Dr. Kendal Williams (Host 1): Welcome everyone to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams.

Dr. Amanda Swain (Host 2): And I am your co-host, Dr. Amanda Swain. Today's episode is all about PMOS, formerly called PCOS. And we are very happy to welcome Dr. Anuja Dokras to the show. Dr. Dokras is an internationally recognized physician scientist and an NIH-funded investigator. Her research has transformed understanding of the long-term health consequences of PMOS, which stands for polyendocrine metabolic ovarian syndrome, which again, formerly called PCOS, one of the most common endocrine disorders affecting approximately 10% of reproductive age women.

Over the past two decades, her work has advanced knowledge of the cardiometabolic, reproductive, and psychological complications of PMOS with an in-depth focus on identifying factors that contribute to cardiovascular disease risk, metabolic dysfunction, infertility, and mental health disorders in women across the lifespan.

Dr. Dokras directs the Penn Polyendocrine Metabolic Ovarian Syndrome Center, which offers comprehensive care to women with PMOS. Dr. Dokras, welcome to the show.

Dr. Anuja Dokras: Thank you for having me. Thank you for that introduction.

Host 2: So, I would love to start with the very recent change from PCOS or what was previously polycystic ovarian syndrome to PMOS. And maybe you could give us some insight into why this change happened and why it is significant.

Dr. Anuja Dokras: Yeah. It's been long coming and a long journey. And as you are probably very aware, it's a misnomer. The word polycystic for the ovaries describing the ovaries was never correct or accurate. And if I might go back sort of down history lane for a little bit, it was in 1935, for the first time in the American Journal of OB-GYN, two surgeons from Chicago described a case series of seven women, and they took them to surgery. They had these large ovaries, irregular menses, hirsutism. So, sort of what we recognize as the modern day would've been PCOS. But the paper described it as polycystic ovaries in women with amenorrhea. And that name sort of stuck for several decades, and it changed at some point. So, it was named after the two surgeons. We called it the Stein-Leventhal syndrome. When I went to medical school, that's what it was called.

Host 2: Oh, that does sound familiar. It was already PCOS by the time I was in medical school, but those names do sound familiar.

Dr. Anuja Dokras: There had been a name change, and we are not entirely sure how that came about. But really, with that very initial publication, those two words had been described. After that name change, there was a lot of research from my group and others showing an increase in cardiometabolic risk, psychological health. It wasn't all about fertility.

And a meeting was held at the NIH in 2012, and the idea was to share all the new research and say, "We're doing so much more. We need more funding for women's health." And the white paper that was written by the panel, it said, "I think you guys should change the name of this syndrome. It doesn't represent what you have shared with us and what you came to present at this meeting." So, 2012 was the first mandate.

We had several attempts along the way, the patient surveys, physician surveys. There's a society called the Androgen Excess PCOS Society. And in 2015, I was the president of that society. And we invited patients to come and attend that meeting, had a separate session on name change. And then, in 2023, there was again a resurgence to say, "We've come ahead. We know a lot more about the syndrome. This name is such a misnomer, causes anxiety for patients." The mother will bring the young girl in, a teenager, somebody has seen a cyst on an ultrasound in the emergency room, and they come to us and say, "Oh, I think I have PCOS. I've read about it. She's going to have infertility. Is she ever going to be pregnant?" And that was the whole focus of the conversation. And so, it was time. The patients were asking for it. We understood that it took away our time from really talking about things that mattered and correcting what was a misnomer. So, it was a name reveal. I had never been part of something like this where we had to keep it under embargo for two months, and then it was finally published. And now, there is an implementation plan for the next three years. You know, all the different steps that would need to be taken for this to be successful.

Host 2: I love that it was in part to reflect the patient experience. I think that's so important.

Dr. Anuja Dokras: It was very important. So the patients, we've surveyed them not just in the US, but in Europe and Asia. And pretty much got the same responses. We have a paper, or my group, from the US that said patients were taking six months to 24 months before a diagnosis was established, and they were hopping between three to four healthcare providers before a diagnosis was established.

So really, the urgency at that time was we need guidelines that are evidence-based, there's consensus. Just changing a name is not going to make it better from a patient perspective, and that was really important.

Host 2: With the previous name being PCOS, do you think that that was particularly confusing because, according to criteria that I'm most familiar with the Rotterdam criteria, that not every person with PCOS necessarily had the appearance on ultrasound of polycystic ovaries? And maybe you can talk a little bit about that criteria and how that's changed with it being named PMOS.

Dr. Anuja Dokras: So, this is great question because what we see on ultrasound in the ovaries are follicles. Each follicle contains an egg, and it's part of a woman's fertility. When you talk about a cyst, it's pathological, enlarged. It could be simple, it could be malignant, could be an endometrioma, and that's a cyst.

So, the impression is somebody has lots of large cysts, they're going to rupture, they're going to cause pain. When you have an ovarian torsion, that's the cyst. And the discussion went down a completely different path. So, what we are talking about or what we know in the pathophysiology of PCOS is small follicles or antral follicles. They look like small cysts because it's got fluid in it, so on an ultrasound, but they're literally two, three, four millimeters, and the diagnostic criteria say less than 10 millimeters, so one centimeter. So, nowhere really where one would be worried in terms of rupture, pain, or torsion.

So follicles, increased number of follicles is part of the diagnostic criteria, but presence of an ovarian cyst is not part of the diagnostic criteria. And this is confusing. And so, yeah, I'm glad you brought it up. This has been the confusion. And you can imagine from a patient perspective, this has been quite a significant area of confusion.

Host 2: So, maybe we can just take a step back even and start with what actually is going on in PMOS. So, what are the common symptoms that patients will present to you with that make you suspicious for PMOS? And then, where do you go from there in terms of diagnosis?

Dr. Anuja Dokras: The symptoms vary with the age of the patient. So, if they're presenting in adolescence, irregular menses. And not the irregular menses that we see at the time of puberty. Some irregularity at 13, 14, 15 is common. But persistence beyond two or three years of menarche would qualify as irregular menses.

It's a diagnosis of exclusion though, because other issues like thyroid problems, prolactin can make your periods irregular. In a young teenager, it could be like disordered eating, weight loss, an athlete, right? So, one has to make sure that there aren't other reasons for the irregular menses. Then, the excessive hair growth, either upper lip, chin, sort of the midline. It's not the hands and legs like the common areas. Or excessive acne, and I'd say those would be more beyond the teenage years. Hair loss being the least common. So, these are all symptoms and signs because of high male hormone levels. And we always reassure our patients that these levels are never in a male range. A male range is 400 to 800 nanograms. The PCOS range is just a little bit above the cutoff, so 45, 50, 55. But that's enough to give rise to some of these issue or symptoms for hyperandrogenism and signs.

And then, the third criteria would be the ultrasound. Now, in the most recent guidelines, we have replaced that with another biomarker called anti-Müllerian hormone. And so, much easier because you can make a diagnosis just based on medical history, exam, and blood test. You don't even need the ultrasound, I think, in somebody who comes at a slightly later age. So, the confusion in the presentation is in the younger girls. You have to be careful that it's not a mimic because the acne could be present as a teenager, irregular menses could be present. And there is no ultrasound cutoff because most ovaries have a lot of follicles. They're so young. It's only two that we go with. In the sort of 20s and 30s, it's all three. And again, as a reproductive endocrinologist, I like getting the ultrasound because I can reassure my patient, "Look at the ultrasound. You have so many follicles. This is going to be great. You have enough eggs in there." Because there's always questions about fertility. And then, as you get into the 40s and 50s, actually the menses do become more regular. So, one loses that criteria.

For those who are listening and the internist maybe if you're seeing an older population, they still could have had a history of PCOS, now have regular menses. But that metabolic risk will remain, and the hirsutism remains because now the hair has been around so long. It's thicker, it's more permanent. So, they still might have some features, but not fall into all three of them.

And I think that's been part of the reason why there's been some confusion in terms of the diagnostic criteria that one really has to take time. It's not one biomarker like a TSH or an A1c, right? And then, you have a nice cutoff. I hope we can get there someday. We thought AMH would be our biomarker, but it doesn't represent the entire syndrome. It just represents the increased follicles for now.

Host 2: I want to talk more about lab values and definitely the anti-Müllerian hormone. But I have a question about how to quantify I guess irregular periods. And so, I find that it's a conversation sometimes. Because when you say, "Are you having regular periods?" or even, "Are you having a period every month?" Some people can take that very literally and say, "Well, yes, you know, I had a period on May 1st, and then I had a period on June 28th." And then, so you're like, "Well, actually that's not what I meant." So, can you clarify, you know, when you say irregular periods, what do you mean? And is there kind of like a point at which you say, well, less regular versus more regular? How do you get into that nuance?

Dr. Anuja Dokras: We discussed this at length when the guidelines were written. And there's a very nice table in the international guidelines that goes over how many years after menarche would you consider regular? What is the 35 days versus 21—so three weeks to five. I find I say, "In the last year, how many periods have you had?" And because we have a younger age group that comes to us, they pull out their phone and they have an app that tells you exactly the dates of the periods and how many. So, less than eight a year, I would say would be a good one for us in our busy schedules to sort of say, "Take a look and how many did you have within the last year?"

So if you've come to see me in May, let's look at last May to this May. And that gives you a good sense of that variability. And if they have less than eight, that would meet the first criteria, and then you would still do some of the blood work and history to make sure there are no other things that are mimicking it.

Host 2: Okay. That makes a lot of sense. Yeah, I mean, that was my next question with labs. So, what's your initial foray into lab work? And then, what would you consider maybe like the next set of labs or will you do everything at once? Or, as a primary care physician, family medicine, what would you think about in terms of our first pass lab-wise?

Dr. Anuja Dokras: I would do-- if a patient has irregular menses, a TSH, prolactin. And you could decide if you want to add in the FSH for the rare patient who may just have premature ovarian insufficiency. That is not as common. But if somebody just has had no menses for a long time and you are concerned, then that would be okay to add that in.

For the second criteria, if they have excessive hair growth. And it's really, again, as I said, the midline, upper lip, chin, chest, above, below belly button. There's a scoring, algorithm that we use. It's called the Ferriman-Gallwey score. It's just freely available on the web. But it's over six. So even if you get two or three areas with excessive hair, that would qualify. You don't always then need to draw a total or a free testosterone level. But I check it, and the reason being we'll talk about treatment, the response to treatment. When you see an improvement, patients like that. They want to make sure that the levels have come down, they have normalized. And then, you may either get the AMH or the ultrasound. So, the blood work would be TSH, prolactin, total testosterone, AMH—four things—and I think as a minimum, and you'd get your answer.

Host 2: That's really helpful I find that I get a little bogged down by all of the labs that can be related to androgen excess. It's a bit of a confusing pot. Kendal, I don't know how you feel about these. But then, I start kind of going back to med school and thinking about like, sex hormone binding globulin or what am I looking for, congenital adrenal hyperplasia?

I was never a big fan of endocrinology, to be honest. So, I think it sounds like it's actually fairly straightforward. And I think the AMH is a relatively new measurement that is being used.

Dr. Anuja Dokras: Correct. Yeah. So just to answer, with the hyperandrogenism, the reason we are getting the total testosterone is to rule out if there's a tumor, right? But that would be rapid growth. Like, oh, over the last two months, I'm shaving, like something changed. That is when for sure I would check the total testosterone more, because I want to make sure it's not in a tumor range.

The gradual increase, which is what most patients with PMOS will complain of, then it's more if you want to monitor response to treatment, or if you don't get enough hirsutism. Sometimes it's my mom has the same kind of hair, my sister. It may be familial, and then you're not sure. So then, it's nice to get that.

The DHEAS, which is for the adrenal tumors, really the yield is extremely low. And so, in the guidelines, we have put it as if you wanted to, you could. But it's not essential because you're not going to really miss as many adrenal tumors. And then, the 17-hydroxyprogesterone is, again, it depends on where you practice and if you have a population that's at a higher risk.

I can tell you, even though, like, we have a center where patients are referred to me, it's very rare that I'm picking up the late-onset adrenal hyperplasia. So in the guidelines, we've really put those two as you can look at the context of your patient population and presentation and determine. So, keep it simple. Just do the total and free testosterone.

And then, coming to the AMH, so this belongs to the TGF-beta family of biomarkers. And over the years, we know it's secreted by the antral follicles and in women, again, with PMOS because their antral follicle count is so high. It's a nice high number. It's a fertility hormone number as well.

So, a lot of patients have direct-to-consumer kits, and they check this as part of how is my fertility? And there's a lot of sort of misuse just because we don't know how to counsel patients just based on that biomarker. But it's great for PCOS because it matches that ovary, the PCO morphology. You only need two out of three criteria, and that gives you different phenotypes. And so, that would be fine to just add it to that panel if you don't want to go down the path of getting an ultrasound.

Host 2: Before we talk about treatment, can you just explain for maybe those of us who have forgotten some of this or those who this may be relatively new to. So, what is actually happening that leads to the lack of ovulation, the anovulation, and that's behind the irregular periods?

Dr. Anuja Dokras: And we've known this for a long time, that the signal from the pituitary and the hypothalamus to the ovary doesn't work as well and is dysregulated. So, the GnRH pulsatility is altered. And because the pulsatility is altered, FSH and LH that should be secreted in sequence, first the FSH to recruit the follicle and then the LH. So, that doesn't happen in a sequence, and there can be sort of random ovulations or just withdrawal bleeds. And hence, there's the signal to, of course, the ovary.

But over the years, one also knows that there is insulin resistance in these patients, and it's occurring more peripherally. So, it's not that they're not making enough insulin, but at the level of the muscle and the adipose tissue, there's resistance. And hence, they're secreting this hyperinsulinemia. But the high insulin also drives increased male hormone from the ovary. So now, you have the LH, which is driving the male hormone because of the dysregulation between the pituitary and the ovary. But now, there may be a second insult of hyperinsulinemia driving the androgens, and so then the hyperandrogenism.

And then, more recently, once AMH was identified, then AMH as this glycoprotein, it also prevents the FSH from working as well and recruiting the follicles and acts as an inhibitor. So, the high AMH keeps all these follicles in a sort of arrested stage. So, it's working at multiple levels and multiple organs, and hence the word polyendocrine. We'll get to that in a bit, I'm sure. But that's why it was not only about the ovary. Well, we knew it was the brain-ovary signal. But now, we know it's the adipose tissue-ovary signal. It's also the adipose tissue going up to the brain. And now, there's gut hormones as well being involved. So, there's a lot more that's been understood over the years. And hence, I think polyendocrine sort of aptly describes what's happening.

Host 2: I suppose then that's why we're thinking of PMOS as both a metabolic disorder as well as a reproductive.

Dr. Anuja Dokras: And an endocrine. Yeah. The endocrine disorder, we always knew it was a reproductive disorder. And then, over the years, once we identified the insulin resistance, then there's a high prevalence of pre-diabetes and diabetes, and starting like in the 20s and 30s. It's not like the typical 40s and 50s.

And then, my group and others began to show dyslipidemia as well. So, all the cardiovascular risk factors and hypertension. We know obesity, the prevalence is much higher in this population. And for the longest time, we only had data on cardiovascular risk factors because there weren't enough longitudinal studies.

So, we were using other markers like coronary artery calcium scores and some endothelial dysfunction. But now, there is data, unfortunately, for our patients that there are increased actual events in this younger age group. The absolute risk is low. And again, because it's just low in this age group, it's higher than somebody who does not have PMOS. And our paper, with the US data, because the data so far for the cardiovascular events comes from Scandinavia, comes from Taiwan and China. So, the US data, our paper will be published in August. It's been accepted for Lancet Women's Health, but shows this elevated risk. And so, that sort of is where the metabolic comes in and then screening, and we'll talk about that.

Host 2: Let's go from we have a woman who comes in, we've established irregular menses, excess of testosterone and/or hirsutism. And maybe there's been an ultrasound done, but we don't necessarily need to do one. And so, if we are now with lab values confident in the diagnosis of PMOS, maybe we can talk about approaches to treatment across the lifespan.

Because I think one common thought is, well, if we're thinking about PMOS, then really all we're talking about is getting pregnant. But to your point, we're talking about a lot more, and women need to know a lot more about their health at many ages. So, why don't we start actually with someone who is not necessarily ready to be pregnant. And what do you think are the important targets in terms of treatment for someone not quite ready to talk about fertility?

Dr. Anuja Dokras: And it's interesting you say that the first thing that comes to our mind is reproduction and pregnancy. When you do patient surveys, the first thing in their mind is weight management. From a PCOS patient's perspective, because most women are trying to get pregnant either once, twice, thrice in their lifespan, but really they want management across lifespan. And the thing that bothers them most is the weight gain.

Host 2: And I would imagine acne and hirsutism are also really, really important.

Dr. Anuja Dokras: Important. And then, an irregular menses. So, that's how the bar graph goes in that figure when we did the survey, and that's been repeated in populations across the world, is their concerns were not always aligned with how we're practicing here. And so, in the teenager or adolescent when the diagnosis is made, again, one has to manage symptoms.

So if they have irregular menses enough that you have no period and then very heavy bleeding, no period, and that happens quite often. You know, six months of no menses and then bleeding. The risk of endometrial hyperplasia or cancer is not that high in the teenager, but you have to manage the heavy menstrual bleeding. And so, the hormonal contraceptives, the combined hormonal contraceptives become first-line treatment. They will also suppress the male hormone because they bind to that free testosterone. And what you had mentioned, the sex hormone binding globulin goes up with the estrogen, and it binds the free testosterone.

And so, the earliest response is to acne, and acne get better sooner. Hair growth takes a little longer. And if it's thick or coarse hair, and body image is so important in that age group, sometimes they may need to do laser therapy or electrolysis for the thicker hair. But usually we start with just a one agent hormonal contraceptives. But it's the counseling that the periods will become regular sooner, acne next, and the hair growth might take some time. But that's sort of the first-line treatment.

And then, it's an opportunity in addition to doing the diagnosis. So, we said it was simple TSH, prolactin, total free testosterone. But really, we should also be doing an A1c and a lipid panel because of this metabolic risks. And we do recommend in the guidelines to do it at least once at diagnosis and then use that to guide you. And so, I would do that in the sort of adolescent, late teenager. And then, talk about how there is unfortunately a tendency to gain weight that may be driven by the androgens.

And in order to maintain weight, we have to talk about lifestyle, exercise, diet, all of that. And that's where mental health comes in because again, for these young girls, depression, anxiety, disordered eating plays such a big role in lifestyle management. We really cannot be recommending a nutrition consult and then not address the rest of it. And a number of us don't have the resource for a nutritionist either. I know we have that set up in our PMOS center. But all the same, I think it's really hard for them to meet a nutritionist, have like a full 45-minute evaluation if we haven't addressed any underlying disordered eating, anxiety, and other factors that play a role.

Host 2: On the topic of oral contraceptive pills, do you tend to choose a pill that has more of an anti-androgenic quality, so like drospirenone, or do you not feel that matters too much? Or what's your take on that?

Dr. Anuja Dokras: Always choose the lowest dose pill for the estrogen. There's no real reason. There was this misconception, "Oh, you're going to need higher doses to suppress the androgens," and that's not true. They suppress beautifully even on a 20 microgram, and there's even 10s now. So again, in terms of patients being able to tolerate them and the side effect profile, the lower the better.

And then, the progestin, which is the question you were asking. So, the third and the fourth generation are sort of more anti-androgenic. Most of the effect is because it raises sex hormone binding globulin and drops free testosterone, and the progestin really doesn't matter. But we do have anti-androgenic ones, so why not? I think it's fine. But the head-to-head studies are not as many, and they don't show a dramatic difference. So if insurance covers one that's a third generation progestin, that's totally fine.

Host 2: I'm also curious, and imagine you're getting to this, but since we're talking about issues that teenagers and young adults would naturally be thinking about on the topic of hirsutism, is this also a population that you would think about starting spironolactone for?

Dr. Anuja Dokras: So, spironolactone is an anti-androgen, weak. Both of you on the screen know this as a blood pressure medication, and it came across to our field as a weak anti-androgen because of lack of, I think, any other medications that are available to this population. So, it's second-line treatment. It's not first-line. I would use it first-line in somebody who has a contraindication to birth control pills or if you use an IUD, right? So if you have a progestin IUD, then you can combine that with spironolactone. But again, being aware that it doesn't drop the testosterone levels because it doesn't work in the same mechanism as a hormonal contraceptive.

But one could use any. It could be oral, it could be patch, it could be a ring. So, any of these forms of delivering hormonal contraceptives would be fine. And then, you could add a second line. And this would be the same management in somebody in their 20s and 30s as well as first-line hormonal contraceptives, second line adding spironolactone, lifestyle management. And then, the third one that we didn't talk about is metformin.

Host 2: Yes. Let's talk about metformin. I feel like it was around, we were using a lot of it in what was previously called PCOS, then it kind of dropped off the radar a bit. And now, it sounds like it's back.

Dr. Anuja Dokras: Because of the word metabolic. So again, it's unfortunate that there are no medications specific for PCOS or approved by the FDA for PCOS. So, we borrowed these from our field with the hormonal contraceptives or the diabetes field. But metformin is an insulin sensitizer, and it does drop the testosterone, not as well as the hormonal contraceptives, but second line.

And it will improve, as you know, the pre-diabetes, diabetes numbers, also a little bit for dyslipidemia, although it's not first-line therapy, but one could use it. And the question becomes: Are we treating someone? And then, you have all your recommendations from the diabetes prevention trial and all of that. But are we using it for prevention? And that's the hard one. Because if you start somebody at 18, how long are you going to keep them on it? And what is the data? And that's why it fell out of favor, because the idea was we really need to talk to patients about lifestyle modification early rather than just prescribing an insulin-sensitizing medication because it's second line. It's not as good for any of the outcomes. It doesn't regulate the menses as well as hormonal contraceptives, doesn't drop the testosterone as well, but it'll do it. Then, it was used for a little while for weight management because we had nothing else. And today, we know it's not our choice of weight loss medication by any means. It's fallen out of favor with respect to weight management.

So, it finds itself a spot where you'd have a patient who cannot tolerate hormonal contraceptives. The weight is still going up, but they're not a candidate for GLP-1s. It sort of, I think, fills in those areas. But after great discussion, and we need to know when to stop it, if at all. Yeah. It's not a fun medicine to be on for a long time either. A lot of patients get GI side effects.

Host 2: Our last episode was on GLP-1 medication. So, this is a great reference, and I think that's a really big question that we have now, which is is PMOS another area where there's a lot of potential in terms of using the GLP-1s because of their targeting the weight and the insulin resistance?

Dr. Anuja Dokras: Absolutely. So, we know from bariatric surgery literature that weight loss regulates menses. And that kind of weight loss almost normalizes the androgens. And so, we say it's sort of a cure for PCOS, although PCOS is a genetic condition. And if the weight goes up, some of these symptoms are going to come back. And so, with the GLP-1 receptor agonist, we're seeing large amounts of weight loss. It's not subtle. And these patients really have fantastic improvement in cycle regularity as well as in androgens. And you may have read on the media the Ozempic babies. It's not a medication that is inducing ovulation. It's because the patient loses weight, and they have not been counseled that you need to use contraception during this weight loss period that there have been some pregnancies. But it was taken up by the media. This might have been last year. I'm not sure if you guys were familiar with that. And it really is not that the medication is causing ovulation. It is the weight loss.

Host 2: Just to reference what you said earlier. So, it's reducing the insulin resistance, which is then having kind of a downstream effect on the ovulation process, and that's how babies are made. Now, we're talking about reproductive age. It sounds like both in adolescent and in reproductive age women, there potentially is a role for GLP-1 medications. In that reproductive age range, are there other medications or therapies that you think of specifically in terms of treating PMOS?

Dr. Anuja Dokras: One needs to sort of tee it up to pregnancy. It shouldn't be that a patient who is trying to get pregnant, 12 months is sort of infertility. Then, they come to see a reproductive endocrinologist. And for the first time, somebody is making a diagnosis of PMOS. This diagnosis should have been made earlier because you can then talk about prevention. But also, if they have any diabetes dyslipidemia prior to pregnancy or hypertension, PMOS is associated with a higher risk of preeclampsia and gestational diabetes.

So if there had been an opportunity to make our patients healthier prior to pregnancy, and certainly not like in the month where they now are frustrated, have been trying for too long, and then you say, "If you lose some weight, this is going to be better," that's a very hard conversation and not the right time.

So, irrespective of what their desires might be for family building, I think talking about their overall health will only help those who are trying to get pregnant. There's also a high prevalence of postpartum depression, and not surprising if they start off with that risk earlier. So again, recognizing some of these things and talking to them about the added risk because they have PMOS and them not hearing it for the first time at their OB visit or a visit at an infertility specialist office would be beneficial for both the provider and the patient.

Host 2: I think you were preaching to the proverbial choir, I think. But I do think even as someone that is in family medicine, sometimes you hear, "Oh, I also have a gynecologist." And I can see how it happens that you just don't have the conversation. You don't ask about periods or pregnancy prevention or concerns about fertility, and then that conversation just doesn't happen when it should.

Dr. Anuja Dokras: So, i'm hoping then with a name like PMOS, that if it's not happened, then the patient might prompt and say, "What about the M part of my syndrome? Let's talk about it." Or if they've been to the internist, "What about the O part?" And like, "What am I doing?" And maybe this will get all of us collectively, rather than in our silos, offer more comprehensive care. Time will tell, but let's hope for the best.

Host 2: Then, another group that I do want to talk about is post reproduction. So, women that are now no longer interested in their fertility, so to speak, and then also maybe approaching that menopausal timeframe. So, what are things that we should be thinking about? Because I think the other piece of calling it PCOS was that it also centered the syndrome around a specific stage of life, and then it was this like, almost like you can cross it off the diagnosis list once someone goes through menopause. But clearly, that is not the case. So if we're thinking about PMOS now post reproductive interest/age, what are we thinking about? What should we be thinking about treatment and evaluation-wise?

Dr. Anuja Dokras: So, the things that we know—and again, we have a lot of gaps because of the lack of longitudinal studies—but what we do know is, if you're not interested in reproduction and fertility, you still need to have regular menses in order to decrease the risk of uterine or endometrial cancer. And so, one cannot just say, "I'm not interested in pregnancy anymore. I can get a period every three or four months. It's fine." The desire to continue a contraceptive beyond a certain point becomes low, these are the reasons why just having some regularity in the periods is still important because of the real risk of uterine cancer.

And then, the other part that we do know is that women with PMOS go through menopause a little later than the women who do not. So, the average age for, like, an American white woman is about 50, 51. And the longitudinal sort of extrapolated studies tell us because they have that high AMH and a lot of follicles, they may be going through menopause a couple of years later. So, it's not unusual that I have a 55-year-old who's still having very regular menses, and they really don't want that at that phase. And they've had irregular menses when they were younger, but nobody really sort of discussed this with them, that this is part of the progression of the syndrome.

In the 40s, when the periods become that regular, sometimes patients have heard in their 20s that, "Oh, you're going to be infertile because you have PCOS." So in their 40s, they think, "I'm not going to be pregnant because I have PCOS," the old name. And now, they have regular menses. And there have been some pregnancies because the discussion that regulation of menses in your 40s gets you to ovulate, and that was the problem. So now that you're ovulating, you do have a chance of pregnancy, and you need to use some form of contraception, whichever one it might be. So, those are all the discussions related to gynecology, not reproduction in that age group.

And now, we know about the metabolic risk, and that's real. Weight increases are real. So if that hasn't been managed over time, then the usual, you know, blood pressure, A1c, lipids becomes important to follow all of that over time. There's not as much data. We have some data that, again, we are in the process of publishing that that mental health risk does remain, even beyond menopause.

And menopause itself can be an aggravator where mental health conditions may be increased. And then, with PCOS, that risk is sustained. So, there will be more information over time. But once they're in menopause, what will remain still will be the metabolic risks associated with the syndrome.

Host 2: And I would assume then in that population, those risks are higher even than the expected slightly elevated risk that comes after menopause.

Dr. Anuja Dokras: Right. Because their trajectory was different. They started at higher risk. Again, if we make a diagnosis early enough and prevention has been done and the response to all our preventive treatments have worked, maybe they will be in a better place. But we don't know that as yet.

Host 2: I do just want to go back. I think you made such a great point that I think is worth reiterating, which is this idea of even if someone is okay with that irregular period and they're not trying to conceive, we don't feel good about that because the buildup of the uterine lining and the endometrial lining, and that can be increasing risk for cancer.

So, there is every reason to manage irregular periods beyond just the convenience of knowing when your next cycle is . I was curious also, you mentioned just now the average age for menopause in white women in the US, and are there other racial or ethnic differences in either the presentation of PMOS or the way that we might be approaching evaluation or treatment that would be good for us to be thinking about?

Dr. Anuja Dokras: Yes. Good question. So in terms of hirsutism, that does vary with ethnicity. In the Far East and Asians just have less body hair. And so, the Ferriman-Gallwey score cutoff is much lower, that even if they score a two, that's going to be usually more than their family members and sisters. But it's never in the 16, 17, 18, the high ranges that we would see. And then, Hispanic, African American, or Black women do tend to have more. And the cutoff again, so there's a range, six to eight, given the ethnic differences.

The testosterone levels also, there are a few studies that describe differences, but they have not been well standardized. And testosterone is really better standardized in the male range, much higher. And for the female range, it's lower. So, we've been working with the CDC to try to get some standardization across all the different labs in the country. So right now, I wouldn't say that there are any differences related to that. And then, with the ovarian morphology, with AMH as well, it's the same issue because the assays are not standardized, that we don't have good cutoffs.

The morphology, there is some sort of description about, again, in the Far East that their volume cutoffs might be slightly different than ours. And then, in the metabolic screening, as you know, the BMI cutoffs are different for Asians versus in the Western world where we use 30.

Host 2: Actually, on the topic of BMI, can you just speak to the experience of normal weight patients with PMOS? Because I think we often think about these patients being overweight or at a heavier weight, but there is a population that is normal weight, and does that change our approach to insulin resistance?

Dr. Anuja Dokras: When I went to medical school, it was the lean and the obese PCOS patient, right? We didn't have the phenotypes and we didn't have Rotterdam criteria. But with the epidemic of obesity, as you look across the world, there's more of the PCOS patients are overweight or obese and fewer are in that lean category as we used to describe previously.

Also, BMI is a crude way of assessing it. The weight is around the waist, right? It's visceral adiposity. So if we had to even look at the waist circumference in the normal weight patients, that's where we're going to get a higher waist circumference. And the peripheral conversion of androgens occurs in the visceral adipose tissue.

So, the data from China and the Asian countries where the weights are lower still support an increased risk of pre-diabetes, diabetes, dyslipidemia. And so, it is independent of the way we are measuring BMI or weight right now. But the guidelines are not so robust to say at what frequency we need to keep repeating these measures. So, at least do a metabolic panel at the time of diagnosis in your lean patient or the normal weight patient. In the obese patient, that's going to guide when you would reevaluate them. But in the normal weight patient, I would do it at least once. And you'd be surprised when you get the high triglyceride, low HDL, the very typical insulin resistance kind of pattern.

We don't recommend checking an insulin level because it really doesn't tell us much, and it varies so much and the reproducibility isn't as good, so we took it away from the guidelines. It's more confusion. The patients get fixated on it. Then, they want to take metformin because of that one elevated level.

So, I think the OGTT really is the best because it's the impaired fasting glucose, but that can be a bit tedious for our patients as well. Nobody likes to sit for two hours at the lab, and they get nauseated with the Glucola. So, a happy medium might be the A1c, which is what I had been referring to. But the glucose challenge is the one that really identifies some of these early borderline cases. And then, for the normal weight, right? That's where you might pick it up, if you did an OGTT.

Host 2: I'm curious, if you have any specific points that you want to make sure that primary care physicians keep in mind when we're seeing these folks in the office either before they have the diagnosis or after they have the diagnosis. Are there some take-home points for us that you want to make sure you communicate?

Dr. Anuja Dokras: Yeah. Well, first of all, thank you for having this podcast because this is one way to get all the information out to them. I would strongly recommend just downloading the international PCOS guidelines, and we're going to change that name to PMOS in the coming months. But they're very well-written. There are very nice tables there for some of the questions, Amanda, that you asked. And, like the periods, like what do we consider as irregular? And just have it as a reference. And also with that, we made handouts for patients, which are all free, that you could download, and that's what I give to my patients. I send it through just Penn Chart as a link.

So, use these resources because that's what they're meant for and to make it easier for everybody because we're all going to see them. The prevalence is one in 10. So, you're seeing these patients, I'm seeing these patients. And the sooner we can help them with the diagnoses and then along the way keep counseling them about different aspects. Not every patient has all of these complications. So again, I don't want our listeners to go away thinking like, "Oh my goodness. Every patient is going to have all of these comorbidities," and that's certainly not true. But we want to be able to identify and pick it up in a timely manner.

Host 1: That was a fascinating conversation, and I really enjoyed it very much. I've always been confused by PMOS. And I was thinking here why is that? And I think that, it creates a link between sort of metabolic syndrome, so diabetes and hyperlipidemia, and so forth, and reproductive endocrinology in a way that I don't think that has been fully fleshed out in the past. And maybe, Anuja, you can educate us. It sounds like it's still being worked on in terms of how these all relate. I was fascinated by your point about how obesity fuels more testosterone and all of this linkage between which changes, of course, period frequency and has impacts in those ways. So. It seems like this is the only condition I know of that links all of those together in a coherent whole.

Dr. Anuja Dokras: Unfortunately, but it does. And through the lifespan, right? Which is sort of it starts early. So, we've identified now it's up to 20 different candidate genes. So, it's a complex genetic condition like diabetes. It's not going to be a monogenic disease. There's no one single gene.

But clearly, the children have a phenotype as well. And hence, I think the next iteration of all of this is are we counseling our patients about their children, and at what stage does one start screening them and say, "Oh, does your mother have a history of PMOS?" So, that would come in.

And then the environmental factor which you alluded to is the obesity making a lot of this worse and altering the trajectory. The metabolic risk is clearly obesity-driven, but there's some residual risk. So, I do think obesity has been a significant modifier. And hence, all our studies have picked it up over the years. And then, the mental health component. and the genes, genetically, there's an association as well, which is pretty interesting.

There is a male phenotype. So, the brothers have metabolic risk, and maybe slightly high DHEAS levels, so it doesn't really have a clinical impact. But if you look at the family histories, there's more metabolic syndrome, as you said, and then related maybe heart disease.

Host 2: Well, we do think about checking a lipid panel in adolescence. That's part of our normal practice. And I can see that it might be helpful to have in the back of our minds, "Hmm, if you get a metabolic panel back, that high triglycerides, low HDL in a patient who is female, assigned female at birth," that maybe the next thought should be, "Hmm, I wonder what's happening with their periods?" Have we talked about that?" Just kind of a little bit of a flag this might be something to address at a future visit.

Dr. Anuja Dokras: What I might leave your listeners with is we think the menstrual history is a vital sign. We should be taking period history on all our female patients because it tells us a lot.

Host 2: Well, I think that's an excellent note to end on.

Host 1: And with that, I want to thank Anuja for joining and thank Amanda for hosting. And audience, thank you for coming and please join us again next time.

Dr. Anuja Dokras: Thank you everyone.