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Ok. Um Good evening everyone. It's great to see everybody joining on the call. We, we're growing in number as the, as the minutes go on. Um My name is Tim Da. It's my absolute pleasure to be joined tonight by uh a familiar favorite to the middle primary care network community Tally Allar. Um We're so grateful to uh to have you with us. Um As always, I just want to very quickly pop up onto the screen that uh familiar QR code. Um If you take phones out, take a moment to download the app, everything is centralized there, all your events, your registrations, you can get your certificates, your CBD certificates, everything is on there as well as finding out about what's coming up next. Let's not jump ahead of ourselves because um we're delighted to have Vikram with us tonight. We're looking, looking forward forward to everything he has to say to us. A very quick word on him first. Well, he is an honorary associate professor in Women's Health at University College London and we're looking forward to that expertise in his talk tonight. So I am going to pull that back down off the straight and hand over to you. I'll be here in the background and as usual, we will run some Q and A at the end, please pop your questions in the chat and I will be keeping an eye on them. Thank you. Thank you, Tim uh for the quick and succinct introduction. Um I love doing these sessions. Uh Thank you for some kind, nice comments in the chat already. Uh So we'll try to hopefully go through poi early menopause in the next 40 45 minutes. I will do my best to kind of go through a comprehensive uh review of what it means to have a diagnosis of poi how as healthcare professionals, we can do the best for our patients. I'm gonna share my slides now so that we go through the presentation last 20 minutes, lots of questions and answers. Now, sometimes we get more than 2, 300 questions. So it's impossible to answer them. All. The team is going to help me to get the most important uh themes for the questions that you will be putting through. So we'll try to answer as many of them as possible. So, sharing my slides now, uh just sharing the screen and you will soon see the slides come up. Thanks so much and that like you, thank you. I think we can, we can say those back. All right. Thank you so much. So, uh we are talking about premature menopause or premature ovarian insufficiency and early menopause. What are the implications for short term and long term health and how can we best manage uh these conditions for our patients? So, just before we go into diagnosis of premature menopause or early menopause, let's just look at stages during journey towards menopause. Now, this would include natural menopause, which happens after 45 as well as some of the women who have natural and not surgically or medically induced early menopause or premature menopause. So, premenopause is the phase before any hormonal changes start. This is when a woman would be expected to be having a regular monthly menstrual cycle. There are normal levels of FSH LH estrogen and there are no symptoms of hormone deficiency, like lack of estrogen or progesterone or testosterone perimenopause is the first phase when hormones start changing. So, hormones will fluctuate. This is usually when FSHLH will go quite up and down up and down cycle. After cycle, estrogen levels will fluctuate within the month or month after month, some weeks or some days, there will be good estrogen levels, other days or weeks or months, there will be low estrogen levels and this will result usually in changes to periods. So the periods may be very frequent to start with twice a month or every 2 to 3 weekly and later on as the ovaries slow down, more and more, the periods will become spaced out. The gaps between periods will increase and eventually there will be oligomenorrhea, long gaps between cycles. Perimenopause with the natural menopause can last for a few years, maybe two years, three years or five years or sometimes even longer for some women. And the same can happen if poi happens or early menopause happens, the perimenopause can be more than 3 to 5 years for some women. Then finally happens, menopause. This is when periods have stopped completely. This is a retrospective diagnosis. We can only say somebody has gone through menopause and they've stopped periods for at least one year since their last menstrual period. And then all that from the time of that one year of stopping periods until end of life, all the 2030 40 50 60 years of life will be post menopause. So women can spend almost one third or even half or more of their life in postmenopause, especially if they have early or premature menopause. It's a long, long phase that they spend life in menopause. And that's why we should be doing better. Looking after the, during these 2030 50 years of their lives, symptoms of menopause can present right in the perimenopause. So even if the woman is having period fluctuations, hormone fluctuations, she's still having menstrual cycle symptoms can present. So previously, we said no HRP, if you're still having your periods that needs to change. So some women may be fine asymptomatic with the early changes. But others, even with irregular periods can start having lots of menopausal symptoms, estrogen deficiency symptoms, for them, introduction of HRT can even be done during this phase of fluctuating cycles and periods. When does menopause happen? We know in the western population based on Caucasian data, the median average age of natural menopause is 51. It can happen any time between the age of 45 to 55 on an average. But if you look at the early menopause, it happens to around one in 10 women, 10% of women will go through menopause between the age of 40 to 45. 1% of women have poi or premature menopause below the age of 41 in 1000 women have menopause under the age of 30. So it's never too young to go through a diagnosis of menopause or poi even women soon after puberty or in their twenties can have diagnosis of poi. It's not common but it can happen. Some studies have indicated higher prevalence of poi in Southeast Asian countries. For example, in India, some studies have shown a higher prevalence of poi or premature menopause. It's not understood exactly how much of this is genetic or environmental and whether the studies are small sample size and so therefore, larger studies are needed to accurately know the prevalence, but it seems to be higher prevalence in some countries or some geographic populations. Now, let's first focus on premature menopause or premature ovarian insufficiency. So, loss of ovarian activity prior to the age of 40. That's the definition of poi 1% of women across the world will have poi varies across ethnicities. It is thought that Southeast Asian or some other ethnicities may have a slightly higher prevalence. It's also called primary ovarian insufficiency or premature ovarian failure or premature menopause. We don't like to use these terms. We try to use the uh agreed term of premature ovarian insufficiency. Uh That's because it's usually standardized research and standardized clinical terminology. Poi covers both natural causes as well as the genic surgical, medical causes of premature menopause. And there are various guidelines. If you look at the BMS British Menopause Society, you can look at International Menopause Society and look at Ashley, which is European Society for Human Reproduction and Biology. All have produced wonderful guidelines on this topic uh which can help clinicians to manage their patients. We talked about prevalence already that it can even happen under the age of 20 in one in 10,000 women. It's a diagnosis with significant consequences. So potentially life-changing for a woman to be diagnosed with poi because it has physical implications for symptoms, quality of life. Lots of psychological emotional consequences, especially regarding fertility issues. It causes chronic hypoestrogenic state, estrogen is not there. So it will cause short term menopausal symptoms and will go through the symptoms a little later, long term effects, of course, are predominantly on bone, cardiovascular health, cognition and fertility. But remember 20 to 25% 1 in 5 to 1 in four women may demonstrate intermittent ovarian activity. So they can fluctuate especially if you, they, they have an immune cause for ovarian insufficiency or unexplained on ovarian insufficiency, about 20% or 25% may later on have some recovery of periods, may ovulate and become pregnant. So never say never. If there is no established surgical medical cause, you can have recovery of ovarian function in about one in four women and they can go on to have some periods, hormone symptoms and even pregnancies. The causes of poi unknown in about percent. So most of our patients will not have a diagnosis because despite doing genetic testing, immune testing or other tests, we don't get a cause other causes where we know a cause would be a genetic cause, autoimmune cause infections can cause poi metabolic conditions, toxin related. And the bigger growing group is the genic. So more and more women are receiving treatment surviving cancer, receiving different therapies like mens, they can have toxicity for ovaries. Many women are having risk reducing surgeries for genetic mutations such as BRCA. And for those reasons, women having genic removal of ovaries or damage to ovaries because of treatments that group is growing. So, chemotherapy, radiation embolization, surgery, removal of ovaries can all cause premature or early menopause. What causes unexplained poi the 80% where we don't find the cause. Why do we think that they stop periods before 40 or why do they go through premature menopause below 30. It's thought that it's because of the way the store of eggs is uh built and the way the body utilizes the ocys or the eggs within these ovaries. So we know there are almost million oocytes in the primordial follicles at birth. So, ovaries contain millions of oocytes or eggs and that pool will become smaller and smaller throughout life. So women keep using the eggs in the ovaries, one of them ovulates every month. So about 400 ovulations happen. But the others in the background are being destroyed. They have apoptosis. What we think is po in women where we can't explain any cause happens because of a reduction in the pool of effect. So the story is smaller to start with or they have accelerated follicle destruction. Myocytes are being destroyed in the background every week, every month, every day and that causes the store to get used up earlier. It's also thought to be, it could be an epigenetic aging which means the aging within the ovaries has started even before the fetus, uh is born or the baby is born in the fetal life. The ovaries are already having some stress which reduces the number of oocytes at birth. So this is the depletion of eggs throughout life as we know that uh most of the women will continue using their eggs in the background, starting with millions of eggs at birth. And as you come towards 40 fifties. Only 25,000 or 1000 eggs remain when menopause happens around 4550. But for women with poi, they may start with a lower Opex or they may have an accelerated drop in the eggs. So they will usually start lower and end earlier or they will have acceleration of the Opex being depleted. And so they end by the age of 40. Now, let's look at the known genetic causes. Uh So now we're looking at the 10 to 20% who may have a known cause, not the unexplained ones. What are the genetic causes? Uh They, they account for about 10% of poi, one third of them. Uh uh of the ex unexplained poi usually have a family history of someone or the other who has gone through early menopause or poi. So they, they have some genetic background for potentially having the poi. But of course, we have not identified all the genetic mutations or all the genes responsible for poi and therefore they may have a family history, but we can't identify the gene in them. The ones we can identify are mainly x chromosomal or autosomal genetic variations. Uh There are many variations of genetic mutations now reported which can cause poi but of course, needs advanced testing in advanced laboratories. Several genetic mutations have been discovered recently, most common, of course, the the genetic cause of poi is Turner syndrome which affects about one in 2500 births. This is a complete or a partial loss of X chromosome which may be deleted, may have translocation, inversion. Isochromosome mosaic patterns can happen and we do follow a large cohort of patients at UCL H. We have a dedicated Turner Syndrome multidisciplinary clinic. Women will usually present with primary amenorrhea. Those who may have a mosaic wide material in the karyotype. It's, they may have strict goard women with mosaic X pattern tend to present at variable times. So, if it's a Turner Syndrome with a mosaic karyotype, they have uh two cell lines, 1 may be 46 xy uh XX and the other may be 45 X. If there's a mosaic pattern, two cell lines, then sometimes ovarian activity will uh persist and they may present much later in life with secondary amenorrhea. If you look at the phenotypic characteristics, we know the diagnosis is based on short stature, lymphedema, webbing of the neck, visual impairment, maybe uh presenting strabismus otitis media. Other uh problems like high arched palate, wide space, nipple shield, chest, multiple knee, uh cubitus, valgus, short fourth metacarpal, cardiac uh problems such as coarctation of aorta aortic anomalies and renal tract abnormalities. These are all the phenotypic characteristics. If we do have Y chromosome material in the go uh in the cells uh then gonna it to prevent gonadoblastoma. Uh which is a cancer. So what do we think in Turner Syndrome? That is poi, that's because they are born with a normal number of follicles, but it appears that they may have uh accelerated atresia. The follicles in the eggs undergo accelerated destruction. What are the long term health issues for women? With Turner Syndrome? Of course, they can have associated hearing learning difficulties, higher risk of diabetes, loss of bone density, osteopenia, osteoporosis, celiac problems, uh hypothyroidism, cardiovascular disease, especially risk of aortic dissection, liver dysfunction, abnormal lipids. And then of course, if they have IVF with like donation, potential pregnancy risks, uh associated with conception. This is just a quick uh slide to show the study we did at UC H uh for women with Turners who had uh usually a mosaic pattern, you can see the karyotypes on the left hand side, there are usually two cell lines there. Uh But even in one situation where there was a peripheral classic karyotype, these women who had some ovarian function that still had gone through puberty, having some menstrual cycles. We tried to do uh ovarian uh cryopreservation by stimulating ovary and collecting eggs. And we did find that they did respond reasonably well so we could store eggs for them. So the takeaway message here is that if you have somebody with Turner syndrome, uh who has a mosaic karyotype and still has ovarian function. Uh If you come across them early enough, you can try and give them fertility preservation by trying to do ovarian stimulation and no site freezing. Not everyone will want to have this and not everyone may be funded by the uh the the health system. But those who do have the option can do egg freezing as a method of storing eggs before they run out in future and have a early onset of premature menopause. The other common cause of genetic uh is Fragile X syndrome. This is a premutation in the fragile x mental retardation. One gene, this affects one in 50 women. Uh and of course affects the copies of the trinucleotide repeat. And the full syndrome of mental disability or autism occurs in males with about 200 repeats. Now, there's a 20% chance of developing poi uh with this premutation and there is increased risk of ataxia with aging, uh which occurs in about 8 to 16% of those who carry the premutation. So that's the second cause of uh poi. If we do find somebody is positive for fragile X pre mutation, it's important that they have genetic screening including for the family members. Uh because it's important that we can identify if they do have the premutation. So we can prevent severe mental disability in their male offspring. Uh as well as for the affected female family members. If they have flex, they might want to consider egg storage because 20% of them will go on to have premature menopause. So if they're young and still have menstrual activity, they can consider fertility preservation with egg storage and then of course, there are rare genetic mutations other than Turner syndrome and fragile x premutation, uh presence of any other phenotypic abnormalities. Uh a associated with poi, we often say we should try and refer to a genetic counselor for consideration of additional genetic testing. So again, the summary here is that anybody presenting at a young age with poi below the age of 35 we usually recommend doing two tests, karyotype, look for turn and fragile x syndrome, premutation test. Those will be the two genetic tests at the initial consultation, autoimmune. Now, the other common reason why P can have those cases where we have a diagnosis is immune related problems. Uh Po is associated with a number of autoimmune conditions. In most about one third of cases. In some studies, there have been one or other immune problems whether it's whether it's type one diabetes, adrenal insufficiency, Sjogren's rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, celiac or myasthenia alopecia, some or other immune process seems to be associated alongside poi. So we often try to find out if there is background immune pathology that may be contributing to poi and the test that we often do again at the initial presentation would be ovarian antibodies. A celiac screen thyroid autoantibodies and adrenal antibodies. So, besides the two genetic tests, I mentioned, this is the ovarian celiac thyroid and adrenal antibodies, which we will perform at the first presentation. Women with poi may have adrenal in about 4%. And it's important to know this because poi may occur prior to development of adrenal insufficiency. So, if we do pick up antibodies for adrenal, then we will often refer women to endocrinologist so that they can then make a plan as to monitor or screen these women or advise them if they have symptoms of adrenal insufficiency and keep an eye on them in the future. Now, iatrogenic risk. So from genetic, we move on to genic causes. Uh and you have surgical menopause, uh which is removal of ovaries for benign or malignant reasons or risk reducing surgery or for cysts, surgical menopause can be difficult because usually ovaries are removed in one go and often there is lack of hormones within 24 hours to 48 hours after surgery. This is different from a natural menopause where the levels of hormones go down slowly. Surgical menopause is very abrupt within 48 hours. So, symptoms can be quite severe for some individuals and they can be quite persistent damage to ovaries. Again, if you look at medical or iatrogenic, medically induced menopause, it varies with chemotherapeutic agents. There are different chemotherapy agents which can be toxic to ovaries and cause menopause. It's more common with alkylating agents. Uh almost 40 50% rate of poi with use of alkylating agents. The risk depends of course, on the dose of the chemotherapy agents, the dose of radiation if it's used in the pelvic area the age of the woman, younger, the woman, less the impact of either chemotherapy or radiation. And we talked about risk reducing surgery for BRCA. This population is increasing as more women opt to have risk reducing surgeries. This is a paper we published for the Royal College of Obstetrics Gynecology. Uh This was a scientific impact paper uh which was led by uh Professor Manchanda. And this basically talks about use of hormone replacement If somebody has risk reducing salpingoophorectomy below the age of 50 let's say for BRCA or any other reasons such as strong family history and surgically induced menopause. How can it be managed with a charity? So that paper talks about it in case you want to access the paper and other uncommon causes of poi besides genetic immune and the genic infections toxins. Poi can happen with mumps, HIV tuberculosis, malaria, cytomegalovirus varicella toxins can cause poi whether it's polycyclic aromatic hydrocarbon exposure, including cigarette smoke exposure to palates or bisphenol in plastic production industry are known to be associated with poi. The common can often come across in the clinic. It's associated with ui is galactosemia which is deficiency of galactose, one phosphate or transferase. Uh and that's associated with accumulation of galactose. Now, having looked at the broad uh sort of range of causes of poi, most of them will not have diagnosed this or a cause. Uh but that's identified, how do we clinically approach or diagnose poi, what is it in the clinic that will give us a diagnosis and how do we manage it. So, diagnosis, of course, presentation and diagnostic criteria, situations of how women present to clinic can vary. But typically the first indication will be lack of periods or amenorrhea or oligomenorrhea for more than four months. So if the gap between periods is going on to be more than four months at a time, that could be one sign that poi may be a possibility, the longer the gap, more certain the possibility, the test that we will often recommend when the gap between periods is more than four months is usually FSH LH estrogen. That's the basic hormone profile. And if you have two elevated FSH levels, more than 4 to 6 weeks apart and more than 25 that would confirm the diagnosis of poi women may present with various estrogen deficiency symptoms, which we will look at. Later. Women may be picked up in the fertility clinics when they come for subfertility, irregular periods. And then often the diagnosis may be made low amh, suggest low side or egg reserve and they could go on to develop poi. So while they have low mh or low follicle count, they may still have some menstrual activity. That's not poi, that's just low ovarian reserve, low store of eggs. But it means that they may be at risk of poi in the near future. An AMH test is not recommended for diagnosis. You can do it to support the diagnosis for fertility reasons for counseling. But it's not mandatory to diagnose poi because there is no diagnostic cut off and a protectable. But the woman can still continue not have a poi for even up to five years. So what are the specific clinical investigations we would do as I talked before when the first presentation happens? So we often tend to see them in a tertiary or a secondary hospital. Once the GP or the primary care has referred the patient, we will often do a karyotype and the fragile x. That is the two genetic test. We will do antibodies for adrenal, ovarian thyroid and celiac. That will be the antibody panel. We will often do tests of general health because if the woman has not had estrogen, she's amino, that can have some implications for her risk of diabetes and abnormal lipid profile. So we'll do a diabetic screen, a lipid profile as I said celiac screen. And then we do a baseline density for the bone density scan, dexa. So it's a dual energy X ray absorption, met a dexa bone density scan right at the time of uh baseline. So often to guide where the bones are. Is there osteopenia or osteoporosis already. And then it helps you to then monitor how effective HRT is. If you start HRT after that, for Turner Syndrome, additional investigation will be doing a heart cardiac echo and that's because they can have cardiac abnormalities. So they need monitoring for their heart. If the baseline, bone density is low, we will continue repeating Dexa in future. Once we start them on HRT or some non HRT um medication for bones, taking into consideration of course, individual risk factors and treatment. So how often you repeat varies depending on medical history. Usually most patients will need a bone density once every 3 to 4 years. Now, let's look at the individual impact of uh a poi on each of the different body systems. So what is the impact of either poi or early menopause and bone health? Women with early menopause poi are at increased risk of osteoporosis. They can lose bone density. It's a risk factor for developing osteoporosis in later life and therefore, they need risk evaluation. Are there any other risk factors for bone density loss? They need education about lifestyle, weight bearing exercise, especially weights or muscle improving exercises. Uh Vitamin D important part of uh either diet uh exposure to sunlight as well as uh taking supplements where your lifestyle may not provide enough Vitamin D calcium rich foods or taking calcium. If the diet is not rich in calcium, all that will be the lifestyle part of managing bone health. HRT of course remains the gold standard for women under the age of 50 HRT until the age of 50 is recommended to maintain bone health. And this is mainly based on prospective and observational studies. We talked about calcium and the Vitamin D that's important. And then specialist advise when HRT is contraindicated. So if they have contraindications such as breast cancer or significant clotting risk, then of course, non HRT medication will help alongside lifestyle cardiometabolic health. We know that there is increased risk of heart disease, cardiovascular mortality from observational data in women, both with poi and early menopause risk factor reduction is important. So they should make lifestyle changes which are healthy for heart stopping smoking, uh moderating alcohol regulating body weight, regular exercise, healthy diet, estrogen deficiency or sp or early menopause doesn't help because it can increase the lipid abnormalities, drive up the cholesterol and causes insulin resistance. So again, HRP tends to be very beneficial. It lowers the long term risk of any cardiac disease. It's strongly recommended at least until the age of 50 it could continue it longer. What about cognitive health, brain health dementia risk? So, again, observational data do show increased risk of cognitive impairment, dementia with poi early menopause. This is not about natural menopause after 45. This is mainly early menopause or poi and there is a window of opportunity. So if we replace estrogen early enough, then usually you will slow down the process of cognitive impairment. So these women again are recommended HRT at least until they get to 50. But what we often don't do well with the psychosexual psychosocial impact. So there's a high incidence of psychosexual psychosocial problems in women with early menopause poi. We need really multidisciplinary team effort. We need to ask about vulvovaginal atrophy or genital urinary symptoms which we often don't ask about and then androgen replacement, especially when there is surgical menopause, there may be sudden drop in sexual desire or libido. So whether testosterone replacement is needed is again neglected and needs to be asked as part of HRT or even uh poi consultations. There are no prob treatments to increase the rate of pregnancy uh with uh on new sites. So what we know is there is about 5 to 10% spontaneous natural pregnancy rate in women uh who have unexplained poi, it can happen 20% miscarriage rate, which is a general population rate. HRT is not contraceptive. So, pregnancies can happen on HRP and I donation is usually the realistic way of achieving conception. So women who have a donation IVF should be carefully counseled because they can have a higher risk of high BP, preeclampsia, low birth weight during pregnancies. There are lots of treatments talked about to improve fertility with poi such as stem cell therapy or platelet rich plasma, different hormone adjuvants or uh follicle activation. These are all research uh treatments. There's no treatment that should be routinely clinically used because we don't have evidence of efficacy and long term safety. So, those women who do consider fertility should have preconception counseling, uh important to know about childbearing and long term effects on their health as well as uh what the pregnancy can cause and welfare of child should be assessed before going for fertility treatment. What are the common symptoms of lack of estrogen that poi women may present with irregular bleeding or periods. Bone muscle joint aches, hot flushes, night sweats, disturbed sleep, dry hair, dry eyes, skin mouth, low energy, low libido, emotional fluctuations, low mood, heightened anxiety, pain, fogging, poor concentration, vaginal dryness, painful sex, bladder symptoms. Many may just present with fertility issue as the primary concern. So there's head to toe symptoms associated with lack of estrogen and progesterone. During menopause, psychological support is crucial. Uh And we need to refer them for psychological help. Uh direct them to various societies, charities such as syndrome support societies or Daisy network or MRF. There are many charities and support societies now where patients may get help. In addition to medical help. How do we address the symptoms and how do we treat poi? Uh Of course, there are many avenues, lifestyle modification, changing workplace nutrition, alternative therapies, non HRP N HRP. And we'll quickly look at each of these and finish the session. So of course, HRT is the gold standard, but what else is available? So women may not wish to take HRT or may have breast cancer or other contraindication. Then of course, lifestyle interventions can help complementary therapies such as acupuncture homeopathy may be sometimes useful, but there is not much medical evidence for these psychological therapies, relaxation, CBT hypnotherapy can help with hot flashes, night sweats, sleep and anxiety, herbal products like Black Cohosh Red Clover. We don't recommend again because of long term safety efficacy data are not being available. Non HRT options. We have SSRI SNRI I antidepressants such as Venlafaxine. There's also gabapentin, pregabaline, cloNIDine. We don't recommend these as first line for women with poi or early menopause because of course, they don't have bone and heart benefits. They're only for symptom management and they can have their side effects like drowsiness, dry mouth, constipation. This can happen. The new drug is the NK three receptor antagonist. This is a novel option. Follinett 45 mg daily orally. This can be useful for women who don't wish to take HRT or cannot take HRT for medical reasons. One can use this to stop hot flashes and improve sleep. But of course, all these non HRT options will be second line because they don't have benefits for bone and heart. The best one is of course, hormone replacement, which can be done as a combined pill or HRP. Which one do we recommend? There's a big trial currently happening at UC H. So if you have uh individuals who would be interested in this uh do go to the website for the to study and you can in this if they would like to take part. But this is comparing pill versus HRT because both can be used as estrogen replacement treatments, head to head. There have been very few trials looking at both treatments and it looks like HRT may be better in the long term rather than the pill because HRT contains for natural hormones and has better impact on bones and heart. But if a woman needs contraception, because we know there is that 5 to 10% chance of pregnancy, then the pill will of course have the the advantage because it can also is the recommendation we often like to achieve physiological levels of estrogen in the blood. So often, if we use 17 beta estradiol, which is part of the patches tablets or oral uh estrogen, 2 mg a day, usually a standard dose and you can go up to three or 4 mg in some women who need higher than normal estrogen. If there are risk factors for thrombosis high BMI or other previous history of blood clotting, then we often recommend about 75 to 100 mcg of a patch or 2 to 4 pumps of estrogen gel or 1 to 3 pumps of estradiol spray. These are the transdermal HRP which does not increase risk of blood clotting. Adequate progestogen cover is very important. Whether you give oral progestogen or a Mirena coil, it's really important to combine appropriate dose. So usually 12 to 14 days every month, that should be combined progestogen, whether it's di progesterone or micronized progesterone, both can be used. Some women will do well on Provera but at least 12 to 14 days a month in a cyclical regimen and then continuous combined means continuous progesterone can be given after 1 to 2 years. Certainly by five years of using cyclical regime, we tend to keep women on a cyclical regime having bleeds, which is to have IV of egg donation of pregnancy and the best forms of progesterone right now is the digester and the micronized progesterone. Vaginal estrogen creams are excellent for any sort of urinary infection, bladder problems, vaginal dryness, painful sex. These don't have any risks of blood clotting or breast cancer and they can be used as long as required, sometimes even life long. So, vaginal estrogen should be offered whenever there are genital urinary symptoms. We don't ask for these symptoms. So it's really important to ask them if they have symptoms and prescribe them vaginal estrogens freely. HRT risks are very minimal for women with early or premature menopause. The benefits for bone heart brain and symptoms far outweighs any potential risk. Thrombosis risk can be avoided by using transdermal HRT. For young women. Risk of thrombosis is so little that oral HRT is safe unless there is obvious risk factor for most women. Oral hr will work really well for some thrombosis risk is higher and you may use the, the patch gel or spray, there's no increase in risk of breast cancer with HRP until the age of 50. So, unlike women above 50 where we say there's a risk of breast cancer. If somebody is diagnosed with premature or early menopause, you can safely prescribe HRP. That itself will not bring additional risk of breast cancer. In these women. How long to take? HRP. Most women will continue till 50 which is when it's recommended. And after that, there is no random upper limit. Some women will continue to get benefit from HRP will continue to use it in their sixties or seventies. Others may come off by 50. Then we gradually reduce the dose and come off. The only additional bit you have to discuss if they continue HRT beyond 50 is then they will have that small increased risk of breast cancer which was not there before the age of 50. So as a summary, some points to take home, we tend to undertreat women with poi with both estrogen and testosterone. We should be treating better HRT offering it with better uh products and better new body identical hormones to women. In our clinics, we should be asking about vaginal bladder symptoms and offering them vaginal estrogen. 17 beta estradiol is the preferred estrogen and progesterone are the best estrogen psycho support is crucial. We should be asking about need for psychological support if it's surgical menopause, a preoperative plan before surgery happens about what to do with HRP. After the operation is really crucial. Again, this is not done and often the diagnosis is late and there is delay in the referral after the surgery. So getting this done early is really critical. So with that, I'll finish. Thank you so much for being there listening to the presentation. I'm going to come out of my presentation now and he will go to question and answers. Thank you. Fantastic doctor. That was fantastic. Um I have been keeping an eye on the Q and A as we've gone through. So let me just pull up some of those questions from the start. Thank you everyone for putting your questions in as we have gone along. Uh She has asked about patients presenting in the late thirties asking if they're perimenopausal, normal bloods have all the symptoms, but that the increasing number of them, she fears putting more people with the label of being in perimenopause, but may not necessarily be any thoughts on how to manage that. Yes, I think it's important to, to kind of have a conversation with women presenting uh in their thirties and early forties. We are also seeing an increase in number of women with regular cycles, normal FSH LH estrogen who are having perimenopausal symptoms, which may actually not be related to perimenopause. So again, I think it's important to distinguish what type of symptoms they are having a check with the woman to suggest that there may be other reasons for this when you have a regular menstrual cycle and of course you have normal bloods. Sometimes a trial of HRT may help. For example, giving the woman expectations to say, look, your bloods are normal. Your symptoms don't look the lack of hormones here and your periods seem to be regular. I don't think hormone replacement is an answer. There may be other reasons, life work stress that may be causing these symptoms or anemia or some other diagnosis which may cause the similar symptoms. So, trial of HRT for three months is often what I do if the patient really wants to try it and then often the symptoms will not improve, which will be an indication to prove to the woman that look, you've tried replacing estrogen over and above what you're having in your own body and it doesn't necessarily sort the problem out. But I think most patients will realize once they have normal bloods, you've had a discussion that these symptoms could be due to something else. Usually very few women will insist on HRP. And if they do nothing stops you from giving them a trial to prove that these symptoms not necessarily will respond to HRP. No. Fantastic. Fantastic. I not a couple of questions coming through there folks regarding reshowing slides and things again, I'll direct you towards the recording of tonight's um presentation for those and we will go through some of the, some of the questions um that, that we can get answers from. Um, rash has mentioned about surgical menopause. Is there any role for prophylactic HRT prior to surgery to prevent troublesome symptoms. I wouldn't do that. Um, and the reason for that is, remember, we try to be very careful with HRT around surgery. Surgery. Depends on what it is. Is it a, is it a, is it a day procedure where they will simply have laparoscopic bso or is this part of a hysterectomy removal of ovaries or cancer surgery which will take hours and which will be taking a longer recovery. Every surgical procedure will be different. So one answer cannot be given. But generally remember if they're having ovarian activity, giving them extra charity, even before surgery will not help, it will simply cause side effects. You're giving extra hormones on top of what they already have. Once they have surgical menopause, now they are not having hormones. The trick is to go with hormones as early as possible. And how soon can you start? HRT. That depends on how the patient is doing after surgery. So, if they recovered well, they are eating drinking, they are mobilizing. There is no risk of thrombosis over and above from the surgery or immobilization. That's the best time to start. So some women will start HRT within 48 hours. That means they won't have lots of symptoms soon. POSTOP, others may need time. If they have infection sepsis, immobility, you might have to wait a few weeks until they are fit enough and no thrombosis risk and then start with HRT. Now you might argue why not keep transdermal that doesn't have risk of thrombosis, but that's in healthy women. So we know that transdermal patches, gel spray don't cause blood clotting in healthy women. That's when the trials have happened. Uh There are no exclusive trials in perioperative women. When they have stress, they have infection, they may be immobilized, they don't have the same amount of alimentation. So in this group, you have to be still careful for blood clotting and then as soon as they are fit and health immobilizing, that's when you go in with the HRP. Not before sure. That makes, that makes perfect sense. Um Marina has asked and I think we maybe did cover part of this. Um but how do you approach treatment of poi in women with that, that do have those complications to H RT maybe just summarize that again. Yes. So very few contraindications exist to HRT. These include estrogen receptor, positive, breast cancer or estrogen receptor positive, other Gyne t like sarcomas, uterine cancers, et cetera. Uh And of course, there will be some who may be very sensitive to hormones per se may not tolerate them. Others with active blood clotting or active liver disease, they tend to be the contraindication to be very few patients like this in these women. Of course, HRT may be risky. And so what you might want to do is try all the non hormonal option, whether it's lifestyle CBD uh antidepressants, you've got the NK three receptor antagonist And again, by the time these women settle, let's say they've settled post a treatment phase after a few years or months, they may still be able to go back to considering HRP depending on how they are doing. So that may happen later on. But for the time being many nonhormonal options you might want to use for them. Sure, Emily has asked um about, should we be aiming for a particular estrogen level? Is there any role for actually testing those estrogen levels or do we just treat based on symptoms? There is no one level that works for women. Some women will have a very low estrogen level of 200 be completely symptom free on HRT and others might keep taking HRT with levels of 1000 plus may still be symptomatic symptoms and the blood levels and and the HRT does not correlate. So the best way to go is go by symptoms. As long as the woman is having symptom control, reasonable with good quality of life and bone density. In the long term. The best objective measure that your patient is doing well on the HRP you've prescribed is the bone density four years apart. If your bone density is stable or better, that means there has been enough estrogen going through your HRT. If the bone density is dropping, that's when it's not working, it's not absorbing. So you're not aiming for any particular level symptoms. Bone density is the critical bit fantastic. That's and again, the first part there about looking, treating the patients with the symptoms rather than the numbers about the bone density is actually really interesting. Um So Jna has mentioned a patient with only one ovary perhaps hadn't moved because of a cyst, et, et cetera. Do we assume that they automatically have poi or should we still be testing their FSH? Despite the fact that I'm having menopausal symptoms, this is a patient 27 year old. Yes, I would certainly recommend doing blood tests. Remember, this is one place in menopause management where we always insist on bloods because the diagnosis of poi has significant implications for future. So, in a 27 year old, although one ovary has been removed, the other ovary may continue to function uh for a variable length of time. So if you had typical symptoms of menopause, it is possible that the other ovary is winding up, stopping to function. But you would have to do bloods to see that this process is happening. You can of course symptomatically treat her in the meantime, but it would be important to establish diagnosis with two sets of blood at some point. Sure. Um When, so we mentioned about the importance of contraception um and H RT not acting as a contraceptive. Um Charlotte has asked when can, when can patients who have po I stopped taking the contraception? Assume there's been no um surgical intervention. So again, the guideline from FSR is what we follow in this regard. If someone stops, their periods goes through menopause under the age of 50 then if they've been menopausal for two years, they can effectively stop contraception. If somebody has menopause after the age of 50 then it's at least one year of stopping periods, then they can stop contraception. Brilliant. So there's some nice discrete discrete guidelines. Um Chucks has asked about, do we adjust the dose of progesterone if we increase the dose of estrogen, is there any way to ratio them to know how we should adjust them or does it really matter at all? It's very important. Uh Recent guidelines uh have been issued by many societies and especially British menopause society about balancing estrogen progesterone. Because if you don't give adequate progesterone as you go up the dose of estrogen, you will end up with breakthrough bleeding. And then there's a small increased risk of endometrial pathology, hyperplasia or cancer in the long term. So if you go to BMS and look at a guideline called guideline for bleeding on HRT, it gives you the exact tables. What estrogen level, what is the dose of progesterone that they should be having? So for example, we often say as long as you are within the first few doses of HRT for estrogen, for example, 2 mg, estrogen or a 5075 patch or 2 to 3 pumps of gel, you will usually use something like 100 micro 100 mg of micronized progesterone. But if you go up to the highest doses such as 100 patch or three or 4 mg of estrogen or four pumps of gel or above, then you need to go to 200 mg of the natural progesterone. This is just one example. So you can look at the table that's provided on the BMS, it's free to use guideline. And so you can find what level, what progesterone should be adjusted. Fantastic. So there's a, there's a reference for everyone to, to check out after tonight's talk. And so she has asked um about different in that patient who presents with really irregular periods for the first time, things that could help us to differentiate between PCOS and POI. Yes. So we are talking about quite different pathologies here. Polycystic Ovary Syndrome happens because the ovaries are active, they are produces of hormones, estrogen levels will be normal, usually they are high and their FSH LH will never be too high. The FSH is usually within normal limits. The LH will be the only one that might be slightly high. And so that's a different set of blood in somebody having irregular periods as compared to poi where you will often see FSH LH, very high estrogen levels will be usually very low on most of the investigations. Similarly, when you do an ultrasound, you will see a Polycystic Ovary if it's because you will see a very quiet ovary with not much folly activity if it's poi. So again, ultrasound, clinical history, any other symptoms like hirsutism, acne uh raised BMI for PCOS uh often there is dryness of vagina, hot flashes more likely to be poi. So clinical history bloods, uh ultrasound, you should be able to confidently diagnose one and the other. Sure, the importance of the of the basics, isn't it? Um Emmanuel has asked an interesting question. Do we ever get through a, a talk nowadays without mentioning, is there any uh evidence to suggest there is a relation between COVID infection and PO not currently? So we looked at this because a lot of women said uh they have irregular periods. A lot of women coincidentally stopped having periods and had a diagnosis of poi soon following COVID vaccine. But we've tried to look at this through different papers or different articles and that doesn't seem to be a direct link between COVID and uh Poi uh COVID vaccine. Uh remember itself is a stress for the body sometimes may cause hypothalamic suppression, sometimes women skip periods or have irregular bleeds following vaccination. Uh That is more of an induced stress causing period irregularity. Yes, there are some parts of the COVID virus itself. Uh which kind of have similar makeup in terms of protein makeup to the endometrial tissue as well as for the ovarian tissue. And that might suggest the period irregularity that happens because of the receptor. Uh sort of identical uh bits with the virus in this, in this gynecological tissues. But as such per S ea vaccine causing po I that's not established no evidence there. Um I have three more questions um at present. So if anyone has any burning questions, please pop them into the chat in the next minute or so, um Rebecca has has asked uh hopefully a fairly straightforward question. Younger women with poi might, might be quite sensitive to estin. Can we give the vaginal component um or the endometrial component of their HRT vaginally? Is there any reason we can't do that? So again, a lot of units now use vaginal progesterone, natural micronized progesterone. My difficulty with that is the data isn't strong. So remember when we use progesterone, like the old progesterones, the Provera, the norethisterone, they've had decades of research. 4050 years of experience with using this medication, natural progesterone only started really getting used widely in the last couple of decades. So about 20 years of experience, most of it is oral vaginal preparations used for micronized progesterone in UK, especially uh has been very little data. Some of the studies did raise concern that long term use of vaginal progesterone may not be adequate for endometrial protection, slight increased risk of hyperplasia, but the data are so little and so limited that you cannot do generalized conclusions right now. So in absence of those large studies, observational data about vaginal progesterone for protection of endometrium. I don't tend to recommend this as first line. If at all, you have a very difficult patient where you've tried all the other forms of progesterone and you have no options left. Then in those cases on an individualized basis, you may have to counsel patient to say, look, we can give you vaginal progesterone as an option. See if it tolerates or see if you can tolerate it many times that may not work. But if you can tolerate it, this is based on the mutual understanding that we don't have a lot of data to back this up. So we'll try to keep an eye on any bleeding, investigate with very low threshold for scanning and again, we can't guarantee about the long so on that sort of a basis, you may have to do off license treatment of planning. Uh But generally, I would say stay away from it unless it's your last option. Sure. Um Just a couple more Amella has asked. Um Do you, I know, I certainly can't remember numbers off the top of my head. But do you know the reference levels? Um for diagnosis of poi for FSH mh and estrogen? Yes, of course. So you're looking at FSH, we don't really look at LH levels because remember the FSH is the one that responds to lack of estrogen. That's the most sensitive one. So FSH level of more than 25 let's say 4 to 6 weeks apart is what you're looking to will fluctuate up and down in the early peri peri premature menopause. And finally, then it will stay high constantly. That's when you stop periods and make a diagnosis of poi estrogen will be low. So it's often undetectable. Like for example, the the hospital I work, the lower limit of estrogen is around 44. So we often get a report that estrogen levels are less than 44 ol. We can't measure it. Now. That means there is not much estrogen happening. So anything less than 100 would be low estrogen level for a person below 40 years of age. Brilliant has asked um when we mentioned PCOS, there trigger this question. Is there any link between PCOS and premature ovarian insufficiency? No, it's the other way around. In fact, because remember with Polycystic Ovary syndrome, women have a higher than average number of eggs, which is why you see ovaries are full of follicles, they are full of eggs and they tend to often have a higher levels of hormones. Amh is high estrogen levels are normal or high. So they tend to have a slightly delayed menopause, maybe one or two years delayed menopause than natural menopause. So often po is very unlikely if somebody has PPC S not that it's, it cannot happen because you could have accelerated depletion of those eggs, but generally PCOS will have late menopause, not poi sure. Um And what I'm going to call in the interest of time, our last question this evening. Um From Sherry. Um could you please ex extend on the concept of white poi patients going through a donation of higher chance of complications? Do refer to when poi patients start cycles and get pregnant, they may have a higher chance of developing um obstetric complications. Yes. So again, it's a, it's a big topic on its own. So we might not finish in the next minute or two, but the general uh it's usually the pregnancy itself. So once a donation IVF has happened, uh and the embryo starts growing and the placenta develops. This is when we see often a higher chance of either gestational diabetes, higher chance of having pregnancy induced hypertension or pre eclampsia. Also, again, sometimes low birth weight needing uh early delivery and higher chance of. PPH. Often these are observational associations, my colleague at UC H uh Doctor Elizabeth by if you can Google uh Elizabeth by and the paper often has produced very good papers on, on relationship between the pregnancy outcomes in women with turn or poi having uh a donation IV F uh some of the papers are published, others, she's publishing. So this would be something to look at. Uh but it gives you the associations uh along with a donation IVF treatment in women with poi what can be the obstetric morbidity. What are the possible hypothesis in terms of placental development that, that this can be happening? Uh uh It's an interesting area of research, ongoing research, quite a broad topic, shall we say beyond the scope of, of tonight's um, presentation? Um Do, can I extend? Uh, thank you for taking time to be with us this evening. Um We really appreciate it um, on behalf of the 100 people in the chat, um, we are grateful for what they've shared with us tonight. Um, I am going to pop back on the screen those couple of QR codes, please provide feedback. Um At me, we do share the feedback with our speakers. It helps inform their, it helps inform their presentation making, it helps inform um so much to us and to our speakers. Uh I have shared the link to the feedback form in the chat and you should get that to your email as well. Thank you. I just, I just want to pop in two little uh advertisements for the next upcoming events. Of course, we look forward to having back with us, but uh let me pop these just into the chat with the links tomorrow night. We're looking at palliative emergencies uh in primary care and that's with Doctor Jane mcauley and then at the start of October coming up, we have another familiar face, Steve Holmes back with us. Looking at best practice in CO PD management. Please register for the events. We look forward to hopefully seeing you at our next event and a last word of thanks to. Thank you. Thank you. Tim and thank you, everyone who gave up time. Uh, hopefully see you on the next one. Good night, everybody. Goodnight. Goodnight. Bye-bye.