Podcast Diaries: The Period Podcast S02E20 – BeYou Online

Podcast Diaries: The Period Podcast S02E20

Why we love this episode:

In this episode of The Period Podcast, Dr Clancy speaks to Dr. Marla Lujan, a PCOS expert and professor of nutritional sciences at Cornell University. They cover lots of topics, including testosterone and how the body makes eggs. SO MANY OF YOU loyal BeYou subscribers and fans have PCOS so we figure this would be a great episode to write up and share with you!

As always, if you’ve not been following this series of podcasts with us then make sure you go and check it out on your favourite podcast app. The Period Podcast has covered so many great topics within the menstruation space – from the history of periods, how they work, why they happen, and all sorts of things in between! Definitely go and support Dr Clancy if you can!

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Transcript: 

Lean women can have PCOS and this is evidenced across the globe because there are numerous countries that are not experiencing the obesity epidemic and they do have women in these countries that are lean can have PCOS.

This is Period Podcast, episode 20. My name is Kate Clancy and I'm a professor researching periods, how they affect our lives, and how our lives affect them.

Today, I am pleased to have Dr. Marla Lujan of Cornell University as a guest. Dr. Lujan is a collaborator for a collaborator of mine, which is like academia's version of a friend of a friend. I've been admiring her work on polycystic ovarian syndrome from afar for quite some time, so it was a real treat to talk to her. I spoke to Dr. Lujan in early 2017, back when I was pregnant. From a personal perspective, some of the things she told me about the latest on PCOS confirmed my suspicions that my previous IVF doctor, not the one who got me pregnant with my number two, but someone I saw before that, didn't actually know what he was talking about. Someday, I will have an episode all about infertility clinics and doctors and how to watch out for the doctors who are risking women's health or doing work that isn't based on the evidence. I'm really lucky that I had a really wonderful one to help me through both of my children. Today, though, I hope you'll nerd out with me and Dr. Lujan on testosterone and ovarian follicles. So, Dr. Lujan, what would you broadly say that you study?

I would say that my group tries to understand processes that lead to regular, monthly ovulations. We know that each month, a group of follicles, which are these small, fluid-filled sacs that contain our eggs, they compete with one another for dominance and eventual ovulation, where typically only one follicle ovulates each month. We know that this ability to ovulate improves a woman's likelihood of being fertile, but more than that, women with a history of regular cycles are at lower risks for certain types of cancers, cardiovascular disease, type two diabetes, metabolic syndrome, et cetera. The list of benefits to long-term health is quite extensive. So, for this reason, my group likes to ask questions related to how ovarian morphology, or what our ovaries look like, whether or not they can give us any information related to a woman's current or future reproductive and metabolic health, so that's sort of what I'm interested, how they ovary can tell us something about overall health.

Mm-hmm (affirmative). So, you're more of a ... what department are you in, by the way?

I'm in a nutrition department.

In nutrition. So then, I imagine you do a lot of human subjects research.

Yep, exclusive. Mm-hmm (affirmative).

Right. So, can you tell me some of the just main ways in which you test hypotheses in your own work?

Sure. We work within Cornell's human metabolic research unit, which is a really nice facility on campus where we can bring in human research subjects to conduct relatively minimally invasive type procedures. So, my group specifically uses ovarian ultrasonography. What we do is that we compare how ovarian morphology differs in women across the reproductive spectrum, so we're interested in looking at ovaries in women with regular menstrual cycles versus those that have irregular menstrual cycles and those that have bonafide anovulatory conditions. We use ultrasound technology to view the ovaries, because we can literally see the competition by these follicles play out in real time. We use information on the number, the size, and the arrangement of follicles within the ovaries to ask questions about whether or not these characteristics of the ovary can predict either the presence of specific types of anovulatory disorders, such as polycystic ovary syndrome, but also whether or not the characteristics of the ovary can tell us anything about the degree of reproductive or metabolic disturbance. More recently, we've started to ask questions about whether or not characteristics of the ovary can help us to predict the response to lifestyle interventions. For example, we've been looking at whether or not ovarian morphology can predict the likelihood of a woman experiencing ovulation if she's undergoing weight loss during a dietary restriction type study.

Oh, interesting.

Yeah, so we think this approach is relevant because ultrasound technology ... it's non-invasive and it's used widely in clinical practice, particularly in a gynaecological setting. So, what we're challenging physicians and clinicians to do is to think a little bit more broadly about the types of information that you can get out of viewing the ovaries on ultrasound, that ovarian morphology can tell you much more than just whether or not someone has an overt pathology.

Mm-hmm (affirmative). So, we are probably going to spend a lot of time today talking about polycystic ovary syndrome since you have so much expertise in that area, but since you have done so much work on a range of ovarian morphology, can you talk to me a little bit about just what the normal range of variation is among healthy women? Because I imagine it's actually pretty substantial.

Yes, it is pretty substantial, but I think that new imaging technology is helping to sort of clean up some of the noise that's existed over the years and so I think that's a really important point of clarification and so some of the work that we've done is actually characterizing that variability in healthy women with regular menstrual cycles and then contrasting that variability against women that have a diagnosis of PCOS based on endocrine status. So, to answer your question directly, related to what is in fact the normative range, we tend to think of the upper limit of normal being up and around 25 follicles within the ovary. So, based on an analysis that we recently conducted using data collected from several laboratories and clinics across the globe, we've noticed that the 95th percentile of follicle counts within the entire ovary is in and around 25 follicles. Once you start to get over that value, then you start to teeter into what we think is consistent with polycystic ovarian morphology.

Oh, interesting. Okay. I have ... we should talk shop outside of this sometime because I have a ton of ovarian images from work that I do in rural Poland. They're not ones where they're counting all the follicles, so they might not be as useful to you, but if you're trying to look at the total range variation, it's a very agricultural, rural population.

Cool.

So, different from the industrialized norm of studying sedentary American women, so it might be kind of interesting to talk about.

Yeah, for sure.

So, what are some of the challenges? So, you've talked a little bit and I imagine this is going to be a lot of what we talk about today, some of the diagnostic challenges or some of the changes in technology that have happened over time as you've been looking at ovarian morphology. What are some of the other challenges or trade offs that you encounter when doing this kind of work?

That's a great question. I think some of the trade offs are certainly related to the interaction with human subjects, so technology plays a big role, but when you work with human subjects too, there's only so much that women are willing to do and frequently. A lot of what it is that we do are longitudinal studies, so we're bringing in women and we're following them over time. When you follow individuals over time, you need to ensure that you're using techniques that are relatively non-invasive and can be done quickly and so that individuals are willing to come in so that we can collect their information in a timely matter in a way that doesn't greatly interfere with their life. So, we do longitudinal studies over the course of a month, but we've also done intervention studies that occur over the course of six months. For that reason, we've tried to develop methods that enable us to collect data consistently and reliably in women for these longitudinal studies. So, in this way, both the researcher and the participant are able to benefit from the interaction with the researcher.

Mm-hmm (affirmative). Are you ... Well, I know some of the work that some of our shared collaborators have done has required daily trans vaginal ultrasounds. Is that kind of what you're talking about, in terms of sort of this longitudinal, intensive participation by your subjects?

Yes, certainly. So, we've adopted a method where we scan individuals every other day. So, yes, so we conduct ultrasound scans of the ovaries every other day, either over a one month period or over a four month period, and now we're going to start to venture into being able to do this over an eight to 12 month period. So, yes, the participants are visiting our researcher every other day consistently for both an ultrasound scan as well as a blood draw.

Wow. Wow.

I find women are more than happy to do a trans vaginal ultrasound scan, but the blood draws are a bit more challenging, so we've got to sort of go back and forth from one arm to another. Sometimes we'll use different vessels, but we ensure that we're using, again, minimally invasive techniques, using very small butterfly needles, and obviously we're experts at doing this and we make sure that participants are as comfortable as possible because it really is an incredible investment in their part to assist us with this research.

Absolutely. Have you ever thought about just having them bring in morning void urine so that they don't even have to give you blood? I only ask because that's what we tend to do so that we don't have to hire a phlebotomist to do all that kind of stuff.

Yeah, we've considered it before in the past. To this point, we haven't really had any challenges in collecting the blood draws. We're able to do it relatively quickly and the women volunteer for it and, as I said, somewhat ... they're more apprehensive than the trans vaginal ultrasound, but they're not resistant, which is the best thing, right? That's the ideal candidate, someone that's willing to do it.

Yeah, absolutely. So, tell me, what are some of the fun things about your job and about the work that you do?

Oh, wow. I love my job. I love my job and there's a lot of fun things that we do. I think certainly the interaction with the human participants is really rewarding. I've got a history of working with animals. I was trained working with rhesus monkeys and I really valued that experience, but there's something to be said about being able to talk with individuals, develop relationships, hear their stories, and have immediate feedback in terms of how the research is either immediately benefiting them or how they're looking forward to the research findings. I think a really important thing that I do is well is that I help in the development of future scientists and I mentor incredibly bright and promising graduate students in my program and I can't say enough about that interaction and watching them grow and develop into both sound scientists and ethical and resourceful individuals, so I really like that part. As an academic, I'm involved in teaching as well and so I really enjoy my interactions with our undergraduate program. I teach anatomy and physiology to a broad range of students within the university and I really enjoy the teaching aspect of my job as well.

That's great. So, why don't you tell me a little bit more about some of the actual research that you've been conducting? So, just for our listeners' sake, we should maybe back up, because I think the bulk of what we'll probably be talking about is polycystic ovary syndrome. Can you tell me what that is?

Yes, certainly. I guess the textbook answer is that PCOS is a complex, and it's very prevalent endocrine disorder. It affects about 10% of women globally. The prevalence is somewhat controversial, just because the diagnostic criteria for PCOS are controversial, but nevertheless, I think there is some agreement that PCOS exists as a spectrum. So, the condition can manifest in several ways and some variants are considered more severe than others. So, the most widely accepted diagnostic criteria for PCOS defines PCOS as the presence of two out of three symptoms and I can tell you a little bit about what those symptoms are. So, one of them is this notion of androgen excess. This refers to there being evidence of over production of male hormones, and this can be detected by the presence of high levels of androgens in the blood, so an androgen like testosterone, if it's elevated in the blood, that would be biochemical evidence of having androgen excess, but androgen excess can also be inferred by clinical signs that someone might be exposed or more sensitive to circulating androgens. So, in this case, the presence of male pattern hair growth, which is called hirsutism. It is the most common clinical manifestation of androgen excess. So, typically when one's diagnosing PCOS, that's one of the criteria that you're looking to fill.

A second criterion is this presence of some degree of anovulation. So, this is inferred by infrequent or entirely absent menstrual periods. Then the third criteria that one is looking for is this notion of polycystic ovarian morphology, which is the area that I typically work in. So, the presence of polycystic ovaries is judged by ovarian ultrasonography. This refers to the presence of a relatively large ovary with an unusual abundance of small follicles. So, it's not the presence of these large cysts in the ovaries, which I think is a common misconception. What we're looking at is this unusual abundance of small follicles, which kind of gives us the sense that that competition within the ovary for dominance in ovulation may just not be going on in a normal fashion. So, in terms of a diagnosis of PCOS, we think of women that meet all three of these criteria as having the most severest form of the syndrome while women that meet two out of these three criteria as having milder variance. So, a woman that is undergoing a diagnosis of PCOS would be expected to have a physical exam, a comprehensive physical exam, blood tests to judge for androgen excess and to rule out other pathologies, as well as a trans vaginal ultrasound scan to view the ovaries.

Great. So, if we could, I kind of want to take apart each one of those and then of course we'll spend the most time on the last one because that's where most of your expertise is.

Sure, certainly.

But I'm kind of curious. So, and this is me first being very navel-gazing, or I guess ovary-gazing because, as I mentioned to you off the air, I had had a point at which there was a chance where my doctor thought I might have PCOS and what was interesting is with the androgen excess one. So, this was an IVF doctor, because my husband is a cancer survivor, and so we were doing just some basic imaging of the ovaries and uterus to rule out any major issues on my end, and again, saw maybe a ring-like appearance of some follicles. I don't have hirsutism in that I had a low testosterone ... I didn't have high testosterone, but one of the things that that doctor believed ... it's not a doctor I ended up staying with, but one of the things that doctor believed is that women who are former athletes can sometimes lead to that.

You know how there's sort of the lean ... at least you can tell me if this is right, sort of the lean athlete manifestation of PCOS and also the sort of more obese or insulin-resistant manifestation of PCOS. He said sometimes you see women with PCOS-like symptoms who don't have the hirsutism or testosterone, but because they've been playing sports and have a lot of muscle mass, that maybe there's still something going on there that they're not able to diagnose. Does that sound right to you? Because I found nothing in the literature after he said that to me.

I would agree with you that there isn't anything in the literature that, in my opinion, would support that, per se. I think that's one of the big challenges that we face is that androgen excess and ovulation and polycystic ovarian morphology, none of those three criteria should be considered exclusive to PCOS, and so that's the main challenge. So, for that reason, the word syndrome is used because it's a collection of symptomology that can exist as a spectrum. So, no, I'm not aware of polycystic ovarian morphology alone as being ... or should be diagnose as PCOS.

Mm-hmm (affirmative), but also that idea that androgen excess could manifest as just someone who developmentally has been an athlete their whole lives and carries a lot of muscle mass if it's not also born out by there being high androgens. Yeah, so anyway, that was what I was kind of curious about. I was like, "That just doesn't make sense if there's nothing ... "

Yeah, athletic status as an indicator of androgen excess, no, I'm not aware of any literature to support that.

Yeah, okay. I just thought that was weird, so. So is there anything else, in terms of things that you would want women to know to understand about that particular criteria? I think you just made an excellent point about, it's not like PCOS is the only diagnosis for which that symptom might be found. Is there anything else you would want women to understand about that one?

Sure, in terms of androgen excess, I think in many ways I do sympathize for the clinicians because one of the challenges that we have faced in measuring androgens in women in general is that the androgen assay that are available commercially, the ones that are readily accessible and the ones that are even being currently used in practice, they just don't do a good job at detecting androgens in women. So, that's historically been a big issue. In women with PCOS, although androgens are elevated compared to women without PCOS, that elevation is not 100-fold or 50-fold what you see in the normative condition. So, although androgen levels are high, they're not through the roof, right? So again, it's even hard to detect that difference if you're not using a very, very sensitive assay.

So, there is a program underway within the United States, by the CDC, where they're trying to standardize methodologies for the detection of androgens in women, right? So they're trying to refine technology and steps involved in both the processing and analysis of androgens that can be standardized across our country and then hopefully globally one day. So androgens are just one of those tricky compounds that are difficult, from a technical perspective, to detect. For that reason, it's always been very challenging for clinicians to diagnose androgen access and so they have come to rely on clinical signs of androgen access, such as this male pattern hair growth that I've discussed, which is called hirsutism. The tricky thing about hirsutism, however, is that, as you can imagine, it's a subjective evaluation, so each individual, as they're assessing either their research participant or their patient may judge excess hair growth in different ways.

The other tricky thing about hirsutism is that we're often being asked to evaluate hirsutism in women that have taken very comprehensive and extensive means to try to get rid of their male pattern hair growth and so that makes it a big challenge as well and so a lot of the times, we're doing the assessment together with our participants and they're telling us whether or not they've had hirsutism in the past, what sort of laser therapies they've gone through, what sort of drug treatments they might have used, et cetera, and so that makes it very difficult to gauge hirsutism. Then again, there's a whole host of factors that affect the development of hair growth and that includes ethnicity. It includes adiposity. It includes age, et cetera. So, it's not very typical for us to correct or consider these factors when we're assessing hair growth and so hair growth in a European population or excess hair growth in a European population may very well correlate with a different hirsutism score compared to excess hair growth in an East Asian population, right? So there's several factors that you need to consider.

Then the last thing that I would say about hirsutism, which is something that we've published on, is that testosterone levels or current androgen production, using the most sensitive assays that are available, which is the one that we use here in conjunction with the CDC, current androgen production does not always correlate with the clinical manifestations of hirsutism. So, hirsutism should really be viewed as a reflection of integrated androgen exposure over time. So, right? So it doesn't correlate as nicely with current levels of androgen that we see in serum. So, again, androgen excess in and of itself is something very challenging to diagnose and interpret.

Absolutely. I wonder if there are other ways then. So, in my lab, a lot of what we care about is life history theory and life history trait timing, so we ask a lot, or if we can, we study younger folks to understand variation over time or ways in which early life conditions might affect adult function. So I wonder if there are exposures or experiences that might happen young that might then lead to or be predictive of hirsutism.

That's a fantastic question. To the best of my knowledge, I'm not sure of any data to predict that, but certainly something that we should consider, because as I said, hirsutism is ... in our hands and in others, it's clearly a manifestation of integrated exposure over time. It doesn't tell us much about current androgen production.

Right. Interesting. Okay, so then the second criteria, this is on irregular or absent menses, right?

Yeah.

So can you tell me a little bit about that one?

Yeah, certainly. So, your listeners are probably well aware that PCOS is not the only cause for anovulation, that there's a whole host of other reasons that can lead to irregular or infrequent menstrual periods. For that reason, anovulation alone is not purely indicative of PCOS. So, PCOS is a diagnosis of exclusion. For that reason, there's a whole host of other hormones that get analysed at the time of diagnosis to make sure that there are no abnormalities in those hormonal pathways. So, examples of that would be thyroid hormones or the different types of thyroid hormones. We know that hypothyroidism, as well as hyperthyroidism, which tends to be rarer, is associated with anovulation and so you need to exclude for abnormalities in thyroid hormone production before you consider it being PCOS. You have to look for overproduction of cortisol secretion, which is secreted by the adrenal glands, because we know that heightened cortisol can interfere with hormone production by the pituitary gland that typically regulates ovarian function. That's just two of a long list of hormones that you need to make sure are within the normative range before you start suspecting PCOS.

Sure. There is some ... so again, there's some maybe disciplinary differences here, but within my discipline, we have a pretty relaxed definition of a normal menstrual cycle, in terms of finding 40, 45 days even to be acceptable for some women, just because in part ... we're not measuring just industrialized women who have adequate energy intake and not too much energy expenditure. We're looking at rural farmers and some of my colleagues are looking at pastoralists and foragers. What would you say is ... In your work, what are you considering more clinically normal and what are you considering irregular?

That's a fantastic question. I would say to you that there's absolutely no consensus either in the literature or in practice as to what constitutes a regular cycle and whether or not it should be based on a particular time span or a duration between one ovulation to the next or day one of one menstrual period to day one of another menstrual period. So, from our perspective, we tend to use the most widely clinically accepted criteria when we classify our participants, but certainly when we're collecting data, we're collecting the data without judgment, right? So we're looking at all sorts of menstrual cycles that vary in length, and so I would say anywhere between 21 and 36 days can be considered normative. I'm saying that in quotation marks. I really think there's something to be said about the predictable nature and whether or not menstrual cycles are falling within plus or minus five days of one another, because I feel if a woman has predictability, that that's a very high indicator of likelihood of ovulation.

Okay. So, certainly it sounds like that is a fairly squishy criteria, which is why, I imagine, so much of your work has focused on, well, we actually have to get in there and image the ovary so we can see what's going on with the morphology. So can you talk a little bit about what that diagnostic criteria is? So you talked a little bit about number of follicles. Is there anything else that you're looking for?

Sure. So, one of the papers that we published, I think addressed this question quite comprehensively. What we did was we assessed various aspects of ovarian morphology and so we looked at, yes, follicle number, because it tends to be the one that's most broadly used now. We looked at ovarian size as judged by several markers and by several techniques to gauge ovarian size. So, we used a metric of volume. We used a metric of area, and then using different equations to calculate those two metrics. We also looked at something that's referred to as echogenicity or the brightness of the ovary on ultrasound. That's thought to give a sense of tissue composition and whether or not echogenicity tells us anything about androgen production or the likelihood of high androgen production. We looked at the arrangement of follicles, whether or not the follicles were arranged in the periphery, much like a string of pearls, which is characteristic, or is thought to be characteristic of polycystic ovarian morphology. We gauged whether or not they were distributed throughout the ovary. We looked at some metrics related to the area of the stroma, which is the inner core of the ovary, and how that relates to the total size of the ovary. That's referred to as the stroma total area ratio.

So, we looked at a whole host of characteristics of the ovary and we asked questions about, what was the likelihood of any of those characteristics, used alone or in combination, to predict the condition of PCOS, wherein the condition of PCOS was defined as being clinical or biochemical evidence of androgen excess in conjunction with anovulation. So if we go in with PCOS defined in that way, a priori, and not give any consideration of ovarian morphology, we notice that follicle count, in and of itself, was the best predictor of whether or not someone had PCOS. Then, from there, we noticed that follicle size, as judged by ovarian volume, was the next best predictor. Then, after that, using a combination of markers would give you decent diagnostic potential for PCOS. So, we have looked at a variety of characteristics using standardized approaches in my lab and we're finding that follicle number and ovarian size are very good markers or predictors of PCOS.

That's really neat. Now, one of the ... I know because you've spent so much time thinking about and doing work on diagnostic criteria, one of the things that you mentioned to me is that some of the changes in ultrasound technology is part of what has shifted diagnostic criteria. Can you talk about that a little bit?

Yes, certainly. So, we've known that ... PCOS has appeared in the literature as early as 1935, but in terms of formal diagnostic criteria for PCOS, those didn't come about until 1990 when the National Institutes of Health first proposed formalized criteria for PCOS. In this situation, they excluded polycystic ovarian morphology as a diagnostic criteria for PCOS. So in the early '90s, ultrasonography, or trans vaginal ultrasonography, was really very much an emerging technology. So, at the time, polycystic ovaries were really just considered suggestive of PCOS and not necessarily definitive evidence, but over the years, as technology has improved and access to technology has improved, it's become apparent that polycystic ovaries are, in fact, a very consistent finding in women that meet an endocrine or a clinical-based definition of PCOS. So, in 2003, at a more internationally-focused meeting on PCOS, that's when these Rotterdam criteria, or the criteria that I just described earlier, those came into wide use. In those criteria, polycystic ovarian morphology was included as a diagnostic marker.

In 2003, 2004, when polycystic ovaries were included as a diagnostic marker for PCOS, a very specific definition for polycystic ovarian morphology was provided, and so they defined PCOS, or polycystic ovarian morphology I should say, as being the presence of 12 or more follicles throughout the entire ovary and/or an ovarian volume greater than 10 CCs or 10 millilitres. So they were very specific, in terms of what constituted polycystic ovarian morphology. What we noticed in the years that followed is that as those criteria were being used broadly throughout the world, there were a growing number of reports saying that healthy women we regular menstrual cycles had polycystic ovarian morphology. So, that came ... that brought polycystic ovarian morphology into question. It didn't seem that it was being specific enough to PCOS, and so one of the things that we noticed in both my group and in other groups was that, yes, that was absolutely correct. Polycystic ovaries, by this definition, was common in healthy women, but we were seeing many more follicles in women with PCOS as well.

When we were contrasting some of the images in the literature with the images that we were seeing with new technology, it was clear that the resolution that was available with new technology was vastly superior to the technology that was used way back in 2003 to provide that definition and so we recommended that a re-evaluation of the criteria occur in light of the fact that ultrasound technology, at present, gave us far better resolution. So, with that in mind, we were able to show that a threshold of 25 follicles per ovary, so a threshold more than double what was being used up to this point, was much more sensitive and specific to diagnose PCOS. So it very much was this huge shift in how we were defining polycystic ovarian morphology and it told us a lot about how imaging technology is really evolving, it's improving, and in light of that, we need to keep up to date with the metrics that we use to diagnose conditions based on imaging.

That's fascinating. Again, just being totally ovary-gazing, part of the reason that they ultimately decided I didn't have the diagnosis of PCOS is, I think, the number of follicles around the ring ... in the pearl necklace appearance was 10 or 11 per ovary. They were like, "Well, since it's not 12, you're okay."

See, well, and that's a huge-

It was last year.

Yeah.

That was 12 months ago or something.

So, but that's another misconception that came from some of these data. So historically, when ultrasound was being conducted by trans abdominal approaches, it was a lot easier just to take this single cross-sectional view of the ovaries and do a follicle count. Then, all of a sudden in 2003, 2004, when we're doing trans vaginal ultrasound and it's a lot easier to take a nice sweep through the ovary and be able to see the ovary as a whole, the transition was made to counting follicles in a single slice to counting follicles throughout the entire ovary. So, it really was proposed that it was 12 follicles throughout the entire ovary, but folks were still using those criteria in a single plane.

So, and I think a lot of that has to do with differences among medical disciples, and so the gynaecologist, reproductive endocrinologist, they tend to look at the entire ovary when they're making an actual follicle count, but the radiologist tends to look at things in cross-sectional views, right? In single slices. So, one of the papers or a couple of the papers that we've published to date have shown that counts in a single cross section in and around nine or 10 are predictive of PCOS, just so you know for your own information. The only problem is that the strength or the ... both the sensitivity, the strength, and the diagnostic potential of using counts in a single cross section is much lower than when you're making counts throughout the entire ovary or looking at ovarian size and so we don't recommend that metric over the others.

Ah, interesting. So, when there was ... it's funny because I remember when the Rotterdam criteria came out because I was in grad school at the time and obviously doing obsessively large amounts of reading of the literature.

Yep, that's our job.

Yeah, exactly. So what's interesting then is it sounds like ... I remember, people have been cracking jokes about this for a while, right? That you could get a diagnosis of PCOS and not actually ever be told you had polycystic ovaries. So, what does this mean, in terms of women who may have been diagnosed under those type of criteria? Are there other potential diagnoses that would have been more appropriate? Or is it just that we were lumping a bunch of normal women into a pathological condition?

Oh, loaded question. Yes and yes, I guess.

Okay.

So, one of the ... so, my take, and I will wholeheartedly say that I love ovaries and so for that reason I'm somewhat biased, is that I think, to this point, we haven't comprehensively evaluated ovarian morphology and so I look at past publications with quite a bit of scepticism because the technology, the imaging technology at that time, I just don't think gave us the capabilities that we have today, right? So now we're in the digital age where we can do all of these comprehensive analyses and we can make measurements with much more reliability than ever, and my group has developed a lot of those procedures that enable us to make reliable follicle counts within the ovaries. So I view a lot of the historic data with quite a bit of scepticism and so I would say that previous definitions of polycystic ovarian morphology have been somewhat unreliable. I think that's not a reflection of the individual, but just a limitation of the technology and so I sort of have been walking into this field of ovarian morphology, using newer technology and understanding that newer technology is going to help us better inform and better describe ovarian morphology. So, yeah, so I'm a bit biased that way.

Yeah, no, no, but that's very helpful. So, I want to change directions a tiny bit, just to just provide more broad information PCOS. I think you mentioned to me that you've done some work with adolescents recently.

Yes.

To help ... so what I wanted to ask was, from your work and maybe the work of others as well, when does PCOS manifest? Or what are you starting to see in terms of how early we can start to diagnose or predict that this might happen to some women?

Yes, and so in a significant portion of women with PCOS, PCOS can manifest as early as adolescence and so that is ... girls that are undergoing puberile development, they can transition into adulthood having never established regular or predictable menstrual cycles. Even in puberty or adolescence, they can show signs of having this androgen access or signs of having increased androgens in the blood as early as their teens and they can carry this into adulthood. So we know that in a significant proportion of women, we can see these signs as early as the adolescent period, but one of the challenges here is that making the diagnosis of PCOS is very controversial and that's because signs and symptoms of PCOS, they overlap with the natural characteristics of puberile development and so-

Exactly.

Right? So, for that reason, experts have been getting together to discuss whether or not we should wait two to three years post menarche before even considering diagnosing or labelling a girl with PCOS. So, we know that that transition to puberty is associated with a rise in androgens, right? That's normal, right? That's that push for puberty is this increase, or the slight increase in androgen production. We know that a girl's first few periods are not going to be this defined number of days apart from one another, and so we also know that there's changes in metabolic status that are promoting growth and changes in insulin sensitivity that are going on during the adolescent period. So, in terms of diagnosing PCOS, how early? It's hard to know. There's no absolute consensus, but we're thinking at least two to three years post menarche is a reasonable starting point.

Mm-hmm (affirmative). Now, there's some data ... I don't know if you're ... this is one of the classic papers that we study in our field all the time, some work by Apter and Vihko from the '70s into the '80s that looked at sort of menstrual cycle length and number of ovarian or ovulatory cycles immediately post menarchial girls. These data are pretty old now. I'm very curious about ... with some of the major lifestyle shifts we've had in the last couple decades, I imagine it's going to be different, but it seems like girls are more likely to resume or have lots of ovulatory cycles if they have an earlier age at menarche versus a later. So, are you finding ... Is there any relationship with age at menarche or age at first period and PCOS?

There are some data. There are some data to support that. I'm not entirely familiar with those data, but it seems like there's an association between ... it's more ... I don't want to misrepresent the data, but certainly girls can experience an early menarche and then there is this accelerated growth profile within these girls where they don't go on to have regular cycles moving forward, but they do show accelerated growth in conjunction with perhaps an early age of menarche, but I don't know much more about that, Kate. Sorry.

Sure. No, no, that's still super interesting. So, what are you working on right now in your lab? What are some of the latest findings or something you'd be excited to tell us more about?

Sure. I have to pick a couple. Let me see. We're working on a lot of cool stuff, so what are the ones that I'm most excited about? Well, we've got some very cool data actually characterizing follicle development in the ovaries of women with PCOS using ultrasound and so these are some of the studies or techniques that I had previously mentioned, where we bring in women every other day and we can actually look at the competition that's going on within the ovaries in these women. One of the reasons why we were interested in doing this is because follicle development in PCOS has been historically considered a form of arrest and so we think that these ... or we've been told that these follicles grow and then they get arrested in development and that is what impedes the potential for regular ovulatory cycles, but the only real way to address that is by doing longitudinal assessments in women.

So, we just completed data collection in a host of women with PCOS where we're showing the complete opposite of that. So, these are the only data of their kind and they're going to come out sometime this year. What we're showing is that, no, those follicles that we see on ultrasound are not arrested in development, and so they are growing. They're trying their best to ovulate. If anything, they're turning over faster than what we're seeing in women with regular menstrual cycles. So, we're really excited about that because we're challenging dogma and we're pushing clinicians to think differently about how the ovaries are functioning in PCOS and what physiologic processes are actually being captured when we use ultrasound to either inform the diagnosis of PCOS or the treatment of PCOS, so we're really excited about that.

Then, in terms of some of the work that we're doing in adolescents that we think is really cool, is that we're showing, similar to what we see in adult women, that ovarian morphology in adolescents can also tell us something about a teen's reproductive status, as well as her metabolic status. So we're excited about this because, as you can imagine, trans vaginal approaches in adolescents is not a widely adopted technique and so we tend to rely on trans abdominal ultrasonography, which, yes, is subpar, right? Because in order to be able to view the ovaries, you have to sort of penetrate the body using ultrasound waves much more than you would have to do it using a trans vaginal approach and so the resolution that you get with trans abdominal imaging isn't as good with trans vaginal approaches, but certainly the new technology that we've got available nowadays allows us to see the ovaries better than ever using trans abdominal approaches. So, we've been using some of the techniques that have been developed in my lab to be able to better characterize the adolescent ovary using trans abdominal ultrasound. We're showing that, similar to what we see in adults, that follicle number correlates quite nicely with androgen production in adolescents and the size of the follicles is also telling us something about metabolic status in these individuals.

So, we're excited about those data because it's telling us that perhaps ovarian morphology can help to predict future risk of chronic anovulation in these girls and perhaps we can equip clinicians with a non-invasive tool that can enable early intervention in these girls.

Yeah, wow, that's so great. Just sounds like there's a lot of exciting things coming out of your lab right now. So, I have one last question.

Sure.

It's sort of a general one. It's to give you a change to fill in any holes, in terms of things I may have forgotten to ask. We've got a lot of listeners who are scientists themselves, but we also have a ... there's also a pretty good number of folks who listen to Period just because they're really curious about their bodies. So, what are some things that you wish more women understood about PCOS, just to help them understand it for themselves, especially maybe if they've been recently diagnosed?

No, I appreciate that question because I think it's a fantastic question. So, I would take it back to the diagnostic criteria that we discussed. I wish women had a better understanding of diagnostic criteria for PCOS because what I often hear from our participants here is that they think that their diagnosis was based on weight gain or obesity or difficulty losing weight that occurs in conjunction with their irregular menstrual cycles. Obesity and weight gain are not diagnostic criteria for PCOS, right? That's why we haven't really talked about that to this point because it's not a recognized diagnostic criteria. We know that obesity alone influences ovulatory function. My group works in overweight and obese women that don't have PCOS to better understand this process. We hope that in the upcoming years, we're able to make strides in this area that can inform clinical practice.

So, similar to that, lean women with PCOS are often told that it's not likely that they have PCOS because they're not overweight. So, lean women can have PCOS and this is evidenced across the globe because there are numerous countries that are not experiencing the obesity epidemic and they do have ... and women in these countries that are lean can have PCOS. So for these reasons, I think that women need to confirm with their healthcare providers that they actually meet bonafide criteria for PCOS because being labelled with a diagnosis of PCOS, that designation isn't benign. It can affect their access to healthcare and insurance and so it's important that they make sure that they meet at least two out of those three criteria that we have discussed earlier.

Mm-hmm (affirmative). Right.

I guess another thing that I would say, along those lines, in line with some of the more current work that we're doing here within the nutrition department is that, yes, in our population anyways, a large percentage of women with PCOS are, in fact, overweight or obese, right? That sort of reflects our demographic, and although women with PCOS have reported that it's harder for them to lose weight, that they have more challenges, that their ability to lose weight isn't the same as their friends, I would like them to know that calorie-restricted diets are in fact very effective in promoting weight loss in women with PCOS. So, my group has first-hand knowledge in this and so we know that when our participants are compliant in consuming a low-calorie diet, they are very successful in losing weight and improving their metabolic health.

In terms of improving their reproductive function, we know from our studies that there is improvements in ovulatory status, and what we're trying to understand is whether or not women can actually revert to having regular menstrual cycles, because I don't think that may be a realistic expectation for all overweight women with PCOS and so we're trying to understand which women can, in fact, regain regular ovulatory cycles versus those that can just show some improvement. In any event, I want those out there that are listening to know that any improvement from baseline is important because it's going to be helpful for both physical and psychological wellbeing when you're living with such a complex condition like PCOS.

Sure. Well, that was wonderful. Dr. Lujan, thank you so much. I really appreciate your insight and I'm just ... I can't wait to see the next stuff to come out of your work.

Great. Thanks so much, Kate. I really enjoyed this. 

Shownotes:

Excerpt: Kate talks to Dr. Marla Lujan, PCOS expert and professor of nutritional sciences at Cornell University. We geek out on testosterone and how the body makes eggs.

Summary: I can’t wait for you to “meet” my collaborator of a collaborator, or friend of a friend, Dr. Marla Lujan! Dr. Lujan is an Assistant Professor of Human Nutrition in the Division of Nutritional Sciences at Cornell University.  She received her Master of Science and Doctor of Philosophy in Physiology from Queen’s University (Kingston, Ontario) and conducted her postdoctoral studies in Obstetrics, Gynaecology and Reproductive Sciences at the University of Saskatchewan (Saskatoon, Saskatchewan). Her research team investigates the link between nutrition, metabolism and egg development in women using high resolution ultrasound. Specific interests include understanding why some heavier women have trouble ovulating, as well as improving the evaluation and diagnosis of disorders like polycystic ovary syndrome (PCOS).

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