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How PCOS Affects Egg Quality

CHR treats some of the most difficult infertility cases and we have noticed that many of our PCOS patients aren't the "classical" PCOS phenotype, but rather, something called a "lean" PCOS phenotype. In this video, Dr. Gleicher explains the difference between the two and how they can affect egg quality throughout the lifespan.

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Hello, I'm Dr. Norbert Gleicher, and I'm the Medical Director here at CHR. One of the questions we hear over and over again asked by our patients (and sometimes even from outside sources) is, "How does PCOS or polycystic ovary syndrome affect egg quality?"And that is a really good question to ask. And it has actually remained a rather controversial issue within the infertility field. And the reason it has been (and still is) such a controversial issue is because studies have reported opposing outcomes. A good number of studies have suggested that PCOS does not affect IVF outcomes in the sense that a mature egg from a PCOS patient will have the same chance to become a good embryo and lead to pregnancy as an egg from a non-PCOS patient. Yet, other studies have concluded differently and have suggested that PCOS patients have poor quality-- meaning an egg from a PCOS patient has a lower pregnancy potential than an egg from a non-PCOS patient of the same age. So, differences of opinion like this in medicine are not uncommon and there are many different reasons why such differences can can happen even if studies are well conducted. And the most frequent reason for these kind-of opposing or confusing results is patient selection and PCOS is an excellent example for that. PCOS (polycystic ovary syndrome), in itself--in its definition--in what it represents, is a highly controversial issue. And it has been controversial for many, many decades, since that term of "polycystic ovary syndrome," was first established. And the reason it is such a controversial issue is because it is really not one syndrome, or one disease. PCOS is really a basket of different conditions and that is generally accepted. But, as we now increasingly understand, it is not different versions of the same condition (of the same disease). It increasingly seems that at least the two main, what we call "phenotypes," the two main types of PCOS, in that basket of different conditions probably have completely different backgrounds, different etiology, different causes, different pathophysiology. All they share is that at young ages women have high androgen levels (those are the male hormones) and because of that, or at least partially because of those high androgen levels, they have what has been called, or is called a "PCOS ovarian phenotype." In other words, if these women have an ultrasound done, the appearance of the ovaries is typical for PCOS and that kind of appearance is also sometimes defined as a pearl chain-like structure of follicles in the ovaries. And that is caused by the fact that women with high androgen levels usually don't have ovaries that mature eggs properly. Instead, those follicles get stuck at a certain stage of their maturation and stop growing. And so, therefore, as a consequence at that stage, they line up in the periphery of the ovary like a pearl chain and that's that typical PCOS ovarian phenotype that we see on ultrasound. So, there are two main phenotypes of PCOS which in teenage years (and even stretching into the 20s) share high male hormone levels and this PCOS phenotype. But, otherwise, are very different. Those two phenotypes are the so-called "classical" phenotype and the "lean" phenotype. And that, in a way, already describes the most obvious difference because women who have the "classical" PCOS phenotype are anything but "lean." They have truncal obesity. They have a very typical appearance often characterized by hirsutism (meaning some hair growth, not infrequently facial hair growth), acne. It's not always a very attractive picture. Maybe most importantly, this phenotype carries over into older age. In other words, it has clinical significance beyond infertility. And that clinical significance is called, "the metabolic syndrome," meaning that women with the classical PCOS phenotype, later in life, are at significant risk for the metabolic syndrome (which means besides obesity and hyperlipidemia, a risk for diabetes and heart disease). So, this classical phenotype, because it looks so different, is what even colleagues, even physicians, see in front of their eyes when they think about PCOS. But this classical PCOS phenotype represents only 40% of all PCOS patients. And the other main phenotype, the so-called, "lean" PCOS phenotype, that phenotype also represents roughly 40%. And then there are some minor phenotypes (at least under current classifications) that fill in the rest. The interesting issue here is that because the classical PCOS phenotype looks so differently, and because it has those later medical--serious medical-- consequences, there was a general belief within the infertility field that this is the "worse" of the two main PCOS phenotypes also when it comes to infertility. And that was further enhanced by the fact that, indeed, this classical phenotype usually is also characterized by anovulation, meaning women don't have regular periods-- often go months without a period-- and, therefore, don't ovulate. While, women with a lean phenotype, very frequently have completely regular periods. So, it's not surprising that, in general, when people are doing studies of PCOS, there are many more of the classical phenotype patients included than of the lean phenotype. But, the distribution between those two, obviously, can vary. And how they are distributed, now largely due to work here at CHR, we understand how it can affect research results in infertility. And today, indeed, we at CHR are convinced that the mingling of those two main phenotypes in many studies is the principal reason why there's so much confusion about PCOS in general, in the medical literature, and also about the question we are talking about today which is, "What's the impact of PCOS egg quality and on IVF?" And the answer is that it depends. It really depends on whether you are a classical PCOS patient, or you are a so-called "lean" PCOS patient. If you're a classical PCOS patient, as I already stated, you start with high androgen levels and those androgens slowly decline, but they remain relatively high even into advanced ages. Paradoxically, that protects your eggs from being affected by PCOS. In other words, if you're the classical PCOS phenotype, there is no significant difference in IVF outcomes if you just look on a per-egg basis and if you control for age and many other potential co-variables. But, interestingly, if you are the so-called "lean" PCOS phenotype, here is a different story and that's the crux of the matter. Again, to remind you, those are the patients we thought were the "easier" ones, the better ones, the less serious ones. Until a few years ago, a colleague of ours here at the Center for Human Reproduction decided that he wanted to do a study on our PCOS patients. He wanted to see what happens to PCOS patients as they get older. And, as we went into our electronic research database, which has by now a few thousand patients, to our huge surprise, we discovered that here at CHR, we had hardly any "classical" PCOS patients. All of our PCOS patients, almost exclusively, were lean PCOS patients. And that raised the question, "How can that be?" All over the world, people have done studies on PCOS, and that distribution of 40% and 40% in most places, has been repeated over and over again. Yet, here at CHR, the lean PCOS patients represented more than 95 percent of all of our PCOS patients. The only explanation we came up with is, that being the last resort center and having patients-- or in principle, over 95% of our new patients are patients who come to us after they have failed usually multiple IVF cycles at multiple centers, we are seeing the tip of the iceberg in terms of fertility severity. In other words, the patients who get pregnant easily, they don't make it to CHR. They get pregnant before. The patients who make it to CHR are the ones who have not gotten pregnant at other IVF centers. And this recognition, suddenly, turned on its head all the assumptions that we have read in the literature over decades, and that we believed in for decades-- namely that the lean PCOS patient is the easier, the better, PCOS patient. Indeed, when it comes to infertility, that does not seem to be the case. At least, if those lean patients haven't tried to get pregnant early at younger years. And the reason, and this is what we since discovered--since our colleague made that observation that we had almost exclusively only lean patients, what we found out is that the lean PCOS patient ages their ovaries in a very different way from the classical PCOS patient. In the lean PCOS patients, somewhere between the mid 20s to mid-30s, something happens that interrupts the usual slow decline in androgen hormone levels. And that slow decline becomes a very rapid decline. And so, by the mid-30s, those patients who started out with very high male hormone levels, with very high androgens, suddenly, after having gone through a period of androgens in the normal range, turn out to have low androgen levels. And those low androgen levels are the consequence of insufficiency in the adrenal androgen production. In women, half of the androgens come from the adrenals, the other half from the ovaries. It's the adrenal androgen production that becomes insufficient, and we, on the side note, believe this is based on an auto-immune process. And because those androgens drop so dramatically, they fall below a certain threshold that ovaries need in order to produce good quality embryos. What I have not mentioned yet is, that there's one other common characteristic for all patients with PCOS (including classical and lean patients), and that is unusually high AMH levels. Indeed, they are extremely high. And the second observation is that the FSH levels are also usually a little high (not as extremely high as their AMH levels), but they are what we call a "high" high situation when we compare FSH and AMH. And most of our listeners will still remember that FSH usually goes up with age and AMH down so that the relationship is usually an inverse one and the correlation is an inverse one. The higher FSH goes, the lower AMH goes. And, therefore, "high" high is an unusual configuration. But, many years ago, we are already (without understanding the reasons), reported that, interestingly, in our patient population, "high" high patients ended up having actually the best pregnancy chances. Now we understand why that is. Because, in those lean PCOS patients, who now, after their mid-thirties, have become hypo-androgenic (have low male hormone levels). If in those patients, we supplement their androgen levels by giving them DHEA or testosterone, suddenly their ovaries kick in again and start producing much better quality eggs. Better quality embryos are the result, and, ultimately, better pregnancy rates are coming. So, in short, we started out with a question of whether PCOS affects egg quality and my initial answer was there's no simple answer to that. The short summary is that if you're a classical PCOS patient, then your egg quality, probably throughout most of your age (your reproductive age) is not affected by your PCOS. But, if you are a lean PCOS patient, the kind of PCOS patient that nobody paid much attention to, then, at least if you are older than roughly 35, you better see somebody, evaluate your androgen levels, and if they indeed are low, have them supplemented back up into normal range. And then you will have excellent pregnancy rates, and once again, there will be no difference in egg quality, but you need those good androgen levels in order to have good eggs. Thank you for listening.

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