The Menstrual Cycle DECODED: Fertility, PCOS, and the New Science of Hormones

28:47And so it's, you know, common in, for instance, competitive athletes or athletes in general, that they'll experience irregular menstrual cycles. And, you know, one of the reasons is this potent suppression of the reproductive axis. And we know that, and this is called functional hypothalamic amenorrhea, particularly with female athletes or females who sort of have this undernutrition phenotype, they have lower estrogen concentrations. And, you know, I think you've had a guest that spoke about the importance of estrogen on bone health and bone accrual. So when you have low estrogen, you sort of have increased presence of those cells that chew away at bone, and that affects bone health as well.

29:31So small, is the right word atropic, or is that extreme for the ovary? If someone was anorexic or going through hypothalamic amenorrhea, a physician does an ultrasound on these ovaries, and these ovaries are small and shrunken. Amorphous is what we would use. Amorphous. Amorphous. And what's interesting, though, is that this is an extreme case. When you have functional hypothalamic amenorrhea, it's not quite as severe as an amorphous ovary. You still have some reproductive access function. What we actually see, and Dr. Judith Adams characterized this, is what's called multifollicular ovaries. And so this is a case where if you look on ultrasound, these ovaries are not necessarily enlarged, but they do have elevated follicle populations.

30:17So there's more follicles than what we would expect in sort of a regularly cycling individual with a healthy BMI. And so what's unique about the follicles in these sort of multifollicular ovaries is that they're a little bit bigger than, for instance, a PCOS ovary. So they're sort of 4 to 10 millimeters in diameter. And when you scan them on ultrasound, you know, it kind of looks like soap bubbles. You know, if you're washing your dishes and you have like soap bubbles and they're sort of all, you know, touching each other and you scan through it, it's just like soap bubble, just soap bubble, just soap bubble.

30:49So they look large and multifollicular. And that would be sort of the classic image of an ovary in someone with functional hypothalamic amenorrhea. What are the other categories? Right. So if we move along the nutrition spectrum, we sort of push ourselves then into overweight obesity with regular menstrual cycles. And this is very briefly, it is a case of reproductive axis suppression. So what we see and what Alexis saw is that in the case of obesity with regular menstrual cycles, we see a suppressive effect on the reproductive axis. So, you know, we can see smaller follicles, sometimes fewer follicles.

31:26We don't really see ovarian enlargement. We see luteal phase defects. When we start moving into irregular menstrual cycles, if you sort of move up into overnutrition, if you will, with overweight, obesity, and then irregular menstrual cycles, before we get to PCOS, when we're sort of in that normal androgen area, we don't necessarily see ovarian enlargement yet, but we do start to see increases in follicle populations. And there's a smaller follicle, so two to five millimeters. And then sort of the most severe ovarian phenotype would be these sort of classic polycystic ovaries or PC, polycystic ovarian morphology, which is part of PCOS.

32:06And these ovaries, a really important thing happens at that level is what we think is happening is there's sort of this metabolic tipping point where, you know, with PCOS, we see this interdependence between hyperinsulinemia, so elevated insulin, which is a consequence of insulin resistance and then androgen excess. And there's a sort of positive feedback, sort of vicious circle between these two. And what happens is in the ovaries, we start to see ovarian enlargement and our ovaries have insulin receptors in them. And not a lot of people know that. But when you have elevated androgens, that is in large part because those small follicles in the ovaries are making a lot of androgens, which is normal under physiological conditions when you have too many follicles.

32:51too many small follicles, you sort of make too many androgens, simply put. And then you add insulin and that sort of exacerbates the situation, right? Insulin is thought of as a co-gnatotropin. So it sort of works in tandem with the hormones coming from the pituitary to promote follicle growth and ovarian androgen production. And so in a PCO ovary, we would tend to see, you know, larger ovaries, we would tend to see smaller follicles. And what's common in a PCO ovary, or I shouldn't say common, but I would say a classic ovarian phenotype would be that string of pearls around the edges. For every physician or medical student, we've all passed our boards now.

33:31That will be the only ovarian, that will literally be the only ovarian question you will get. Is that the string of pearls? Yes. And it's not a common phenotype in PCOS, which is, you know, I personally have not seen that classic string of pearls as often as I thought it would, having been in the field of PCOS now for a decade. Oh, oh, sorry. It's time to record an ad for the show. Thank you to one of the sponsors of the show, Timeline. And listen, my kids still sleep with me. And after 470 nighttime snack requests, bathroom breaks, my husband's snoring, my cell is there like, yo, gee, we're tapped out.

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35:31There is. Yeah. Yeah. Do you want to, I mean, I know that you touched on that, but the ovarian transition, you are the only person in the world that has studied this. I think that it deserves another explanation. And you're very generous. And I really want to emphasize, you know, I was the one who did the ovarian tracking, you know, a lot of collaborators of ours from Australia did some really important formative endocrine work. This is very fair. And I will say all the best scientists are humble. And yes, we all stand on the shoulders of giants, which you which you have in addition you have been you have spent 10 years your time your energy your focus when you're not in the pain cave furthering this work and I do think that that is fair to highlight you and the work that you're doing you're very kind I'm not that kind just ask anyone on my team um sure so to the ovaries the transition to menopause uh so what was really interesting about the transition to menopause is that, and I'll call them rogue follicles.

36:32So in someone undergoing the transition to menopause, this didn't happen in all of our participants, but in a subset, what we saw is a follicle start to grow around selection when the follicles shouldn't be growing. This is, you know, when estradiol is supposed to be suppressing FSH, there should be no follicles growing, but one little follicle, sometimes two, starts to grow, starts to grow, starts to grow. And at around the LH surge, these follicles on average were around nine to 10 millimeters in diameter, which is when they actually do start to express those LH receptors. And what we saw in these cases, we called them, you know, atypical luteal phase dominant follicles, where they also seem to respond to the LH surge.

37:16And then most of them would just take off and grow and they would produce or it was associated i should say with two or three fold higher estradiol concentrations than what we would expect and so this was initially the the endocrine side of this was characterized by a group in australia and in women undergoing a transition to menopause and they wanted to know like what's going on yeah and so it's related in the ovaries and so it's just these rogue follicles that are starting to grow and they are they they are you know sufficiently large enough where they can start responding to an ovulation cue destined for a different follicle.

37:51Is it the body's last-ditch effort to get pregnant? Is it for the body's way to make up for the loss of estrogen? Is it overcompensating? Why is this happening? Great question. What we think is happening isn't actually a compensation strategy. it's just a failure to regulate self-regulate so there's this other player that i haven't mentioned it's called anti-mullerian hormone or amh and amh is also a break in the ovaries the ovaries you know they produce since there's a lot of hormones that serve to like put the break on on the pituitary and the hypothalamus so what we think is actually happening is that the the local break in the ovary to tell follicles to stop growing, wait, wait, wait, is declining because that break is produced by that ovarian reserve.

38:47So the fewer follicles you have in the ovaries, the less of that break you have. And what that means is that follicles might be able to respond to much lower concentrations of FSH than what you would expect 10, 15, 20 years earlier. You mentioned 10, 15, 20 years earlier. Is there a way that someone could go to their physician's office or maybe not now, but in the future, take a look at the ovary, look at how the follicles are aligned during that time and potentially predict menopause, predict the transition? If memory serves correct, when we looked at these women who were the features of these participants who had these sort of atypical follicles growing, I think the only difference was the difference in the number of follicles.

39:37And I'm sorry for the life of me, I can't remember which way it split. But there was no obvious difference, if memory serves correct, between these participants who had these follicle waves, these atypical or rogue follicles versus not. You're asking me, though, if I were to go to the doctor today, right? So I'm hopefully a few years out from the transition to menopause. So if I were to go to the doctor today and I were to say, can you look at my ovaries and can you tell me, is it like 50? Is it 52? Is it 54? How much time do I have? Is it four years before you become symptomatic for menopause?

40:10When you're going to get these changes in FSH or relish? Whatever it is. Because women, because the science is so behind where I think we all agree it should be, what opportunity do we have with modern technology? What is the potential? I think to be able to answer those questions, you'd need to do longitudinal work. The nice thing, though, is a lot of clinics and physicians, they scan ovaries as part of standard of care for a variety of reasons. And so I'm not a physician myself, so I really can't speak to that. But we could have an opportunity where we look at follicle populations in women of different ages and we see whether or not it's sort of predictive of time to menopause or time to the transdent menopause.

40:56In general, we know that the fewer follicles you have in your ovaries, the closer you are to menopause. And of course, this breaks down, though, in context of like PCOS, right? Because that's sort of characterized by elevated follicle populations. But I think we would need to really do those studies. And from my understanding about the age of menopause, it's strongly genetically determined regardless. So can't fight that one. That's right. If you are a woman, God willing, and you live long enough, you will go through menopause. When it comes to the ovaries, is there an age where I would say on a population base that we see these ovaries change?

41:38and from becoming, quote, healthy to more unhealthy, is there a unhealthy phenotype or is it kind of just an age thing? That's an interesting question. I don't think I would say that ovarian phenotype or ovarian morphology changing over time would be an indication of unhealthy. I think we're just learning about it now for over the past 10 years, right? What I would say is what we know about your ovaries. It's, you know, your indication of where your ovaries are at. You know, one thing that we lack in general is really good, robust normative data of ovarian morphology across the lifespan. I don't think I can say healthy versus unhealthy.

42:21We've characterized follicle ovarian morphology enough in conditions of, you know, like obesity or PCOS or under nutrition where we can say like, yes, this ovarian phenotype is an indication of an underlying condition. And the Illusion Lab, so Dr. Marla Illusion has done studies in her lab with grad students that I've been a part of where we induce a weight loss diet to see what does that phenotype improve. And so in that context, I think we can use the ovary as an indication of health status. With the menstrual cycle, we talked about how there's a specific length of time, again, this 28-day cycle.

43:02With the ovaries and, you know, perhaps we look at the menstrual cycle and then the ovarian cycle, what does it mean if someone is, say, for example, having delayed ovulation? Is there a long-term health outcome or impact? So when you say delayed ovulation, are you saying in the context of your 28 days, or are you thinking like a woman with irregular menstrual cycles? Well, no, I think that that's a great question. The idea is most women should have a regular cycle. Those cycles may not be 28 days. It also seems as if the hormones are not as straightforward, the LH, FSH. It just seems that there is a lot of inter-individual variability.

43:50There is, yes. I would love to touch on that because we're all taught this one way. And because we're all taught this one way, I think people become very frustrated if they're not able to get pregnant or if they're moody at weird times because we're talking about it as if it is a standardized experience for all women. Right. And I think it's not helped by certain apps that exist that tell women what they should be feeling. Like, oh, you should be at this phase of your cycle you can expect this you can expect that and it's again benchmark against this textbook case we know that there is tremendous amounts of intern intra-individual variability in terms of the menstrual cycle and the ovarian cycle i think you're asking whether or not that's associated with health outcomes and from you know what i would say is to some extent yes, right?

44:48So if someone has a 28-day cycle and they ovulate on day 21, what that probably means is that that ovulation will produce an insufficient CL, and that will lead to luteal phase insufficiency. So a short luteal phase is an indication of luteal phase insufficiency. It's one of those diagnostic features of luteal phase insufficiency. So I think it can indicate potential pathology. I think pathology might be too strong of a word though. But that said, it also could just be an off cycle, right? And so just because you have one disrupted cycle, maybe it was attributed to stress, right? Maybe I'm a professor.

45:31I give final exams. I remember what it was like to take final exams. Those are stressful events that can lead to transient disruptions. I have a daughter and I'm not looking forward to her growing up because she's so cute at six. But eventually she is going to get her first period. I would love to learn about the time at which that should happen. And if she goes through it early, does that come with it other long-term health effects? And how can we frame it up? In our research, we consider sort of a normal window age at menarche, which is a girl's very first period, to be between 10 and 15 years, right?

46:09and I know sort of different countries have different cutoffs and thresholds. In general, we see at the population level, the age of menarche starting to get a little bit earlier. I think where we actually see this even more is the start of puberty, which is the first breast development, sort of the initial start of thalarchy. And that is happening earlier and there's good data to support that. But back to menarche, you know, we do think that menarche is starting to occur earlier and earlier and earlier in part, you know, over time, nutritional status has contributed to that. We know that reproductive maturation, puberty is all very closely tied to nutrient adequacy and metabolic sufficiency, right?

46:56So when menarche occurs earlier, we have good data to suggest that it's associated with a whole host of long-term health outcomes like obesity, type 2 diabetes, endometrial cancer. Endometrial cancer. Other reproductive cancers. The list is eluding me, but it's a long one. And serious. And serious. Yeah. To be clear, that's any age before 10. Well, that's what, so it's different how it's defined study to study. And what's interesting, a lot of these studies are, what they do is they look at like earlier versus later. And so, you know, what that means can be very different from study to study. So it's, I really don't want to put like a specific age.

47:45That's fair enough. And, you know, we're talking about the degree of inter-individual variability regardless, right? So earlier timing of first menarche is and has been associated with a whole host of cardiometabolic and reproductive diseases later in life. Interestingly enough, though, not PCOS, right? So PCOS is not associated with earlier age at menarche. What's also really interesting, and we're just starting to learn this now, and this could reflect a change in our environment affecting reproductive maturation. So I had mentioned earlier, when we achieve menarche, in some disciplines thought of as the end of reproductive development.

48:25You are now a fully functioning, reproductively mature adult. But that is absolutely not the case, right? the the lights kind of like flicker for a long time there was a study that was done by a group out of harvard where they looked at apple the apple app data so after talking about the app speed as it may you know what one thing that came out of that study is is a huge sample size what they found though is that on average and participants or respondents people who are entering data in their their apple apps health apps were recording that it was taking longer to achieve regular menstrual cycles than it was maybe in the 70s or in the 80s and so what that's telling us is that these years after menarche when the reproductive axis is sort of calibrating ideally towards regular ovulatory menstrual cycles this is taking longer and it may not be happening on a I don't want to say normal, but on a sort of healthier or typical trajectory.

49:27And that's the work that my group does is to try and understand what a normal trajectory looks like and what a sort of atypical or divergence from normal development looks like. But I thought that that was really, really surprising data because it suggests that, you know, adolescent development right now, you know, may be very important. I would love to dig a little bit deeper there. The adolescent development, we're talking about sexual reproduction. You mentioned a statement about the environment. Are we talking about the caloric environment or are we talking about something else that is affecting early menarche?

50:04Timing of early menarche has been associated with a lot of different aspects of our diet, both earlier and later menarche. A lot of this is sort of, there are correlation studies. We can't do these randomized control trials where we put a group of adolescents on one diet and another on another one and see who achieves menarche first. These are all observational studies, so correlation does not equal causation. It's a really important point. But diet has been attributed to earlier menarche. There's bodies of literature that I'm less familiar with that suggest other aspects of our environment and our life are also associated with the timing of menarche.

50:40But I certainly couldn't comment on those. Is it caloric excess or is it body composition? You know, a friend of yours and colleague, Dr. Melanie Cree was a guest on the show, a very excellent scientist. Yeah. Is it excess calorically or is it a body composition problem? Great question. So when I, with puberty and pubertal development, there's still a lot we don't know, which is, you know, it's a continually developing field but there's two phases to puberty first is metabolic sufficiency and so you know do you have sufficient metabolic status or health that you can sort of proceed through puberty and the two sort of endocrine signals that sort of signal metabolic sufficiency or insufficiency would be leptin or ghrelin that sort of you know from from my understanding is the okay you are you know you are go for launch right but you don't actually get the you don't actually you know get the ship into the air, the spaceship into the air.

51:40That is sort of just permissive. And then you sort of have the what's triggering puberty, what is releasing the break that's been holding the reproductive axis quiet for so long. And that's another sort of dynamic and less well understood aspect of reproductive development. And we have seen, you know, different metabolic signals that are thought to be a part of releasing the break, triggering, you know, timing of first ovulation. there's aspects of diet that have also been associated with these as well but I think it's you know the jury still has like precisely what it is but what I would say is we appreciate there is a group of factors it's probably not just one it's probably probably a lot of redundancy in the pathways that are sensing permissive effects you said something really fast I mean listen you've said a lot of very fascinating things but there are metabolic cues can you touch a little bit about leptin touch on leptin and how it would relate what is it and how it would relate to ovarian health yeah so leptin um is an adipokine so it's a it's a hormone that's produced by our fat cells in our body and so the you know the more fat cells that we have the more leptin we can sort of measure in circulation so leptin is a good correlate of adiposity and so leptin also is a there are sort of leptin receptors in the brain that when leptin is sufficiently high enough, it sort of triggers GnRH responsiveness.

53:11And GnRH is a neuroendocrine hormone produced in the hypothalamus that sort of tells the pituitary what to do. So leptin is a very potent and very good signal for the command center of the reproductive axis in the hypothalamus that, there is sufficient adipose tissue on board for reproductive function. And we need that? Yes. Yes. Do I have this correct that the higher the leptin, it should have an appetite regulating effect, meaning you have reached a level of, say, circulating leptin, and you are then less hungry? Yes. It kind of regulates. And there's this whole concept that we have leptin resistance, which would then make us overeat.

53:55and things of that nature. And are you saying that with increased leptin or is it increased leptin or decreased leptin? I know we're getting a little technical here, but the reason I'm asking is because insulin probably relates to this picture. Yes, very much so. What we're looking at is if it's an adipokine and it is something that is coming from adipocytes or fat, the more fat one would have. probably again i don't know because uh dr melanie cree really threw a wrench into everything that it wasn't about the adiposity itself it was the intermuscular oh adiposity so yeah um yeah i i defer to to melanie on all topics related to muscle that is not my field but the fat relationship um when is enough enough and when do we get to the quote metabolic tipping point where at 32 % body fat, we see a dysregulation in reproductive health.

54:57Yeah, I can't answer that question. What I can say, though, to your point earlier is the neurons in your brain that are responding to leptin to suppress appetite are those same neurons that are also responding to leptin to talk to another neuron called the kispeptin neuron that tells GnRH, yes, we are good to go, or no, we're not good to go. So those same neurons that are modulating appetite regulation are also involved in reproductive function. It's a really interesting integration site up in the brain. Now you have studied nutrition and you do study nutrition. And I know that you are a scientist and you don't see patients, but from your perspective, do you think there is a certain type of diet or something that we need to be aware of or something that you're seeing in patterns that would negatively or positively affect reproduction?

55:49The short answer for me would be I cannot recommend a particular dietary pattern. We can talk about this in the context of PCOS. This is where I'm very familiar. There was a systematic review that was done a few years ago that did summarize the data related to timing of first puberty or timing of first menarche, sorry, suggested that certain macronutrients were helpful versus less helpful. In terms of a dietary pattern, what I would recommend would simply be the dietary guidelines for Americans, for people living in the United States, or if you have listeners from other countries, the guideline for healthy eating in their country.

56:32And I say that because we know that on average, Americans do not adhere to a healthy dietary pattern. So, you know, from my vantage point as a scientist, I feel like any way we can move in the direction towards a healthy eating pattern, and this is what happens in these studies, is the foods that pop up in, you know, as being sort of helpful or beneficial, they're part of a healthy dietary pattern. And when I say healthy, I'm referring to, you know, the dietary guidelines for Americans. That's, you know, as a non-physician, as a non-registered dietician, that's really where what I would say and that's where I say the evidence is at right now.

57:12And I want to add a little context to that. Sure. I'm very excited to see the next set of guidelines come out because the essentially the 2025 guidelines and beyond which they're working on right now are going to increase dietary protein. It's going to liberate some of the restrictions on fat. I think it's going to be extraordinary. The first part of your statement is absolutely correct. Americans are not following the guidelines on average, on average, that are put in front of them. So essentially, anything is better than a highly processed over carbohydrate diet that we are currently eating.

57:54Currently, on average, Americans, 98 % of them are over consuming consuming refined grains and food of that nature. So what about myths? What are some of the biggest myths that you, and actually you teach a course on evaluating data and how to, what is the assignment that you give your students? So the course is women's reproductive health and nutrition across the lifespan. So menarche to menopause. So it's a fun time for me because I get to sort of geek out with my students in the class and we get to talk about reproductive physiology and the different changes that occur and the role of nutrition, what we know, and more often than not, what we don't know.

58:36But their final project in lieu of a final exam is, you know, there's a long list that I compiled after sort of talking to friends and collaborators and on myths they've heard around, or not even myths, but, you know, if it's not a myth, like something they've tried or they know themselves or they've heard their patients say related to nutrition and women's health. So my field is, you know, PCOS, a lot of PCOS related research. And so I do tend to get a lot of those myths trickle in. So, you know, one of them is, you know, eat, you shouldn't eat fruit if you have PCOS because it makes your insulin resistance worse.

59:13And that's a good one. That's a real banger. It's, you know, patently false. I can say that quite confidently. And there's the data actually show the exact opposite, right? Because, you know, fruit is, It's chock full of fiber and really important nutrients. It helps with satiety. That's one that I hear I've heard and seen. Another is timing your diet with different phases of your menstrual cycle. Yes. Talk to me about that. Is that a myth or a true statement? And we have to pause on this because we're going to double down. What is the myth that you hear? Well, it manifests in a few different forms.

59:54One of them is seed cycling. where at different phases of your menstrual cycle, which is sort of overlaid with your ovarian cycle in this case, that you should eat different seeds at different phases of your menstrual cycle. And for the life of me, I couldn't tell you which seed. And I really also couldn't tell you what it's supposed to be doing physiologically because the data aren't there to support that. Another one that I've heard is, you know, at different phases of your menstrual cycle, you should be eating different foods, right? You know, this is another one where to do this kind of research, it would be very challenging to test this hypothesis rigorously.

1:00:33And conceivably, where I suspect these claims or these ideas came from would probably be from animal studies, right? Which save non-human primates, you know, the rodent models, they don't menstruate, right? So we're not looking at a typical reproductive cycle that we would see in women and what's done in rodent models, for instance, typically those nutrition exposures are several fold greater than what we as a human would eat. So any evidence that might exist is probably not translatable to humans. Two myths that you've just taken off the table. Number one, seed cycling is a myth. We do not have evidence for that.

1:01:13Number two, that you should eat various foods or change your dietary patterns, is that fair to say, depending on your cycle, where you are in your cycle? I have not seen convincing evidence that would support that that is a good idea. Do you have another big myth? Sure. So one, it's, that I think can cause a lot of grief is that you can cure PCOS with nutrition. To make that claim sort of really it's not taking into full account how complex PCOS is, right? It's, you know, we know now that it's a complex trait. There's some genetic predisposition and there's environmental factors that can trigger sort of a genetic predisposition towards PCOS.

1:02:01I have not seen any dietary intervention trial that has fully resolved the PCOS phenotype. Dr. Marla Lugin up at Cornell she in her lab you know we did two different dietary interventions in women with PCOS and we did not see a full resolution of the phenotype you know in a subset of participants the phenotype got worse it was a small sample size so I really caution against you know worrying about that finding per se but what I would say is you know there really isn't data to suggest that diet can cure PCOS. There is no cure for PCOS right now. And hopefully one day we will have one. Maybe GLP-1s will.

1:02:45The data are so promising there. I know. Maybe they'll be. Yeah. I mean, that's so exciting. What about the myth that you can balance your hormones with a supplement or balancing your hormones with food? Even the notion of what it means to balance your hormones is a bit of a giveaway in and of itself because we know that our hormones are constantly changing day to day to day to day. Certainly you can have, you know, chronically elevated hormones, but the notion that you can sort of balance your hormones at any given point with anything, it it doesn't physiologically make a lot of sense to me i i would have to say that that one is a myth and what i know of evidence around um turmeric for conditions or other sort of supplements not to call one specifically out but there isn't good data i would say there are good supplements with tier one evidence and that's great and as we see this repertoire expanding of well, it could be turmeric or it could be ginger.

1:03:55I think that if you are trying, what's the statement where if you're trying to chase all the rabbits that you're probably not going to catch one or whatever it is. Anyway, I like that one though. But you know, we could double down on the supplements or the bioactive ingredients that are promising for various things versus again, and diluting our brains and diluting even the science. And there are, you know, to that point, I don't mean to sort of paint with broad strokes earlier, but, you know, there is good mounting evidence that certain supplements could be beneficial for different phases of life, right?

1:04:34So fish oil has been studied for the context of, you know, dysmenorrhea, so menstrual cramps. I didn't know that. Do you know much about menstrual cramp? And I just opened up a can of worms because I did not know a can of fish. That is really funny. tell me yeah tell me about that there is pretty good evidence to suggest that you know the fish whales the even dha epa they can be beneficial for alleviating cramps and part of that is the pathophysiology of menstrual cramps relates to sort of inflammation and the inflammatory process of shedding that endometrial lining there have been a couple of studies and i do cover this in my class that make a really interesting case for it.

1:05:16I would honestly have to go to, you know, a really good systematic review to see what the, you know, what the overall effect estimate is in multiple populations. You know, I never want to hang my hat on one study, certainly not. But that would be one example where, you know, I think with a few more really good studies, I think we could get there. And same, you know, with PCOS, right? There is no PCOS diet per se. I think that reflects lack of evidence. I see a lot of recommendations coming from physicians that really target this relationship between PCOS and type 2 diabetes and sort of making dietary recommendations that are intended to interrupt that process.

1:06:00And, you know, I think what we really need is more well-designed studies to really see whether or not, you know, does how beneficial is this particular dietary pattern for this particular outcome. All that to say, regardless of physiological outcome, and improving, you know, a dietary pattern is associated with an overall improved quality of life. And that's a really important endpoint for all of us. I would agree with you. For sure the menstrual cramps that's novel i've never heard that that there might be an improvement with dha or epa what else check that for you we'll fact check it we'll fact check it um anything else that was surprising actually whether it's again you know the menopause transition is a very hot topic and there's so little information from the ovary standpoint of menopause and it's kind of the landscape is you are perimenopause and then you're menopause.

1:07:00And that transition can take a long time. It can take a long time. What I would say, and some general recommendations for anyone, the best evidence, you know, that you'll be able to find from my vantage point related to nutrition and reproductive health will be going to a very authoritative body. So like the the menopause society for instance they do have on their website a section about dietary supplements or nutritional supplements and menopausal symptoms right so rather than going to tiktok you could just google the menopause society is way more fun there is some other work so really nothing comes to mind other than the fish oil that is a bit innovative that you had not heard of before fish oil is a really interesting one that surprised me um something i heard about was dairy causes inflammation, which makes PCOS worse.

1:07:51And that's not something that I've seen data to support as a claim. Okay, so that's fake. Yeah. We talked about nutrition kind of globally, eat well, don't eat a bunch of junk food. No deep details. Again, if you guys want more details about my perspective on nutrition or what I believe and what I feel that the evidence supports, um i you can definitely find it your lab has done very unique research and that if we're talking about nutrition and there's the idea of the individual foods but then also the microbiome the microbiome plays a role in our overall health and wellness tell me about this new bile acid sure paper yeah yeah absolutely you know we think about bile acids as you know molecules that digest lipids, right?

1:08:43That's sort of how we learn about them in school. Working with collaborators, Mark Roberson from Cornell and Alejandro Lomninsky from Dalhousie up in Canada, where I'm from, what we saw is that during puberty in a rodent model, so during reproductive development in a rodent model, that there are these special type of bile acids that are only formed by the gut microbiome. So bile acids are formed in the liver and then they're formed in like one way, it's called primary, and then they go down to the microbiome and they're converted to a secondary bile acid and they get sort of resorbed into the bloodstream.

1:09:18What they found in the rodent models was that during puberty, or rodent puberty, there's this massive shift in circulation in the type of bile acid that's in circulation, so from a primary to a secondary, and that happens because of the microbiome. They also saw that there was a distinct change in the communities in the microbiome to make those secondary bile acids. And what's really cool is that they were also able to show the presence of that secondary bile acid receptor in the hypothalamus. And when they activate it, it increased or stimulated reproductive access activity. Wait, wait, wait.

1:09:58I think I just hallucinated. Bile acid affecting the brain? What they were able to show in this sort of ex vivo model first is that by activating the secondary biolocid receptor in the neurons that are in the hypothalamus, they were able to increase GNRH activity. And then in a rodent model, what they found is that when you prematurely activate TGR5, you advance the timing of first ovulation, timing of vaginal opening in these rodent models. and so what we did what i did is i looked in my data sets we did a sort of secondary analysis of two different data sets looking at changes in bile acids in girls and we found exactly the same shifts in bile acids so in one of those studies we have the stool from these kiddos and we're going to analyze that hopefully later this year early next year and the other part of this question though.

1:10:56So what this does is it implicates the microbiome in a very hypothesis-driven way in participating in or modulating the reproductive axis and reproductive maturity. And we took it a step further. And Hannah, she was a student in my lab. She's just starting her PhD now, actually. She looked at whether or not there's this sort of difference in bile acids in these adolescents who would go on to develop PCOS versus those who did not. And we have samples from a postdoc for a cohort study that we did, that I did when I was in my postdoc that we were able to analyze. And so we also see these distinct changes in biolasses.

1:11:39And that paper is getting written up right now for publication. Very compelling and new and novel, the relationship between the microbiome and the brain and its effect on ovulation and reproduction and fertility. you posted dr heidi it has been an incredible pleasure to have you on the show truly thank you i i've enjoyed it i thank you for being a wonderful host and hopefully this was helpful i certainly can attest that it was helpful not just to me but for everybody listening and watching we will link where your lab is sure many publications and i know that you've got some great students so students listening i have a assignment for you which i will get back to we are going to do a series of debunking tick tock instagram in lieu of real science it'll be fun