← The Dr. Gabrielle Lyon Show
The Dr. Gabrielle Lyon Show
The Menstrual Cycle DECODED: Fertility, PCOS, and the New Science of Hormones
01:12:35
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- [00:00]
A
There's a heavy discussion on the menstrual cycle.
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B
Over the course of the menstrual cycle, we have two things going on in two different organs. We have what's happening in the ovaries, and that's the ovarian cycle. And then we have what's happening in the uterus, and that's the uterine cycle.
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A
I have never read about it, but I don't even think that there's many people that study it.
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B
There really isn't data to suggest that diet can cure pcos. There is no cure for PCOS right now.
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A
What is the myth that you hear.
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B
You shouldn't eat fruit if you have PCOS because it makes your insulin resistance worse? The data actually show the exact opposite.
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A
There are challenges with fertility now, it seems now more than ever on both sides.
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B
In those women with regular menstrual cycles and obesity, the majority of those ovulations met the criteria for luteal phase defects. And that can certainly affect fertility. 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. When Menarche occurs earlier, that's associated with a whole host of long term health outcomes like obesity, type 2 diabetes, endometrial cancer.
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A
Can you get pregnant while on your period?
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B
I've seen ovulation during menses. Now let me explain what that means.
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A
You are a reproductive physiologist and you are the only person that has studied the ovarian transition from being reproductively robust to menopause.
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B
The transition to menopause, yes. Under the supervision of Dr. Angela Bearwald. But, yeah, I was the one doing the work. Yeah.
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A
Pretty incredible. Exactly why I wanted you on, because you have a unique perspective. And I'm going to open with a banger of a question.
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B
Sure.
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A
Can you get pregnant while on your period? Inquiring minds want to know.
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B
Yes. Okay, great. The short answer is I don't know. But the long answer is I've seen ovulation during menses. Now let me explain what that means. So during my master's degree, while I was characterizing how the ovaries work during the transition to menopause, this involved, you know, bringing women in every other day or Monday, Wednesday, Friday, I think. Was that protocol for six to eight weeks? And these were women who are 45 to 55 years old. One participant in particular. One thing that we found, I can go into this later if you'd like, is that we started to observe specifically in this Transition to menopause. Follicles in the ovary growing at unexpected and unusual times. And right around the time of ovulation, those follicles that were growing at this unexpected time seemed to respond. Respond as well to that ovulation, not by ovulating themselves, but by continuing to grow and producing a lot of estrogen. So this one particular participant, she had a follicle that responded to this LH surge and continued to grow and produce estrogen. And then while she was menstruating, sort of the end of her luteal phase, when she was menstruating, that follicle didn't regress, it ovulated. And we saw a subsequent rise in progesterone. So we had ultrasonographic and endocrine confirmation of ovulation, which was surprising to us. And, you know, we've seen anecdotally in other publications looking at other life stages, like adolescent sort of atypical timing of reproductive hormones. So I think what we saw in the transition of menopause could also happen at other life stages. It just hasn't sort of been characterized in that same way.
- [03:36]
A
What's compelling to me, and as someone who has been consuming information, and I think a lot of our viewers and listeners, there's a heavy discussion on the menstrual cycle. But prior to this podcast, I had never heard of a uterine cycle. I had never thought of an ovarian cycle. And it made me think that there are probably different phases which we know of the menstrual cycle, which I'd love for you to touch on. But what about these other cycles?
- [04:06]
B
When I teach the menstrual cycle to my students, I use menses to menses. So the start of one menstrual event, menses to the other, is one menstrual cycle. Over the course of the menstrual cycle, we have two things going on in two different organs. Right. We have what's happening in the ovaries, and that's the ovarian cycle. And then we have what's happening in the uterus, and that's the uterine cycle. Would you like me to go through them?
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A
Yeah, I would love it. Our producer doesn't know much about it, which he would love to. But seriously, for the guys listening, the more educated they are on this, the better they can support their partner. And for a whim, for a woman, you're going to go through it. You might as well know.
- [04:45]
B
Absolutely. So I'll start with the uterus, because that's sort of the easier one to explain. And then I'll move to the ovaries, because that's, in my mind, the really exciting one at the start of menses, it's that shedding of what's called an endometrial lining. So in a woman's uterus, we have three different layers. The innermost layer is that endometrial lining, and that's what builds up and sheds monthly in a sort of a textbook menstrual cyc. So the uterine cycle sort of starts with that shedding of that endometrial lining. And then once that's shed, then that endometrial lining starts to proliferate, which means it starts to thicken. And that's happening because of estrogen coming from the ovaries, estradiol specifically. While estradiol is being produced from a dominant follicle, which I'll talk about in a second, that's causing that endometrial lining to develop and develop and develop. And then when ovulation occurs, which if we're talking about a textbook cycle, is mid cycle, the then that developed endometrial lining starts to sort of fill in with secretions, and that's called the secretory phase. And that's under the influence of progesterone, which is also a hormone that comes from your ovaries, from a very special structure called the corpus luteum. In the luteal phase, that endometrial lining is producing a lot of secretions, getting ready for implantation if implantation were to occur. Because in humans, the structure that makes progesterone, it has a self destruct button. After about seven to 10 days, if there is no signal from the uterus that implantation has occurred or fertilization has occurred, then that endometrial lining sheds. So you have, you know, the shedding, the proliferative phase and the secretory phase. That's the uterine cycle. Then we go to the ovaries. And so this is really interesting and I think it's really cool because it's not in textbooks, at least to my knowledge.
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A
Yet I have never read about it, but I don't even think that there's many people that study it.
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B
There aren't.
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A
There's probably, what, four, five?
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B
About that. Yeah, it's a very small, um, but, but it's an important contribution. So Dr. Angela Bearwald, or Angie, she did this for her PhD research where she wanted to study, you know, how ovarian function worked across the menstrual cycle in healthy, regularly Cycling women to do this type of work, you have to bring your participants in every single day for this particular study for, you know, four to six weeks. And what she found. And so what we do in this case is you scan the ovaries, and we capture these video clips through the ovaries, and that allows us to look the follicles in the ovaries. Before I go any further, I just want to do a little bit of background. What follicles are in our ovaries? We have our eggs. And those eggs don't just exist by themselves. Every single egg is surrounded by its own little capsule or structure called a follicle. In their most primordial form, it's just a single layer of cells. But as follicles start to develop, they fill in with fluid. And that fluid filled part of the follicle is called an antrum. And. And that's what we can see on ultrasound. If you or your viewers were to Google an ovary on ultrasound right now, they would see these pictures of these ovaries with these black circles. And each of those black circles is a single follicle. In each and every one of those follicles is an egg. What we can do is when we scan these ovaries serially every day or every other day, we take the time to track the growth of every single one of those follicles that we can see. We can learn a lot about how the ovaries are working. This is what Angie did, and so what she found, and I'll summarize this, is starting it around menses. So the start of menses, there's a group of follicles that all start to grow at the same time. And that's because they're being recruited to grow by a hormone from our pituitary called fsh, or follicle stimulating hormone. We're very creative people.
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A
Yeah, that makes a lot of sense.
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B
Follicle stimulating hormone.
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A
Got it.
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B
Check. So this group of follicles starts to grow. And so this is a wave of recruited follicles that are growing. From that wave of follicles, one gets selected for preferential growth. And that physiological transition is a very important one for a few reasons. Once that follicle is about 8 to 10 millimeters in diameter, which is it's large in the world of an ovary, it starts to produce estrogen. Remember, estrogen is what's stimulating that endometrial lining and that proliferative phase, it's producing estrogen, which suppresses fsh. And another really important Feature that happens in that selected follicle is it switches from being dependent on FSH to being dependent on a different hormone entirely called lh. That means that that follicle can produce estrogen, suppress fsh, which prevents all of those other follicles from that wave from continuing to grow. So they all regress and they undergo atresia. And they have the one sort of follicle that's selected for growth. And it gets bigger and bigger and bigger, and we watch it get bigger and bigger until it gets ready to OV ovulate, where it's almost the size of the entire ovary. It's a big follicle on ultrasound. Once that follicle reaches a certain diameter, morphologically, it's also producing a lot of estradiol, or estrogen. That's what's triggering ovulation. And ovulation is an LH surge. The endocrine event that triggers ovulation, I should say, is an LH surge. Ovulation occurs. That egg is extruded from the ovary into the peritoneal cavity, be taken up into the fallopian tubes. And that now empty follicle, it transforms itself into that structure called the corpus luteum, or the cl, and that's Latin for yellow body. That's because when the CL forms, tremendous amount of lipid accumulates in that cl, and it's needed to make progesterone, because progesterone is what's going to develop that endometrial lining. And progesterone potently suppresses those hormones from the pituitary, the fsh, and the lh, to prevent any other follicles from growing. Supposedly what was really novel about this work is that around the time of ovulation, there was also another rise in the fsh, again, that allowed another group of follicles to start to grow. Another wave of follicles grew in the luteal phase. And that was particularly novel. In some of those cases, one of those follicles would develop to be large enough to produce estradiol, but it would never go on to ovulate. Of course, as I alluded to later with the transition to menopause, this sort of structure for these follicle waves developing over the course of the menstrual cycle, that starts to break down a little bit. But that's what's happening.
- [11:17]
A
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- [12:01]
B
Notes.
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A
Is there a reason why one egg or one follicle gets selected over another one?
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B
That's a great question. So I think you're asking why, why, why this one follicle gets selected? And there's from my knowledge, there's two real theories and I don't know that in humans we've been able to really pin down mechanistically what's happening. One thought is that that particular follicle is just bigger than every other follicle. And so a really unique feature about follicles is they have very different endocrine profiles. They're as they get bigger, as they sort of get larger in size, the hormones that they're producing changes. The receptors that are on, on those foll granulosa cells, those change as well. And so one thought is that the follicle that gets selected for preferential growth for ovulation might be a little bit bigger than the other follicles or intrinsically there's something within that follicle that allows it to express those LH receptors a little bit sooner than the other follicles. Because that's really what's key. Right. To prevent those follicles, to prevent atresia, that follicle has to switch. You know, it's, it's growth source to be from FSH to lh, to be able to continue to grow.
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A
You know, it's really compelling. I did not know that the lipid accumulation was related to progesterone release, the steroid hormone. And you look at, does nutrition play a role in that? Because we're talking about very specifically to the ovary.
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B
Yeah. I genuinely couldn't tell you whether or not a particular diet would improve or affect specifically luteal function. I really couldn't tell you that. Those data may exist in rodent models or another type of model like an ovine model or a sheet model. But I don't know the degree to which they exist in humans. What I can say is that there are metabolic states that are associated with impaired luteal function. An example would be, for instance, the disease of obesity or undernutrition. So functional hypothalamic amenorrhea, we know that there's impaired luteal function in those cases. Whether or not it has to do with the ability of that CL to accumulate lipid, I don't know.
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A
And then the outcome of a pregnancy, it seems as if it would be dependent on multiple factors. The ability to produce enough estrogen, the ability to produce enough progesterone. And in the landscape of how we're talking about it, insulin cycles, it seems as if these cycles are a standard 28 day cycle.
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B
Right, right.
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A
Yeah, but that's probably unlikely.
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B
It's not as common as we think it is. Yeah, yeah.
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A
Talk to me about the variation talk to me about the variation between these menstrual cycles and then these ovarian cycles. And also within the same woman.
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B
One thing that, that I teach my students, and we have evidence of this in adolescence, in obesity, in, in regularly cycling women, or in conditions of functional hypothalamic amenorrhea, is that just because you're menstruating every 28, 35 days does not mean that your ovaries are doing what they, what you think they might be doing. Okay. So it's sort of disentangling this notion of regular menses from regular ovulation, doing these types of studies where you're characterizing follicle waves, that we understand that and. Exactly. We can sort of see where things are going wrong, if you will. One example I can give you is I'll start with adolescence. So my lab, we study these early post monarchical years. We're really interested in what it looks like when the reproductive axis is sort of turning on, you know, after puberty. Our reproductive axis is not like a light switch. Right. It's not just like, you know, we achieve menarche and we have regular ovulatory menstrual cycles. That is absolutely not what happens.
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A
But you would believe that if you read a textbook or watched online or went to TikTok maybe, I guess, I hope not.
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B
We can change that.
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A
You are about to change that.
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B
What we know now is it takes a few years to establish regular menstrual cycles. If you are sort of on that trajectory towards regular menstrual cycles, but then it takes approximately five years for the majority of those cycles. To be ovulatory. I know from work that I've done. I collaborate with a number of investigators to ask some of the questions that we ask. I know from our own data, as well as published data from other labs that an adolescent in these early post miracle years can have 28 days between menses, but nothing is happening in the ovaries. That's endocrine data. We don't have ovarian data to corroborate this, but looking at the changes in those hormones that we would expect to see. So that's sort of one example where you can have an adolescent who experiences regular menstrual cycles, but she may not be ovulating, which is probably part of normal development. Right. And so I don't say that to worry someone. It's more or less this is just part of the reproductive axis turning on right after a very, very long period of quiescence or childhood in the context of obesity. One study that we did, well, I was a PhD student in the Lusion lab up at Cornell, as we sort of characterized follicle waves in a series of women with different metabolic states. We characterized them in the context of PCOS, and that was Dr. Brittany Jarrett's dissertation work. And then we characterized follicle dynamics in the context of obesity, but regular menstrual cycles. And that was Dr. Alexis Oldfield's PhD research in the context of obesity. What we found is that there were differences in follicle waves that were growing, that were unique to obesity and regular menstrual cycles. And something that Alexis found that was quite surprising but really informative is that the majority of those ovulations in those women with regular menstrual cycles and obesity met the criteria for luteal phase defects. Right. So that means that there was sort of impaired or lower progesterone. And that can certainly affect fertility.
- [18:22]
A
There are challenges with fertility now, it seems now more than ever on both sides. There are challenges with sperm quality, and there are challenges with women and pregnancy. We see it every day in our clinic. You said something that I had. You know, I've never heard about these waves. If I'm understanding correctly, it's one wave would be considered that there is this group of follicles. One becomes the dominant follicle. That dominant follicle grows and can be released or sometimes or should ideally be released, but it might not.
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B
And.
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A
And is that correct? And then on the back end, there's also additional follicles. And is that what is defined as these waves? Help me put it into context.
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B
Yeah, sure. Great, Great question and great point of clarification. These waves, if you think about them as this group of follicles, all starting to grow at the same time, and that's what a wave is. You can visually, if you think of like a wave in the ocean, you know, that's sort of what we see is these groups of follicles getting bigger and bigger and bigger in women. What Angie found is that women with regular menstrual cycles, healthy, they have two waves. One of these waves is the ovulatory wave. From that wave, one follicle is selected and that goes on to ovulate. Then there's this second wave that occurs during the luteal phase, which is the second half of that ovarian cycle after ovulation. She also found that some women exhibit three waves of follicle development. In this case, you'd have a wave that starts to develop around menses and then it doesn't. It's not the ovulatory wave, it regresses. And then you have another wave that develops, and that's the one that goes on to ovulate.
- [20:05]
A
What would be the benefit of understanding this from a, say, a clinical aspect? I'm sure that this is being done or I'm not sure done in fertility clinics.
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B
Yeah, that's a great question. So something that I think Angie is pursuing or has tried to pursue is whether or not we can sort of leverage these. Target these follicle waves for assisted reproductive therapy. Right. So I personally don't do any research in, in this space, but my understanding of ovarian stimulation cycles is you're sort of. You're stimulating follicles to grow. And this is a very controlled part of assisted reproductive therapy because you have to make sure that you don't overstimulate because that can cause ovarian hyperstimulation syndrome. That's very dangerous. One therapeutic implication of follicle waves is perhaps over the course of the menstrual cycle, rather than having sort of one time at the beginning of a menstrual period where we think we can recruit, we can target follicles for assisted reproductive therapy. Maybe you can target them again in this luteal phase wave or so. So it's, it's, it's thinking about leveraging this knowledge of waves to optimize assisted reproductive therapy. That's sort of one implication or one example of how it can be important.
- [21:24]
A
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- [22:55]
B
First and foremost, basic understanding of women's reproductive health.
- [22:59]
A
How do we not know that yet? Right.
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B
And this is something that, that I've, I've share, shared with my students and that I'm transparent about. I'm, I am honored that I get to be a part of this group of scientists, you know, who study follicle development. But my goodness, this should have been done like 30 years ago. Right? And, and, and it's, it's, it's cool that I get to discover things as a scientist and I, you know, hope that I can continue to support this field with, with my team in my lab. But I think just the basic understanding of filling in our gaps about how human physiology works. I think it's also helpful to give women answers and give parents and teenagers answers to why they might be experiencing symptoms across their menstrual cycle. Knowledge is power and the more we know about the ovaries and what's going right and what's going wrong and what that looks like. I think the more empowering and hopefully reassuring it can be. I would love to see this continue to be leveraged is transitioning in our understanding of follicle development and understanding when we see disruptions in, in sort of the coordination of ovarian follicle growth. This manifests in the ovary and we don't. What. What, you know, Dr. Marlous work has really spearheaded in her lab, and I worked on this while I was a grad student with her, is we can see, looking at the ovary in one cross section, we can see these distinct patterns of follicle assembly within the ovary and follicle populations. And this can tell us. It gives us insight as to what might be happening longitudinally. So we can look at the ovary as a biomarker of underlying reproductive dysfunction and then some of the ovary as.
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A
A biomarker for underlying dysfunction or positive and good health, right?
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B
Yes. And, you know, the ovary is used diagnostically and prognostically in a number of cases. The diagnosis of polycystic ovary syndrome, or pcos. You know, physicians look to the ovaries when they are assessing for risk of ovarian hyperstimulation. We look at the ovarian. We look at follicle count as a marker of ovarian reserve. So an indicator of potentially premature ovarian.
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A
Failure, which would be menopause before the age of. I think it's before the age of 40 or around 40.
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B
That sounds right. I don't know the exact age, and I do apologize, but it's early menopause and is premature depletion of the ovarian reserve. And that we can see that we can see sort of this depletion of the antral follicles. You know, we can't see those earlier follicle stages. We can't see those primary or secondary follicles. And those are the ones that don't have the fluid in them. But the ovarian, the number of follicles in our ovaries do give us an indication of ovarian reserve. What's also a more sort of novel aspect of the ovary as a biomarker is whether or not the ovary can also give us insight into metabolic health. That's something that, you know, the illusion lab has done a lot of work in it. I've been so grateful to contribute to that research. We published a review article on this topic a few years ago where we summarized our hypothesis about how the ovarian morphology, the features of the ovary and ultrasound present in distinct ways all the way from extreme undernutrition through healthy BMI to, you know, overweight or obesity in and pcos. And so we hypothesize that because the ovary is integrating these reproductive signals coming from the brain and integrating these metabolic signals coming from our body and Our nutrient status that it, that, you know, leads to these very specific and unique features that we can see on ultrasound.
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A
What would it look like if someone, if we were to break this down into categories.
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B
Yep.
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A
What would someone who is undernourished, what would their ovarian morphology look like?
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B
If you start from the most extreme, and this is work that was done a long time ago and in cases of extreme undernutrition, so in literature this would be severe anorexia nervosa. What we see are small amorphous ovaries. So the ovaries are small, they don't have any follicles. You can't see any follicles. And what that represents is very, very powerful suppression of the reproductive axis. So something to remember about, you know, our reproductive axis is, it's, it's a luxury. And physiologically, you know, we need our brains to survive, we need our hearts to survive, we need our lungs to survive, but we don't necessarily need to ovulate to survive. And so, and, and the act of ovulation is energetically expensive. The act of, of, you know, pregnancy is energetically expensive. And so what that means is if the, if the body senses energy deficiency, it shuts it down. Right. And our reproductive axis is very sensitive to undernutrition.
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A
Are the ovaries more so sensitive to undernutrition versus, I don't know, say the uterus or another organ system or another sex organ system?
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B
That's a great question. So what I would say is the ovaries are producing those hormones that are stimulating that lining in the uterus to develop. So the uterus is really following what the ovaries are doing. If the ovaries are not getting the signals from hypothalamus in the pituitary to support follicle growth, those ovaries are not going to make estrogen, they're not going to make progesterone, and that's not going to develop the endometrial lining. And 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 under nutrition 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. Those cells that chew away at bone, and that affects, you know, bone health as well.
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A
So small is the right word, atropic, or is that extreme for the ovary? If someone was anorexic or going through hypothalamic amenorrhea.
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B
Right.
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A
A physician does an ultrasound on these ovaries, and these ovaries are small and shrunken.
- [29:47]
B
Amorphous is what we would am. 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. This is a case where, if you look on ultrasound, these ovaries are not necessarily enlarged, but they do have elevated follicle population. There's more follicles than what we would expect in regularly cycling individual with a healthy bmi. But 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 there's 4 to 10 millimeters in diameter. And when you scan them on ultrasound, it kind of looks like soap bubbles. If you're washing your dishes and you have soap bubbles and they're sort of all touching each other and you scan through it, it's just like soap bubble, just soap bubble after soap bubble. So they look. Look large and multifollicular. And that would be sort of the classic image of an ovary in someone with functional hypothalamic amenorrhea.
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A
What are the other categories?
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B
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 we can see smaller follicles and there's fewer follicles. We don't really see ovarian enlargement. We see luteal phase defects when we start moving into irregular menstrual cycles. If you move up into overnutrition, if you will, with overweight obesity, and then irregular menstrual cycles. Before we get to pcos, when we're in that Normal androgen area. We. We don't necessarily see ovarian enlargement yet, but we do start to see increases in follicle populations. There's a smaller follicle, 2 to 5 millimeters. Then the most severe ovarian phenotype would be these classic polycystic ovaries or polycystic ovary morphology, which is part of pcos, these ovaries. A really important thing happens at that level is what we think is happening is there's 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 is 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. 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, too 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 cognatotropin. 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 ovaries, 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.
- [33:26]
A
For every physician or medical student. We've all passed our boards. Now, that will be the only ovarian. That will. That will literally be the only ovarian question you will get.
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B
Is it this string of pearls? 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.
- [33:53]
A
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 breakfast Breaks, my husband's snoring. My cells, they're like, yo G, we're tapped out. Enter Mitopure. Timeline nutrition is one of the most thoroughly researched products I have come across in over a decade. Look carried in my purse. They have peer reviewed published science and this is where it gets really interesting. So for those of you who are following the muscle centric lifestyle, when you increase bioenergetics, you improve improve muscle function and health in adults. 40 + timeline has been shown to increase muscle strength and endurance and no change in activity. So whether you've been active resistance training your whole life or you're just getting started, or you're not getting a lot of sleep and you've got a million requests, your muscles and your mitochondria need help and they have just launched their low sugar vegan, non GMO gluten free gummies, which by the way, way I am eating by the handfuls, which I shouldn't, but they taste delicious. Timeline is offering our community 20% off. Your first order. Go to timelinenutrition.com DoctorLion and use the code DRLION to get 20% off. I recommend trying their starter pack with all three different formats and of course their gummies, which are incredible. How fast, if we were to. And really what you've done so nicely is you've described this continuum. Are there any more? Well, there also is the menopause transition.
- [35:31]
B
There is, yeah, yeah.
- [35:33]
A
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.
- [35:43]
B
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.
- [35:55]
A
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.
- [36:17]
B
You're very kind.
- [36:18]
A
I'm not that kind. Just ask anyone on my team.
- [36:22]
B
Sure, sure. So to the ovaries, the transition to menopause. So what was really interesting about the transition to menopause is that, and I'll call them rogue follicles. So in someone undergoing the transition, menopause this isn'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 9 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 atypical luteal phase dominant follicles, where they also seem to respond to the LH surge. And 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 endocrine side of this was characterized by a group in Australia in women undergoing the transition to menopause. And they wanted to know, like, what's going on? Yeah, and so that's really 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.
- [37:52]
A
Is 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?
- [38:05]
B
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, synthesize a lot of hormones that serve to like put the brake 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 those, that ovarian reserve. So the fewer follicles you have in the ovaries, the less of that break you have. And what that means is that follicles might become, be able to respond to much lower concentrations of FSH than, you know, what you would expect. You know, 10, 15, 20 years earlier.
- [39:04]
A
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.
- [39:24]
B
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 their just, just was. Was the difference in the number of follicles. And I'm sorry, for the life of me, I can't remember which direct. Which way it split. But there was no obvious difference, if memory serves correct, between these participants who had these follicle waves or these, these atypical 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, like, can you look at my ovaries? And can you tell me, is it like, like 50, is it 52, is it 54? How much time do I have?
- [40:06]
A
Is it four years before you become symptomatic for menopause, where you're going to get these changes in fshrl, 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.
- [40:27]
B
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 and, you know, in women of different ages, and we see whether or not it's sort of predictive of time to, you know, time to menopause or time to the transition to menopause in general. We know that the fewer follicles you have in your ovaries, the closer you are to menopause. And of course, this, 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, to really do those studies. And, you know, from my understanding about the age of menopause, it's strongly genetically determined regardless. So, yes, can't fight that one.
- [41:22]
A
That's right. It's if you are a woman, God willing, and you live long enough, you will go through menopause.
- [41:29]
B
Menopause, yes.
- [41:30]
A
When it comes to the ovaries, is there an age where I would say on a population, population base that we see these ovaries change and from becoming, quote, healthy to more unhealthy? Is there a unhealthy phenotype or is it kind of just an age thing?
- [41:49]
B
That's an interesting question. I don't think I would say that that that ovarian phenotype or ovarian find morphology changing over time would be an indication of unhealthy. I think it's. We're just learning about it now for over the past 10 years. Right. I would, 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, that we lack in general is really good robust normative data of ovarian morphology across the lifespan. I don't think I can say sort of healthy versus unhealthy. We've characterized follicle ovarian morphology enough in conditions of obesity or pcos or undernutrition where we can say, yes, this ovarian phenotype is an indication of an underlying condition. The illusion lab. So Dr. Mellowsian 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, well, does that phenotype improve? And so in that context, I think we can use the ovary as an indication of health status.
- [42:56]
A
With the menstrual cycle. We talked about how there's this specific length of time, again this 28 day cycle with 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, health outcome or impact?
- [43:20]
B
So when you say delayed ovulation, are you saying in the context of your 28 days, are you thinking like a woman with irregular menstrual cycles?
- [43:28]
A
Well, now, 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.
- [43:50]
B
There is, yes.
- [43:51]
A
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.
- [44:10]
B
And I think it's not helped by, you know, 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 sort of 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. So if someone is, has a 28 day cycle and they ovulate on day 21, what that probably means is that ovulation that 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 a too strong of a word though. But that said, it also could just be an off cycle. And so just because you have one disrupted cycle, maybe it was attributed to stress, maybe. I'm a professor, I give final exams. I remember what it was like to take final exams. Those are stressful events that can lead to transient disruptions.
- [45:38]
A
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?
- [46:01]
B
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. And I know sort of different countries sort of 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 like the sort of first breast development, sort of the initial start of, of of thaylar and that is happening earlier. And there's good data to support that. But back to menarche. You know, we, 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. So when menarche occurs earlier, we have good data to suggest that'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.
- [47:21]
A
To be clear, that's, that's any age before 10.
- [47:25]
B
Well, that's what. So it's, it's different how it's defined study to study. And it was interesting. A lot of these studies are they, 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, I really don't want to put like a specific age.
- [47:45]
A
That's fair enough.
- [47:47]
B
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 of 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, you are now a fully functioning reproductively mature adult. But that is absolutely not the case. The lights kind of flicker for a long time. There was a study that was done by a group out of Harvard where they looked at 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 in 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 they 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. Or typical trajectory. And that's the work that, 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. 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.
- [49:46]
A
I would love to dig a little bit deeper there. The adolescent development. You're. 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?
- [50:05]
B
Timing 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 other correlation studies. You know, we can't do these randomized controlled trials where we put a group of adolescents on one diet and another on another one and see who achieves menarche first. So these are all sort of 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. But I certainly couldn't comment on those.
- [50:43]
A
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.
- [50:54]
B
Yes.
- [50:55]
A
Yeah.
- [50:55]
B
Is.
- [50:56]
A
Is it excess calorically or is it a body composition problem?
- [51:01]
B
Great question. So with puberty and pubertal development, there's still a lot we don't know which is. It's a continually developing field, but there's two phases to puberty. First is metabolic sufficiency. And so do you have sufficient metabolic status or health that you can proceed through puberty? And the two endocrine signals that signal metabolic sufficiency or insufficiency would be leptin or ghrelin. That sort of, you know, from, from my understanding, is like 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 that 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, 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 let us 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.
- [52:26]
A
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?
- [52:41]
B
Yeah. So leptin 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. And 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 access in the hypothalamus that, you know, there is sufficient adipose tissue on board for reproductive function.
- [53:33]
A
And we need that.
- [53:34]
B
Yes, yes.
- [53:35]
A
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. And you are then less hungry. It kind of regulates. And there's this whole concept that we have leptin resistance which would then make us overeat and 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, pretty much 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 Dr. Melanie Cree really threw a wrench into everything that it wasn't about the adiposity itself, it was the intermuscular adiposity.
- [54:36]
B
So yeah, I defer to Melanie on all topics related to muscle. That is not my field.
- [54:43]
A
But the fact that that relationship, 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?
- [54:57]
B
Yeah, 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 kisspeptin 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.
- [55:30]
A
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?
- [55:50]
B
The 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, timing of first menarche, 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, other countries, are the guideline for healthy eating in their country. And 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, any way we can move in the direction towards a healthy eating pattern. And this is what happens in, in these studies is the foods that pop up in, you know, as being sort of helpful or, 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 dietitian, that's really where what I would say and that's where I say the evidence is at right now.
- [57:13]
A
And I want to add a little context to that.
- [57:16]
B
Sure.
- [57:17]
A
I'm very excited to see the next set of guidelines come out because 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. Currently, on average, Americans, 98% of them are over 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?
- [58:16]
B
So the course is women's reproductive health and nutrition across the lifespan. So men are key 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. But their final project in lieu of a final exam is, you know, they're, 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 they've tried or they know themselves or they've heard their patients say, related to nutrition in 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. And that's a good one.
- [59:16]
A
That's a real banger.
- [59:17]
B
It's, you know, patently false. I can say that quite confidently. And there's the data actually show the exact opposite. Right. Cause you know, fruit is chock full of fiber and really important nutrients. It helps with satiety. That's a one that I hear, I've heard and seen. Another is, you know, timing your diet with different phases of your menstrual cycle, exercise.
- [59:42]
A
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?
- [59:52]
B
Well, it manifests in a few different forms. One 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 it's, it, it the, the data aren't there to support that. Another one that I've heard is, you know, at different phases you're much like you should be eating different, 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 and conceivably. Where I suspect these claims or these ideas came from would probably, 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 of cycle that we would see in, in women. And, 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.
- [61:07]
A
Two myths that you've just taken off the table. Number one, seed cycling is a myth. We do not have evidence for that. Number 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.
- [61:24]
B
I have not seen convincing evidence that would support that that is a good idea.
- [61:29]
A
Do you have another big myth?
- [61:30]
B
Sure. So one, it's it 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, that we know now that it's a complex trait. There's sort of genetic predisposition and there's environmental factors that can trigger sort of a genetic predisposition towards pcos. I have not seen any dietary intervention trial that has fully resolved the PCOS phenotype. Dr. Marla Lujan up at Cornell, she in her lab, we did two different dietary interventions in women with pcos and we did not see a full resolution of the phenotype in a subset of participants. The phenotype got Worse, it was a small sample size. So I really caution against worrying about that finding per se. But what I would say is 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. Will. We will have one.
- [62:44]
A
Maybe GLP1s will.
- [62:45]
B
The data are so promising.
- [62:47]
A
I know.
- [62:47]
B
Maybe so promising. Yeah, there's. Yeah. I mean, that's so exciting.
- [62:52]
A
What about the myth that you can balance your hormones with a supplement or balancing your hormones with food?
- [63:03]
B
The. Even the notion of what it means to balance your hormones is a bit of a giveaway in it in 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, 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 turmeric for conditions or other sort of supplements, not to call one specifically out, but there isn't good data.
- [63:42]
A
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. I 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.
- [64:06]
B
I like that one, though.
- [64:07]
A
But, you know, we could double down on the supplements or the bioactive ingredients that are promising for various things versus, again, diluting our brains and diluting even the science.
- [64:21]
B
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. So fish oil has been studied for the context of, you know, dysmenorrhea. So menstrual cramps.
- [64:39]
A
I didn't know that. Do you know much about menstrual cramp now? You just opened up a can of worms because a can of fish. That is really funny. Tell me. Yeah, tell me about that.
- [64:50]
B
There is pretty good evidence to suggest that, you know, the fish oils, the dha, epa, they can be beneficial for alleviating. 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, a really interesting case for it. I, I 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, 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. And 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.
- [66:27]
A
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.
- [66:39]
B
Let me facts check that for you.
- [66:40]
A
No, no, we'll fact check it. We'll fact check it. 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. I mean it's kind of of the landscape is you are perimenopause and then you're menopause.
- [67:01]
B
And that transition can take a long time. It can take a long time. What I would say and this is general recommendations for, for anyone. The best evidence, you know that, that you'll be able to find from my vantage point related to nutrition and reproductive health will be going to in very authoritative body. So like the, the Menopause society, for instance, instance they do have on their website a section about dietary supplements or nutritional supplements and menopausal symptoms. Right. So rather than going to tick tock, you could just google the menopause. I don't know.
- [67:31]
A
Tick tock 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.
- [67:43]
B
Fish oil is a really interesting one that surprised me. Something I heard about was dairy causes inflammation which makes pcos Worse. And that's not something that I've seen data to support as a claim.
- [67:56]
A
Okay, so that's fake.
- [67:57]
B
Yeah.
- [67:58]
A
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, 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 paper.
- [68:35]
B
Yeah, yeah, absolutely. You know, we think about bile acids as, you know, molecules that digest lipids. That's how we learn about them in school. Working with collaborators Mark Roberson from Cornell and Alejandro Lebninski from Dalhousie up in Canada, where I'm from, what we saw is that during puberty in a rodent model, 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 bio 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. What 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. 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.
- [69:57]
A
Wait, wait, wait. I think I just hallucinated bile acid affecting the brain.
- [70:04]
B
What they were able to show in the sort of ex vivo model first is that by activating the secondary bilastid receptor in the neurons that are in the hypothalamus, they were able to increase GNRH activity. Then in a rodent model, what they found is that when you prematurely activate TGR5, you advance timing of first ovulation, timing of vaginal opening. In these rodent models, what we did. What I did is I looked in my data sets, we did a 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 in one of those studies. We have the stool from these kiddos and we're going to analyze that hopefully later this year or early next year. The other part of this question though, 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. We took it a step further and Hannah, she was a student in my lab. She's just starting her Ph.D. now, actually she looked at whether or not there's this difference in bile acids in these adolescents who would go on to develop PCOs versus those who did not. And we, we have samples from a postdoc, from 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 biolases. And that paper is getting written up right now for publication.
- [71:42]
A
Very compelling and new and novel. The relationship between the microbiome and the brain and its effect on ovulation and reproduction and fertility.
- [71:53]
B
We'll keep you posted.
- [71:54]
A
Dr. Heidi, it has been an incredible pleasure to have you on the show. Truly.
- [71:59]
B
Thank you. I've enjoyed it. I thank you for being a wonderful host and hopefully this was helpful.
- [72:04]
A
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 TikTok Instagram in lieu of of real science.
- [72:27]
B
It'll be fun.