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Hello, everyone and welcome to our latest event. Uh It's great to have you. Er, today I have Vikram with me. He is amazing. I've heard him speak before. He actually, er, er, gives a lot of talks on, learn with nurses, which is an amazing, amazing organization to tune into. It's really interactive, super friendly and I would encourage anyone to sign up to one of their events. Anyway, today we've got Vikram with us talking about Polycystic Ovary Syndrome. Um, an update, uh what's gonna happen is he's gonna give his talk and at the end er, of his talk he'll have space for questions and answers. So as we're going through, pop your questions in the chat and then he'll get to them at the end. OK. As always feedback, that form will be coming your way at the end of this hour. Er, once it's filled out your certificate will be on your medal account. All right, like I said, pop your questions in the chat. Vikram will get to them at the end and we're gonna have a great hour ahead of us over to you, Vikram. Thank you. Thank you so much, Sue. Uh for the quick introduction. Uh And of course, we're gonna talk about Polycystic Ovary Syndrome. So we have one hour for the total session. Uh being mindful of time, I'll try to stick to 40 45 minutes so that we have at least 1520 minutes at the end for the questions. Uh I'll try to touch upon the main themes because it's a mixed audience. I'll try to avoid the too far complicated bits or uh technical bits as much as possible. And so what we'll try to do is get an overview of various options and diagnostic criteria. Please feel free to ask any number of questions at the end and I'll try to go through them as, as much as possible. So why are we talking about PCOS? It's one of the commonest endocrinopathies uh in women. Uh uh The condition was first described by ST and Leventhal. This was around 1935. So we're almost coming to 100 years and there are various criteria for diagnosis which have been used since then. Uh The most commonly used criteria across the world is the Rotterdam criteria. It was uh basically agreed at the Rotterdam uh conference in 2003. And how we diagnose PCO S or Polycystic Ovary Syndrome is the presence of any two of the three criteria as agreed at V. So what criteria of course, is oligo or an ovulation? Uh So the woman doesn't ovulate uh frequent enough or on a monthly basis and clinically that would be apparent by changes to periods. So, gap in periods or oligomenorrhea, two monthly, three monthly, six monthly periods is an obvious sign of oligo ovulation or anovulation. Second is clinical or biochemical hyperandrogenism. So, that includes clinical symptoms such as hirsutism, uh scalp hair, thinning, oily skin, uh excess acne uh and all that would come under clinical signs of hyperandrogenism. And of course, you can have biochemical uh evidence of hyperandrogenism that would be raised, testosterone or other androgens in the blood. And finally, you have ultrasound appearance. That's the third criteria. You can define a Polycystic Ovary as morphology that has ovarian volume of more than 10 ml or more than equal to 12 follicles per ovary. Of course, there have been recent guidelines which have now changed these thresholds up to 20 follicles per ovary. And we'll touch upon that uh in uh in the next few slides. So if you have two out of these 31 will confidently make a diagnosis of PCOS. There have been further modifications to the criteria that we just talked about androgen access PCOS society in 2006, modified the definition according to which hyperandrogenism, biochemical or clinical is a must feature to diagnose PCOS. Of course in 2012 and IH A S RN consensus then recommended extension of the Rotterdam criteria and they included details of P CS phenotypes. So according to this two, out of three criteria, hyper ovulatory dysfunction and the morphology on scan. Uh they are required to diagnose PCO S but you can further classify the condition into specific phenotypes based on which are present. Whether it's just the uh ovulation problem, whether it's the morphology or hyper endogen and they have ABCD phenotypes. The more important bit of classification is it, is it standardizes the nomenclature, helps with research to know exactly which patients you're including in your research and also helps uh dictate your clinical decision making and treatments. If you classify into further phenotypes for most uh clinicians, though this sort of classification is not part of day to day practice and we will stick to the three main criteria by for now, phenotypes A and C out of these ABCD are including women who are hyperandrogenic. Whereas the phenotype D includes non hyperandrogenic women. Now, what are the latest changes to scan criteria? So, of course, in 2018, there were international evidence based guidelines which were revised on PCO morphology for ultrasound diagnosis. And we now have a cut off of 20 follicle numbers per ovary rather than 12 because many people felt that having 12 as a cut off was too low. And that would mean we would over diagnose polycystic ovaries. So a cut off of 20 has been suggested, not all units still follow 20 follicles as a diagnostic criteria, but that is the recent norm. Now, all diagnostic criteria, whichever you use and when you make a clinical diagnosis. Remember you're excluding any signs, symptoms or evidence of hyperolactone thyroid dysfunction, nonclassical adrenal hyperplasia, androgens, secreting tumors, rare syndromes of insulin resistance. And then of course, use of any anabolic or androgenic drugs. And there is also the overlapping diagnosis of idiopathic hirsutism, but there's nothing else just the hirsutism on its own. Now, this will be the differential diagnosis of PCOS. The majority of patients, the diagnosis will be clear cut based on the two out of three rotten criteria. PCOS is not the same as having Polycystic ovaries. So we distinguish the syndrome from just having a morphology of Polycystic ovary because almost 20% of women will have Polycystic ovaries. They will have more than 20 follicles in the ovary. But that is not as having syndrome because those may not over secrete androgens. Those ovaries may not cause anovulation. So if there are no menstrual or hormone related issue, just the scan morphology of having more than 20 follicles or a bulky ovary, that is polycystic ovary morphology. It is not equivalent to having the syndrome. Now, let's look at P CS, why it affects women and how uh in what mechanism does it cause any changes in the body. What are the effects of it? P CS is a multisystem disorder. So, of course, uh it's a common gynecological endocrinopathy. It is seen in women between uh reproductive age groups of around 15 to 45. But of course, it can have ramification even after around 15% of women will be affected by Polycystic Ovary Syndrome. And that depends on ethnicity. So, for example, in certain ethnicities like Southeast Asian ethnicity, the incidence will be much higher diagnosis will be much higher rate. As come back to say in the western world. Combination of hyperandrogenism, acne hirsutism, scalp, hair, thinning or oily skin, chronic oligo anovulation or problems with periods, heavy painful uh periods after oligomenorrhea. And of course, polycystic morphology of the ovaries. That is the combination we are looking at when we make a diagnosis, there are metabolic implications of PCOS. There are reproductive implications for fertility and the most neglected. One is the psychological impact of having the condition. This is as healthcare professionals, we are not good at uh supporting our patients with. If you look at the wo classification of anovulation or anovulatory sub fertility, then of course, uh PCOS falls in type two anovulation. Type one being issues related to uh hypothalamic or uh GNRH related issues. Type two is the one where PCOS is part of this is anovulation with variety of menstrual issues. There is endogenous estrogen here, unlike type one, anovulation and the gonadotrophins, the FS H LH often tend to be within normal range. Unlike with type one or type three anovulation. There is a new classification from Figo for ovulatory disorders and that again, a slightly different way of classifying the different forms of anovulation. Whether it's hypothalamic pituitary ovarian and it puts PCO S type four where you diagnose and categorize it as recommended by the International PCO S Network. I won't go into details of this because we don't have time. But remember that there is a fi ovulate reclassification and then you can access this on the internet uh easily if you're interested. Why does PCOS happen? We still haven't figured out the exact pathophysiology, but we know a few components that may be responsible how PCOS develops. So you have first aspect of pathophysiology, which is dysregulation of the hypothalamo pituitary axis. There is increased GNRH pulse frequency that increases the frequency and amplitude of LH. And therefore, there is utilizing hormone hypersecretion, increased LH pulses and this leads to increase androgen secretion from the the cells in the ovary. So one part of the pathophysiology is there may be defect at the level of the brain where there is hypothalamic secretion of increased gener h pulse, increased LH pulses that causes high LH stimulates the T cells of the ovary causing hyperandrogenism. The second is insulin resistance and hyperinsulinemia. So again, there appears to be problem with insulin sensitivity receptor defects have been noted in the insulin receptor. And so there is abnormal signaling how insulin is utilized in muscles, adipocytes and ovaries and excess insulin. Of course means that the thicker cells will secrete more and more androgen. And that again is a vicious cycle of systemic insulin existence. And high parentalism. The third is increased level of antimalarial hormone. So you often find women with P CS have a higher level of A H as compared to uh the control population or women without P CS. And this is thought to be a consequence of increased number of small follicle. There are lots of follicles, there, there is some sort of arrest of maturation of follicle development and that causes increased number of amh, increased level of amh. But actually many of those eggs have had a rest of their maturation. P causes menstrual problems. We all face this in our day to day clinical practice. Uh menstrual irregularities, it could be either too frequent heavy periods. For example, cycles may be less than 21 days apart or more commonly, it will be oligomenorrhea. So cycle more than 35 days apart. And so the cycle length, menstrual cycle length may be anywhere between six weeks, up to six months and sometimes even amenorrhea for more than a year. In terms of a per year, number of menstrual cycle, eight or less menstrual cycles in 12 months or per year is considered as irregular cycle pattern. The most common cause of cycle irregularity with PCOS is because there is no ovulation on a monthly basis. And ovulation causes cycle irregularity and this will be seen about 60 to 70% of women with P CS. You must remember that there could be regular periods in about 15% of women and some with menstrual abnormalities may resume regular cycle. So it doesn't mean that if a woman has PCOS and is having very irregular periods, she will never go on to have regular periods with changes to her body changes to lifestyle changes to many other factors. These women can have regular periods in future and they may resume regular ovulatory cycles. Some women notice this, for example, after pregnancy, they tend to start having ovulatory cycles with the change in ovarian milieu. But that is why it's always important to remember that PCO S can have a variable picture throughout the life course of a woman. Why are we worried about PCOS in terms of endometrial health or womb lining health? So, of course, it's 2 to 6 fold, increased risk of endometrial cancer in women who have PCOS. But remember the absolute risk is very, very small. So, although as compared to general population of women without PCOS, you think that the risk is double overall, it's in very few numbers per 1000. So the absolute risk is very small, but it's important to be vigilant because if these women don't have regular endometrial sharing, they can go on to have endometrial hyperplasia or develop cancer. So we should have a low threshold for investigating for endometrial pathology in women with P CS or if they have a history of P CS. And it's often done by doing a transvaginal scan. And if the transvaginal is not possible. It's transabdominal scan. And then if the scan is suggestive of a pathology, uh follow that up with an endometrial biopsy or in some situations, cystoscopy, there are about risk factors to look for. For example, prolonged amenorrhea, suspect endometrial pathology, abnormal vaginal bleeding pattern more than expected by anovulation, excess weight, other factors such as uh besides high BMI family history of cancer, persistent thickened endometrium on your skin. All these will be markers to go more in favor of a biopsy or a histopathology diagnosis rather than just relying on the scan, routine ultrasound screening of endometrial thickness in all patients is not recommended. So it's equally important to know that period irregularity is common. And as long as there is some endometrial sharing in in women who don't have any other risk factor, routinely doing ultrasound screening or trying to do biopsies based on ultrasound screening is not going to be help uh helpful and you must try and individualize. Who do you offer the scan based on the risk factors P CS and endometrial cancer. Again, optimal prevention strategy is not known. People are still trying to find out what would be ideal regimens. When do you intervene? We haven't come out with uniform uh agreed guidelines on this combined pill or progestogen therapies are used in those with cycles longer than 90 days. So the general agreed sort of management. If a woman has prolonged oligomenorrhea is not bleeding, a anor, then if it's more than 90 days apart. Then generally, that would increase the risk of endometrial hyperplasia. And what is suggested is either use the combined pill or a withdrawal with a cyclical progesterone. And that would again mean you can also have the option of Mirena coil. For example, as long as you're using some form of progesterone therapy or a withdrawal with the pill or a progesterone, that ensures that endometrium has been shared and will reduce the risk of endometrial hyperplasia. So, four bleeds or five bleeds every year or at least one bleed every three months is what we recommend on a day to day clinical basis. Most commonly used progestogen. You have the progestogen only pill, which can be used on a continuous basis to keep the endometrium thin. You can use Provera or norethisterone or utrogest on a cyclical basis. You can also have the Mirena, some may have contraceptive implant. All those would be useful ways of keeping the endometrium thin. What about impact on fertility? So, PCO s and fertility, the most common cause of abilities of fertility is PCO S affect 70%. There are of course other causes of anovulation which may be similar picture, for example, thyroid disorder or hyperprolactinemia and there is late onset or nonclassical congenital adrenal hyperplasia. So, again, uncertain, uh differential diagnosis should be ruled out if there are signs, symptoms uh or possibility of these other conditions. There's an overlap between two conditions which is often not recognized, which is PCOS and hypothalamic amenorrhea. These two conditions are both endocrine conditions which often affect young women and they will overlap. Sometimes it's very difficult to distinguish the diagnosis and there might be a mixed element of both conditions because the ovarian morphology on scan may be similar in both conditions. You might see multiple follicles in the ovary. The serum A MH can be high in both conditions. Women with hypothalamic amenorrhea may have high MH, normal or low A H PCO S has high A H and there are these many overlapping features besides the clinical elements. For example, amenorrhea will be common in both conditions. But some things may tell you one diagnosis is more likely than the other. For example, there's obvious weight loss, anorexia or dietary changes or stress or excessive physical activity exercise that will more likely mean this is hypothalamic amenorrhea. And if there is over hyperandrogenism, that will make it more likely that this is PCO S another diagnostic category that has been suggested. Therefore, if there are features of both conditions is P CS hypothalamic and maoria mixed picture because you can have a woman with PCOS who then loses weight and develops hypothalamic suppression so that both can coexist together. This is just again, a recap of how we diagnose type one or type two anovulation. And I won't dwell on this right now. We'll come to this when we come to question section. But remember that if you have type one anovulation, which mainly affects the hypothalamus or the pituitary gland, then you find FSHLH will be very low with a low estrogen. Well, if you compare to PCO S, you will have normal or normal to high LH normal FSH with a normal estrogen. And that's how you differentiate type one and ovulation from type two. Looking at the ovarian morphology on a scan on, on the left hand side, you have a classical Polycystic Ovary, uh echogenic dense stroma and you have lots of these follicles in sides which are arranged in the periphery. And if you look at often the uh ovary with the hypothalamic suppression or type one anovulation, you might be inclined to say this is Polycystic Ovary, but you often find the follicles are tightly packed together with very little intervening stroma. And that might differentiate your multifollicular ovary from a classical Polycystic Ovary. Let's look at overview of the Polycystic Ovary treatments now, so I'm just going to try and get all these together in one graph. Ok. Bye, bye. Sorry for that. So let's look at how we deal with various forms of PCOS symptoms or long term health effects. Um So we know that there is increased testosterone, increased androgen and that's going to be affecting the hair, follicle, acne hirsutism, uh scalp hair thinning, all those are effects of excess androgen. And there are various medications which are non hormonal, which can be used as treatment of the hyperandrogenic symptoms of PCOS and the common ones are cyproterone, acetate spironolactone, flutamide, and finasteride. So, these are likely non hormonal. Although you could argue that cyproterone is not a classical nonhormonal treatment, but these are not uh using the combined estrogen progesterone pill, which is the other group of treatments. So, of course, the other group of treatment is CP which is a combined oral contraceptive pill. This suppresses the FSH and the LH. So there is no more secretion of androgen but also increases the SHBG, the protein that binds the androgens in the liver. And so therefore, it will suppress androgens and estrogen and that's how it affects the PCOS symptoms. Uh You also have other modalities which are really important. You have lifestyle changes such as exercise, diet and Metformin in selected women. And these will all help improve the insulin resistance. So there'll be better insulin sensitivity, less androgens in the body. And again, that will help with ovulations as well as with the hyperandrogenic symptoms of hirsutism. So you have three broad categories. You have the hormonal treatment. You have the nonhormonal options and you have the lifestyle and metabolic options. Let's look at the nonhormonal ones which are popular. And again, I don't have time to go through details of every medication, but more than happy to take questions and do another um another webinar just on these medication. But the whole uh principle of using is one you've got the CP, the combined pill uh and mostly used are the third generation pills if it's for hers. Uh or androgenic symptom. Dyane and Yasmin have been particularly popular in young women, but of course, you can use any other pills. Uh because long term use of Yasmin or dyane is generally not encouraged. You have topical uh hirsutism treatment such as the eflornithine cream, which is nica, this blocks the proteins in the hair follicle and prevents the hirsutism on the chin or the face. Besides, you have mechanical methods such as electrolysis or laser, you have topical acne treatments which are often offered by dermatologists such as roacutan. The ones that we use are spironolactone, flutamide and finasteride. And these are only used if somebody doesn't want to take the pill or has contraindications for the pills such as high BMI. Then we tend to use non hormonal methods such as the spironolactone, which is very useful. And you also have flutamide and finasteride which are androgen blockers. It's really important that we to tell the patients that they cannot conceive on these. And that's because these are teratogenic and contraindicated if the woman is trying for pregnancy combined pill, of course. Uh we we all use combined pills so commonly and just a quick summary to say it suppresses the follicle activity in the ovary suppresses testosterone by increasing the S Hbg in the liver. You have 20 mcg to 35 mcg pills and the higher dose is more effective but can cause more side effects. One of the important side effects to remember is that pill can make uh uh uh the mood low. So emotional fluctuations, low mood can happen with the use of pill. And that can sometimes uh put women off using the pill, but it can uh you can reduce the dose as the symptoms improve in monitoring. BP is important when prescribing the pill. And there are of course contraindications, you should not be using the pill. If somebody is obese smoking, migraines with aura, uh there's a vte risk factor, high BP and if they have a strong risk of breast cancer, this is a recent trial again of spironolactone which was published in the British Medical journal. This was a randomized controlled trial which suggested that spironolactone about 50 to 1 50 mg is a very good non hormonal option for treatment uh of hyperandrogenic symptoms such as acne. Uh And again, you can access this on the internet. I'll be happy to provide the link. What do you do for fertility? Of course, PCO s and fertility. Uh important uh implication. Lifestyle modifications are the best first form of treatment for anybody with high BM. I uh losing weight is a very, very effective form of improving fertility. So, dietary modifications and exercise always are the first line options. Even 5 10% loss of body weight can improve cycle regularity, ovulations and fertility important to stick to simple dietary modifications which can work and which are within the patient's uh day to day lifestyle. Uh Because if you give complicated regimes where the patients can't stick to doing this lifestyle modification, then they will do it for some time. And then in the long term, they won't be able to follow that. So making sure less of carbohydrates, less of sugar, less of uh saturated fats, generally Mediterranean sort of diet is very useful. Exercise is really, really key at least 2.5 hours every week or more of regular physical activity is really important for those who don't respond to lifestyle or cannot adhere with that and need ovulation induction. Then of course, we now have the letrozole which is aromatase inhibitor or you have clomifen citrate which is an anti estrogen. These two are the first line medical treatment options. Uh Letrozole is favored over clomifen right now. That's because it doesn't uh withhold endometrial growth and it often causes one follicle to grow rather than multiple follicles. The aim of ovulation induction, fertility treatment is monofollicular growth to avoid multiple pregnancies. What about other modalities of treatment? Most patients will respond to oi and ovulation induction should be the first line fertility treatment for those who don't respond. Of course, you can offer them gonadotrophins. So, injections of FSH LH or HMG and laparoscopic ovarian drilling, which are the second option for treatment. And both these techniques have their pros and cons uh and should be discussed with the patient in vitro fertilization. IVF is a third line treatment required for small number with PCOS unless there are other issues, for example, uh increase age or that's male factor or pelvic pathology. Generally, most PCOS patients won't need IVF. And it should be reserved for those who have gone through ovulation induction and have not been successful because IVF does have a significant risk of ovarian hyperstimulation. And that's why we try to keep it as the third option. And if it is needed, then again, I don't have time to go into details. The gene Rh antagonist protocol with J Rh and agonist trigger is the one that is used for oocyte maturation to try and avoid the uh oss risk besides to freeze all policy lifestyle interventions and weight loss. So this is what we should focus on for all patients who have problems with BM I because that is what will really help. In the first instance, excess weight exacerbates, infertility. It attenuates response to some of the ovulation induction treatments. It causes adverse pregnancy health later on increased risk of diabetes, high BP in pregnancy. So we have to target this with multicomponent um therapy that includes diet exercise and behavioral strategies. Even 5% of body weight reduction will have a positive impact and it does improve pregnancy rate. But again, studies about improved live birth are lacking and that real world difficulties in following weight loss plan, often muddies the scientific evidence. What sort of diet do we recommend? Uh again, high carbohydrates is not good. It accelerates increase androgen insulin resistance. So avoid high complex carbohydrate diet. Suggestions are of a Mediterranean type of diet. Others have suggested a diet with low glycemic index, general healthy eating principles. That's the most important bit and there is no evidence that one specific diet is better than other. As long as general healthy eating principles are followed to achieve weight loss. It's not generally a deficit of 30% 500 kg calories a day will be required but allow the flexibility. It's sometimes it's very disheartening when a woman goes to a healthcare professional and they say lose weight and come back without individualized approach, without being, without working with the patient, how they may be able to lose weight. It's really important to take the patients views, look at their lifestyle, how they can effectively achieve weight loss rather than being prescriptive exercise wise. Again, at least 1 50 minutes per week of moderate intensity exercise would be ideal and the goal should be realistic. So one should not be needing expensive gyms or fitness centers. It's really putting on those minutes even at home with simple exercises, that is the key. So again, working with the patient, allowing them time to get used to this exercise pattern is really key. How about using antiobesity drugs? So we don't usually use this in most patients and tend to be second line. But there are some drugs which have been considered in the past. For example, you have a pancreatic lipase inhibitor, which is orlistat, this acts by decreasing the fat absorption. You had a drug called sibutramine, which was then withdrawn from the market, which was an antiobesity agent. It was withdrawn due to cardiovascular risk. And of course, the recent tide is of the glucagon like peptide one receptor antagonist or GLP one receptor agonist. These act like the GLP one hormone released in the gut and they'll produce more insulin suppress appetite. So there has been a lot in the media about GLP receptor agonist. Uh the semaglutide, the liraglutide and they should be combined with diet and exercise. But it's really important to know the effects, the long term effects and the contraindication and they should not be used without proper consultation. So, studies of the GLP one receptor agona do show significant weight loss. But the problem is the participants tend to regain the lost weight when they stop taking medication. So do we really encourage our patients for a short term gain? Yes, in some situation that may be beneficial. Say, for example, to qualify for fertility treatment or achieve fertility, but it's not a long term solution for weight loss. The lifestyle becomes the key side effects of GLP one receptor ago. Uh dizziness, fatigue, nausea, diarrhea, constipation, abdominal cramps, headache, bloating and they should not be prescribed if there is history of thyroid cancer, gallbladder, disease, pancreatitis or multiple endocrine neoplasia in those conditions, it's contraindicated for any antiobesity drugs. The caution is that you should consider the safety of the drugs if the woman conceives because we don't have good studies. What happens if a woman conceives on this medication? The safest one appears to be the orlistat because it has a favorable profile, low absorption and first pass metabolism. But uh and only that can cause improved ovulation rates as compared to Metformin, almost similar. But again, use it as a last resort lifestyle is always the best one. Surgical option to lose weight, improve ovulation, chance of fertility. Yes, some women may opt to go down the bariatric surgery route, especially if the BMI is more than 40 or BMI about 35 and they already have diabetes or comorbid condition. There are various forms of bariatric available. You have laparoscopic gastric bending or sleeve gastrectomy or, and then of course, that consultation happens with the bariatric surgery team who will discuss the pros and cons because there are risks of surgical complication, recovery time from the procedure. Often, nutritional intervention will be required after the surgery and they'll have to wait 12 to 18 months at least before they start conceiving or trying for conception. All the next point would be PCOS quality of life, emotional wellbeing. This is where we don't do well. There is a high prevalence of moderate to severe anxiety, depressive symptoms that can come with PCOS and we should be routinely screened for. We should be asking patients how much the condition affects their mood affects their wellbeing. So we should have available resources for counseling for intervention if we feel PCOS is contributing to depression agents, hormones that exacerbate PCOS symptoms. For example, weight gain, need careful consideration. So sometimes we may prescribe a pill for periods for ovulation or contraception. And it might be that it exacerbates symptoms of PCOS. And actually women feel even further lower request on medication. This should really be actively taken into consideration when we choose our treatments. Of course, you can always sign post people to helpful charity websites or signpost people to useful information on the internet because they can get empowered, they can learn more about their condition. And what is available as option. Rarity is the PCOS charity in the UK. Uh and highly recommend for women who have PCOS to go and look at the website as they will be able to get loads of information. The recent paper we did uh in place of ovulation induction. Again, emphasizing the point that for most women with PCO S lifestyle followed by ovulation induction should suffice for fertility treatment and very few women will need to go on to uh more challenging treatment. For example, IVF now I'm not going to go too much into details of ovulation induction treatment because this happens in specialist unit now and not, it may not be relevant to all the audience today, but it is basically administering clomifen or letrozole usually at the beginning of cycle or an induced period and then doing weekly scans to look at the growth of the follicle. And we often trigger the follicle release oration using a CG trigger. And usually the success rate is 20% every cycle on the NHS, we can offer up to six cycles which are the favorite agents. Letrozole, of course, is the favored agent. Now for ablation induction, there is a big trial that's happening in the UK comparing letrozole to clomifen. But so far, the evidence favors letrozole. It basically blocks peripheral conversion of androgens to estrogen and therefore prevents the feedback by oestradiol on the central hypothalamic pituitary receptors increases secretion of FSH. And that's why ovulation happens. Uh ovulation rate like rates are improved and are better with letrozole. As compared to clomifen. There are some side effects. For example, hot flashes may be there but less common uh uh than Clomifen. Uh patients may feel fatigued or dizzy while taking letrozole for the first five or of the days. Uh There is uh unconfirmed concerns about high rate of congenital anomalies. Uh And it's actually recent studies do not show that there is any increased risk of congenital anomalies with letrozole. So it is safe to use and it's a first line ovulation induction agent in women with PCO S clomifen used to be the favorite one before, still used very commonly in many areas or in many countries. It's a selective estrogen receptor modulator has both estrogenic and anti estrogenic property blocks estrogen receptors on hypothalamus and increases the ef causing ovulation. There's a slightly higher risk of multiple pregnancy, almost 5 to 7% with clomifen. And that's why it is uh second line if letrozole doesn't work, Metformin, this is an underused medication in PCOS. It's the most widely studied insulin sensitizer in women with PCOS uh efficacy has been controversial. It's not a frontline fertility medication with PCOS, but it improves insulin sensitivity and it can be used in a dose of 500 to 2000 every day on its own. It does improve ovulation, pregnancy rate but is not used as a formal ovulation induction agent. We often use it in women who have uh high BMI more than 25 because it will help with the process of regularizing cycles or ovulation while preparing for formal ovulation induction treatment. It does have some side effects such as the gastrointestinal side effect. But if you start low with 500 gradually increase the medication, you'll often find that women tolerate it better and you should always monitor for vitamin B12 levels uh when you use Metformin because it can uh cause a deficiency inositol. This is another uh substance that has come into recent highlight in relation to PCO S, it's a relatively new compound insulin resistance has been attributed to deficiency of Deyo inositol. And so, taking inositol has been thought to be helpful. And there are some limited studies which do show some effect in selected women with P CS. Currently, we don't recommend this to everyone. That's because there are small studies which suggest improvement in metabolic profile or fertility outcomes, but high quality large trials are missing uh and use prior to IVF has been suggested. But again, we don't recommend this routinely. Hopefully we'll have better research evidence in future and we'll be able to recommend this. I will skip the gonadotrophins because this is a second line pharmacological treatment for ovulation. Um and may not be relevant to everyone. So when letrozole or clomifen doesn't work, uh we often choose gonadotrophins as the next line of treatment with FSHLH or HG the gonadotrophins are effective, improve pregnancy rate. Uh However, they can cause a small increased risk of multiple pregnancy and o HSS hyperstimulation. So, it's really important. Uh it's carefully controlled ovulation induction with scan guidance is performed if gonadotrophins are used for ovulation induction, ovulation induction, of course is an art. There are very few centers which offer it and one size fits all approach does not work. So it's really important to look at the woman, her demographics, her clinical factors and then decide what form of ovulation induction is best we touched up on laparoscopic ovarian surgery. The drilling, uh this is usually used nowadays in women who have PCOS as a second line option for ovulation induction, especially if they are not responding to medication and they have a high LH uh you do multiple ovarian biopsy or the ovary in four or more places. You can use laser as well. And the rule of four is to do 40 be energy for four, second, four punctures on each ovary. Uh The downsides, of course is uh it's an invasive procedure needs general anesthetic or anesthesia and of course, needs the laparoscopy. Uh There's a small risk of adhesion formation after surgery. Uh And of course, there's a very tiny risk of reduced ovarian reserve because you're destroying some healthy ovarian tissue. So you could drop down the ovarian reserve for the person. But of course, comparing laparoscopic surgery to gonadotrophin, there wasn't much difference. Um There was improvement in uh pregnancy rates in vitro fertilization. Uh the most important bit is to look at the risk of ovarian hyperstimulation and try and use techniques which are used in your units to try and minimize ovarian hyperstimulation syndrome. Finally looking at PCOS in pregnancy. Uh So of course, getting the woman pregnant is the first challenge if there is sub fertility. But of course, it's equally important to look at what happens in pregnancy because PCOS does carry an increased risk of gestational diabetes, pregnancy induced hypertension and preeclampsia during pregnancy. So, when counseling for prepregnancy preparation, it's really important to counsel women to say you should try and achieve a good BM I because that will cut down your risk of diabetes, high BP during pregnancy, glycemic status, lipid profile. Therefore, we check in all patients at baseline every 1 to 3 years. So this is something missed by many primary care physicians or doctors who look after women with PCOS. It's important that if you have diagnosed somebody with PCOS, you counsel them about lifestyle, but also do their baseline assessment, whether they are high risk for diabetes and high cholesterol and do that every three years, at least to monitor how their metabolic health is. For those with very high risk family history or ethnicity. An oral glucose tolerance test is best but if not HBA1C can be a crude marker of metabolic health. PCOS has been linked to increased risk of miscarriage. There's lots of controversies, conflicting data uh because often many women will have high BMI that could be an association, exact mechanism remains unclear. Some people blame the insulin resistance for this, but there are no recommended treatment strategies. Uh and often Metformin is thought to be an option to continue in the first trimester of pregnancy. But again, there is no recommended treatment strategy because the data are conflicting uh in terms of PCO S and miscarriage. What about long term health PCOS causes an ovulation and so long term health uh has to be supervised in terms of cardiovascular disease risk because all women with PCOS will have slightly increased risk of diabetes and heart disease in future. So they should have their BP measured annually. A annual BP check is important weight monitoring, monitoring for excess weight advice. Whenever possible, if the weight starts going up, monitoring should be at least annually in the GP practice or in the doctor's office, whichever settings you practice in weight height BMI I ideally based circumference should be monitored. And those women with PCO S high BM, I should have their fasting lipid profile right at the baseline. And as we said before, at least 2 to 3 glycemic status. Similarly, HB A1C or OGTT, we tend to do it at a baseline for all women with PCOS. And thereafter every three years, those with very high risk such as A or very high BMI and OGTT is better than other tests in pregnancy. We recommend oral glucose tolerance test to all women with PCOS. Uh first preconception, then just below 20 weeks and then repeat between 24 to 28 weeks. And any time the results are abnormal, the diabetic physician should be involved in the care of that pregnancy. So that's in a nutshell is the overview of how we diagnose PCO S. What are the main options from lifestyle to medication to surgical options in relation to fertility, hyperandrogenic symptoms and psychological impact. Finally finishing up with the diabetes P CS and diabetes. So I'm going to stop here and I'm going to let you ask as many questions as you want and I'm going to try and go back and stop sharing uh my screen so that I can answer your questions. There we go. Yay. Perfect. Brilliant. So yes. Uh as become said, do put your questions in the chat and we'll start working through them. All right. Are you happy to read them or do you want me to read them? Read them? So, because I'm, I'm seeing too many things on the screen. Ok. Well, if I don't pronounce correctly, touch me on it. Ok. So, uh Rosanne says, thank you for this session. I was wondering how common is it for females to get pregnant without any intervention needed? And are there any factors that might be the cause or is it just pure coincidence? Well, I think it depends individualized. Uh I can't give one figure that will become uh clearer only when we know your clinical history. So every woman is a bit different. How often does she have ovulation? What is her cycle frequency? Does she have regular periods or not? If you have PCOS, which is severe, you don't have ovulations every couple of months or you have a period every three months or six months, then of course, chance of pregnancy is going to be low and it will be maybe less than 15% perhaps. But if you're having PCOS, but managing to have slightly irregular periods every five weeks, six weeks, you have a bleed, you have a late ovulation, but it happens consistently. You'll probably have the same chance as anybody else of conceiving 70 80% within the first year. So, it depends on how severely the hormones are imbalanced. What's your ovulation rate? That will determine how easy it is to conceive naturally. As long as you have good lifestyle, good BM I and your period frequency is more or less similar to once a month, you will conceive naturally. You probably won't need any medical intervention. But if there are long gaps in your periods, uh then and and ovulation is quite severe, then medical intervention will be likely. Ok. Perfect. Next question from ae what about the use of fat dissolving injections to treat obesity and PCO S? Are they safe to use? And do they work? So, I'm not sure which medication you are referring to if it's about the semaglutide or liro glutide, the GLP one receptor agonist. Then as I said, currently, we don't recommend this as a treatment only for PCOS. This is really for women who are going on to have need bariatric surgery with very high BMI or comorbidities. Uh We only sometimes reserve it in, in situations such as if there is not much time to go to fertility, you're running out of time because of biological clock or age, then we might suggest quick weight loss. And in those situations, GLP receptor may be considered but otherwise, uh, lifestyle diet exercise is the gold standard for weight management and, and conception. Ok. Another question from Rosanne. Another question about diabetes, uh, as they are susceptible, susceptible, is it common for young females? 25 to 30 to get diabetes or is it present? It's usually later in life? Remember? It's a, it's a pathophysiology. It's long drawn out. So if you're starting to have an ovulation, insulin resistance, it won't present straight away with diabetes. And if you then do healthy lifestyle changes, actually, you can prevent any of these changes happening way later in life. So most women with PCOS and some anovulation insulin resistance, you see the onset of diabetes in the fifth decade of life. So fifties and sixties, that's when the type two diabetes comes into picture, very early diabetes is not a classical feature of P CS. However, individuals differ, there may be a small number of women who might have onset of diabetes very early on in life. Ok. From Priscilla, firstly, thank you for such a compassionate, empathetic and thorough presentation on PCO S. Thank you, Vikram is the master on, on this kind of things. I have to say great talks. Um I just wanted to ask for a small clarification regarding in in acetal supplements. Do you think it should actively be avoided until further information comes out or is it ok for each individual and their doctor decide if they see a benefit on a case by case. Yes. So we say it's empirical therapy. So you can of course choose to take it so far, we haven't had any reports of harm from taking inositol. It may benefit or may not and therefore with no harm, potential benefit, you can of course choose to take it and decide with your health care practitioner to use inositol. All we are saying is at the moment, studies are very small and poor quality. So we don't have confidence that it certainly will benefit you. Perfect. Mab says, firstly, thank you for this session. But what is the first and preferred treatment for PCO S? And that depends on what you're treating. And so it's difficult to give an answer if it's uh if you're talking about the hyperandrogenic symptom, like the acne hirsutism or scalp hair thinning. Then of course, if you prefer hormonal treatment, it's the combined pill. As long as there are no contraindication. If it's non hormonal, we tend to use spironolactone as the first line. Uh Of course, if it's the metabolic issues, it's the lifestyle also for fertility. It's the lifestyle. That's the first line. But besides that, it will be the ovulation induction for conception. OK. So let me ask w which is better medical intervention for obese women with PCO D diane 35 YZ. Well, it depends on personal response. Uh Dyane is usually favored because it has the best effect on hyperandrogenism like acne or hirsutism, Danet has become the first line pill in many of the countries, many of the health care guidelines. Uh Yasmin is another one. it tends to have less uh fluid retention effect. So some women prefer Yasmin because it has some sort of uh less fluid retention effect, which may, which may happen with other pills which bloating and fluid retention can happen. So again, it's personal preference slightly. Uh you can choose one or the other uh depending on which one you respond to. Better. Perfect. Next question from Usama, we've got two here. If we use ovulation inductions, there, there are how much chances of multiple pregnancies and what can we do for prevention of multiple pregnancies? So, ablation induction, usually if you do with Clomid, the chance of multiple pregnancies 5 to 7% with letrozole, it's less than that 2 to 3% or even lower if you use scans. And if you're using gonadotrophins, then it's up to 12 to 50%. The way to reduce multiple pregnancy is use the lowest effective dose and aim for one follicle. So the most important intervention here is the scan. If you're scanning patients at least once a week and you see two follicles or more developing, there's a chance of multiple pregnancy, you may want to not continue with that cycle. You might want to redo the cycle with a lower dose where you get one follicle. That way you will actively avoid having multiple follicles and multiple pregnancies. In practice, some tend to treat PCOS with hormones, estrogen. Is it effective or does it disturb the cycle's hormones more? No. So remember with PCOS, the problem is anovulation, there is an excess of androgen, there is insulin resistance. The egg is not being released every month. Estrogen levels are pretty fine. So what you're effectively trying to do is reduce the androgen, reduce the FSHLH which are causing the problems with ovulation, giving somebody ethinyloestradiol, which is the synthetic estrogen in the pill suppresses your own estrogen suppresses your own FSHLH. And that's why you become uh you have artificial periods, no ovulations on the pill, but you reduce the testosterone and the SHBG increases which mops up any testosterone in the blood. So the androgenic symptom, the acne, the hirsutism will disappear as long as you're taking the pill in the background. The pill is not doing anything, just suppressing your natural periods. Ok. When do we start screening for HTN or DM? In young women who had history of P CS after it resolves. Well, I would start at a very young age. So prevention is always better than diagnosing a condition when it happens. So if you diagnose somebody with PCOS in your clinic today, that's when the clock starts. So I for example, would recommend that they have an annual check for their weight for their waist circumference BMI and BP every 2 to 3 years, they have a check for a diabetic screen and a cholesterol check. All that has to start right in the beginning because once these women tend to gain weight, they get through the high BMI, then it's very difficult journey for them, for the symptoms, for the problems with periods and everything that follows. So start early with regular checks at least annual basis for these women. Perfect. Some patients don't suffer from obesity. So is Metformin also necessary or, or they have the risk to be obese? No, so you can individualize patients. Metformin will usually be more useful in women with high BM. I having said that women who have a high LH and although they may have a normal body weight but have irregular periods or anovulation will still benefit from Metformin, it's important that they tolerate it. Some women may not tolerate Metformin in that situation, but some actually do very well. And these are women who will then drop their LH, drop their androgens because you're making insulin work better. They may still benefit although they may not have high BMI three more. What if patient was told PCO S has regular? What if patients was told PCO S has regular period with normal BM I? But somehow A MH is between eight and nine and high testosterone level free and total. Do you still recommend patient to take D hea to increase fertility chance or for IVF I don't recommend DHEA to anyone. The current studies on DHEA in relation to improving ovarian reserve or IVF response or fertility response. They're not good enough for me to recommend this to any of my patients. I know dhe is commonly used in low variant reserve infertility units. But if you take a neutral standpoint and look at the actual scientific evidence, there is no evidence or good scientific evidence that it helps. So again, on a no harm empirical basis, some units use it. I don't recommend it. OK. Uh Gabriella ask her question is uh can PCO S cause vaginal or vulva atrophy? And can an individual with normal BM? I have PCO S? Yes. So PCOS will usually not cause vaginal vulval atrophy. There will be some other cause because PCOS has normal estrogen or in sometimes even slightly higher estrogen levels and vaginal or vulval atrophy is usually down to lack of estrogen such as premature menopause or menopause. So if you're having uh if someone has vaginal or vulval atrophy, it's probably not PCOS some other pathology alongside of PCOS, it could sometimes happen as a result of pill. So pill can sometimes cause your natural estrogen to drop and you might find that some women have vaginal dryness, but that's different from having vaginal atrophy, which is usually hypoestrogenic cause uh you can have normal BM I and PCO S Absolutely. OK. Used two long words that I'm not sure if I'll pronounce properly. Um I think I can see uh question there what if, if it's only hirsutism and no acne, can we still prescribe Spiro? Yes, you can. Spiro helps with both excess hair growth, hirsutism and acne. So you can definitely try that. Thank you. And finally, I think it's Priscilla, right? Uh For long term management of PCOS annual checks for weight hypertension diabetic screening. Would you recommend working with a gynecologist and, or an endocrinologist? Or is it primarily managed by GPA lot of GP si know, manage this at the primary uh care. So they do actually look after their patients, ask them to get actively involved in the care. Remind the GP once a year, once every 23 years to actually have these monitoring checks. But there are some GPS who may want to have a referral to a specialist clinic, get some guideline plan for these patients and then follow it up. It's individual choice. I would say the GPS are perfectly uh in a, in a good place to do this unless there are real resource constraints. Uh and that's something that needs to be balanced against uh providing the monitoring care. Anything else, any other questions exactly what I was gonna ask? And I was just about to, I'm trying to get the link for learn with nurses because learn with nurses have some incredible events and Vikram's on, learn with nurses. Um but I've got their er, I've got the, the link, I've just put it in the chat, learn with nurses I know it says learn with nurses and some of you are maybe doctors or wanting to be doctors. But honestly, they cover such an array of topics, don't they, Vikram? It, it really is a great um webinar to pop along to and they host them all the time. Every week comes with certificates, the same as us, comes with certificates, uh feedback and certificates. So please do follow them, log, log in and have a look at some of their stuff. Cos Vikram does talk on, on, on there too. Um, so does anyone have any more questions? Um, do pop them in? No, I think everyone's very happy with what they've received. It was really good, really informative. As I said, your feedback form will be in your inbox. Now, um, uh, if you can fill it out, what I'll do is once we've got in about a week's time I can send all that feedback on to Vikram and who knows he might decide to do something more with us in the new Year. All right, everyone. So we'll say goodbye to everyone now. Er, take care and we'll see you at our next event.
