to use a clinical diagnosis for menopause as opposed to check levels. There are maybe some scenarios, like if she is had a hysterectomy or she has an IUD, and the question is whether or not her symptoms related to menopause. That does not happen very well.

Dr. Taylor: You worry if they are not absorbing depending on what vehicle you use, if they have GI issues, and maybe you want a patch instead of oral, you can measure the level, see if they are getting it but rarely. There is another question here. The vasomotor symptoms differ for women who have had partial hysterectomy who did not necessarily have premature menopause. I think by partial hysterectomy, I think probably the question means having the uterus and cervix removed, but not the ovaries. Although after hysterectomy there is a trend towards a slightly earlier menopausal transition in general that does not affect hormone levels. There is such a variation in timing of when someone goes into menopause. Not something you can really measure or predict and count on. Not a big enough difference that it would take them outside of the normal range of menopausal transition.

Dr. Kling: Excellent question.

Dr. Taylor: Let us see. Here is a question on testosterone therapy. Does testosterone therapy help in any way with fatigue and libido in menopause?

Dr. Kling: Indeed, the evidence supports that testosterone therapy in postmenopausal women can help with libido, specifically for hypoactive sexual desire disorder. A low libido associated with distress and not caused by other things like painful intercourse or a partner that does not treat you very nicely. When the libido is on its own with distress, we do see that testosterone is helpful. If you are interested in learning more and giving a talk tomorrow morning at ACP at 8:00, that will cover all the data around that.

Dr. Taylor: I think it is also important to make sure you replace the estrogen first. If they are having sleep disturbances, hot flushes, vaginal dryness, and pain with intercourse. Maybe fix that first before you add the testosterone.

Dr. Kling: Such an important point. No matter how much testosterone you give, if it is painful or if she is fatigued, that it is not going to help with libido. The largest study, it was a systematic review by Dr. Sue Davis from Australia looking at testosterone, and women asked the question about the other outcomes too. Does it help with energy? Does it help with muscle mass? It did not in that systematic review. We are mostly using it for libido, but as Hugh saying, we have to address all of her other menopausal symptoms before we can really focus on target that.

Dr. Taylor: Yep. Shall we?

Dr. Kling: Yeah. Let us move on. Go ahead. I will let you take over.

From Hormones to Hypothalamus: Navigating Treatment Decisions in Menopause Care

Dr. Taylor: Now I am going to give you some of the data and background on hormone therapy. This is called from hormones to hypothalamus because the hormones do affect hypothalamus, and it is the hypothalamus that controls ovarian hormone production prior to menopause.

Patient Case Follow-up: Athena, 56-Yr-Old Black Woman

We are back to our friend Athena. She comes back to us that 56 year old woman now here for her follow up. Again. she is two years from her last menstrual period. She meets the definition of menopause, which is a year out from the last period. Although importantly, I think if somebody is symptomatic, you can treat them prior to meeting the definition of menopause. Again, this is our patient with the diabetes and hypertension and obesity. She started her GLP-1 and she increased her physical activity as she discussed. Lo and behold, her weight is better, her BMI is better, her A1-C has improved. She is really doing well and responded nicely, but she is still frustrated by her vasomotor symptoms and sleep problems. She is talking to her friends and her church group and she decides she really wants your help with this. What can we do?

Patient Case 3-Mo Follow-up: Visit Summary

I think it warrants a more detailed discussion of exactly what her menopausal symptoms are. We went over quite a few of them just in the last section. When you question her more about her menopausal symptoms, either in a discussion or by filling out one of those questionnaires that we mentioned, she has those vasomotor symptoms, the hot flashes, she has sleep disturbances, she is not getting enough sleep, and she does not have restful sleep. She is waking up at night with night sweats and hot flushes. She is depressed and irritable, and she does report pain with sex. What are your options here? The decision was to initiate hormone therapy. Hormone therapy will treat the vasomotor symptoms, the sleep disturbance, and importantly, there is really nothing else that takes care of that vaginal atrophy that leads to that discomfort during sex.

Poll 3

Here is another poll question. Which statement reflects your approach to treating menopause related vasomotor symptoms in your practice? You can select all that apply.

A. I avoid hormone therapies because of a suboptimal risk benefit ratio;

B. I prescribe hormone therapy for select patients;

C. I avoid nonhormone therapies because of the suboptimal risk benefit ratio;

D. I prescribe nonhormone therapies for select patients;

E. I avoid combination hormonal and non-hormonal therapies, or

F. I prescribe combination hormonal and non-hormonal therapies for select patients;

This is good. We have people who select which patients are appropriate for each treatment and prescribe both hormonal and non-hormonal therapies. I think that is the right answer, and there may be advantages or disadvantages to each.

NAMS 2022 Hormone Therapy Position Statement

Let me start off with the North American Menopause Society 2022 hormone therapy position statement. This therapy, this statement was issued in 2022. Really, it stayed the same. The only thing that has changed from this statement is the name of the society. They are now called the Menopause Society, but their recommendations really have not changed at all. Hormone therapy remains the most effective treatment for vasomotor symptoms and genitourinary symptom of menopause, that vulvar and vaginal atrophy, and has been shown to prevent bone loss and prevent fracture.

The risks of hormone therapy differ depending on the type, the dose, the duration of use, the route of administration. Importantly, the timing of initiation and also whether a progestin is used. We will talk about that in a lot more detail in the next slide. Treatment should be individualized using the best available evidence to maximize the benefits and minimize the risks, and importantly, periodically re-evaluating the benefits, and risks of continued therapy. Those risk benefit profile changes as patients age.

History of HT for Menopause Symptoms: WHI Study and Beyond

The WHI or Women's Health Initiative is really what has turned hormone therapy on its head, and we are now coming back full circle, with the FDA rescinding most of their concerns about hormone replacement therapy. Prior to 2002, when the results of that were first published and released, we thought hormone therapy was basically very good for everyone.

In addition to managing the vasomotor symptoms and preserving bone and reversing vaginal atrophy. People thought hormone therapy had a lot of other benefits, including preventing cardiovascular disease, and decreasing dementia. The Women's Health Initiative when it came out did not verify all those things. Certainly, they verified the reduction in vasomotor symptoms, the bone density, and really prospectively showed that fractures were decreased. There was not the cardiovascular protection that was expected.

As a matter of fact, as they reported it, there was some cardiovascular risk and there was not the reduction in dementia that was expected. There was actually an increase in the older patients in dementia so quite a shock. I think a lot of this, as we will talk about in a minute, was because the observational studies before the WHI looked at women who were average age at menopause, around 50 came in and started hormone therapy early on in that menopausal transition, whereas the WHI enrolled patients between 50 and 79 stopped, followed them for five to eight years.

Many of them were in their 80s, even by the time the study concluded. As we will talk about in a minute, there is a big difference in risk benefit profile in the 50s versus the 70s. In general, the effects of hormone therapy are much better in the younger, newly menopausal women than the older woman. The WHI came out, the reports of that increased risk in breast cancer, which really did not change. We always knew there was a risk of breast cancer associated with hormone therapy.

It is small, and since only about 4% of women die of breast cancer and well over half of women die of cardiovascular disease, the emphasis was placed on something that we thought would prevent cardiovascular disease. In reality, that did not turn out to be true but the increased risk in cardiovascular disease, stroke, pulmonary embolism really led to people stopping hormone therapy in large numbers. It went from very commonly used to rarely used.

The WHI again, lumped together patients of all different ages, the newly menopausal women, and those 70 year olds who were started on hormone therapy when they were not having any vasomotor symptoms and did not have any of the indications we would usually have used to start hormone therapy. The subsequent analysis over the years really broke that down, and there is a big difference as to whether you are taking a progestin or not, especially in breast cancer risk.

There is a big difference whether you are 50 or whether you are 70, especially when we are talking about cardiovascular risk. As this became well known, people's perceptions started to change. This culminated in a statement by the FDA just this past November, where they removed those black box warnings from hormone therapy related to cardiovascular disease, breast cancer, dementia risks. We are not using these drugs in 80 year olds. We are using them in 50 year olds and those risks just do not apply.

As a matter of fact, this was the strongest statement I have ever seen come out of the FDA. They talked about the misinformation and fear created from the exaggerated review or exaggerated results of the WHI and stress that we should put this in perspective. That these risks are quite exaggerated.

WHI: Benefits and Risks of HT in Patients Aged 50-59 Yr

This table really shows the risks. This is the 50 to 59 year olds, very different than what we heard about from the WHI in the 60s and 70s and even into the 80s by the time they finished that trial. The 50 to 59 year olds did not have the risks that we saw in the older women. The estrogen alone trial shown on the top, and there is a slight increased risk of clotting, as we know, DVT or pulmonary embolus. Again, that dotted line shows a risk of less than 10 per 10,000 per year, less than one in 1,000 very low risk.

You can see that pulmonary emboli. There were three more in the CEE group, the conjugated equine estrogen group. Three more out of 10,000. There were not even three because there were less than 10,000 women enrolled in this trial. Those risks are low, but interesting. Look at this. Coronary heart disease risk lower, and that became statistically significant in these younger women. Breast cancer risk lower, and as we follow these women out many years after the WHI, that decreased risk persisted and became statistically significant. Our biggest fears that were generated after the WHI increase in heart disease, increase in breast cancer are not there when we use estrogen alone.

On the right side of that graph you can see fractures were down. That we knew that was validated. Death from any cause. All-cause mortality is actually decreased and we almost never hear about this, but diabetes is also increased. Now I am not suggesting we go back to the days where we have talked about in the past, using hormone therapy to prevent coronary disease or to prevent diabetes. No, we have better ways of doing that. That you know better than I do as primary care physicians.

We are not going to go back to saying it should be preventive treatment for these conditions, but it certainly is not the risk that the WHI data suggested. The other big difference, though, is if you look at estrogen plus progestin, and if you have a uterus, you need to protect the endometrium from the effects of unopposed estrogen. Estrogen alone stimulates the uterus can cause hyperplasia. You need to add a progestin or something else to counteract estrogen.

If you do that as was done in the WHI trial, you see the risks are a little higher and the benefits a little bit less. The clotting risk slightly higher. We saw a slight increased risk in coronary disease. Again very low. Did not even reach statistical significance, but not the benefit we were seeing from estrogen alone. We do see a slight risk in breast cancer with the combination of estrogen plus a progestin. Still fractures decrease. Still all-cause mortality decrease. Still diabetes decreased, but a very different risk benefit profile than was thought and publicized in 2002 that caused women to abandon hormone therapy in large numbers, who are now sometimes paying the consequences with osteoporosis, having suffered through these vasomotor symptoms, and other conditions.

WHI Study Analyses: Guidance for HT Timing in Menopause Reflects CVD and Mortality Risks

This summarizes the over 60 versus less than 60. You can see coronary heart disease. If you are less than 60, it is decreased. It is neutral if you are over 60. Total mortality again under 60 decreased if you use hormone therapy. Generally, we recommend using hormone therapy when our patients actually need it. When they turn 50, they go through menopause and start complaining of those vasomotor symptoms and vaginal atrophy. Starting it within 10 years of menopause, unless there are some contraindications like pre-existing cardiovascular disease or breast cancer.

Indications for Hormone Therapy

The first line therapy to manage vasomotor symptoms that are FDA approved rather hormone therapy is the first line therapy to manage vasomotor symptoms and FDA approved to treat those vasomotor symptoms, prevent bone loss. Important if you have premature estrogen loss, as we talked about earlier, and important for reversing those genital urinary symptoms. Some better bladder support, but prevents that vaginal atrophy and pain. In patients with a uterus, again, unopposed estrogen may lead to endometrial cancer. We should not use it. We add a progestin or we will talk a little bit more about it in a minute. There is a SERM now called bazedoxifene that can be added to estrogen that also reverses estrogen action on the uterus and protects the uterus. Very promising.

Warnings and Contraindications for Hormone Therapy

Again, there are certain contraindications to using hormone therapy and certain things that we should think about and proceed with caution. The absolute contraindications are an estrogen dependent cancer, active clotting disorder thrombophilia. Because estrogen does increase clotting risk. Unexplained vaginal bleeding certainly get a biopsy and figure out what that is before you give hormone therapy. Severe liver disease or if they have pre-existing cardiovascular or cerebrovascular disease, estrogen will increase the clot risk and could potentially increase those conditions.

I think we need to think about and being a little more cautious if the patient is personal preference to avoid hormone therapy, some patients are just going to be made nervous by hormone therapy. They still remember the WHI. They still remember some of these risks and prefer to avoid it. We need to take that seriously. History of breast cancer is not an absolute contraindication. If they have had a small well-differentiated breast cancer that has been removed and they are truly cured, it is probably safe. Most patients with a history of breast cancer, we avoid hormone therapy.

History of a blood clot. Venous thromboembolic disease. Established cardiovascular disease. Lipid disorders, primarily hypertriglyceridemia or estrogen will lower cholesterol, improve HDL, lower LDL, but triglycerides are raised. Diabetes if it is led to cardiovascular disease, or again, in the older patients, where we can presume that our 50 year olds really do not have significant underlying pre-existing cardiovascular disease. Once we get over 60 or more than 10 years from menopause, that becomes a higher risk.

Hormone Therapy Options

There are lots of options available and I will not go through them all now. You have these slides available to you. You can download them and see them, but several different oral estrogens that conjugated equine estrogens were historically the most commonly used. These days we use a lot more 17 beta estradiol. There are vaginal preparations if someone does not need hot flash relief. If we want to just treat the vaginal atrophy, these work quite well. They are conjugated estrogens or estradiol creams or tablets or inserts.

You can use the estradiol transdermally. It does not have that first pass liver effect may have a lower clotting risk, and we will come back to this in a minute. There is also that what is called the tissue selective estrogen complex that uses an estrogen with that SERM bazedoxifene to protect the uterus. Similarly, several different oral and transdermal estrogen plus progestin combinations. There are all compounded hormone replacement therapy regimens that are not FDA approved and really have not been proven in any way to be safer or superior. Then come with a package insert or a warning on the label so people can assume they are safe and are sometimes told they are safe by these compounding pharmacies. Really, I avoid those.

Tissue Selective Estrogen Compounds

Let us talk a little bit about this tissue selective estrogen complex. This is a combination of conjugated equine estrogen plus a SERM called bazedoxifene. This bazedoxifene counteracts estrogen, but it has tissue specificity. It blocks estrogen action right where we want it to breast and uterus. It offers that endometrial protection without a progestin.

As I mentioned earlier in the WHI estrogen alone did not increase breast cancer. The combination did. If we get away from using a progestin in a patient with a uterus, this is a really wonderful solution and it decreases the vasomotor symptoms. Both the estrogen and the SERM increase bone mineral density. You get great bone mineral density with this. It prevents that vulvo vaginal atrophy and probably does not have the same risk of breast cancer. Again, this bazedoxifene, the SERM in this combination is very similar in its characteristics to raloxifene. Raloxifene we know is already approved for reducing breast cancer risk.

Every other combination of hormone therapy mammographic breast density increases, which is a predictor of potential breast cancer risk. In this combination, it does not. You get a decrease in breast density, suggesting there may be some mitigation of that risk. I love this regimen for somebody with a uterus. The only drawback is it only comes in one fixed low dose.

Number of Hot Flashes With Bazedoxifene/Conjugated Estrogen

Hot flushes go down nicely with this combination. Again, the bazedoxifene and conjugated estrogens. You see a nice decrease. We always have a little bit of placebo effect when we talk about hot flushes, but the bazedoxifene brings down those hot flushes very nicely.

NAMS 2023 Nonhormone Therapy Position Statement

Going to the NAMS or now Menopause Society hormone position statement for non-hormone therapies. We will talk about non-pharmacologic on this side and pharmacologic non-hormonal therapies. When hormone therapy is either contraindicated or when the patient has a personal preference to avoid hormones, we have got some recommended options. Cognitive behavioral therapy can help. Hypnosis helps. Weight loss will help a little bit. Stellate ganglion block is on this list, although I do not use that. It is a little brutal, but not recommended or all the things you see here. These things may be helpful in other ways. Certainly not going to discourage patients from exercise and yoga. They may find those helpful, but they are not really robust ways to treat hot flushes.

Nonhormonal Therapies for VMS

We do have several nonhormonal pharmacologic therapies, though, that work quite well. The antidepressants, SSRIs and SNRIs work, and one of them low dose paroxetine, is FDA approved for treating vasomotor symptoms. You really should not use it with somebody on tamoxifen because there is an interaction with tamoxifen metabolite. We thought that would be the one answer when somebody had breast cancer and we could not use hormones. This was the first one FDA approved but really not appropriate for those on tamoxifen.

What has really been the game changer that we will talk more about now are the NK3 receptor antagonist fezolinetant and the dual NK1, NK3 receptor antagonist elinzanetant. Also gabapentin, oxybutynin work, but not as well as these. This is paroxetine. Again, you can see a placebo effect, and on the left you see a decrease in frequency of hot flashes with paroxetine. On the right you see a decrease in severity. Again that decrease in number is good, but the decrease in severity really does not maintain statistical significantly difference from placebo over the long term. Not as effective as we would like.

VMS Pathophysiology: Rationale for Targeting NK Receptors

Let us talk now about the NK receptor antagonists. The hypothalamus has these KNDy neurons which are the kisspeptin, neurokinin, and dynorphin neurons. These impact both reproduction. They send a signal to the hypothalamus that controls GnRH release and estrogen release, and there is normally feedback from estrogen that dampens that these neurons from activity. These neurons also control the thermoregulatory zone. They help with heat dissipation when we feel hot and we sense that the temperature is inappropriate these neurons are what control blood flow to the periphery that cause these hot flashes, signaling the body that we need to dissipate heat sends blood to the periphery.

Again, this interplay between heat regulation and reproductive hormone production comes into some disruption at menopause. When those hormones go away that normally repress these KNDy neurons, these KNDy neurons hypertrophy and become overactive. The NK3 receptor antagonist, or the NK1 receptor antagonist dampen that overactivity. They block that activity of the neurokinins or substance P on these neurons and help dampen that activity and mitigate these hot flushes.

Novel Nonhormone Therapies: Neurokinin Receptor Antagonists

Again, fezolinetant was approved in 2023. It is an NK3 receptor antagonist and elinzanetant it was just approved this past fall. It is a dual NK1, NK3 receptor antagonist. They fezolinetant you need to check liver functions. There have been some concerns about rising liver functions before starting medication. Then monthly out to three months, then at six and nine months. For elinzanetant as long as it is suggested you check liver functions prior to starting.

SKYLIGHT 1/2 Pooled Analysis: Fezolinetant for VMS in Postmenopause

Here are some of the data. This is the fezolinetant data. You can see the daily frequency of hot flushes on the left compared to placebo in blue, goes down quite a bit when you switch the placebo group to receive the fezolinetant. It goes down even further. The 45mg is the clinically available dose, and severity of hot flushes is the same thing. A nice decrease in severity of hot flushes. This is quite effective.

SKYLIGHT 1/2 Pooled Analysis: Fezolinetant Response Onset and Rate

This number looks at those receiving or achieving over 50% reduction in those vasomotor symptoms, and you can see the fezolinetant 45mg by week one works very fast. It is down to about 30%. Have a greater than 50% reduction, and by week 12, nearly 60%. Remember that number. We will come back to that nearly 60% when we compare it to the other newly approved drug in the NK3, NK1 receptor antagonist.

SKYLIGHT 1/2 Pooled Analysis: Fezolinetant for Sleep Benefit

Here is the pooled data on sleep benefit. You can see compared to placebo. There is some improvement in sleep as shown here.

Fezolinetant Is Effective and Safe When HT Is Unsuitable

This is effective even when hormone therapy is not suitable for your patient. Again, I will not go through this all the numbers in detail. This will be here as a reference in your slide deck.

SKYLIGHT 4: Safety of Fezolinetant for VMS in Postmenopause

The same thing for safety here. There are really no big concerns, no serious adverse events.

OASIS-1/2: Elinzanetant for VMS Frequency in Postmenopause

Now here is the OASIS trial. This is elinzanetant. This is the newer NK3, NK1 dual receptor antagonist nicely decreases the frequency of vasomotor symptoms decreased number, and this is the two OASIS trials essentially showing both the same thing. Two large, randomized trials showing nice reduction in vasomotor frequency.

OASIS-1/2: Elinzanetant for VMS Severity in Postmenopause

Here in those same two trials nice reduction in severity of hot flushes so number goes way down. Severity is greatly improved.

OASIS-1/2: Elinzanetant Response Onset and Rate

This is the number who achieve at least a 50% reduction at the end of week four and week 12. You can see here 71% and 74%. Very nice, even a little better than we are shown in the last trial.

OASIS-1/2 and NIRVANA: Elinzanetant for Sleep Disturbances

Then here is a trial looking at elinzanetant for sleep disturbances, and you can see that there are many fewer awakenings at night, less arousal, more time in various stages of sleep with these drugs, particular benefit for sleep.

OASIS-4: Elinzanetant for Endocrine Therapy-Associated VMS in HR+ Breast Cancer

Even here again, I am not going to go through the details here. This is another trial, OASIS-4 that looked at the use of this drug in women with hormone receptor positive breast cancer. Bottom line, it works just as well in patients with breast cancer and is safe.

OASIS-3: Elinzanetant Efficacy and Safety at 1 Yr

Then this study looks at a one year safety data. Again, no serious safety concerns.

Matching-Adjusted Indirect Comparison: Fezolinetant vs Elinzanetant Efficacy at 12 Wk

Finally, this looks at the matched results between fezolinetant and elinzanetant at 12 weeks. You can see a change in vasomotor frequency on the left. They favour elinzanetant little bit before matching but after they are controlled and matched about the same overlap. Same in severity, but where the newer one the elinzanetant wins out is about sleep. On the far right hand side, you can see that elinzanetant performs better in reducing sleep disturbances. If sleep disturbance is an important part of your patient's complaints, this would be the preferred drug to use.

Meta-analysis: Pharmacologic Treatments for Menopausal VMS

Looking at this meta-analysis. Again, there is a lot of data here and I am not going to go through it all, but it is in your slide deck which you can download to review later. This compares those different drugs and their ability to reduce hot flushes. These drugs compare very well to traditional hormone replacement therapy when we are talking about reducing hot flashes.

Patient Case Follow-up: Athena, 56-Yr-Old Black Woman

Let us come back to our case. Athena, that 56 year old black woman. She is presenting again for follow up about her vasomotor symptoms now. She has already improved her exercise. She started on our GLP-1, but she is still frustrated by her vasomotor symptoms and her sleep disturbances.

Patient Case 3-Mo Follow-up: Visit Summary

You have described potentially initiating hormone therapy. Let us talk about what might be the optimal approach to a patient such as this, I think. Her vasomotor symptoms could easily be treated with many of the different options we talked about. I think the big factor here that would drive me to use a hormone therapy would be the discomfort during sex, which really needed estrogen to treat. Although you could potentially treat that locally with a vaginal estrogen and use another means for correcting vasomotor symptoms and sleep.

Dr. Kling: Would you factor in her diabetes also to considering hormone therapy because of what you showed from the women's health?

Dr. Taylor: Well, there is an improvement in diabetes with hormone therapy. Again, I would not recommend hormone therapy as a treatment for diabetes. We have better ways to treat diabetes than hormone therapy, but it certainly is an advantage here.

Dr. Kling: If we are putting all the pros versus cons for Athena's case.

Dr. Taylor: She does not have the risks, and she certainly could with one drug here, hormone, traditional hormone therapy receive all the benefits.

Dr. Kling: Excellent. I know we have a Q&A section and we are starting to get so many wonderful questions here, but I thought I would ask at least one of them because this is related to something we were talking about before this session. Somebody asked, are there studies looking at differences between CEE and bioidentical or 17 beta estradiol?

Dr. Taylor: We were together involved in a study called the Keep study, where we did look head to head at estradiol, transdermal estradiol, and oral conjugated estrogens at a low dose. Very similar. They both nicely reduce vasomotor symptoms and have a similar profile, but there has not been a head to head study that is powered enough to find any distinction. They both performed similarly in our study, with maybe that one exception that I think you were talking about with the sexual function being better in the transdermal. I think that is more the route of delivery than which estrogen was used, whether it was conjugated equine estrogens or 17 beta estradiol. There does seem to transdermal has less of that direct liver first pass effect on sex hormone binding globulin, and probably better for sexual function.

Dr. Kling: Perfect. You alluded to this. There is some questions about bioidentical. I think that gets used to describe custom compounded bioidentical. The compounded pellets and such, but bioidentical itself just means it looks like the same hormones our body make, like our ovaries.

Dr. Taylor: Bioidentical means 17 beta estradiol what our body makes and progesterone rather than a synthetic progestin. Those are both available much less extensively from a traditional prescription. You can buy estradiol or micronized progesterone, and a traditional prescription for a lot less than the compounders charge, and probably a more accurate dosing.

Dr. Kling: Yes, you get some advantages in consistency in dosing and safety with the FDA approved bioidentical hormone.

Dr. Taylor: When somebody comes in and wants a bioidentical hormone, I do not start measuring levels and concoct some strange combination that has to be compounded. I prescribe them estradiol and progesterone.

Dr. Kling: Excellent. I know we will have a very lively Q&A, and I will let you start looking at those questions while I do the third portion here. How is everybody doing? It is getting late. You are hanging in there. Fantastic. Well, thank you again for being here. Those of you virtually who are probably all in their pajamas, I am so jealous but anywho.

Engaging Every Patient: Employing Cultural Competencies in Menopause Care

Let us talk about cultural competencies and menopause care and wrap up this discussion until we get to our Q&A.

Follow-up Visit: Discussing Athena’s Options

We are going to bring this back to Athena again. You know her well by now. You know that she has been successful with the treatment plan we talked about with that initial time she came in, but now she is back and she knows that hormone therapy was recommended. To be honest, she is hesitant to take it. She would like to know what other options are available.

Patient Case Treatment Discussion: Visit Summary

Some observations for us to help as we think about the cultural aspects to how we care for Athena, may be to really dive in more to what her reservations are about hormone therapy. It turns out after you talk to her more, she is really scared about reproductive cancer, specifically breast cancer. She heard all that information that you heard you talking about with the WHI and she now thinks that she is going to get breast cancer if she starts hormone therapy. That gives us the opportunity both to dispel some of that information, but also to talk about other non-hormonal therapies and really narrow down on the things that are most impacting her and causing the most impact to her life. In this case, it would be very reasonable to recommend one of the NK antagonists. Because she is also reported sleep issues to us, elinzanetant, because of that dual benefit to both vasomotor symptoms and sleep may be ideal in her situation.

Poll 5

We'd love to hear from you with another poll here. Which statement reflects patients responses to menopause therapy in your practice? Go ahead and select all of them that you think apply. The first is

A. Estrogen decline is part of life. I do not want to add it back; or

B. I am concerned about cancer with hormone therapy;

C. I avoid non-hormonal therapies because of suboptimal risk benefit ratio;

D. My friend tried an antidepressant and she did not think it was very helpful; or

E. I would like to wait until there is more information on new therapies before I use them;

Still a lot of concern about cancer.

Dr. Taylor: That is what I find in my practice, too. that is the number one concern patients have.

Reasons for Not Actively Seeking Menopause Symptom Relief

Dr. Kling: We can certainly dive more into that when we are in the Q&A, and we can also talk about here are the things that patients are telling us that they are concerned about. Not actively seeking out menopause symptom relief. Many do say, "Menopause is a natural part of life," which is certainly true. Menopause is not a disease. It is a process, but it does come with a lot of symptoms that can impact quality of life. Women also report that the symptoms are not that bothersome. They just push through and make it through. Here is one that that definitely pops out uncomfortable going to get care now.

I see this asterisk here that might have been during COVID-19, which makes sense. I wonder if there is more here too. If people do not feel like they are going to be received with a conversation by a clinician, that is going to be able to either is trained to handle these questions or is not able to apply a culturally agile lens to taking care of that patient.

Dr. Taylor: Especially after that WHI publicity came out. There are a lot of people who have not been trained in hormone therapy. It fell off so much that I think even us physicians are not comfortable with it.

Dr. Kling: I have heard a lot of patients tell me that they have heard from other clinicians. You just got to tough it out. You got to get through it because we did not train all of us. We were not trained with this data. All of us in this room and watching virtually are now trained and are going to go out there and reverse these trends, but that is certainly what our patients are seeing. Other things include concerns about medication safety, which makes a lot of sense, as well as insurance and cost challenges, which I bet is something that all of us are thinking about.

Culturally Sensitive Menopause Care

The SWAN study, which was a large study looking at women across the US, found many findings as it relates to culturally sensitive menopause care. They had a very diverse group of women that they have studied and are continuing to follow. Finding that cultural stereotypes, women's background, and how women deal with menopause related changes direct how they experience menopause, too. This makes it really important for us to acknowledge the cultural sensitivity aspect and approaches to menopause care.

Claims Data Analysis Suggest Disparities in VMS Management

Claims data suggests that there is disparities in vasomotor symptom management really in these three different areas. There is the potential for underdiagnosis, which goes back to what we are talking about. If we are not being trained to even recognize what menopause is, then it is certainly likely that we are going to underdiagnose menopause, lower odds of vasomotor symptoms, diagnosis, or even treatment for groups. Then we see Black, Asian and Hispanic women are more likely to discontinue vasomotor symptom related treatment versus non-Hispanic White women.

BECOME: Menopause Transition Perceptions Across Racial, Cultural, and Ethnic Groups

This BECOME study looked at the menopause transition and perceptions across racial and cultural groups and certainly found that there are differences based on different races and ethnicities. Acknowledging that our approach may be more equitable if we recognize those differences.

Reasons Women Did Not Take Prescription Menopause Therapy

The reasons women tell us that they are not taking prescription menopause hormone therapy. This first one here, and the largest piece of the pie is that we are not suggesting it. We are not bringing it up, we are not diagnosing it, and we are not suggesting it. Then the patient related factors include many of those things that fuel how we all think about our health care being afraid of adverse effects, thinking that the symptoms are not bothersome enough or not aware of the treatment options, which really probably goes back to that red slice of the pie here too.

Patient Perspectives: Healthcare During the Menopause Transition

This table here talks about things that women have shared about their healthcare experience during the menopause transition, and we can lump them in these themes here on the side. Unhelpful care from health care professionals. What helpful care from health care professionals can make a difference. This is great. This is the positive spin that those of us that are really passionate about taking care of women in midlife and beyond, if we are being proactive, that that does truly make a difference. The sex of the health care practitioner can influence and then pharmacotherapy versus whole person care. Likely this is reflecting if our knee jerk reaction is, oh, I have got a medication to treat that as opposed to recognizing the big picture and talking about all of those options, including those non-hormonal options. Women may feel like we are missing the mark.

Principles for Culturally Responsive Menopause Care

The principles for culturally responsive menopause care include a few things that we could implement across the board for all of our patients, and I do recognize that it is hard to implement these in a very busy practice where we are seeing patients every 15 minutes or more. Taking that opportunity to listen to the patients, to not rush them, to ask them about their menopause experience, just those three things can make a huge difference. Being curious, asking questions respectfully, and using shared decision making, in addition to laying the groundwork with not rushing them, is going to profoundly impact their experience.

Framework for Culturally Responsive Care: Avoiding Biases and Stereotypes to Cultivate a Safe and Trusting Relationship

Another way to think about this is from these different frameworks using cultural curiosity, respectful query, and connected care. Asking questions about I do not know, and I would like to know so that I can better care for you, especially if you are getting the sense that there is some other hesitation or a reason that a patient is not interested in the treatment that you are recommending for them, partnered with listening actively and then using our toolkit of shared decision making is going to make sure that we are doing this culturally sensitive and culturally sensitive way.

Respectful Queries for Identifying Cultural Influences

A few questions that maybe you can take back if you are not already using these are questions like, how do you feel about menopause and the process of going through it? Do you manage your menopause symptoms and how do you manage them? I think that is a really great question because sometimes I will just assume if somebody is coming in to ask me about menopause, that they are not managing them, or they have not tried anything, but giving them the opportunity to share how they are managing them can be really helpful. Another question could be, do you have any cultural practices that are related to menopause and important for you to observe? Do you follow a religious faith or spiritual practice? Does this influence how you feel about your care?

Follow-up Visit: Discussing Athena’s Options

With those things in mind, if we go back to our case as we wrap up here, Athena was hesitant to take hormone therapy, and we put into practice some of those strategies. We listened. We asked her those questions, and she shared with us that she was concerned because of gynecologic cancer, and that gave us the opportunity to share those other options, including non-hormone treatments for which we recommended elinzanetant.

Patient Case Treatment Discussion: Visit Summary

Hopefully, you can all fill in the gaps here. Imagine what happened with Athena, but in my mind, she went on and did very well with this medication. After we navigated the approval process and the cost of the medication, are you all thinking that too? Certainly something we can talk about.

You and I were talking about earlier, but once she receives the medication notices. Wonderful improvement. This gives us an opportunity to talk about minimizing missed opportunities. How can communication be improved to identify culturally appropriate individualized approaches for Athena and other patients? We have dug into quite a bit of this. I wonder if there is anything else you would add here from your experience and expertise working with patients.

Dr. Taylor: I think this is very common that patients are concerned about cancer risk or concerned about something about hormone therapy. The last thing we want to do is give them a medication that they are either never going to fill the prescription, or that they are going to feel very nervous and uncomfortable all the time they are taking it. I think this gives us a really nice solution with the NK receptor antagonists that we never had before. We never really had non-hormonal therapies that were anywhere near as effective as hormones. I think the other thing too this is a great chance to give Athena some education about what those risks and benefits are. I quote those WHI numbers and the estrogen alone breast cancer risk actually coming down.

I talk about conjugated estrogens with the bazedoxifene as another option that may not have that same breast cancer risk, even for somebody with a uterus who needs some endometrial protection. If she really loves her n k antagonists, which I suspect she will, but still has some vaginal discomfort, you can really talk about local vaginal application of estrogen as well. You do not need to worry about the progestin. You do not absorb enough to have any systemic side effects. It is really quite safe and very, very effective at eliminating that vaginal atrophy.

Dr. Kling: Does not increase your risk of breast cancer, as you said, if we go back to that, which thankfully the black box warning has come off. It is not quite an uphill battle when we are treating patients with those low dose vaginal estrogens.

Dr. Taylor: Even my oncologists who treat breast cancer patients will allow us to use some vaginal estrogen because you do not increase your risk there.

Postactivity Assessment

Dr. Kling: Fabulous. Well, I wonder if we should do the post activity assessment and then we can dive into the questions. I think they keep coming here.

Dr. Taylor: We got a lot of questions.

Dr. Kling: That means you are all up. Get your tablets out. We have some questions.

Posttest 1

I think some of these you may have seen before, but we want to see if after this education you might answer a little bit differently. Posttest question number one here. Your patients, the 48 year old woman who comes to you with a list of symptoms, including vasomotor symptoms and sleep disruption. Which of her other symptoms would you suspect is being related to the menopause transition?

A. Heartburn;

B. Moodiness;

C. Shortness of breath with exercise; or

D. Swollen feet;

Dr. Taylor: I think everyone was pretty good the first time around, so I would expect this to be very good.

Dr. Kling: Nice.

Dr. Taylor: There you go.

Dr. Kling: 93% to 94%. You are right.

Dr. Kling: Everybody knew this one from the beginning.

Dr. Kling: Okay. I do not know if we have to go through that rationale. They did so well.

Dr. Taylor: Everyone knows that.

Dr. Kling: Let us go to posttest question number two.

Posttest 2

This one is your 54 year old woman who was receiving tamoxifen to treat her hormone responsive breast cancer. She has been on the treatment for two months and has developed hot flashes, night sweats, sleep disruption and brain fog. Which of the following best characterizes considerations for use of NK antagonist therapy for this patient?

A. Liver function testing is required before starting fezolinetant but not elinzanetant;

B. NK antagonists should not be used with tamoxifen due to drug interactions;

C. Sleep benefit may be greater with elinzanetant versus fezolinetant based on indirect comparison of trial data; and

D. Vasomotor symptom benefit may be greater with fezo versus elinzanetant based on indirect comparison of trial data;

Excellent. Look at that. From 39% to 83%.

Dr. Taylor: Everybody got that. Wonderful. Definitely better sleep with elinzanetant.

Dr. Kling: Maybe, just to reiterate, it is recommended that both with fezo and elinzanetant to check baseline LFTs.

Dr. Taylor: Baseline, but with fezo the continued monitoring is necessary for a little longer because there had been some more of an incidence of elevated liver functions.

Posttest 3

Dr. Kling: Perfect. Posttest question number three. You guys are doing great. Your patient is a 49 year old woman who emigrated from India 20 years ago. You prescribed hormone therapy for menopausal symptoms, but she has not started it. Even though vasomotor symptoms and sleep disturbances impair her daily activities. Which of the following best represents a culturally responsive next step?

A. Do you acknowledge to her that you know women in her culture might not want to use hormone therapy and offer another option;

B. Do you ask her if she would be willing to share her perspective on menopause and its treatment;

C. Do you question her to determine if she is using natural remedies;

Do you examine to her that hormone therapy is a natural type of treatment because it replaces lost hormones;

Lovely. You all did really great on the pretest and even better on the post-test. We also agree that B is the right answer.

Dr. Taylor: Absolutely.

Dr. Kling: Excellent. Then a couple of questions we would love to know from you rather.

Poll 6

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

Poll 7

Now please take a moment to enter one key change you plan to make in your clinical practice based on this education.

Question and Answer Session

Lovely. Shall we get started with our Q&A?

Dr. Taylor: Bunch of questions here. First question here is why would you start hormone therapy in perimenopause for a patient with symptoms? Why wait? I could not agree more. Let us start. As soon as someone has symptoms, you do not have to wait until they reach that arbitrary definition of one year without a period. Waiting that long really just prolonging that suffering. We can relieve their symptoms much earlier. The only problem with doing that is if you catch somebody very early in that menopause transition or perimenopause, it could be possible. there is some residual ovarian function left. They may produce some estrogen. May even have some bleeding, breakthrough bleeding if a period resumes because of high estrogen production. As long as you anticipate that and are not concerned by it, that is fine. Treat them.

Dr. Kling: I 100% agree. No reason to wait. I think one consideration, just to keep in mind and talk to your patient about is until she is gone 12 months past her last menstrual cycle, she is still at risk of getting pregnant. If she does not have a contraceptive option, then she should have one, especially if you are starting menopausal hormone therapy. That might also be an option for your treatment. You may consider a low dose continuous birth control, something like anywhere from 10 to 20 micrograms of ethinyl estradiol, which would also help with the bleeding if she did start noticing some breakthrough spotting or intermittent bleeding.

Dr. Taylor: Control the bleeding and provide contraception, especially somebody who is transitioning in the 40s and might still be at risk for pregnancy. By 50, it would be pretty rare to see someone get pregnant. You have to remember that birth control pills are much more estrogen than is in hormone replacement therapy, and you would want to taper them down once you know they are past that average age of menopause.

Dr. Kling: That is such an important point. I do not know if you have heard this in your clinic, Hugh, but I think a lot of patients just assume menopausal hormone therapy is a much higher dose than birth control. Clarifying to them that, no, it is actually the opposite way around, which means that the birth control will treat their vasomotor symptoms and their sleep and all the other things too, that they are coming into your office for.

Dr. Taylor: Very important. Somebody asked whether we could use estrogen bazedoxifene for women greater than 65. I would say absolutely. I think for every patient there is no firm stop end date when you can no longer use hormone therapy. You really have to individualize it. I think we were afraid to start hormone therapy for too long. I think thankfully we are starting to see that uptick again, but the decision about when to stop it has to be very individualized long term, and at older ages there is some risk. If you have got a relatively healthy patient in her 60s, without underlying cardiovascular disease, I think it is and still maybe having vasomotor symptoms. She stopped her pills for a little while. She forgot to take them. Has hot flushes coming back. I think you can still have that discussion risk benefit every year with your patient to continue to treat. There is no date when you absolutely have to stop hormone therapy. It is always a risk benefit discussion. If they are sexually active and need vaginal estrogen, it is a reason to continue some hormones. If they are still having the vasomotor symptoms, it is a reason to continue the hormones. If they have developed underlying severe cardiovascular disease, maybe a good reason to stop the hormones.

Dr. Kling: In fact, the Menopause Society, in their most recent position statement, updated their verbiage about this to say there should not be an arbitrary age cut off to stop hormone therapy. I think many people have heard after five years or around age 60 or with the beers criteria at 65. The reality is the science does not necessarily support that and individualizing it. What about starting hormone therapy at 65? What are your thoughts on that?

Dr. Taylor: I have never had to start hormone therapy at 65 because people just do not start developing vasomotor symptoms at age 65. They start that when they go through that menopausal transition in their 50s or sometimes late 40s. It is extremely rare to find somebody who comes in with new onset vasomotor symptoms in the mid-60s. They may come in with vaginal atrophy at that age, and I may use a vaginal estrogen, but I generally do not start systemic hormone therapy in somebody in age 65.

Dr. Kling: I bet all the internists in the room are thinking about hot flashes and night sweats at 65. I agree, it is not going to be menopause if it is a new onset, hot flashes, night sweats, you are all thinking cancer, thyroid, an endocrinopathy, and certainly make sure you evaluate for those things.

Dr. Taylor: That's what you should be thinking.

Dr. Kling: Most common or medications, that is the other one. They have started a new medication and now have those symptoms. What I am starting to see in my practice, especially with this increasing swell in social media and media about menopause, and then the black box warning getting removed is some of those older women that are still having hot flashes from the time of menopause are upset. They feel robbed, like they did not get hormone therapy. If you are also seeing those patients and they are 65, although we have talked about that the benefits outweigh the risks. If you are starting less than age 60, you could still evaluate that patient and look at her cardiovascular disease risk. Look at her breast cancer risk. Look at our dementia risk. If those are all low, have a shared decision making conversation about considering starting hormone therapy. Certainly you would want the safest formulations so a non-oral, a transdermal patch or gel or spray at a lower dose is what we typically do in our practice.

Dr. Taylor: I would agree if they were having those hot flushes persistently and had not been on hormone therapy, and now they saw the FDA is changing their position. They come in asking for their hormones that they have suffered through without menopausal hormone therapy for years. Absolutely would start it, but you have the same risk benefit discussion. Even if breast cancer risk, it would not if they have had a hysterectomy, they can take estrogen alone without worrying about that breast cancer risk. I might use the estrogens with the bazedoxifenes, even in somebody who had not a diagnosis of breast cancer, but was at risk for breast cancer. You can still use hormone therapy.

Dr. Kling: Yeah, 100% agree. I know one of the questions that I did not ask you earlier was about a lot of what we were talking about with see the conjugated equine estrogen, but just for those that might be interested, there are studies that looked at estradiol and its relationship with breast cancer and found estradiol alone also was associated with lower breast cancer risk. It is not just CEE that we see that relationship, and so you can feel comfortable with the formulations that many of us are using in practice the 17 beta estradiol to share that.

Dr. Taylor: If your patients had a hysterectomy, you do not have to worry about the cancer risk, and it may even be a long term benefit reducing cancer. Again, now with the bazedoxifene, often we do not even somebody with a uterus, you can really eliminate that cancer risk.

Dr. Kling: It is really exciting.

Dr. Taylor: Let us see. History of nonhormone responsive breast cancer. Is this a contraindication? By nonhormone responsive I think you mean estrogen-progesterone receptor negative.

Dr. Kling: Like a triple negative breast cancer.

Dr. Taylor: Those are often the worst prognosis, and even though they are not hormone receptor positive even the nonreceptor positive cancers can respond to hormones through either nonclassic receptors or very low levels of ERP that are not measured when they initially measure ER positivity of breast cancer. I would not use hormones in somebody who has a breast cancer diagnosis, especially a poor prognosis, breast cancer like that, that is triple negative that really can still respond and grow in response to estrogen.

Dr. Kling: How I have heard this discussed with the breast community is your risk of recurrence is high and the prognosis significant with triple negative, but that risk of recurrence goes down after five years post treatment. For your triple negative patients if they have successfully been treated and they are five years post treatment, that may be the time to consider a shared decision making conversation about hormone therapy. The difference is with hormone positive breast cancer, you never lose your recurrence risk so that gets a little trickier. I think you are probably talking about just systemic hormone therapy in either of those cases, like low dose vaginal estrogen would be fine.

Dr. Taylor: Vaginal estrogen. Absolutely. I would not use the systemic hormone therapy in somebody who has got a breast cancer. At what age do you stop hormone therapy? I think we discussed that. There is no absolute age to stop. Let us see. You start hormone therapy for a woman who was 65 years old for bone protection and has low risk of breast cancer, low risk for cardiovascular disease.

I probably would not start just for bone protection. We have other good bone drugs. I would want to get a better history and find out what other symptoms or risk factors she has. Again, if it is just for bone protection, she is not having any hot flushes. She has not had vaginal atrophy or is not sexually active, I would probably use something else that is more focused. What do you think?

Dr. Kling: Yeah, those are tricky because that is really when you lean into that culturally sensitive assessment. If she has very strong interest in hormone therapy and she is low risk in other things, bones may be the deciding factor if she is at an elevated risk. I agree with you that typically it is going to be those patients with symptomatic vasomotor symptoms that I am more inclined to prescribe treatment.

Dr. Taylor: It certainly does improve bone density and reduce fracture. We have great data to show that it works. And if somebody wants to use it for that indication, there is no reason not to, but it might not be my first choice. Let us see. We talked about one question about bioidenticals. I think we have covered that. History of migraines. Is HRT contraindicated?

Dr. Kling: I was trying to remember the other questions. There were a couple of questions about migraine, I think specifically migraine with aura because as you all know, that birth control hormones are contraindicated for premenopausal women that have migraine with aura. We do not see that same risk with menopausal hormone therapy formulations, especially non-oral menopausal hormone therapies. Typically, it is not considered a contraindication. Certainly for those women that have very frequent migraine with aura. If I am starting something, I will try and get her migraines under control. If she notices increasing migraine frequency with the treatment, we might have to decide on something else because the estrogen is likely contributing to it. We just do not see that same stroke risk that we see with the oral, higher dose ethylene estradiols as it relates to migraine with aura.

Dr. Taylor: Sometimes you will see people with either new onset or worsening migraine right after menopause that is probably triggered by estrogen levels being too low. Sometimes estrogen is exactly what they need.

Dr. Kling: Good point.

Dr. Taylor: Someone writes I thought being an obese patient would make more estrogen and not have as many menopausal symptoms. That is just not what we see. I think the fat is making that weaker estrone not so much the estradiol. Just not enough to control the hot flushes.

Dr. Kling: In fact, in the nonhormone position statement, the most recent one that we talked about, they added weight loss as a tool to treat your vasomotor symptoms because there is two studies that were quoted, but both found that losing weight actually improved vasomotor symptoms as opposed to being obese. Although I always feel like you have to have a caveat there, when you are telling a woman that is coming in to see you for menopause symptoms. Losing weight is going to help with vasomotor symptoms, because she is probably also telling you that she is having a really hard time losing weight. You are going to have to partner with her to figure out collaboratively how to have that happen.

Dr. Taylor: What are safe options for postmenopausal women over the age of 65 with menopause symptoms? I think we discussed that again, there is no absolute cut-off and you can still use hormone therapy over the age of 65. There are fewer benefits and more risk the older you get, but there is no absolute cut-off and you have to really individualize it for your patient. Should systemic hormone therapy negate the need for vaginal estrogen, or is it reasonable to offer both?

Dr. Kling: That is a good question.

Dr. Taylor: Usually systemic is sufficient.

Dr. Kling: Yeah, especially at the higher doses, I do find some women it does not penetrate quite enough. If that is the case, I wonder if you have used both together. It should be safe to use a low dose vaginal estrogen as well as a systemic hormone therapy.

Dr. Taylor: It is certainly safe too. I find if you give a sufficient amount of oral. I hate to have people taking two different medications if they do not need it. Sometimes I will go up a little bit on the dose of the oral before I will add a vaginal, and just hopefully with that one therapy, they can take care of it rather than start a second medication. Let us see. Another question here is about using both. Can we use both hormones and non-hormonal therapies together?

Dr. Kling: Sure.

Dr. Taylor: Why not?

Dr. Kling: Why not?

Dr. Taylor: It depends exactly what you are treating. But often some of the non-hormonal therapies will have better benefits.

Dr. Kling: We will start seeing more of that, especially with fezolinetant being available.

Dr. Taylor: We do not have great studies that tell us the way to do that or what the added benefits might be, but I think absolutely no reason not to.