In the mid-2000s, research findings on hormone therapy and breast cancer risk made HRT prescription rates tank – but further analysis shows it can be a safe and even long-term option for some women. Gynecologist Mindy Goldman, MD, offers keys to individualizing care in menopause and beyond by looking at factors ranging from family history to having undergone hysterectomy. Discover which formulations optimize benefits and which hormone alternatives, such as antidepressants and cognitive behavioral therapy, have value.
I am going to be speaking to you on menopause and there's so many different aspects of menopause. But what I really wanted to focus on today was primarily about when we use hormones, how we use hormones now in 2022. Um a little bit about alternatives to hormones from managing menopausal symptoms. And then just at the end just briefly touching on integrative and um botanical and lifestyle options. Just some disclosures. I am a medical advisor for a couple of companies uh small startups, one developing an ultrasound device to treat vaginal dryness and menopause and breast cancer patients. And other using ai to predict breast cancer in young women. And I will actually be working part time at U. C. To join a startup. That is a digital health startup focused on menopause and breast cancer survivorship. Um so as I said, I'm going to primarily be talking about hormone replacement therapy and where I feel like looking at the literature, where are we in 2022 I wanna given that my area of expertise is in high risk women. I want to talk about HRT in women who have either had or at high risk for breast cancer. I want to talk a little bit about bio identical and compounded hormones because we all get asked about that. And then briefly about alternative treatment options prescription alternatives, herbs uh Integrative therapies and botanicals. So hormone therapy is really the primary treatment for menopausal hot flashes. I think no one would argue with that. The controversies about hormone or more for prevention of disease. But I think everyone would agree that hormone therapy is the most effective treatment for leaving a alleviating menopausal symptoms. And studies suggest that almost half of women who started hormones stop it within one year. Um As I said, current recommendations are used for treatment. Only My understanding is that there is an arm of the US preventative Services task force that is currently reviewing the literature and there may be changes in guidelines that um regarding prevention of disease for younger newly menopausal women, if women have a uterus, we need to balance estrogen which treats symptoms with progestin therapy for uterine protection. And in general in the past guiding organizations have suggested when you're looking at using hormone therapy, calculate the risk for heart disease and breast cancer and consider using alternatives if higher risk for either. And I'm really going to focus in on that comment as it pertains to higher risk for breast cancer. In the past recommendations were used the lowest dose, shortest duration, typically for less than five years. Thinking after five years, the risks outweigh the benefits for women. That is changing. And we're going to talk about that. And general recommendations if you're stopping your patients or for a slower green queen rather than abruptly stopping. Um so where did much of our guidance come from? In terms of current recommendations and we know much of that has really come from the women's health initiative, which was published now in the early 2000s and prior to that hormones were really used as the main treatment, not just for symptoms, but for prevention of disease, as we all know cardiac disease, osteoporosis, and potentially dementia. So then in the late 19 nineties, the first well designed trials, the her study um came out looking specifically at high risk women. So women who had already had a coronary event to see if you gave them hormones, did it modify the risk of a secondary cardiac event? And this was all um, Placebo-controlled trials and they found that it did not prevent further secondary events, either heart attacks or death from coronary heart disease. And that was published in the late 1990s and people thought, well that's sort of interesting. But what you really want to look at is healthy menopausal women who don't have established heart disease and see if you give them hormones doesn't prevent them from getting heart disease. And is it associated with any health outcomes? And that was really the design of the women's health initiative? I would say. I still think this is the gold standard. It is the largest prospective primary prevention randomized controlled trial ever done. Um, and again, designed to see if hormones protected against heart disease and healthy postmenopausal women of note, it was not designed to study to see whether hormones helped with dealing with menopausal symptoms. There were a whole bunch of different parts of this trial. I'm sure most of you are well aware of this trial. Um but I'm going to be focusing on just briefly talking about the hormone therapy part. Gold standard randomized control trial done at 40 centers throughout the US more than 68,000 women enrolled ages were 50-79, average age of 63 and only 10% of subjects were between the ages of 50-54. Um The way the hormones were given is if women had a uterus at, they were randomized to an oral hormone Prempro that is Premarin plus mod roxie, progesterone, acetate versus a placebo. If they had had a hysterectomy, they did not need progestin is to protect against uterine cancer. And they were randomized to oral Premarin alone versus a placebo. Two reasons those drugs were chosen in the late 90s and early 2000s. That was the most commonly prescribed form of hormones as well as the drug company that made those helped to underwrite the wh i because they anticipated finding a cardiac benefit. The study was scheduled to be completed in oh five and there was a lot of bad press when the combination Prempro arm of the study was stopped early in May of 2002 because it did not protect against heart disease and it was associated with an increased risk of breast cancer stroke. And DVT interestingly, the estrogen only arm of the study did not find a higher risk of breast cancer. It continued and it terminated 11 year earlier than planned because of an increased risk of stroke and no protection of heart disease. And the press totally took off with the results. And I know most of you probably know the study inside and out, but I just wanted to sort of review the background of that. I'm not going to go into the numbers of the details, but basically the negative outcomes from this for the group that got Prempro were heart disease, stroke, venous, thrombosis, bolic events, breast cancer. For the group that got Premarin alone, negative outcomes were higher risk of stroke. There were beneficial outcomes for the group that got Prempro, there were lower risk of colorectal cancer, reduced hip fractures. For the group that got Premarin alone, reduced hip fractures and breast cancer now. So with that as a background, let's just talk about, where are we now, many years later. Um I think that the this original data has resulted in a decline of prescription use of HRT that's well documented in the literature and that has continued to today. Um There have been multiple analysis of the women's health initiative done since that was originally published and I think it is well established now that the risks that they found from the women's Health initiative. We're very different in younger women And for women under 60 And within 10 years of menopause, the benefits are thought to outweigh the risks versus if women have this long gap time and don't start hormones until around the age of 60, the risks are thought to outweigh the benefits. The specific risk for younger women are lower cardiovascular risk and lower all cause mortality. And that's led to what we now all use which is called the timing hypothesis. That basically says the risks and benefits of hormones differ depending on the age of the patient. And years since menopause there have been a number of follow up studies like keeps and elite that have all reinforced the benefits of hormones in younger women. Um based on that the prior statements that say we should all be giving our patients the lowest dose for the shortest duration of time change to what the current position statement is from the North American menopause society, which says we should be using the type the dose and duration of menopausal hormone therapy that is appropriate and individualized to the symptomatic women in menopause. So how should we be prescribing hormones in 2022? Um In the W. H. I. As we said, they showed higher risk of strokes with oral estrogens. And we know that transdermal preparations are thought to have more favorable effects on markers for coronary heart disease as well as less effects on clotting factors. And so based on that first line therapy, if you're going to give your patients estrogen should be a transdermal, there are more dosages available compared to oral estrogen. And if a patient has had a prior hysterectomy, there is no need for progestin how to give progestin since. Well, sorry, in the women's Health initiative, the synthetic progestin is that they used which was mod roxie progesterone acetate. The trade name is pro vera. Those synthetic progestin are thought to negate some of the beneficial effects of estrogen on lipids and endothelial function. Additionally, remember I stated that the com the Prempro arm of the study was stopped because of the finding of a higher risk of breast cancer that was not seen in the estrogen. Only arm of the study. There have been studies since the wh I that suggests that natural progesterone owns which are my Cronyn Ized Are thought to have less negative effects on the breast. Including there was this nice meta analysis published in 2016 that actually showed no increased risk of breast cancer with natural progesterone. So if you were giving hormones to someone who has a uterus, you should be not using synthetic progestin and should be using a natural progesterone like micron Ized progesterone that can be done either in a daily fashion or in a cyclic fashion where you give it every month or every other month depending on what the dose of estrogen is cyclic formula. If we say that progestin are the component of hormones that have the negative effects on the breast cyclic formulations are less likely to have less risk to the breast because you're not exposing the breast to it that often? But that needs to be counterbalanced with ensuring that you are providing enough endometrial protection. Other formulations like oral pills, combination patches, gels, vaginal introduce you to our own progesterone. Those are all appropriate. And depending on the clinical situation we may prescribe some of those. Someone has psoriasis or eczema. Bad skin reactions were not going to be giving a transdermal. Um What about do you need to start based on age? We saw in the W. H. I. That the risk of clots and strokes increased in women who started hormones after an average age of 63. So in general if you have your patients who are older than that average and they are higher risk for strokes like uncontrolled hypertension. That is someone who I would not keep on hormone therapies. But if they are healthy and they are gaining benefits of their hormones in terms of their quality of life there is no need to stop them purely based on age alone. So case studied just to think about let's say you have a 49 year old comes to you. She's had bilateral mastectomies for ductal carcinoma, insight. You she comes to you with significant hot flashes and night sweats and is interested in whether she can use HRT her other friends are on it doing well and they suggested she try it. So would you be willing to give HRT in the setting of prior D. C. I. S. If you would give it, how would you give it? And would you limit the time that you give it? So let's move on to H. R. T. And high risk women. And this is defined by women with the family history of breast cancer, a prior history of breast cancer in themselves, a prior history of DCs or a prior history of a tibia. And it's important to realize that there are currently no national formal guidelines for the use of HRT and women at high risk for breast cancer. So to look at this question, let's go back again to the W. H. I. The combination Prempro arm of the wh I was stopped early when it did not protect against heart disease and it surpassed the threshold for breast cancer. The estrogen only arm of the group for women who had a hysterectomy did not find a higher risk of breast cancer and was stopped because of a higher risk of stroke and no protection of heart disease. And the big question was was that a fluke because we've always thought that estrogen increases the risk of breast cancer. And what would happen when these women were followed longer? So this if you haven't seen this is a great article. This was published in Jama uh in 2020. This is 20 year follow up from the wh I. Looking specifically at breast cancer outcomes. So the group that got Prempro the combination estrogen progestin arm compared to with the placebo 20 years out after they had stopped their hormones still had a statistically significant, higher risk of getting breast cancer, but no significant difference in dying of breast cancer. The most fascinating thing, the estrogen only group estrogen alone group compared to placebo associated with a statistically significant lower risk of getting breast cancer and a lower risk of dying of breast cancer. So what that tells us is it is the progestin component of hormones and not the estrogen that has the negative effects on the breast. So why is this? The biologic reasons are not clear some theories. The average age in the wh I was 63. So there was a long gap time without estrogen and that's thought to result in adaptive changes that make tumors that affect tumor sensitivity to estrogen induced cell death. Another thought is that progestin in induces a progestin increases breast epithelium stem cell pool and that leaves former estrogen plus progestin users with a persistent and long term increase in breast cancer risk. So more breast epithelium that can be sensitive sensitized from hormones. Another theory is that the anti inflammatory effects of synthetic progestin which we know about may have been neutralized by estrogen induced apoptosis or cell death. Although those are theories, I think the best um current theory is based on this KB ranked pathway. So there is increasing data that progesterone may play a role in both breast stem cell proliferation and carcinogen icis via activation of this nuclear factor KB. Ranked pathway and this pathway interferes with memory epithelial differentiate differentiation and mediates the major proliferator of response of the mammary epithelium to progesterone and progesterone driven expansion of mammary stem cells. And I think we're going to find a lot of publications coming out looking at this rank pathway. Um Okay moving on. Does hormone therapy. So that sort of gives you, where are we with our thoughts now in 2022 now the question is does hormone therapy increase the risk of breast cancer further in women who already have a higher risk based on their family history And I would say to you most studies suggest that the risk of breast cancer and H. R. T. Are the same with and without a family history of breast cancer meaning they are independent. Much of the data comes from older studies that include formulations and regimens of hormones that are less likely to be used today and have had mixed results. So this is just an overview of these were big uh meta analyses, large trials that had shown a positive association, so Higher risk of breast cancer with family history. Again, most of these are 1990s to current day. And then this is a list of all the large trials included in here is the women's health, nurses health study. Uh Grambling is the W. H. I. Um that did not show um a higher risk of breast cancer with hormone use in those who already had a family history. I think if you look at the data from the W. H. I. Which we considered the gold standard, there were no higher risk for women with and without a family history. Although they only asked about family history at the beginning of the trial, There was a more recent large registry study out of Finland where they have a centralized healthcare system. Uh this was published in 18 and they also showed no difference. Uh for people with them without a family history, interestingly they did show more high risk features and the breast cancers that develop in women with a family history. So my general take is that the risks of hormones are independent of the risks with family history, which is why when I talked about in the beginning with the guidelines that say calculating out the risks of breast cancer and if they are high consider alternatives, I would disagree with that. I think that in the short term you certainly can use hormones. Even for people who have a family history and I'm going to talk a little bit more about that in a moment. Um So if you are going to do it, counsel your patients that the risk related to hormones are likely independent of the risks related to family history, how are you going to do it? I use the safest formulations. Transdermal estrogen and if they have a uterus natural micron ized progesterone. This is the one with how long? So if we say the best data we have comes from the wh I they saw a higher risk of breast cancer in the combination estrogen progestin arm after about four years now, even though there is a thought that natural progesterone may not increase the risk of breast cancer. If that is what your patient is most concerned about Is breast cancer risk. I would counsel them after 4-5 years. It is reasonable to wean them off their hormones and consider other um other therapies to treat their symptoms. If your patients have had prior hysterectomy and they are on estrogen alone, I would counsel them that the most recent data suggests that that decreases the risk of breast cancer and question I just throw this out. Maybe we should be continuing on that for long term. Um Okay, what about for people who they themselves have had breast cancer and this is still considered a contra indication. Older observational studies have suggested um that HRT after breast cancer is not associated with an increased risk of recurrence or any effects on survival. But there's actually only ever been to our cTS published looking at this One was called habits. This was published a long time ago though, back in '04 and it was stopped early because of an unacceptable rate of breast cancer in the group that got hormones. Um the other one was the Stockholm trial. This also published a long time ago in 2013. Um this trial was closed prematurely when the other habits trial reported their interim analysis. But then at 10 years of follow up they showed no difference in new breast cancer events. So these are the only two randomized controlled trials showing uh conflicting results. Um It's hard to compare them. They use different types of hormone therapy. They had different trial participants. There was less continuous hormones in Stockholm, more patients that had no positive disease and habits more tamoxifen use in the Stockholm, a prior tamoxifen use in the Stockholm group. But I would say until if we ever get an RCT looking at that, until we do have that data, you should not be giving your patients with prior hormone positive breast cancer hormones. What about hormone negative breast cancer? This is less common as two thirds of breast cancers are sensitive to hormones. This is the worst disease upon diagnosis because chemotherapy is the only medical treatment option. However, there is no data that H. R. T. Increases recurrence and it is safe to use if someone has had long disease free recurrence. So the highest risk of recurrence is in the first couple of years. I would not give hormones during that time period if after that. Um My general approach is as long as they are still being followed by oncology. I'd like to work with them to make sure we're doing this as a team approach. But I have many of my patients with hormone receptor negative cancer that I do have on hormone therapy. Okay what about D. C. I. S. So as we know D. C. I. S. Is noninvasive and there's a lot of controversy of whether we should even be using the word cancer in the description. You cannot die from D. C. I. S. The problem with D. C. I. S. Is 50% of the time when it Rikers it comes back as invasive cancers. And there are a lot of current questions whether the typical markers that we think of for looking at high grade D. C. D. C. I. S. Like grade presence of camino necrosis. Crib a form papillary solid micro papillary histology is whether those truly predict recurrence. Um There's a fair amount of research now going on. Looking at gene recurrence scores as a means of potentially having a better prognostic significance uh as a better prognostic factor. Um But that's just sort of general stuff about D. C. I. S. What about H. R. T. And D. C. I. S. If you have a patient that is treated by lumpectomy or simple mastectomy So they either have both breast remaining or one breast remaining. Generally it is contraindicated to use hormone therapy. However if they have had bilateral mastectomies and they do not have breast tissue. Although there are rare reports of recurrence of invasive disease it is likely to it is likely safe to use hormone therapy as the risk of recurrence really is considered minimal without breast tissue. So going back to that case, we have 49 year old, she had D. C. I. S. She had post bilateral mastectomies and she wants to know whether she can use hormones. So would you be willing to, I would argue. The answer should be yes. She had bilateral mastectomies. How would you give it? I would give it in the safest formulation, a transdermal estrogen and micron. Ized progesterone. Would you limit the time you would give it if she is healthy? I would argue. No. Okay so putting this section altogether. I think the majority of recent evidence suggests that family history and M. H. R. T. And one thing I apologize in some places I saw I used HRT and other places. M. H. T. H. R. T. Is hormone replacement therapy. M. H. T. Is more of the newer proper term which is menopausal hormone therapy. Um Anyways that family history and HR tr independent risk factors and I would counsel your patients that having a family history does not likely impact the risk of getting breast cancer. If they are using hormones meaning they are independent risks they are at higher risk if they have a family history but that hormones doesn't add on to that risk if you are using combination HRT give your patients a transdermal estrogen and natural micron. Ized progesterone. Either daily or cyclic. If breast cancer is what they are mainly worried about. Maybe consider other options after 4-5 years. If they had prior hysterectomy I would use transdermal estrogen alone and I would counsel them that it may be associated with a lower risk of breast cancer. Based on the most up to date data. If they had prior hormone positive breast cancer I would not use HRT if prior hormone negative cancer and they are disease free for at least two years. Okay to use if prior D. C. I. S. And lumpectomy or unilateral mastectomy would not use. But if D. C. I. S. And bilateral mastectomy. Okay to use the one that I forgot to put in here is what about a tibia? In general if someone has a biopsy that shows a tip to their risk of getting invasive breast cancer is about five fold higher. And in general I would counsel against the use of hormone therapy in that situation. Um Okay. Just a statement about bio identical hormones versus compounded because I think we all get patients walking in saying I want to use something bio identical because it is natural and it's safer bio identical means hormones in the product that are chemically the same as those produced in the body. And what I try to Consul patients is there are many commercial bio identical formulations available. The transdermal is we use our survival. That's the trade name for one climb era. Those are bio identical formulations. They are estradiol. Um They micro nyse progesterone that is a bio identical formulation. I think the confusion comes both for providers on our end as well as for patients that they confuse the term bio identical with compounded, bio identical. So compounded formulations are customized formulations that are made in specialized compounding pharmacies and they may include many different types and doses of hormones given in variable formulations in creams, pellets, implants, pills, a lot of different formulations. All of the large guiding organizations, the american College of O B. G. Y N. North American Menopause society, american endocrine society all have position statements regarding these compounded formulations. Basically a evidence is lacking to support the superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy and that efficacy and safety data are lacking because of variability in purity. There's no control or regulation of these. So, I would counsel you tell your patients they are getting bio identical and tell your patients to avoid compounded bio identical formulations or I have patients if they want to take it, they can take it. But I will counsel them that if they are taking them because they think it's safer that I would argue. We have less data on that because they haven't been studied in uh these standard uh you know, good meta analyses randomized controlled trials and that there's a lot of concerns about variability in purity and so that I think in general we have left safety data. Okay. In the last section I want to talk a little bit about alternatives to hormones. So um prescription alternatives. We have a number of prescription alternatives. Nothing may be as good as estrogen but in my breast cancer survivors I try to tell them you do not have to feel like you need to suffer. There are a number of low doses of some of the antidepressants I highlight in yellow the drugs that probably have the best randomized controlled trial data, vanilla vaccine or affects her. Uh And cloNIDine has been studied the anticonvulsants, gabapentin, pregabalin, the overactive bladder, med, oxy Buchanan. Uh And then we're going to talk just briefly about some of the natural therapies and integrative therapies. So with some of the non hormonal pharmacologic treatments, there are many good quality studies in individual randomized controlled trials, pooled analysis and meta analysis. Much of the data though are short trials usually less than 12 weeks of duration. Uh number of S. S. R. I. S. And S. N. R. I. S. That have been looked at Uh they are all off label use except for this brilliant marketing ploy for low dose paroxetine. We all know of paroxetine or Paxil as an antidepressant. The doses for depression. Start at 10 mg and go up from there. A lower dose was studied for hot flash 7.5 mg dose ng founded effective. Got it through the FDA as the only non hormonal FDA approved treatment four hot flashes and then they went and changed the name. So the trade name is Briz Dill so that patients don't have to think they're on an antidepressant. Um in my experience. Um uh sometimes I'm having trouble getting insurers to cover bristol and I oftentimes would just give them for oxygen With the paroxetine. There's some concerns about interaction with Tamoxifen because they're both metabolized by the cyp portion of the P450 detoxification pathway. Um it's more theoretical but some uh there are some concerns. It's important to realize that when you're using these antidepressants for treating hot flashes, the beneficial effects are in days um as opposed to weeks for depression and the doses I'm going to talk about this but much lower typically than those used for depression. There are also good randomized controlled trials with gabapentin, pregabalin. Uh some limited trials with cloNIDine and oxy Buchanan. Understanding the dose differences probably as I said, one of the best study that's been the vaccine We know for treating depression or you all know the doses go up as high as 375 mg A day. The most effective dose for hot flashes is 75 migs daily. You can start as low as 12.5. The lowest dose that comes as 25 it's scored, I'll start at 12.5 work their way up. There are long acting formulations of 37.5 and 75 and I worked their way up and Once I get them on whatever dose seems to help put them on a long acting form, they will not get a benefit in terms of hot flashes. If you go above 75 mg uh there is better tolerance and less discontinuation with these lower doses uh for gabapentin and pregabalin I would say we have more data with gabapentin as we know they're used for both anti seizure and neuropathic pain. Um The exact mechanism is not clear is thought maybe to work by regulating regulating calcium flow in and out of cells, which we know that that's how it works but maybe that regulates cell temperature and body temperature. The big thing with this one, the dose is different. So whereas neuropathic pain you can go up 1000 5000 mg a day. The most effective dose for hot flashes is 900. Um much less than what's used for neuropathic pain. Um I usually start at either 300 at night or if they're very drug sensitive 100 at night. Um This one will cause causes sedation. So if I have someone who has their hot flashes more often occurring at night. So night sweats disrupting their sleep. I'm going to use Gava Penton first line. Um If they don't get too sedated, I'll use most of the dose at night and then lower doses during the day. Um Pregabalin. Uh It's less well studied. It's also more expensive than gabapentin but you can start as low as 25 mg. But the recommended doses go up to here. Um I'm just pushing our guidelines among the survivorship panel for the National Comprehensive Cancer Network. And we actually have guidelines on all of these treatment recommendations. Um Every year it's updated. We have the specific drug, the commonly used daily dose and then comments about when to start and any comments about that. Um So what are my clinical pearls? I would say none of these drugs are any better than the others. They are all off label use except for like I talked about with low dose paroxetine. I would take advantage of their side effects like sedation with gabapentin, overactive bladder symptoms. I would use oxy butin start with the lowest dose possible for drugs that are anti depression depressants. You can see beneficial effects in days rather than weeks. And in general I would try not to mix and match. I do have some patients. I will give low dose Gabba Penton at night before bed and maybe even the vaccine during the day. But in general I try not to mix and match um just briefly in the last few minutes on integrative therapies and lifestyle modifications. We'll talk a little bit about acupuncture botanicals. CBT mind based therapies, yoga hypnosis. Um lifestyle modifications. Um I think that they can really help out for mild symptoms. What I tell people about that is try and identify what your triggers are. For a lot of people people it's caffeine, alcohol, spicy foods. If you know what your trigger is, you can try and avoid that. Use fans or lowering room temperature exercise regularly is important not to close to bed. That may affect nighttime hot flashes, reduce stress weight loss if obese. Um we'll talk a little bit more about these. So some of the specific ones. CBT. That's actually good RCT data showing a benefit um definitely for improving sleep a little bit uh for hot flashes. But this was limited by the need in the studies that looked at it. They were in person visits. This was presumed data um hypnosis. Two studies have shown significant improvement in hot flash frequency improving sleep. Um I think some of the problems with the hypnosis data is you need to ensure that there's this standard procedures um to ensure comp competency. So I'm not sure that hypnosis is a great option. Weight loss has really owned to be bent only been to be beneficial in reducing hot flashes in obese. Women who underwent a structured weight loss and behavioral program for people with a normal B. M. I. Uh if they lose a little bit of weight. Uh It's not gonna be beneficial. Uh Mindfulness studies looking at mindfulness showed a decrease in being bothered by hot flashes, but no effect on hot flash intensity. Um specifically looking hot flashes but may have many other beneficial effects yoga mixed results but may help with sleep exercise as we talked about, you need to watch because it can cause a rise in body temperature. Uh so that can maybe exacerbate some. But exercise we know is good for so many things. Um Just to move on again. We already talked about lifestyle interventions. Um the theory with some of these is that you narrow the thermal regulatory zone and I think for mild hot flashes, lifestyle interventions alone may be enough. Um My clinical pearls with lifestyle and Integrative therapies. I would say overall there may not be studies showing a significant benefit for hot flashes, but they can be useful for many other things. Weight loss, maybe cardiac disease, like exercise, bone health, decreasing stress and emotionally making people feel good. And for the vast majority nothing suggests harm um supplements and botanicals. This is an area that tends to be very underfunded. So generally, I think there's a lack of good quality data compared to like the medications that are FDA approved. Um some of the problems in this area is, there's also often a lack of purity in the compounds and lots of variation in the quality of studies. Also, one of the biggest things is in botanical medicine. It's okay to use the whole plant or an extract. But it makes it hard to compare data from trials that are using different formulations of the earth if they're using the whole plant. There's also a whole bunch of compounds in it. And so it's hard to know what may be active in contributing to the results. And I think certainly there's a call for better research with uh supplements and botanicals. I just want to mention the two that are commonly used black cohosh the doses if you're going to recommend to patients of 40 to 80 mg a day and has been shown to be beneficial in some but not all studies. Um Again, hard to compare the trials that are out there mechanism not clear people ask what about breast cancer. Um One recent trial published a year ago suggested may be beneficial and safe in general. What we've said through the NCC N is there's not enough data to fully say that it is safe. Soy phyto estrogens. They're essentially sermons selective estrogen receptor modulator. They have both estrogenic and anti estrogenic properties. Lots of variation in the types of phyto estrogen studied and the overall quality of studies. I think there's been mixed data in our cTS meta analysis in Cochrane reviews I think certainly reasonable to have patients try again, I get asked in breast cancer if it's safe dietary forms. Probably okay going to a health food store and getting soy phyto estrogen tablets we don't have enough data to say. Um So in conclusion I am hoping you now know a little bit more about when and how to prescribe HRT understand when and when not to use HRT in high risk women know the difference between bio identical and compounded formulations. Uh no, a little bit about some of the prescription alternatives to treat Hot Flash and really understand the dozing differences. And then I understand a little bit about some of the integrative and herbal therapies for treating menopause. Um and thank you very much.