NOTE: This podcast discusses Polycystic Ovary Syndrome (PCOS) which has recently been renamed Polyendocrine Metabolic Ovarian Syndrome (PMOS).
Click here to learn more about the PCOS to PMOS name change
Hello, everybody. Welcome to the Journal Club Global of Fertility and Sterility. We are broadcasting from Paris, France at 7 p.m. But we also have participants from the other side of the ocean.
We are going to discuss a publication on international evidence-based guidelines for the assessment and management of PCOS. PCOS is one of the most frequent endocrine disorders that exist. And for this discussion, we have the pleasure of having world experts to actually present those guidelines and then discuss them.
I will let Paul Pitea to introduce those participants. And I wish you a pleasure time participating and listening to this Journal Club Global. Welcome to everybody.
Hello, everyone. So my name is Paul Pitea. I'm actually in Paris, too.
But from Europe, we actually have Madeleine Banvelli. So in tonight's topic, we're going to cover the new guidelines for the management of PCOS. And for this, we're going to have a presenter, Dr. Dokras, who is actually Executive Director of Women's Health Center for Clinical Innovation in Planned Medicine.
And actually, she's a co-author of the paper. Unfortunately, Professor Laban had some technical issues and will not be able to join. So hopefully, we have Anja here with us to help us.
Also, as discussed, we're going to have, as mentioned, Madeleine Banvelli, which is an epidemiologist in Amsterdam University. She's leading the Cochrane and the SDI group in Amsterdam. But most importantly, she's a methodologist editor in Human Reproduction Update.
So hopefully, she will try to put questions for the author of the guidelines. And last but not least, we have Richard Legro, who is actually Department Chair in Obstetrics and Gynecology at Penn State College of Medicine. And he has written so many on PCOS, and we count on him for a good question.
So, Dr. Dokras, please, you can start presenting your screen and slides. All right. Thank you so much, Paul.
And I know I have an unfair advantage as being one presenter and more people to ask questions, but I'll do my best. So here, I'm going to go ahead and share my screen, and let me know if you can see the screen. Perfect.
You can see the full screen now? Yes. All right. Hello, everyone.
So we are going to start off with giving you first an overview of the guideline development process, just very briefly, because, as you know, these are international guidelines, and a lot more work goes behind the scenes compared to guidelines which only come, say, from North America or Europe or one particular country. So we had initially published guidelines in 2018 and had the GDGs, which are the guideline development groups that you see written here in the pink part of the circle, and some of these groups were modified depending on the scope of what was going to be discussed for the 2023 update. These guideline groups came together.
They sourced the scope by surveys of patients as well as healthcare professionals, and once those questions were put together, the PICO questions, between May and October of 2022, can you see my pointer? There was just a lot of background work in terms of the systematic review and evidence building, and up to about 52 systematic reviews and meta-analyses were completed that then informed the formulation of the guidance. Many of these meta-analyses are now in the process of being published, but you can also access the details in the technical bulletins. And then from November to February, all the GDGs got together.
I was chairing one of them, the GDG2, and our work really was to look at that evidence and then formulate the guidance. And believe it or not, there are 254 different recommendations as well as practice points. By no means am I going to cover all of that today, but we'll just give you some highlights, and then we're going to do more question-answers, but I certainly recommend using it more as a reference as you come up with the questions as you manage your patients.
And so this is part of the dissemination process today that we are going around conducting webinars and participating in a number of these symposia to get the message out. So the first GDG looked at the assessment and management of PCOS diagnosis and screening, and this is a brief algorithm or a synopsis of the diagnosis as well as I'll go into the risk assessment and lifestyle stages in the next few slides. But essentially step one is if your patient has irregular menses and clinical hyperandrogenism, and then you've excluded other mimicking causes such as hypothyroidism, hyperpalatinemia, et cetera, you can establish the diagnosis based on these two criteria.
If the patient does not have clinical hyperandrogenism, then one can go down the algorithm and test for biochemical hyperandrogenism, again, excluding other mimicking causes, mainly like the adrenal tumors. And then if they only have irregular periods or hyperandrogenism, one or the other, then the recommendation would be to get an ultrasound and an AMH level in adults or an AMH level, not an. And then in adolescents, neither of these are recommended.
So we are using just the two criteria. I have a few slides that I quickly added in to elaborate on what we mean by the clinical hyperandrogenism. And so we've kept that modified FG score of four to six, and that range is primarily because we recognize that there may be some variations with ethnicity, so that has not changed from the prior guidelines.
We continue to emphasize that it's the total and the free testosterone levels that should be evaluated and assessed, and, in fact, have made a specific point of saying that androstenedione or DHEAS have poor specificity, especially if the total and free testosterone is not elevated. And really, again, strongly recommending using validated assays such as the mass spec. And then the third criteria, just to, again, remind the audience that we did not change anything here.
The follicle number per ovary is still 20 or more. The one thing that got added in is the follicle number per section, which is equal to or more than 10, could also be used. And these are just the criteria for polycystic ovarian morphology.
What everybody was waiting for and probably very excited about is the inclusion of AMH. So now there's enough evidence to say that AMH can be used to define the polycystic ovarian morphology. It should not be used as a single diagnostic test for the diagnosis of the entire syndrome, and it should not be used in adolescence, same as we're not recommending the ultrasound criteria in adolescence.
And here is the forest plot showing the evidence as to why AMH was included in these 2023 guidelines. However, there's no real cutoff the same way as we don't have a cutoff for the total of free testosterone levels. And we are really suggesting looking at your own local assays and the range, whatever might be applicable, in terms of determining what that upper limit is.
So these are sort of the controversies, and there have been challenges with these diagnostic criteria. I just mentioned the defining cut points has been hard. I think we've done a good job over the years now transitioning from that original NIH to Rotterdam, and now this evidence sort of confirms and reaffirms the Rotterdam criteria.
So that's how I would conclude that the diagnostic criteria within the international guidelines provide us evidence to confirm the original Rotterdam criteria with some nuances in terms of just strengthening some of that evidence. But more to be done, and by no means are these perfect, and I think we all recognize that. The one other thing that got added here in terms of the long-term risk evaluation is that there is more data based on population studies to suggest that there's an increased risk of myocardial infarction, and I'm looking to see on the slide where that shows up.
But I think these three different ones are showing you the increased risk for myocardial infarction, stroke, as well as coronary heart disease. Thank you so much. Am I allowed to ask a question? I think so.
I think the slide comes up later, but we have now said that there is enough evidence to consider as a coronary disease risk, and hence we should be assessing these risk factors. So moving on then to GDG2, and we looked at the assessment and management of PCOS emotional well-being. And again, not a lot of new data here, a little bit suggesting that there is reduced quality of life for our patients, and it's across all the different domains depending upon the different surveys that we use to assess quality of life.
There's a lot of data supporting an increased risk of depression and anxiety symptoms and scores. And what's new here is the study in the adolescents. So the earlier forest plot here is for the adults, and then this is for the adolescents.
So fewer studies, but the signal is consistent with the higher risk. And as a result of which, just going back, that in the recommendations, we now say that at the time of diagnosis we should be screening adults and adolescents for depression, but we should be screening adults for anxiety, and there isn't adequate information in terms of adolescents. Going on to GDG3, and this is looking at assessment and management with respect to lifestyle.
And so we again recognize that a healthy lifestyle is really important to prevent excessive weight gain. And for the overweight or obese patient, a goal of about a 5% to 10% weight loss is what is recommended. There's no specific diet for PCOS that has really been proven to be better than any other diet, but a combination of dietary intervention as well as exercise is included in the recommendations.
And similar to previous recommendations, it needs to follow sort of that smart algorithm of specific, measurable, activating, realistic, and timely. And psychological weight gain is really important, and what we talked about in GDG2 is really screening also for eating disorders and the anxiety and depression because if patients have any of the psychological factors that impact their ability to engage in lifestyle modification, it's going to be hard for them to then achieve these healthy goals. And then finally, we also talked about having a multidisciplinary and a patient-centered approach in our models of care, but no specific model.
There's really not enough research to indicate that any one specific model of care works well for this population. Here is a nice summary, and there are a few figures within the guidelines which I think are very useful. There are also a number of patient-friendly handouts that you can download from the Monash University website, but I'm not going to read all of this, but this is a nice synopsis in terms of the recommendations for exercise.
So this is the figure that shows the metabolic risk assessment, and very few changes compared to previously where step one is sort of the weight and the BMI assessment. Step two was the glucose screening where you can see in number A, it includes the oral glucose tolerance test or fasting glucose or an A1C. So it's not only an OGTT anymore.
The other recommendations didn't change, and then the blood pressure checks. Lipid screening becomes more relevant because now we are recognizing PCOS as a risk factor for long-term cardiovascular and cardiometabolic risk. We still have limitations in terms of how frequently one needs to repeat these, and then what was new was the obstructive sleep apnea data, which was pretty strong to consider at least screening, and then maybe a sleep study would be needed if the patients tested positive on the initial screen, and then to increase awareness of the risk of endometrial cancer.
So then moving on to the next GDG group, which looked at treatment of non-infertility issues, and the first-line treatments remain the lifestyle modification as well as then the combined hormonal contraceptive pills. And again, we have a very nice figure here that goes over the different choices that are available, but the bottom line that is in the summary is that there is no one specific preparation that is superior to any other. We recommended using the lowest-dose pills that the patient would tolerate and had adequate control of their symptomatology, and giving enough time, so not to switch very quickly.
For example, this particular box says hirsutism requires treatment for at least six months, so being aware of that, and then also considering the other risk factors, like if our patients have a high BMI, if they have some dyslipidemia or hypertension, keeping all of that in mind as we prescribe the birth control pills. This is a summary for the second-line therapies, and so the second-line therapies could include the addition of metformin, and there are a few studies head-to-head that looked at that comparison. The real recommendation here is one could consider it in an overweight or an obese population.
The addition of the antiandrogens, again, there were not many studies that were added in this iteration of the guidelines, but if there's a suboptimal response after a minimum of six months, then the recommendation is to consider these additional therapies. And then similar with respect to metformin alone, one could consider that in somebody with a BMI of over 25 if they were not already included in this first group along with a birth control pill. So here are some of the forest plots, and as you can see, a few studies, and some of them that got added with the next versions of these guidelines.
Prior to really helping our patients get pregnant, we do want to make sure that we discuss the impact of PCOS on pregnancy outcomes and use that as an opportunity to ensure that the patients are healthy prior to getting to that antenatal time period. And so, again, these guidelines that were added here more specifically ask healthcare professionals to recognize that pregnancy can be a high-risk state for a PCOS patient and to review some of these complications with them prior to helping them with their fertility journey. And so what is that infertility treatment? So here is the very nice algorithm.
It's the number 5 for GDG5, and essentially if you go down the blue line here, that's the algorithm or the pathway for the best practice evidence. And this box, I think, is really important that a lot of time was spent on optimize that preconception health and lifestyle prior to starting off with the oral agent, so letrozole, and there's adequate data now to support that letrozole and evidence-based recommendation that letrozole should be a first-line treatment and can increase the doses required. And then the evidence shows that clomiphene plus metformin is preferred to clomiphene alone as the next line, and then clomiphene alone or then metformin alone.
And really, metformin alone is a low-cost, low-efficacy, no-monitoring, so it's not really the preference, but was added more in an algorithmic manner, as were the gonadotropins. But if there's no ovulation detected here, one can then go down the algorithm to gonadotropins and not much changed in these boxes with second-line therapy or IVF, which hopefully would be just a few patients for that particular, that need to go all the way to IVF if it's the only diagnosis, this is PCOS. I think this was included earlier, and this is when I was trying to swap in some of the slides, but just to ensure that we talk to our patients about the risk prior to helping them get pregnant.
So I think that was my last slide there. Thank you so much, and I'm happy to take questions along with the other people on the screen. And let me make sure I can – did I stop sharing my screen? Not yet.
Do I need to click something, or we're good? You can go and stop. If you want to show some slides that you want the audience to see all the time, it's perfect. In the meantime, I just want to mention to the audience that they can ask questions in the chat.
So please ask questions. Those will be actually posted, those who you want them to ask for. So please don't hesitate for questions.
So thank you very much, Dr. Drokras, for the nice presentation. Now I'm leaving our two discussants to see whether they have questions on your talk. Well, of course we do.
Wonderful. Thank you. First, congratulations on this huge job.
It's, of course, a wonderful, wonderful article and so helpful and needed. When we go back to diagnosis, PCOS at our center is mostly diagnosed on basis of oligomenorrhea or amenorrhea and PCOS on ultrasound. And so the new thing of this guideline, I guess, is the addition or the possibility to use AMH instead of looking at the polycystic presence of PCO.
But how do these two compare when you will take as golden standards the Rotterdam or the PCOS criteria? So just going back to the first part of your comment. If PCOS is only diagnosed with the first criteria, which is the irregular periods, and then the third criteria, which is the ultrasound. We view that as the phenotype D, right? It's the reproductive phenotype.
And in terms of counseling the patients about their long-term cardiometabolic risk, I think it's really critical for the patient to know, as well as the healthcare professional, if they have the second criteria, which is either clinical or biochemical hyperandrogenism. There are studies that show that it's the biochemical hyperandrogenism that sort of is associated with the higher risk of cardiometabolic comorbidities. So the way our algorithm was even in the 2018 guidelines is that you make the diagnosis based on the irregular menses and the hirsutism, and you really don't need the ultrasound.
But if you get the ultrasound, that's an add-on to tell you if you have the complete phenotype. So in my mind, and I'd be curious to see what Dr. Legro thinks, because I know he was attending to something in the background while the question was asked. But it was more, Madeline was talking about how at her center, the diagnosis is typically based with irregular menses and an ultrasound.
And so I was going down the algorithm to say the importance of either confirming clinical or biochemical hyperandrogenism to counsel our patients about their long-term risk. Otherwise, we only know about their reproductive phenotype. We don't have a good sense if we don't evaluate the third phenotype.
Do you have comments on that, Rick? Yeah, I think I would echo is we know that whenever hyperandrogenism is present, that likely the reproductive and definitely the metabolic phenotype is worse. So I think it is always good to characterize patients for hyperandrogenemia as well as the ultrasound morphology. And then going back to your other question was how is the correlation between AMH and the PCO morphology, right? Was your second part of that question, right? And can you really now just swap out, which might be so convenient for our patients if they can just go and get blood work and not have to stop at a radiologist's office, depending on the different health care systems, and not need an ultrasound at all? I think our colleagues who are medical endocrinologists and the GPs and internists would love that option.
For us as reproductive endocrinologists, I think we get ultrasounds anyways. I find it's really nice when the patients, you know, know that they have a certain antral follicle count. You can reassure them and have the whole discussion about fertility that I have my own biases to get the ultrasound.
But I also understand that we have several ultrasound machines in our offices. So it's convenient. But the correlation between the PCOM, the morphology, and AMH levels is pretty high and strong.
And I think that signal has been there for a while. The challenge was because of the lack of standardization of the assays that the cutoffs and what does one recognize as a cutoff for diagnoses has been the bigger challenge. And so I still believe that implementing AMH might be a bit of a challenge, even in our own practice here.
The upper end is so variable in the report that we get from our lab that I don't think. And that's also what you see in the first plot. It's quite a lot of heterogeneity and that makes it more difficult to interpret.
Yeah. Yeah. So I think if it's clearly above the normal range and you can say, OK, now you get you have the third criteria.
But again, if you are following the algorithm and making a diagnosis based on irregular menses, the hyperandrogenemia, and then this is the third add on. I think you're going to be pretty accurate. Thank you.
We can't hear you. But we can't hear him. OK, so while Dominique is fixing the microphone, I have a question from the audience.
So with regard to laparoscopic drilling, the first question, do you measure AMH before it? And what is the level where you accept drilling to be performed? I don't think as part of the guidelines, we really looked at AMH levels to make the recommendation for laparoscopic drilling. It was more after the drilling. What is the success in terms of ovulation? Rick, were you on that GDG for fertility or were you on the first one? I was on the infertility one.
Did you talk about laparoscopic ovarian drilling? We probably had about a five minute conversation about it. And I think at least although the group I think was was fairly worldwide in representation. I think that most people and this is a question I'll have for you later, are moving on to IVF if the first line therapies don't work.
So and there was really no new data about ovarian drilling, ovarian diathermy from the prior guideline. Right. So Paul, from the way I'm understanding your question, I'm not sure if people are really choosing LOD based on an AMH level necessarily or just failure of first line therapy and a failure to ovulate to the highest doses of be it letrozole or you try second line clomiphene with a combination of metformin.
And then if there aren't any resources to use gonadotropins, if it's too expensive to go on to IVF and one needs to try LOD, then that becomes the second line for the algorithm. And it wasn't a question within the guidelines. It wasn't a PICO question to say, is there a certain cutoff for AMH to recommend this? So that wasn't really looked at.
But I agree with Rick. There haven't been many studies in the interim to even support some of this data related to LOD. Yeah, I fully agree with that.
I think that there is not much data. And of course, nowadays, people switch to ART before going to surgery and so forth. Dominic, now we can hear you.
I'm back. I have a question. I mean, this document puts a new emphasis and a strong one on the depressive symptoms.
My question is, is there any connection between this and hyperandrogenism? Or is it overall across the board of PCOS, including those that do not have hyperandrogenism? Yeah, these are very good questions, Dominic. And so we have a number of studies now from different world regions showing that depression scores are elevated in women with PCOS. Independent of BMI, there aren't many that have looked at it with the PCOS phenotype.
So going back to your question, hyperandrogenic, where is the non-hyperandrogenic phenotype? We're lacking that data in terms of that correlation. And so I don't think we have a good answer. The moderate to severe symptoms are high.
There are a few studies that have also looked at the actual DSM diagnosis of depression. But we don't have much data that has separated out based on hyperandrogenic versus non-hyperandrogenic. So the recommendation right now is let's screen all comers, because we do believe that maybe the underlying reasons why we see this high prevalence could be multifactorial.
Right. It could be body image distress, infertility, just a lot of other things that are going on. Versus is it truly related to the pathogenesis of PCOS and is there a link with the high androgens? There is an animal model with our colleague Lisa Vittorin-Stenner's lab at Karolinska that does show that a PCOS animal model strongly links with anxiety-like behavior.
Oh, that's interesting. Thank you. I also have a question on this.
I would just add, I mean, it's long been known that depression is associated with hypercortisolism. I think the link with hyperandrogenism or hyperandrogenemia is less strong. But we know disorders like bipolar syndrome, for instance, have been associated with both the development of polycystic ovaries and with hyperandrogenemia in those patients.
So, I mean, I don't think it's certainly not unprecedented that psychiatric and mood disorders can have a corresponding reproductive phenotype. But quality of life and depression and anxiety, they're not only worse in PCOS, but also in other fertility disorders. I mean, similar results have been found in endometriosis patients and unexplained infertility in male infertility even.
And the comparisons in PCOS were mostly done women with PCOS versus women without PCOS. No selection on infertility was usually made. And the population that come to the clinic, these are infertile patients.
These are most relevant to us. So. I mean, is this special then for our population for PCOS or should we give this attention to all our patients? You bring up a very important point, and I think, you know, one could sort of and hence one could say just let's screen everybody and not have a selection.
And of course, you're saying even broader outside PCOS, maybe we need to consider screening in the general population. The data and, you know, they will we will be publishing the meta analyses that will be updated for 2023. But in 2018, we specifically looked at the referrals to the medical endocrine kind of academic clinical setups versus the infertility to try to get to the bottom of that question.
That is that is this a comparison with the infertile population and is there an adequate representation in the two groups? And and so there is some data looking at that. Again, fewer studies. So so I hear what you're saying and I think we have to be aware of that.
Even just obesity in the general population is associated with a higher prevalence of depression. So there's so many risk factors here for our population. I don't think we go wrong by screening them, because if we are going to pick up a signal in a large proportion, this is our opportunity to intervene and help them.
May I go for another question? This regards treatment, and we agree that the pill is probably the first line treatment. My question is, I didn't see any discussion on possible differences as to whether the pill is taken on a 21 day basis with a one week pose versus continuously. Evidently, data, even outside of PCOS, have shown that during the seven day pose, there is an increase in FSH and a re-increase in follicular activity.
And you might deduce that there is also a re-increase in androgen production. So is there any evidence that the continuous treatment, possibly with a pose every three or four months, is superior to the intermittent 21 day out of 28? Yeah, Dominique, I completely agree with you. The 21-7 or the 24-4 pattern is not really recommended in PCOS if you think about we are trying to suppress androgens, and why do we need a break, right? So I think a lot of us agree with it in theory.
From what I recall, it was again not a PICO question. So the way the guidelines are framed are, there's a set of questions that get prioritized, and then they do the systematic review, look for the high quality studies, and try to see if there's enough evidence to give an answer. Not all of these questions, which are all very relevant for our patients and important, were not included in the guidelines because they did not get that priority.
And as you saw, we still have 254 recommendations or practice points. So I don't think, from what I'm recalling, that that was a specific PICO question. I've heard this being discussed several times, and I don't know if in the PCOS literature there's enough evidence for us to go one way or the other.
But as a practice point, a number of physicians do use continuous pills, just like you described, and then give a break every third or fourth month, primarily if the patient has breakthrough bleeding kind of symptoms. If they don't even have that, I have sometimes had patients just continue because they're doing really well and they're quite happy to be on a continuous pill. Thank you.
I just want to ask, actually, in your opinion, what is the role of metformin in first-line treatment for non-infertile patients? I think that was looked at as a PICO question, and maybe I had that on the slide, or you had included that on the slide. Yes. Oh, can we hear you? Did somebody say yes? Yes, it's in the algorithm form, but I just wanted to emphasize on that because I think it's important for attendees to see that.
Yeah, I was going to give you an opportunity to talk if we could hear him. I wasn't sure if we could hear him. No, you cannot hear him.
Okay. So the metformin by itself is recommended for prevention of cardiometabolic risk factors, and I think it was the cutoff as a BMI over 25, so overweight or obese patients. It's not necessarily a weight-loss medication.
I think we all recognize now with the several very effective weight-loss medications on the market, metformin pales compared to that. So it's more generally for the prevention of cardiometabolic risk that we can initiate the treatment. It's a hard one because we then don't know when to stop the treatment, and do we just leave our patients on it for long periods of time? So I think the quality of that evidence is pretty low, even though there's a recommendation.
What I would suggest as people look at these guidelines, to look at that very last column, and that gives you a sense of the grading as to is this high, moderate, low quality and the level of evidence, because we could have a guideline recommendation, but I think you have to look at where did that recommendation come from and what's the quality, and then use that evidence in a more personalized manner for your individual patient. Thank you. And I think I would add to that.
I mean, dysglycemia is defined by an impaired fasting glucose, impaired glucose tolerance on a 2-ROGTT, or prediabetes by a glycohemoglobin level, to me is an indication for metformin for studies done outside the PCOS world for the prevention of diabetes. So I think that dysglycemia, which is recommended to screen for, is an indication for metformin. I would like to... Sorry.
I would like to ask a question to Rick, particularly, but to everybody else as well. In one of the numerous articles that Rick had in the New England Journal of Medicine, how many people have so many? I don't know. But Rick compared letrozole and clomiphene.
And the difference was in favor of letrozole, but particularly so in the obese patient. Is this... First of all, why? Do we have any indication as to why the difference is more pronounced in the obese patient? And second, is this still true? So why? I mean, again, aromatase is present in many tissues and certainly in adipose tissue. So again, letrozole is working everywhere, right? Ovary, adipose tissue, brain.
So I think primarily it's inhibiting peripheral conversion of androgens to estrogens in those women, in the obese women. And is it still true? I mean, I can't tell you because I think one of the things that came out of the guidelines that Dr. Teague shared with us during ours is that the clearest evidence of which there were four circles and four stars was that letrozole is the first line infertility treatment. It beats everything else, whether it's clomiphene or network meta-analysis compared to other treatments.
So, I mean, that's the strongest treatment. And again, Don, we can debate, just like we still debate, why is clomiphene effective? And we might not understand it. And for, you know, the neurologists of the world, I mean, I don't think they understand any anti-seizure medication, how it works.
So I think we're among good company of not fully understanding the mechanisms but welcoming the results of the therapy. Okay, thank you. Rick, I think the follow-up question, though, and I'm also curious if you looked at that is, is there any difference based on BMI? Is one option better than the other? Or was it addition of metformin? Was there a PICO question that specifically asked if we would counsel our patients differently? Well, in the network meta-analysis that we did that was in the BMJ about two or three years before it, it appeared that, again, I can't say about letrozole versus clomiphene, but at least in the network meta-analysis, the patients that benefited the most from clomiphene and metformin were those with a BMI greater than 30, maybe even 35.
But certainly obesity are the patients that would benefit from combined therapy. I mean, one of the questions from a grant that never got funded is, I wanted to look at the combination of letrozole and metformin in obese patients compared to letrozole alone. And that question has been asked at some of the presentations that you and I and others have given at national meetings, and there's really no evidence to support that right now.
So, again, that's something well worth studying for all you hungry young researchers out there. It's, I think, a question worth studying. So, I will have a question, given that you have mentioned the diverse pregnancy outcomes.
Now, the question is, would there be a cutoff for the BMI for women before conceding, given that obesity always goes hand in hand with polycystic ovaries? And so there's been a lot of debate in terms of, is there a cutoff when we discuss IVF? But for general ovulation induction, in general, I haven't heard as much debate in terms of cutoff, because with the epidemic of obesity, our population tends to be more overweight and obese. You know, the question is, do we believe in them being metabolically healthy, and you could have a high weight on the scale, and then that's okay? Or are we going to just look at the scale, and if they go through that screen and the hypertension numbers are good, lipids good, 2RGTT is good, is that okay to proceed? In my mind, I think if our patients are metabolically healthy, you know, I think that's the first line of action. And then giving the general counseling about weight management, because clearly weight will go up in pregnancy, and there are more adverse outcomes as the BMI goes up as well, is all important and relevant.
But again, in my mind, I don't think there's an absolute cutoff for the ovulation induction part of it, or the oral ovulation induction part of it. When it goes to IVF, there are cutoffs just primarily because, at least in the U.S., some of the IVF centers are in sort of standalone buildings, not near a hospital, and they just don't have the ability to take care of patients at a higher BMI safety. Everyone agree with that? Rick, do you have a comment? Okay.
I'll say one thing. I think that a lot of the BMI cutoffs are largely coming from countries with fertility care covered, and it's a way, I think, to, if you want my opinion, limit care, because there's not good evidence that women with mild obesity really have horrible obstetric outcomes. So in the U.K., it's a BMI, I believe, of 35, and in Australia and New Zealand, it's a BMI, I think, of 32.
But I fully support for what you were saying, Anuja, that these patients are likely going to respond fairly well. I think what we worry about is super obesity in the U.S., which we call BMI greater than 50, and I think they're definitely in a lower prognosis of responding to ovulation induction and certainly a much higher chance of obstetric complications. I think that's a different category to consider.
Yeah. But, Paul, I think what the data shows, and there are a number of studies that have looked at pregnancy, adverse pregnancy outcomes, and these hold true even when they control for BMI. And for BMI match studies or controlling for BMI, there is a higher risk of gestational diabetes, preeclampsia.
So I think there is a real risk in this patient population, independent of their obesity status, but it sort of emphasizes that we need to use that preconception period, not just to say, here's your birth control pill prescription, come back and see me whenever you're ready to be pregnant. I think we need to engage with these patients and help them get as healthy as possible for the day when they're ready to start their sort of fertility journey. Yeah, that's a great thought.
I mean, I like both of your answers because that's true. I work in a country that fertility care is free, and therefore we limit access to care through some kind of cutouts for overweight. And this is why I wanted to see whether there is real evidence behind it to support it.
Clearly, just, I mean, 35 is probably where it stands, and therefore we can probably start ART to go forward. Now, there is a question from the audience. Paul, can I just clarify that? That's really only for ART that you're talking of the cutoffs, and the majority of women with PCOS, if PCOS is your only diagnosis, there's no male factor, tubes are open, are not needing IVF, right? I think if we are patient and engage in enough cycles of ovulation, these patients should have a fairly good chance of getting pregnant without the use of ART, and then the cutoff would not be an issue.
Exactly, yeah. Yeah. So there is a question from the audience.
What about endometrial receptivity and embryo implantation in PCO patients? Do they have a role? Does Letrozole or metformin help? Oh, Dr. Legro just dropped off, and I was going to let him answer since he was on the fertility guideline. He's back. I'm still here, yes.
Well, first of all, how do you assess endometrial receptivity? I think we can agree that there's a lot of debate that there's no valid test of endometrial receptivity, whether it is a histologic test or whether it is a molecular test. I think everything has always fallen short when it's been scrutinized, at least in randomized trials. I do think what we can assess is the serum milieu of the response, and I think what Letrozole does compared to clomiphene, at least when you study it in the luteal phase, it gives a higher progesterone level with Letrozole than with clomiphene, and a more physiologic, let's say progesterone to estradiol ratio than you get with clomiphene, which tends to have, I think through its multifollicular recruitment, more of a superovulation effect on the endometrium.
And I would go so far to say that the more physiologic response of the ovary to Letrozole mimics a natural cycle more than clomiphene. I would like to emphasize the fact that, and I appreciate that, the guidelines indicate that the incidence of PCOS is essentially the same all across the world. And this goes against a common belief that there are areas of the world, like the Middle East, where there is an increased incidence.
I think it is good that the guidelines have reset the numbers right. There are people whose tendency to have hirsutism because the follicular growth sensitivity to androgens is increased. But in true fact, the incidence of PCOS is probably, as the guidelines say, roughly identical across the world.
Do you want to comment on that? You're absolutely right. And we've spent so much time on talking about under-diagnoses of this condition and not enough people getting the diagnosis at the right time. But we also have concerns about over-diagnoses.
And this is in certain world regions, be it because of increased hirsutism or be it just because of the epidemic of obesity. In the East and Southeast Asia, as the population in general, the weight has gone up, there has been sort of an eagerness to label a lot of the young women with the diagnosis of PCOS based on difficulty losing weight. And the non-traditional PCOS diagnostic criteria, right? It's not the criteria that we have been trying to emphasize.
So we need to caution healthcare professionals at both ends. Do make a diagnosis and make an accurate diagnosis, but also don't over-call and make an over-diagnosis. Thank you.
Yeah, Dom, I'm just going to echo. I think one of the things, when you look at the forest plot of prevalences and incidence of PCOS, it's really quite extensive, the amount of data. And there's data from all four major continents, nothing from Antarctica yet.
I don't think we'll ever get anything from there. It would melt. Yeah, but, you know, I think it goes along with what, you know, what we, you know, Joep and I and others have seen in the genetic data that there's basically been large GWASs in Chinese and mainly Northern European Caucasians.
And the genes they identify strongly overlap, you know, so implying, again, that this is a worldwide disorder with some common roots and common prevalences. And I think that's part of it. May I ask another question related to over-diagnosis? Because the guideline recommends to use all kinds of screening tools in these women to look at sleep apnea, depression, anxiety and more.
And is it doable for clinicians? I mean, there's quite a lot of women with PCOS and about half of them will have a mental disorder. And what are we going to do then? Are we going to send them to psychologists? Are they available? So is this realistic then? I think if you ask the core question of should we be helping our patients and treat them all, then the answer is yes, that's the right thing to do. Then the next level is can we do it and which health system can do it the best? We clearly have a lot of constraints in the U.S. with our health care system.
And there isn't much published in terms of the models of care that are going to help best for PCOS. But I think understanding that PCOS is not a gynecologic disorder alone, understanding that it's an endocrine disorder that has reproductive manifestations, cardiometabolic and psychological, if you think about it that way and think about it as a bigger picture, then I think we might start making the referrals. And the ideal way would be a primary care physician taking care of these patients, not necessarily the subspecialists you're seeing on the screen here.
And then this escalation. Then if you have the mental health issues, you go to so and so. If you have the reproductive issues, not everybody is going to need help from a fertility doctor.
Not everybody is going to get the diabetes. But it probably needs to be the primary care physician that then looks after a lot of these different aspects of the syndrome. Patient organization in the Netherlands, they really ask for PCOS polyclinics.
Yes. Yeah, that would be wonderful. Absolutely.
Yeah. And I think, you know, the challenge is at least in our U.S. health care, Rick and I and a few others have these multidisciplinary centers, but that's hard. And it's hard for patients to travel this far and come to these centers that are set up only like essentially in a few places.
And the way to scale that, I think, is through a primary care model. Great. I think we're getting close to the time of wrapping up this fantastic journal club.
Maybe Anja wants to draw the primary bullet points for people to remember. But before I understand that, Paul has something to say. Yes.
There's another question from the audience. Whether there is an impairment of oocyte quality in PCO patients. I think, Anuja, you're ideal to answer that.
You've studied that. Well, what we've studied is when we looked at the large SART data set in the U.S., which is a Society for Assisted Reproduction and Technologies. We looked at patients with the diagnosis of PCS alone, single diagnosis, and then use tubal factor as the control population.
And the number of oocytes was higher across the age range of the low 20s all the way up to 45. It doesn't tell us about quality. So then the next question we asked was the pregnancy and the clinical pregnancy rates and the live birth rates.
And those graphs pretty much tracked a little higher in the PCOS population, both for clinical pregnancy, live birth, and then overlapped more in the later 30s and 40s. But there have been studies subsequently as well that show us that if you make embryos and they will make more embryos because they have more oocytes. And if these embryos are frozen, then the cumulative pregnancy rates, even in an older age group, are higher in the PCOS population.
So if you want to use surrogate markers of live birth, which I think is probably the right marker when you're asking about oocyte quality, then for sure it's not impaired. It's either just as good or actually even better if you look at cumulative pregnancy rates. One quick comment that we might make is that in the past, before we used to trigger ovulation with agonists and at the time that we feared OHSS, all of us doing IVF were tempted to actually reduce the amount of gonadotropins toward the end of the stimulation in order to prevent the OHSS.
Even go to the point of coasting. And that, in essence, was bad. Now that we don't do this anymore, I think, as I agree with you, Anja, and we can say to all the audience that, in general, oocyte quality is not impaired in PCOS.
It's not impaired in the high responders. I wonder whether you all agree with that. Yes.
Yes. So, Anja, we have this journal club, European Time. This is an effort that Fertility and Stability does to actually expand the journal clubs also on different time zones.
We'll soon have some on the Asian time zone. But this was on Paris time. And Anja, could you possibly, at the time of concluding, come up with a couple of bullet points for the audience? Wow, that's going to be challenging.
A couple of bullet points from the 254 recommendations. Exactly. So, diagnosis-wise, again, I would say follow the algorithms, irregular menses, hyperandrogenemia, and then use your ultrasound or AMH judiciously and as needed.
Screen our patients because there's more there than just reproduction. So, screen them for diabetes, hypertension, lipids, of course, their BMI. And then in terms of the management, yes, currently it is still birth control pills.
But again, judicious use in terms of the lowest dose for the shortest amount of time that's needed. Addition of metformin seems to still be okay. And in terms of the fertility treatments, great evidence now for letrozole.
You've heard the discussion in terms of maybe even why letrozole might be better than Clomid in terms of its mechanism. And then some adjuvants, you know, you might add the metformin to the letrozole. I think a smaller proportion of these patients go all the way to ART, although we spend more time talking about them.
But think about the patient as a whole, a holistic approach rather than just a very narrow reproductive approach. That would be my conclusion. Anybody wants to add anything above that? I don't think so.
Are you all okay with that, Rick? Rick? Super. You did a great job. Thank you to everybody.
Thank you to Paul. It's time to actually conclude this Journal Club held by Fertility and Stability on the European-Parisian time. And I think we had a great discussion.
We learned a lot. I hope you did too. And we'll meet you again for another Journal Club Global.
Bye, everybody. Bye. Thank you.
