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You are so warmly welcome to this Metal Primary Care session. We are really honored to have you join us and we're really looking forward to an amazing session. Er This session is gonna be hosted by er Jing Jing Wang and she'll be introducing our speaker this evening. I just wanted to share a little bit of work that we've been doing at Metal. If this is your first time er joining us here, you're really warmly welcome and we're really passionate about making great education, great resources accessible to healthcare professionals free at the point of use to help you in your everyday uh career and importantly to help patients in uh in that process. And one of the things that we've been doing is building out resources within the Metal app which Jingjing has popped a link to in the chat on the right hand side in particular. I just want to signpost you to some tools which may be helpful. Er er based on some of the conversations that we're gonna have er this evening when you download Metal on your phone, it looks a little bit like this and we've been working really hard to make it really easy for you to share er, great resources with your patients. And sometimes those conversations can be challenging. We've tried to make it really easy for you. So if you've got a patient and you want to discuss menopause with them, um or any other uh condition, you can simply go to patient leaflets in the metal app and you can actually pull out um menopause leaflets, search for it, give them a QR code and actually share that information with the patient. It's uh best uh evidence uh content uh directly from the NHS. Really eas easily shareable uh with the QR code. So you can just give the patient the QR code and they've immediately got some really great resources to help them and it hopefully helps you in your conversations. There's a patient information leaflet for uh almost everything um just hit the reference button at the bottom and then patient information leaflets. And it's a really easy way to begin to share best resources with the, the patients that, that we're seeing every day. I hope you find it really helpful. Uh We'll share a QR code on how you can download the app. At the end of this event. You can find it in all the app stores, just type in metal or use the links on the right hand side. It will also let you get your certificate at the end of the event and you'll also be able to get the slides and recording in the app as well. And without further ado I'm gonna hand over to Jing Jing. You're also warmly. Well, thank you very much Phil. Um and as Phil said, so welcome to me primary care. Er joining us today is Doctor Vikram who's an honorary associate professor in Women's Health at the University College of London. And as a British menopause Society, menopause specialist, Dr Vikram brings a wealth of expertise in menopause care. He is recognized as a principal trainer for the menopause special skills module at the Faculty of Sexual and Reproductive Health Care at the Royal College of Obstetricians and Gynecologists. And he is also a trainer for the BMS Principals and Practice of menopause care course. Today, Doctor Vick Gram will be teaching us about managing H RT and we have about 45 minutes for the presentation and there'll be some time for questions. So do put your questions in the chat. As we go along at the end of the event, there'll be a feedback form, email to you and once completed your attendance certificate will be on your Meadow account. That's all for me. I'll let doctor take it away. Thank you so much. Thank you, Phil. Thank you, sue me, Jingjing. Uh for that quick and fast introduction, very succinct to the point. Thank you for that. Now, we have a lot on our hands today. H RP can be a subject you could talk about in 10 hours. So we're going to squeeze that in the next 45 minutes and we'll try to give you the highlights of what is important when prescribing or managing HRT. Uh, I'll talk for about say 35 40 minutes, uh, quick, rapid fire, uh, through the slides and then I'll leave around 1520 minutes. So I can go through as many questions as I can. At the end, we may not get through all. We have about 1700 registry. So there'll be 100s online. So we'll try to get through as many questions. But hopefully we'll pick up the theme of the questions and do other webinars in future to try and answer uh some of the remaining questions. So I'll start sharing my slides in a second. Um There we go. And Jingjing do tell me once I get to the full slide uh mode that it's actually uh playing. Yeah, we can see it in four slides. Thank you. Thank you. So conflict of interest declaration. Uh So I work in NHS at UCL H Hospital. That's my main clinic. I do also do private work at 10 Harley Street for menopause Clinic, London. I have done previous webinars GP teaching for a number of Pharma companies and I'm a co-founder of the Menopause Research and Education Fund uh charity. So let's look quickly through stages during the journey towards menopause. And the reason to do this is to understand when H RT prescribing comes into play. So we know that before any hormonal changes have started the first phase where the hormones are happening in a cyclical manner. Naturally within the normal range is the premenopause. Uh But the the woman will be having normal natural menstrual cycles. There won't be any menopausal symptoms, estrogen, progesterone, LH FSH, all hormones will be within a normal range and happening cyclically. Perimenopause is the first phase. When menopausal transition begins, this is when hormones start fluctuating the FSH and the LH will fluctuate. Widely, estrogen levels will also fluctuate. And so there'll be some days when there'll be enough estrogen from ovaries, there will be other days when the production of estrogen will not be as much on, on from the ovaries and you get symptoms which can come in at this point. So many women will start feeling some of the symptoms right at perimenopause. Although they may be still having regular or irregular periods. This is the time when most women will have some changes to their periods. Initially, the periods will be frequent and then later on, there will be long gaps between periods and perimenopause usually will last for 2 to 5 years between the ages of 45 to 50 for the majority of individuals then comes menopause. This is when periods have stopped completely. This is a retrospective diagnosis one year after the last menstrual period. So we only know someone has gone through menopause one year after their last period. And from that point on one year until the end of life is post menopause. So this is a long phase. This could be 1020 3040 years of a woman's life where she will be in post menopause. And it's our duty to look after women's health during this point in time and protect the long term health. Now, why the slide is important? First, you can offer HRT even during perimenopause. When the menstruation is still happening. This is a shift in concept because previously, when a woman was still having periods, even if she had symptoms, the traditional thinking was we shouldn't be giving HRT because of course, the periods are still happening. But you know now that the the amount of estrogen produced during the cycle will vary during perimenopause. And so if the symptoms are affecting a woman's life, affecting quality of life, even though she may be having regular or irregular periods, one can still offer hormone replacement therapy or other nonhormonal interventions for symptoms at this point also remember that symptoms can go on longer. So a average duration of symptoms may be five or seven years for most women. But menopausal symptoms can go on much longer for 1015 years or more for the proportion of individuals. So therefore, HRT may have to be given long term uh with annual reviews if the individual desires it timing of menopause, average age of menopause is 51 in the western population in Caucasian based data. Uh 10% of women have menopause between 40 to 45. This is called as early menopause. 1% of women, they have menopause below 40 which is premature menopause. And about 0.1% can have menopause even before the age of 30. So even if there's a young woman who has stopped periods is presenting with typical symptoms, menopause should never be downplayed. Uh There's no one actually too young to go through menopause. If there are significant symptoms, then all these uh uh a diagnosis of premature menopause should be kept in mind and proper investigations should be done with hormones. Ethnicity becomes important. We know that for example, Afro Carribean women may have menopause 1 to 2 years earlier. Similarly, if you look at Southeast Asian women, women from India had menopause five years earlier on an average at 46 rather than 51 again, that becomes important when you are prescribing HRT, considering HRP the ethnicity of the individual will give you clues as to the origin of symptoms and help you confirm diagnosis of menopause. What is HRT HRT is replacing the three key hormones, the estrogen, the progesterone. And for some women addition of testosterone and I put a slide there to say improve libido because that happens to be the one indication which guidelines recommend use of testosterone. But some women may have other effects from testosterone which haven't yet been proven to randomized trial studies. So currently use of testosterone remains of license in the UK and the main indication will be low libido, systemic or local HRT. Systemic HRT is the one that's given through oral route or transdermal route. Uh It can be tablets, capsules, patches, gel spray or implants or coils. Local HRT is something which is vaginal. So, vaginal estrogens can be a form of local HRT at the moment. Systemic estrogen replacement therapy remains the most effective treatment for menopausal vasomotor symptoms. There are of course, alternative options, alternative therapies, nonhormonal options for symptom but head to head HRT is the most effective treatment and therefore, we need to balance the benefits of HRT and risk. Uh When we're counseling women about the efficacy and safety of HRT, what is the choice of HRT in modern HRT preparation? Which ones do we go for? And this is a common question which many uh providers will ask. Uh there are more than 35 preparations of HRT around which one do I choose for my patient? Well, we know that at the moment, we want to choose as natural and body identical hormones which appear to be the safest. So, estrogen wise, it is the 17 beta estradiol. This is the preferred estrogen in HRT. It is the body identical estrogen that is obtained from yams or SOYA uh often plant based and this is the most studied estradiol uh in various randomized trials or observational studies. We quote, progesterone is natural progesterone, which is body identical progesterone or di progesterone, which is known as the body similar progesterone. These are the best ones because they are better tolerated than some of the synthetic old progesterone like noretisterone, Mexate progesterone, Provera or or GRE because these two are less androgenic, they stimulate androgen receptor less, they have less impact on thrombosis. So less risk of blood clotting and of course, there is less impact on the risk of breast cancer. These are the two most breast friendly progesterones. So beta estradiol along with natural progesterone or di progesterone would be the first line choice for HRP. But of course, for some women, it may not be working well for them. In which case, there are alternative regimes, progestogen sensitivity uh can affect about 10% of individuals. So often if the woman is very sensitive to progesterone and she has side effects from progestogens, then think about what sort of type of progestogen you use? What can be the dose? What can be the route? Can we change the frequency of administration of progestogen? And we'll talk about that a little later when they come to side effects, body identical and body similar HRT. That's a slide that's showing you that that's very little difference between the micronized progesterone, which is often commonly available in the UK as gaps or progesterone and the hydrogesterone, which happens to be very similar, just a simple way how these two progesterones are, are actually formulated. That's the difference between the two. The efficacy safety almost remains head to head similar. And that's a table that shows you why the progesterones differ in their efficacy and safety. If you look at the various progesterones, on the left hand side, look at the natural progesterone and progesterone, they do have action on the progesterone receptor, but they don't stimulate the androgenic receptor. While the old synthetic progesterones tend to do both the progesteronic receptor but also the androgenic receptor. So, a lot of women may have oily skin or acne or scalp hair thinning or hirsutism. And also there is an increased impact on the risk of thrombosis and breast cancer. Now, what route of HRT is popular? Of course, you can have oral HRT where estrogen is in the tablet form, often combined with the progestogen. You have transdermal estrogen preparations like gel, spray implant or patches. And we have the low dose vaginal estrogen preparations. First, looking at the oral preparation, when we might prefer oral preparation. Of course, it can be one of the choices for women who are healthy below the age of 60 there are no risk factors for thrombo embolism or vte oral preparation can be a choice. Patients may prefer to take tablets because it's more convenient and they can be given the choice. Patient adherence might be better. So some women find taking tablet daily is a routine rather than having to remember when to change the patch or the gel can be messy, patient and BP or previous cardiac history. Transdermal preparations will be the first choice in that situation to minimize the risk of blood clotting or stroke. Low dose vaginal estrogen. Of course, estrogen is available as green gel pessary or vaginal ring. That is mainly for vulvovaginal symptoms, urogenital symptoms. And this can be used in conjunction with systemic HRP. If there are systemic symptoms of menopause as well, when should HRT not be used? When should you be careful? Of course, the ones I've listed on this slide are traditional contraindications. Caution. If you open a leaflet that comes with an HRT preparation, this is exactly what you will read through, but we always individualize. So even in some of these situations now with the availability of transdermal and body identical hormone on case by case basis, we can offer HRT once the pathology has been treated. So, for example, ideally, contraindications include current past or suspected breast cancer, known or suspected estrogen dependent cancer, undiagnosed, vaginal bleeding, undertreated or untreated endometrial hyperplasia, current venous thromboembolism or arterial thro embolism, liver disease and pregnancy. All of these would be contraindications. But of course, if the thromboembolism episode has been treated, we have already had hematology input. We know that they are on anticoagulation. You can of course, offer transdermal HRP for many safe with breast cancer, which was triple negative, having had counseling and they've tried all non hormonal therapies and still wish to consider HRT on a case by case basis, we sometimes offer a charity after counseling and involving oncologists. So there is individualization there. But generally in the primary care, these would be contraindications. You can prescribe a charity with caution in women with porphyria where progesterones, one has to be careful with diabetes with multiple complications or previous venous thromboembolism history of endometrial hyperplasia, migraine migraine like headaches or increased risk of breast cancer due to genes or family history. Again, you need to counsel the patient appropriately and be cautious with what type of HRT you prescribe. Hopefully we'll touch upon that as we go along, some of the prescribing tips from myself in the clinic. Of course, one size fits all approach does not work. We all know that different women will respond differently to the same HRP. And so therefore, it's a method of trying what will work best for that particular individual. You may have to set up realistic expectations and say that we'll have to work through maybe two or three preparations over the next 6 to 9 months until we get the HRP that takes care of symptoms without giving you any major side effects. So the aim is to start with the lowest dose of HRP that treats the symptoms and then gradually increase the dose based on symptoms side effects and we always avoid excessive of license prescribing. So stay within the product's upper limit of dosage. Unless there are very exceptional situation. When the patient doesn't absorb licensed dose, that is very few. I always try to stay within the licensed dose of a preparation. Blood test can help occasionally when poor absorption is suspected. So if you reach the highest licensed dose of the product, and you wonder why menopausal symptoms may not still be controlled in these situations. You can do a blood test to get some estimate of how much estradiol the patient is absorbing. And if the levels are very low, something less than 150 by com, then that suggests that the woman is not absorbing that preparation. That's when you can increase the dose further or change the preparation completely. Women who are young who are below 40 have premature menopause often need more estrogen. So you're likely to need the highest licensed doses of oral or transdermal estrogen. And when you choose the H RT for somebody who has had premature menopause, of course, you have two options. You can use the contraceptive pill or you can use the H RT that has estradiol and the progesterone. At the moment, there is a big randomized trial that's going through called as the Poise. Uh We are recruiting for it at UCL H and there are other scientists. If you do have women who may be interested in recruiting for Poise, do sign post them to the study at UCL H head to head. If you look at the pill and the natural H RT, there is not much to choose. The pill has the advantage of contraception for those who may have 5 10% chance of a pregnancy. The HRT of course is more physiological. So, in the long term, we think HRT does better for bones and for heart and for metabolic outcomes. However, women still have the choice, they can still use the pill if they would like to avoid heavy periods or would like the contraception. Now, when do you prescribe a cyclical bleed, HRT versus a bleed free HRT. So anybody who's just gone through menopause within the last one year, we always recommend cyclical HRT giving a bleed every month and we do that for a year or two and then transition to bleed free HRP. The aim for that being to avoid too much breakthrough bleeding because if you go directly with bleed free HRP, right in the early part of menopause, and there is still some ovarian activity that can be lots of breakthrough bleeding. So, bleed free continuous HRT will be better once it's been more than a year after the last period and certainly by 4 to 5 years of using cyclical HRT, it's recommended that you move on to bleed free HRT. That's because if you keep cyclical HRT longer than five years, for women who are around 45 or above, there's a small increased risk of endometrial pathology. So best is after five years or even before 2 to 3 years down the line of cyclical A charity, you can switch to a completely bleed free. A RT. Now, women who may want fertility like premature menopause or poi, they may prefer having cyclical HRP. That's because it may help them to prepare their endometrium when it comes to the IVF treatment with a donation. So sometimes we recommend that these women stay on cyclical HRP if they are desiring fertility treatment. For those women who have heavy bleeds, heavy bit trouble, bleeds, endometriosis, uh PMS symptoms with cyclical HRT. Of course, we either offer bleed free HRT. We don't want the cycles or they can go on to the pill if uh there are no contraindications. A quick word about vaginal estrogen. They are very effective for vulvovaginal dryness, irritation and painful sex. It can help reduce urinary frequency urinary incontinence. It can help reduce urinary tract infections. So, very useful for that. They also help with pelvic muscle health in suitable women, vaginal estrogens. If started for menopausal vaginal symptoms, they can be used as long as required. Uh and then of course, no or little absorption in the body. You don't have to give separate progesterone uh for vaginal estrogen use and they are safe to be used in the long term. There's often two terms which come in the uh press. One is called body identical H RP and bioidentical H RP. Body identicality is the one that we recommend in the UK and in most of the countries, uh this is a combination of plant based estrogen progesterone that we know are well studied and regulated. So, most of the preparations we use now in the UK, for example, that contain estradiol or progesterone, they will be body identical and safe to use well regulated. We know the long term safety data for 5, 1015 years, but the bioidentical are compounded. HRP. These are slightly different individual clinics on high streets, mix different plant estrogens and progestogen like compounds and often produce their own preparations. And a lot of women find that these work for them. What we don't know is the long term safety data. Often it's not published. So for 5, 1015 years, safety data is not available. So, bioidentical preparations currently are not recommended as per the guidelines. This is a quick HRT guide for clinicians who may be new to prescribing. So I won't run through details of the whole flow chart because we have 45 minutes only. But let me just quickly give you the highlights here. So this is menopausal symptoms, vasomotor symptoms and you have uterus intact and post hysterectomy. Two groups of patients. If the woman has had a hysterectomy, we know that she only needs estrogen. So this could be oral estrogen tablets or transdermal estrogen as patches, gel spray or implant. This is estrogen only. Now, there are some situations where despite hysterectomy, you may have to give progesterone alongside estrogen. And that's mainly for uh endometriosis or endometrial cancer in the past. But you still have to give continuous progesterone uh as part of suppressing any rebound growth of endometriosis or endometrial cancer. Again, we individualize that for patients. If the uterus is intact, then of course, it depends on when they had their last period. If it was very recent within the last one year, and we start with a cyclical combined HRP. Estrogen and progesterone are given cyclically for a year or two after which you can move to a continuous combined bleed free HRP. And you can combine various forms of oral or transdermal estrogen with either oral or transdermal or intrauterine forms of the progestogen, including the coil. And then of course, if the last period was more than a year ago, you can go straight to bleed free continuous combined. HRT. You don't have to keep cyclical HRP and that's either oral or transdermal estrogen combined with various forms of progesterone. So that is just break down into simple terms, how to determine what HRT will be the best in the situation. So when do we start? HRT, stop, HRT. How long do women take it now? Not all women need or wish to take HRT, but if someone wants to take it to suppress their symptoms and there are no contraindications, it should not be denied. We can start HRT very early in perimenopause or early menopause when the symptoms come in and some women may wish to take it much later, having tried other approaches first. So there is no absolute arbitrary starting time earlier you start HRP more the benefits in perimenopause or early menopause, there should be no arbitrary limit for stopping. HRT. So previously, we thought maybe HRT should be used for 2 to 5 years and then stop. But with the more safe hormones, there is no arbitrary upper limit. Most women will use a RT for 10 to 15 years between 50 to 65. But if people want to continue beyond that, then it's completely up to them. And so we individualize benefits and risk every year, we have an annual review and make sure that the person who wants to stay on HRP understands their benefits and they are balancing it against their risk. And if the benefits out the risk, we continue and what are those benefits? Of course, HRT benefits, bones prevents osteoporosis. It benefits heart especially if you start it within 10 years of HRT prevents or reduces risk of heart disease. In future. It helps with reducing the risk of uh diabetes and improves metabolism. It helps with symptoms, quality of life and all these benefits. We're trying to balance them against risk of blood clotting thrombosis, risk of breast cancer and endometrial cancer. And we'll look at that in a few minutes for women who have poi early menopause premature menopause. The minimum recommendation is that they take H RT until the age of 50 so that they have prevented any osteoporosis or heart disease. And then after 50 it's individualization, some women manage to continue longer while others may come off. HRT. What about testosterone? Testosterone has been the long neglected hormone as part of HRT. But of course, the assessment and interpretation of testosterone blood levels in women is not straightforward because of the way testosterone is measured and the essays that we have, the indication that it's mostly recommended for is low libido. So, despite improving uh symptoms with the HRT, if the libido still remains persistently low, that's when testosterone is usually added to HRT. We should also be careful to consider other causes. So low libido can be due to medications, could be due to background, medical conditions could be due to antidepressant, just a vaginal uh pain or vaginal irritation and um a dryness can cause again, low libido as a reflex. So we must be treating all those first and then if still there's persistent low libido and generally testosterone would be worth trying. There are no testosterone, uh specific female use license product in the UK. Currently, all the products are used off license, whether it's the Toran, the Testogel in the NHS or whether it's the Andro cream in the private sector, they are all off license use of testosterone in women. What are the types of products we use? We of course use gel creams and there are some implants which are available for subcutaneous use. Uh The gel creams often are used in a dose of 5 mg daily. So whatever preparation you have, we try and divide the dose into 5 mg daily. We try to monitor the response clinically. Uh as well as looking at total testosterone or free androgen index. You can use one of the two and we tend to do it at six months of starting testosterone and then making sure once a yearly there is a total testosterone that's within a normal range. We try to keep it to the upper normal range if possible tibolone. Just a quick word about it. Remember, tibolone is not a hormone, it is a steroid which mimics actions of estrogen progesterone and testosterone. It's like a continuous combined HRT but additional testosterone like action and it has its unique place in HRT. So sometimes when standard HRT may not work, tibolone may work as a good bleed free HRT with some androgen effect. What are the side effects of testosterone? And the risks? Of course, testosterone can increase body hair. It can cause hirsutism. These are very uncommon if you stick to the small dose that we intend to provide and generally, these will not happen. There may be some hair growth at the site of application to the thigh, but there should be no generalized hair growth. If excessive doses are used, then this can be a problem. Sometimes women may report scalp, hair loss, acne, greasy skin and in too much, too much doses, it can cause deepening of voice or enlarged to risk. These are rare side effects in common use in, in, in sort of general day to day clinical use. We don't seem to see these risks of testosterone are minimal. So far, whatever IZED controlled trials we have, they don't seem to show an increased risk of cardiovascular disease or breast cancer. They seem to be quite safe in terms of the long term disease risk or long term side effects. Of course, testosterone has only really been consistently used since about 2013 in the last 10 or 15 years. So we really need long term bigger trials. And there is a talk about testosterone in I hr trial for menopausal symptoms besides low libido. Hopefully that trial will give us much more data in future right now, though long term risks remain uh unreported or less reported. So it looks that the low dose of testosterone remains safe enough. Now, let's look at the side effects of HRT. So we've talked a lot about the good bits of HRT, what it can do. But how do we balance that against the side effects? And what do we do when we encounter side effects, breakthrough bleeding. This is one of the commonest problems with HRT is that there may be some or other breakthrough bleeding, whether it's on a cyclical preparation or it's a continuous combined bleed free and it's very common in the 1st 3 to 6 months. So any bleeding in the 1st 3 to 6 months, you can safely reassure the patient unless there are some additional features like it only happens postcoitally or there is pain associated with bleeding. Then of course, you will investigate, you will examine but generally, if it's just bleeding that has started after starting HRT for the 1st 3 to 6 months, one would assume this is coming from the HRT product and it takes the body a little bit of time to go completely bleed free, especially for the continuous combined HRT. So you can reassure and wait to see if the bleeding improves. But if it persists and the persistent breakthrough bleeding continues on HRP. And of course, the first thing to check is compliance. One of the commonest reasons why bleeding may be happening is missing of doses. So the tablet has been missed. A couple of tablets have been missed or a patch was not put on time. These are usually common reasons why bleeding happens, assess the risk factors. How major risk there is of an endometrial pathology and this is what is the focus of the new BMS guidelines. So British Menopause Society produced guidelines just a couple of weeks ago. This is on irregular unscheduled bleeding on HRT and they look at major or minor risk factors for endometrial pathology and decide when the scan should be done. And you can of course, start doing scan, uh request a vaginal scan if possible. And that would be usually giving you uh confidence in ruling out an endometrial pathology. In the meantime, you can of course change the dose of the type of progesterone. Most bleeding happens because the progestogen is not enough. So changing the dose or the type of progesterone usually will stop the bleeding from majority of the and the scan will then confirm at six months that the endometrial pathology doesn't exist. So you can confidently continue to modify the HRP. Urgent scans are usually recommended. Those who have major risk factors for endometrial pathology like very high BMI or history of cancer genes in those sort of situations. Then uh an urgent scan is recommended for those who don't have major risk factors, minor risk factors, you can do a scan within a reasonable time of 4 to 6 weeks rather than urgent cancer pathway. Remember that the chance of finding an endometrial pathology is much lower than the bleeding happens on HRP because this is usually induced by hormones. This is different from the two week pathway we do for post menopausal bleeding with postmenopausal bleeding. The bleeding is likely to be pathology because you're not taking any hormones. But the chance of finding a pathology therefore is much lower if it's bleeding on HRP because this is more likely related to hormones rather than a structural pathology. And that's just to highlight the guideline that came off. So if you're interested in knowing more, please do access BMS guideline. It's very useful in managing bleeding on H RP. According to other common side effects when starting HRP. So you have breast tenderness, bloating, nausea and headaches. These are the four most common and know side effect of HRP and usually will happen for the 1st 3 to 6 months. Most women will see that these side effects disappear after a course of 2 to 3 months. But if they persist, then one of the things you can do is reduce the dose of estrogen first and that should make them disappear and then gradually build up the dose for women. The breast tenderness, headaches, bloating may come from the progestogen. So try and reduce the dose of progestogen but keep it within the safe limit for endometrial protection or change the type of progestogen. And that may also help with the bloating and the breast tenderness. Headaches can be triggered by cyclical HRP, migraine like headaches may happen. So trying to bleed free or noncyclical HRP and that may take away the headaches as well. Now, finally coming to HRP risk. So what are the risks that we talk about the stroke, the thrombosis risk, the endometrial cancer risk, the breast cancer risk and the heart disease. Let's look at them one by one. We know that the absolute risk of stroke is very, very small in women under 60 if they are healthy. If they don't have any predisposing risk factor, then the absolute risk is very, very small. So they can safely have all options of HRT including oral, as well as all the transdermal forms of HRT. We know that taking oral estrogen, oral HRT does increase risk of stroke. And how much is that? It's about 4 to 5 cases per 1000 over a period of five years. Use of HRT. So the absolute number is very, very small but nonetheless, oral estrogen does increase a very small risk increase in the risk of stroke. Transdermal estrogen patches. Gel spray implant is not associated with risk increase, which is why they are seeing so much more transdermal patches or gels being used because especially in women after 50 there will usually be one or other risk factors such as high BP or or uh high BMI in those situations. Transdermal estrogen is preferred because it does not increase risk of stroke. This was a very nice study which was published in the BMJ around 2019. They looked at various forms of estrogen progestogen combinations. And if you look at that transdermal estrogen did not increase risk of blood clotting. Some of the old synthetic progesterones like medroxyprogesterone or norethisterone, they seem to increase the risk. But if you look at the modern progesterones like the dip progesterone, then look again, it doesn't increase the risk, the body similar progesterone. So the modern ones, the utrogestan, the dip progesterone don't seem to increase the risk just like the pons, dermal estrogen. It's the older progesterones or oral estrogen that seems to increase the risk. What about endometrial cancer risk? So, we know the role of progestogen is very important if a woman has a uterus and they are giving combined HRT progestogen is very, very important even with post endometrial ablation. Uh and in fact, if there's been endometriosis and hysterectomy or subtotal hysterectomy with some remaining endometrium, even in those situations, it's always recommended that progesterone should be given alongside estrogen to reduce risk of endometrial cancer. How much do we give? What is the minimum required recommended progestogen? So we know that if it's non hysterectomized woman, woman who has a uterus daily progesterone is required at least for 12 to 14 days because less than 10 days in every cycle will increase the risk of endometrial hyperplasia. So sometimes you have patients who have been prescribed less than 10 days of progesterone within a month. And they're doing that every month for less than 10 days, that would increase the risk. So it's minimum 12 to 14 days of any progesterone as part of a monthly cycle. After five years of using cyclical HRT, it's always good to change to a bleed free H RT because after five years of use, there seems to be an increased risk of endometrial pathology. So, switch to bleed free H RT and continuous combined estrogen progesterone has the lowest risk of endometrial cancer, which is why we often say long term H RP should always be continuous combined estrogen progestogen H RP. There was a recent safety alert about uh using uh off license very high doses of estrogen. And so the the message there is if you keep increasing the dose of estrogen, try to avoid going off license with the product and try different products, which may still be within the license of the limit of estrogen use. But if you have to use high doses of estrogen, then you have to increase progestogen accordingly. So the latest guidance says that if you hit the highest dose of estrogen like 4 mg, oral 100 patch or four pumps of gel or more than three space of the LTO, then you should increase your progesterone dose. So 200 mg of natural progesterone daily if it's bleed free and 300 mg cyclically for 12 days. And so with the other progesterones, you need to go up the dose to enough protection for the endometrial lining with high dose estrogen. What about nice conclusions on breast cancer risk with H RV? So, estrogen alone, we know has very little impact on risk of breast cancer. And again, this is important to know because often estrogen is blamed for breast cancer. But if you look at randomized trial studies, the w especially estrogen alone doesn't seem to increase the risk. It's the estrogen and the progesterone that brings in the risk with the combined HRT and the risk of breast cancer relates to the treatment duration. It will reduce after stopping HRT. This is based on observational data. If you look at the observational data, longitudinal studies that have been done to see what is the actual extra risk of breast cancer with HRT, then this particular picture might help to explain. So this is for a typical scenario where a 50 to 55 year old woman is considering HRT for menopausal symptoms. And if she asks a question, what is my extra risk with HRT with regards to breast cancer? And it's about one in 50 extra individuals over a period of five years. So if you look at that, this is the 50 women in menopause not taking HRT three of them would be diagnosed with breast cancer over a period of five years. If you, if you give HRT to these women and then follow them for five years, then one extra person in 50 will be diagnosed with breast cancer. So that's the very, very little extra absolute risk that comes with use of HRT. Now, this is based on observational data. Let's look at the randomized trial data. What does that say? Mainly based on the study? So we know that if 1000 women in menopause say between 50 to 55 are followed for five years, then 23 of them will get a diagnosis of breast cancer as a background, giving them H RTA combined estrogen progestogen HRT will increase the four extra cases. So that's very, very small absolute increase. Four out of 1000 women who will use HRT for five years. If you estrogen only a charity, actually, for less women will get risk of breast cancer. So, estrogen not only not increases the risk in this particular randomized trial data. Actually, it reduces the risk of breast cancer. If you look at the combined pill, it has the same risk as the HRT. And if you look at say two or more alcohol units per day, then that's extra risk. Much more than HRP. Smoking has a risk. Almost similar to HRT being overweight increases the risk significantly extra 24 women getting breast cancer diagnosis in five years and of course, exercise is always protective. It reduces the risk. The importance of this slide is that HRT has almost a similar increase in risk to many other lifestyle factors and much lower than high BMI. But we often talk a lot negative about HRT as compared to the other lifestyle factors. What have been the more recent analysis and publication since wh I of course, there have been two papers, one in Lancet and one in Jama, which was actually the long term follow up of the wh I study, the Lancet paper suggested based on observational data that breast cancer was increased by both estrogen only and estrogen progesterone combinations and it was detectable even before five years of use in the 40 to 50 age group. While the w randomized trial, long term follow up suggested that estrogen alone does not increase the risk. In fact, lowers risk of breast cancer. It's the combined HRT which increases the risk slightly but not the mortality. So this is in sort of agreement with the nice guidelines which says estrogen alone doesn't increase the risk. The estrogen progestogen combination is the one that increases the risk slightly finally coming to the heart disease risk. So you have HRT and coronary heart disease. We know that if a woman starts HRT early on within 10 years of menopause, it's a favorable benefit risk profile. So she will have less risk of heart disease if she starts HRT early and cardiovascular risk factors like BP, diabetes, as long as they are controlled, they are not a contraindication for HRT. If someone starts HRT after 60 it's not that you can't start it. The benefits of heart protection may not apply. The benefits may have already been exhausted, but there is no increased morbidity or cardiac events. So you can offer it even after 60. Uh but individualized use the most safest transdermal estrogen and the body identical hormones. This is another useful piece of guidance from BMS uh very recently and you don't necessarily have to stop HRT even if a woman has had myocardial infarction. As long as you've done assessment, you've done individualization and counseling and you use safe body identical forms of hormones and transdermal estrogen final slides about treatment of GSM vaginal estrogen is very effective for vaginal vulvovaginal atrophy symptoms and can be used as long as needed. There are various preparations, you can even use it in women who have had fast breast cancer, especially if they are taking tamoxifen or it was a receptor negative tumor. If they are on aromatase inhibitor, small observational data suggest increased risk of recurrence. So you need to individualize and offer it on a case by case basis. After discussion with the oncologist, if non hormonal treatments have not been successful, there is a preparation of DH A as a pessary which is also available. Now, for those who may not be able to use vaginal estrogen or do not feel it works. You can use vaginal DH A which is converted into estrogen androgens locally. And there is an oral il selective estrogen receptor modulator tablet 60 mg once daily. This is oral treatment of GSM for women who may not want to insert vaginal preparation. The contraindication for this is any history of thrombosis, but it can again be used off license if uh women are having severe vulvovaginal symptoms after the treatment of breast cancer. Uh but there are no uh trials specifically in breast cancer or population. So, as a conclusion, since publication of some of the very negative studies, which happened around 2002, 2003 a lot has changed. We have better hormones now which are body identical. Uh We have transdermal preparations which are a game changer. Every woman's experience of menopause is unique and individualizing is important. You can always find an HRT that will take care of symptoms and minimize the side effects. As long as you keep working with the preparation and the dose and you kind of balance estrogen progesterone and if required testosterone based on how that individual person reacts to the HRT safety comes first. So again, avoiding off license prescribing is important. It may be necessary in very few individuals who do not absorb estrogen or progestogen appropriately. But generally, most women will be able to find the licensed preparation that works for them with that. I'll stop now, thank you so much for listening. Uh It was a bit rapid fire. I know, but I've tried to include everything that would be practically important in the talk. I'll stop sharing my slides and we'll straight away, go to the question answer session and try and take a few uh or as many as we can uh within the time. There you go. So let me go to question and answer there. I guess there are lots of questions. Do we know how many there are? So I can't see how many uh number but there's definitely about 30 odd. Um OK. OK. So let me actually start going through some of them. I guess we still have about 10 minutes. So I'll crack on with this. So, in a woman with past history of endometriosis, intact uterus, should you give a usual dose of progesterone and which progesterone would be preferred? So, again, this depends on individual patients history and I won't be able to generalize. But yes, the answer is if there is past history of endometriosis, you don't want endometriosis coming back with estrogen only a chart. And so therefore, it is always recommended that you should always have progesterone. If it's hysterectomized woman with intact uterus, of course, you will have to give progesterone outside estrogen to protect the endometrium. And it will be the uh usual doses of progesterone that are usually recommended whether it's your progestone or any other form of progesterone. If you look at the next one, then it says I have a Asian patient who is 55 year old. Uh sorry, I might have missed that. OK. Just coming back to the original one. OK. So I have an Asian patient who is 55 years still get fairly regular bleed. Uh But have we recently been investigated with hysy normal? Has adenomyosis with two small fibroids? Does not want Mirena. Do we need to give a cyclical or can we start continuous combined? HRT as these periods may be anovulatory somebody who still has menstrual activity of their own. It is always important to do cyclical HRT because if you try and do HRP, which is continuous combined, they will have lots of breakthrough bleeding. Of course, Mirena coil will be very useful in this situation because all other forms of HRT may not work. So you have to counsel them accordingly. It's either cyclical HRT or using Mirena or treating her other conditions first, whether the fibroids or adenomyosis. And then considering HRT after that, the next question is suggestions for uh CT with intact uterus postmenopausal using estradiol patch. Uh but having intense bleeding, taking progesterone, any recommendations for a client that seems to not tolerate progesterone. So I don't know what CT means here. Uh I guess that you're asking me questions about uterus postmenopausal using estradiol patch, but having bleeding with progesterone, you have many options. You can consider a Mirena coil. You can consider a non progesterone or a synthetic progesterone like Provera norethisterone. You can of course, consider less often progesterone which is in the form of either vaginal or in the form of three monthly progesterone regime. Uh You will need some form of endometrial surveillance because these are off license use of progesterone. If somebody doesn't tolerate progesterone, you could also have the option of tbone. Uh These are various options that you can talk about with the woman. Uh and decide which one she might prefer. What are your thoughts on using higher than licensed dose? We talked about it. Usually you always find a preparation, a gel patch spray implant that usually within licensed doses will give you the estrogen effect you need. If someone has documented low absorption on the highest licensed dose of estrogen, then you can prescribe higher, but you have to document why you're doing it, document the blood test that they need higher doses and then find which dose works for them. Uh You have to be careful to in increase the progesterone to match that higher dose of estrogen cyclical progesterone. Is it given for 12 days of cycle as per BNF for 14 days as per specialist? So the minimum number of days is 12 days and you have to give either 200 for 12 days or 300 mg for 12 days depending on how much dose of estrogen you're giving them. What are the natural progesterones body identical prescribing? Yes, of course. Your progesterone and Gabre right now are the body identical progesterones. Uh Others are something like biosimilar progesterone, which is the dip progesterone which is part of the stone range. Those are the best ones around. There's again another question about a 51 year old lady who had sequential HRT as she was still having periods which were regular for last eight months, she was applying a patch twice per week, taking utrogestan for 12 nights and had a monthly bleed, changed to estrogel pump due to poor adherence and she's not having monthly bleed. Should I change her to CCT? Yes, this would be a good time to try continuous combined HRT she may be ready for it and she may not have any bleeding. So you can spread your utrogestan dose to the whole of the month. It may be that she's not absorbing the gel and that's why she's not having enough build up of endometrium and that may be causing her not to have bleeds. So you may have swapped her to the estrogel but she may not be getting enough estrogen. So just check that she's getting enough by doing one of blood test and also check that her symptoms are not coming back or breaking through. As long as she's absorbing enough, her symptoms are fine. You can of course, try going to continuous combined charity at this point. Drospirenone is also anti-androgen by its VTE risk is high. Again, it depends every progesterone type of preparation has its own unique vte risk depending on what type of receptors it stimulates. It is not only the androgen receptor stimulation that causes the risk of VTE, it also depends on inherent nature of which progesterone stimulate the liver pathway that activates clotting. And there are other mechanisms other than androgen receptor stimulation. So it could be causing a higher risk of DVT through other mechanisms rather than the androgen stimulation. Ok. Then why do you prescribe with caution in diabetes? Migraines. This is a general caution because they may have multiple issues. So, migraines, for example, especially if they are complicated migraines with aura, there is a documented higher risk of stroke in these patients with use of hormones, this can be minimized using transdermal HRT because transdermal HRT does not increase the risk of blood clotting. But this is in healthy women. It it large trials specifically in migraine patients haven't taken place, but we extrapolate data from healthy to the migraine patients. So when it says caution, it is choosing the right type of HRT. So for migraines, the transdermal choice will be important to discuss with the patient. Similarly, diabetes with already existing cardiovascular problems or blood clotting issues. It's important you use transdermal important to avoid a synthetic progestogen and give it with transdermal estrogen. So caution applies to using the type of HRT which is most body friendly. That's why it's included in the caution list. What happens if you had surgical menopause age at 34 and they're put on normal conventional dose for average age of menopause and the patient is now over 45. Have you missed the both? No. So remember, you usually monitor somebody who is going through menopause at 34. And if they've been started on any form of HRT, the best indication that they are getting enough estrogen replacement is their bone scan. So a bone density would be usually recommended every 3 to 4 years. And so if you're doing bone scans, you will know that the body is receiving enough estrogen because the bone density will be stable or going up. If it's going down, then that means you're under replacing hormones and you might want to pick that up. Similarly, some of the symptoms will also be telling you whether you're replacing enough. So as long as they've had good symptom control with HRT, their bone density is looking stable and strong. Their lipid profile looks good. That means they have been already replaced with enough hormone and they can of course continue. It doesn't mean that every woman who has premature menopause or surgical menopause will need high hormones. There are many women with poi and surgical menopause who do perfectly well on average dose of HRT, but there are some who need more hormones. I've had a few women on transdermal cyclical HRT who start bleeding early while still on your proge. Please. Can you advise on how to manage this again? 1st 3 to 6 months, expect some bleeding on both forms of HRT. So I would be just giving them enough time to get adjusted to transdermal estrogen with progesterone proge by 3 to 6 months by six months, they'll be getting into a monthly bleed. If that doesn't happen, you may need to increase your progesterone dose. But if it's been six months or more, do get a scan done to make sure that the lining looks healthy and then increase their progesterone. That would be my first suggestion. But again, individualized, I don't know the full history of the patient. So that could be just a general suggestion. Then we have what is considered a good level of estrogen, some on HRT. So the first thing to say is I don't measure levels of estrogen on HRT. It's all the symptoms that I guide the HRT on. And also the bone scan for women with premature menopause or early menopause. Uh level of estrogen is only to check somebody's absorbing. If the menopause symptoms are not at all changed on HRT, then it's always worth doing an estradiol level and levels more than 150 to 200 means good absorption. Uh Even if a woman has 500 or 1000 biomes of estrogen, she may still be symptomatic. And another woman with 2 to 300 biomes will be having no symptom. So the symptoms don't correlate to blood levels necessarily, which is why we don't recommend testing or aiming for a level of hormone on HRP that is more uh to do with absorption. So, one of tests to make sure that the woman absorbs estrogen is fair enough. The rest of the monitoring has to be on the symptoms and the bone scan for those with premature or early menopause, perimenopausal and poop. Do you give continuous combined HRT? Yes. Again, remember progesterone only pill is not a licensed form of endometrial protection. So you would have to either give them a complete separate cyclical HRT with both estrogen and progesterone or a continuous combined estrogen progesterone alongside their progesterone only pill. Now, some women use doubling dose of the pill as an off license way of taking progesterone, but usually that's not recommended in the long term because we don't have good studies and it may mean that they go on to have some breakthrough bleeding in future. So best is to give both estrogen progesterone combined. HRT alongside of the poop for contraception. Ok. We've got last couple of minutes. I guess. What HRT do you start? When um women who have had surgical menopause following pelvic radiotherapy? Remember that it's best to start with continuous estrogen progesterone following pelvic radiotherapy. That's because often the cervix will be stenosed or sometimes if the uterus is still in place, you will find that there is uterine scarring. The, the lining of the endometrium becomes very thin with the stenosed cervix. In that situation, when the uterus is still in situ and the radiation has been given, then it's important that you give a continuous combined HRT so that you don't induce bleeds because sometimes there is a risk of collection of blood in the cavity and hematometra. Of course, for other women who have had a hysterectomy and also have had to have a radiotherapy. It's only estrogen only unless there has been previous endometriosis OCP use for endometriosis. So why HRT which is low dose contraindicated with untreated endometriosis? Uh That question is not clear to me. Uh I think what you're saying is if you can use the pill as a treatment for endometriosis. Then why? HRT, which is low dose contraindicated with untreated. Again, HRT is not contraindicated with endometriosis. You can certainly give HRT. It's important combine estrogen progesterone continuously with endometriosis because if you're inducing bleeds or if you're giving estrogen only a charity after hysterectomy, any pelvic endometriosis can grow back or recur. So if you give continuous progesterone, that's unlikely or less likely to happen. I think we might have to stop there because we're overrunning the session. Uh But as I said, thank you for so many useful questions. And what we'll try to do is if I have time in the next 2 to 3 weeks, I'll try to log back in and answer some of the remaining questions. But if I don't, hopefully I'll catch you at another webinar. Uh We have more than 1700 people there. So II don't think I'll be able to answer all the questions today, but hopefully next time, thank you so much. Thank you so much, Doctor Vick Row. That was really, really informative. We really appreciate you running the session and thank you very much to everyone who joined. You'll be sent a feedback form to your emails. 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