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A

Welcome to the Huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Doctor Natalie Crawford. Doctor Natalie Crawford is a medical doctor specializing in obstetrics and gynecology, reproductive endocrinology, and infertility. She also holds a degree in nutrition science. Doctor Crawford runs a clinical practice, seeing patients daily, as well as being actively involved in public education, both through social media and through her popular podcast entitled as a Woman Today, Doctor Crawford teaches us about all aspects of female hormones and hormone health and fertility, beginning as far back as in utero, when we were still in our mothers womb, and extending as far forward as menopause. We discuss topics such as the timing of puberty and what the timing of puberty in girls means for their fertility. And we discuss birth control, both hormonal and non hormonal forms of birth control, and how birth control may or may not relate to long term fertility and different aspects of female health. We also talk extensively about measuring fertility, that is egg count. We also talk about egg retrieval, aka freezing one's eggs, as well as in vitro fertilization. And we also take a deep dive into the popular and important topics of nutrition and supplementation as they relate to fertility as they relate to pregnancy, but also how they relate to female hormone health generally. Indeed, Doctor Crawford provides us with a masterclass on female hormones and fertility, one that I know that all women ought to benefit from and that men would benefit from listening to as well. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. Our first sponsor is element. Element is an electrolyte drink with everything you need and nothing you don't. That means plenty of salt, magnesium and potassium, the so called electrolytes, and no sugar. Now, salt, magnesium and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electrolytes need to be present in the proper ratios. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. Element contains a science back to electrolyte ratio of 1000 milligrams. That's 1 gram of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium. I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes. And while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, if you'd like to try element, you can go to drink element. That's lMnt.com huberman to claim a free element sample pack with your purchase. Again, that's drink element. Today's episode is also brought to us by waking up. Waking up is a meditation app that includes hundreds of meditation programs, mindfulness trainings, yoga, Nidra sessions, and NSDR non sleep deep rest protocols. I started using the waking up app a few years ago because even though I've been doing regular meditation since my teens and I started doing yoga Nidra about a decade ago, my dad mentioned to me that he had found an app turned out to be the waking up app, which could teach you meditations of different durations and that had a lot of different types of meditations to place the brain and body into different states and that he liked it very much. So I gave the waking up app a try and I too found it to be extremely useful because sometimes I only have a few minutes to meditate, other times I have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain and body into lots of different kinds of states, depending on which meditation I do. I also love that the waking up app has lots of different types of yoga Nidra sessions. For those of you who don't know, yoga Nidra is a process of lying very still but keeping an active mind. It's very different than most meditations. And there's excellent scientific data to show that yoga Nidra, and something similar to it called non sleep deep rest, or NSDR, can greatly restore levels of cognitive and physical energy, even with just a short ten minute session. If you'd like to try the waking up app, you can go to wakingup.com hubermanda and access a free 30 day trial. Again, that's wakingup.com huberman to access a free 30 day trial. And now for my discussion with doctor Natalie Crawford. Doctor Crawford, welcome.

B

Thank you so much for having me. I'm honored to be here.

A

Well, I've been paying attention to your content for a long time, and I find it to be incredibly clear, informative, and for many people, actionable. So today I'd like to talk about both fertility and, of course, hormones. But as we both know, fertility is not limited to a discussion about hormones and actually relates to things like behaviors, sex behaviors and other behaviors, nutrition, supplementation. So we'll get into all of it. But if we could just back up developmentally and talk a little bit about female puberty, because I think pretty much everything we'll talk about today is related to what happens puberty forward, mostly in females. But we will also discuss male fertility and hormones a bit. And the question I have is, is there anything about a woman's timing, or, let's just say, patterns of puberty. Right. How frequently they menstruate early on, what the timing of menstruation is in terms of their age, etcetera, that provides hints or maybe even facts or directives about her future fertility or how long her fertility might last.

B

This is a great question, and I think defining some terminology before we begin is helpful. So if we go all the way back to when you're a fetus inside your mom. So when there's a female fetus inside your mom, you have the most eggs you're ever going to have. At about 20 weeks gestation, you have about six to 7 million eggs. By the time you're born, you've already lost more than half of those, and you continually lose eggs all the time. So the analogy that I always use, and you do too, is imagining that there's a vault inside the ovary where all your eggs are kept. And every single month since the moment you have an ovary, you lose a group of these eggs. And when there's more inside, you're losing more. So you're losing all of these eggs throughout early fetal development, and then up until the time period, even of puberty. When you reach puberty, you have a lessening of the number of eggs in your ovary to the point where it can start to respond to the signals from the brain. So we think about puberty onset in females. First, we have really thylarchy, which is the development of breasts. That happens about two years on average before you have menarche, which is your period starting. What happens is the brain, as we know from the hypothalamus, sends out GnRH, and then we have fsH coming out, which really starts to stimulate those follicles. So fsH, or follicle stimulating hormone, well named hormone for the female. Of course, men have it too, and it's less well named for them. But it starts to get those follicles which house the eggs to grow and make estrogen. Women have about two years of estrogen exposure alone. So unopposed estrogen with no progesterone, because they're not yet ovulating. And that's when you start to see breast budding, and you start to see the development of some of those secondary sex characteristics before you actually have a period.

A

What are some of the other secondary sex characteristics that precede menarche? So you said breast bud development, and then breast development, on average, about two years before.

B

About two years before you have sexual hair development. So actually, adrenarche is one of the first, usually comes right before, at the same time with breast buds. So two to three years before you'll see your period.

A

So genital hair, underarm hair, exactly, yeah.

B

General hair, usually first and then underarm hair.

A

And we're getting right down into the weeds here, which is good. A goal of this podcast is to normalize all aspects of health, including sexual health and reproductive health. Is that commensurate also with the development of body odor? Cause as a young boy who eventually hit puberty and became a young man, and now, I suppose I'm in middle age, I'm 48, I can tell you that the locker room smelled a lot different before and after middle school. Right?

B

Right.

A

In other words, boys start to smell stinky.

B

They do, yes. And that's usually around that same time of sexual hair development, is when you start to have those glands around the hair making some of those odors that start to produce stink.

A

Do they reflect hormones themselves?

B

Not the smell. The actual smell doesn't actually reflect levels of hormones or anything like that. It is just that youre body, your gonads, whether it is testes or ovaries, are now starting to respond to those brain signals. The brain is turned on, they're starting to respond, and your body is starting to mature in a way to get to the point where it can support reproduction.

A

The reason I asked that question is not to get people thinking about stinky smells, but, and by the way, some people love the musty smell of their own armpits or others. You know, we're referring to adults, by the way. But the reason I ask is that there's a wealth of data in animal models, including nonhuman primates, suggesting that exposure to the odors of others can either stimulate or accelerate puberty. Is there any evidence for that in humans?

B

So there's mild evidence, and it's murky, because we also know that anything that could be an endocrine disruptor, which a lot of scents or fragrances are, also can accelerate the onset of puberty by disrupting part of this system. And so we know that toxins and, you know, scents and a lot of the world that we're exposed to is part of the reason why we're seeing puberty happening at such a younger age now. In females specifically, but in both, but in females than we have before, we have young girls seeing their onset of menarche or their period at a much younger age.

A

How much younger? I've seen the various graphs for different countries, but can we say that ten years ago, on average, girls in the United States and northern Europe were hitting menarche at about, what, twelve to 13 years of age?

B

We'll use menarche for the purpose of this. So having your period ten to 20 years ago, you will see most data would say, oh, 13 to 15 would have been the average age. Now we're really seeing it shift to be starting at ten to eleven and completing by 1314. Most girls are definitely going through the puberty change earlier. And the other thing to note is that most girls get their final height growth right before they start their period, too. So not only are we seeing a change in this getting starting earlier, what we're also seeing is probably some reduction in height from having gone through puberty at an earlier process. Because once you start actually menstruating, once the ovaries have really started to learn how to respond to that FSH and grow the follicle, and it gets to the point where you can start ovulating. So about two years later, then that ovulatory period, those high levels of estrogen are going to go and they're going to close those growth plates. So you've really started to limit your final adult height as well when you go through puberty earlier. And that's definitely something that's a huge concern for precocious puberty or very young puberty. Right. And we can use blockers when there are children who start to exhibit signs of puberty. And one of the main reasons people do that is to try to get them to a greater adult height if they're really starting to go through puberty at a very young age. Is that also true for males, that it's happening earlier?

A

That earlier puberty means that your growth spurt in terms of height is going.

B

To be truncated, not the same. And you probably most men will say, oh, but I had my growth spurt after I started having some of the puberty change that happened, but because it is this estrogen related process in women that we see that growth spurt, really, your final height is within that year of when your period starts.

A

Interesting. Yeah. This discussion is certainly not about me, but I was one of these. What I thought was kind of an odd duck. I hit puberty about 1314. Let's just say I knew I did, but I didn't shave until I was after college. My growth spurt between freshman and sophomore year, I grew a foot, right? So I was like, I grew a full foot, but I was the same weight. So I was like, real tall, real skinny, or pretty tall, real skinny. And then it seems like some people in my life would argue that puberty is still occurring for me, but it feels like it's very long and protracted. Which leads me to a very specific question. If puberty arrives again, defined as menarche, for sake of our discussion right now, if puberty arrives early in a girl, does that mean that her fertility will shut down earlier as well?

B

Great question. It does not. So the age of which you start, the onset of your period, does not impact how long you're going to have a reproductive lifespan. And that's because you have the eggs inside that vault. You're losing them every month no matter what. So you lost them all those years before your period started. No matter if your period came at ten or at 15. It's just about when did they start allowing your body to ovulate, determined by being able to carry a baby, your body now thinks you can be pregnant.

A

I think this is so important to highlight because it puts together what you said earlier about the loss of eggs. Even as a fetus, I think most people sort of assume that the reduction in egg count is due to ovulation and the fact that one egg ovulates typically, but that other eggs are deployed in that ovulatory cycle, and then those basically are taken out of the vault and out of the opportunity for fertilization. But what you're saying is that the eggs are constantly being culled from the vault, starting from early to embryonic development, and that ovulation is a. A distinct step in some sense unrelated.

B

To the loss of eggs.

A

To the loss of eggs. I think this is going to be very important for our discussion later about potential egg harvest, because I think some people have it in mind.

B

There's a lot of misconceptions that you're losing eggs from your vault, and that's not the case. You're just accessing the ones outside.

A

Gosh, so you're not. So we can just answer this now. Perhaps it seems, if I understand correctly, that if one were to harvest eggs for IVF or for embryogenesis in a dish to set them aside later, freeze them for later if they want to use them, eggs or fertilized embryos, that one is not reducing their total number of eggs any more than they would had. They just let their cycles proceed naturally.

B

Exactly.

A

That's such an important point. I think a lot of people believe the opposite.

B

That's probably the number one thing that patients fear when they come talk to me about egg freezing or going through IVF is I don't want to harm my future fertility. I don't want to cause myself to run out of eggs earlier or going to menopause earlier. And it's explaining this process to them that your ovaries are on a pathway that you can't change. Those eggs are coming out of the vault. Regardless of, if you're on birth control pills, you're pregnant. We do IVF. What we're modifying is one's not going to ovulate and have the rest of them die. We're going to try to give you medication to get them all to grow so we can take all of the ones that have been released from the vault that month and give them a chance for later. And the next month you'll have another group come out.

A

So IVF is not about stimulating hyper release or excessive release of eggs. It's about stimulating the growth of the ones that have been released so that they can be frozen at stage, either for later fertilization or fertilized in addition than frozen as embryos. Is that right?

B

Exactly. And we just use the hormones that your body normally makes in a different way. The medications we use are FSH and LH to get the eggs to grow. So people will say, I don't want to take all these weird hormones or strange medications, but we're just manipulating that normal process that happens in the natural menstrual cycle in order to say, hey, this month, let's get all these eggs to grow. Let's try to improve the efficiency of finding which eggs are going to be normal or not and help you along this process.

A

I think a good number of people are now going to head to the IVF clinic, I think, again, I really want to highlight this. I think most people that I've spoken to assume that the process of harvesting eggs for freezing, for fertilization, then or later, is going to diminish their fertility because they're basically pulling more out of the savings account, so to speak.

B

Right.

A

Okay.

B

You're making the withdrawal no matter what.

A

Great. Well, such an important point for people to know and propagate. Getting back to puberty a little bit later on, I wanted to get into endocrine disruptors and things of that sort. But since you brought it up, you know, I've heard things such as, okay, things like evening primrose oil, if mom is putting evening primrose oil on or has it in her shampoo. That I've heard of young males getting precocious breast bud development. Keep in mind, folks, that some transient breast bud development is characteristic of some normal puberties in males. It sometimes shows up and goes. I knew some kids like that in the neighborhood. They got teased a little bit and then they stopped getting teased. Hopefully nowadays they don't tease those kids. But when I was growing up, those kids got teased not by me, but by other people. But it was normal and it passed. For some, it occurred normally and then passed. But I've heard that things like exposure to evening primrose oil, maybe even just through contact with mom, can increase the frequency or degree of that male breast bud development. Is it also true that young girls can undergo precocious puberty, or let's just say accelerated or exacerbated puberty through contact with things like evening primrose oil, which is a, I think has some pseudo estrogen like properties.

B

It's important to differentiate that the secondary sex characteristics we see, like breast bud development, are from estrogen, but it's not really puberty being initiated when it's from an endocrine disrupting chemical. So taking, you know, being exposed to evening primrose or lavender or tea tree oil in a male isn't going to cause them to start to go into puberty, but it is going to expose him to estrogen when his body is not, and therefore stimulate some breast bed development. Same thing can happen in young girls, meaning they could show some of those secondary sex signs earlier than they normally would. And this is why, if that's happening at a really young age, kids should go to a pediatric endocrinologist who are going to check things like bone age and see if you've really started the puberty process or nothing. Or is it an outside exposure which is causing it? Interestingly, about the young child exposure and development, the other thing to say that's really interesting and relevant in my field is that when we think about how many eggs are in the vault and everybody's born with this different number and I'm sure we'll talk about ovarian reserve. What we now know is that the vault your ovaries are most susceptible to whatever your mother does when she's pregnant with you. And that epigenetic, that programming which is happening is predisposing young women to probably having some of them low ovarian reserve, some of them having diseases we associate with infertility like PCos or endometriosis. And we haven't yet characterized what all they are. But if we look at the incidence of some of these disease that we see now, what we do know is that the time period of which these people were pregnant, the eighties and nineties, was not the healthiest time. When it comes to endocrine disruptors and plastic exposures and chemicals and all of this processed stuff. Let's just say that people have been exposed to that. We're really seeing that ovarian susceptibility to egg quality and quantity happens in that fetal development period.

A

It's interesting because there are some parallels to male fetal development, like the fact that you have these early organizing effects of hormones like dihydrotestosterone, which essentially stimulate the growth of the penis, but also then establish a propensity for hormones during puberty to activate growth of the sex organs, but also activate the brain areas that are responsible for a host of different things. So I only mention that because what I'd like to illustrate in the background here is that basically our reproductive health begins really prior to conception. Really. It's dependent on mom and dad, but certainly to a great degree on mom. But then fetal development is going to be important. So sort of us being able to pick our parents. I do have a couple questions about lavender tea tree oil and evening primrose oil. I was aware that evening primrose oil, excuse me, can somehow bind estrogen receptors or mimic some of the estradiol or something similar to it. I wasn't aware of tea tree oil or lavender here. Are we talking about oils? What about aromas? And how concerned do people have to be about this stuff? Because, I mean, you'll go into a restaurant bathroom, there'll be potpourri. Some people wear perfume. I mean, we don't want to set up paranoia. No, but I think I. People should know about this stuff. Tea tree oil is in a lot of those natural shampoos.

B

A lot of the shampoo.

A

The ones that burn.

B

Yes, the ones that tingle your scalp. Some people love them, though. Constant exposure is very different than a one time hand washing in the bathroom. And I think that's the big difference for everything when we talk about chemicals or toxins or exposures in the world. You can't live in a toxin free world, but choosing what you put in and on your body on a regular basis does set the tone for certain physiologic changes. And so using unscented products, especially with children, is a really important thing because we want to make sure that their lifetime exposure to some of these things, especially during critical times, is much less. And so you'll see people recommend things like your laundry detergent. What sensor in your laundry detergent? The shampoo and conditioner are a big one, and the soaps that you use on a day to day basis in your house or the oils you put on your body. Lavender is huge because there's this whole community of people. They want to rub lavender oil on their baby's feet and help them sleep. But really, we can see, and if somebody goes and shadows a pediatric endocrinologist for a day, they'll see. Some kids come in and this will be the reason why.

A

What about cloth diapers versus non cloth diapers? I've heard that you have your very strong cloth diaper proponents, and that because they seem to feel or believe that non cloth diapers somehow contain things that can get into baby's skin. And maybe there's a bigger question here. Is baby skin more permeable than.

B

I don't know that baby skin is more permeable.

A

I don't either. To me, it seems like it'd be hard to imagine. It is. But babies do seem to have this incredible skin. Their skin is so smooth, and you want to squeeze their cheeks and all this kind of stuff. The idea they would be more permeable.

B

I think it's more that their development is this time is very important and setting the stage for a lot of what happens later versus in adulthood. Those stepwise developmental processes have already happened. So I think that's why we pay so much attention to what happens in the childhood period of time, because we're now learning about those later consequences of what you're exposed to. It's not that, you know, regular diapers versus cloth, whatever we want to say, one's necessarily better than the other. It's more, honestly a personal preference. Babies are exposed to them a lot, and there's been a lot of attention to that. But similarly, somebody could use cloth and wash it with a detergent that then, you know, has certain chemicals in it. So there hasn't been a study shown that this one thing is an exposure for a baby that somebody needs to be worried about. There's definitely companies now which are promoting and talking about traditional diapers that they are making sure have less toxins in them. And I always think anytime you can decrease toxin exposure to a child is going to be very important.

A

Is there any evidence for breast milk versus formula in terms of impact on future reproductive development or reproductive status of a child?

B

That's a complicated question because breast milk exposure, at least for the first six months of a child's life, certainly helps with the immune system development. And we know that poor immune development can lead to higher risk of autoimmune disease later, what people call leaky gut. And some of those diseases certainly are correlated with fertility. So I wouldn't say we've gone so far to say that if you don't breastfeed your child, they're going to have fertility issues. But we do know that there's an in between correlation with things that breastfeeding is protective against and how those diseases themselves may relate to fertility in the female later on.

A

Okay, so if we're thinking about a young girl woman. Cause we're talking about puberty, right? So I don't know what the exact nomenclature is there. You know, my experience is I'll offend somebody no matter what. But a girl who undergoes puberty, right? So a young woman who's maybe 13 or so, so she's early teens, undergoes puberty and therefore is continuing to lose eggs from the vault, but now is undergoing, presumably roughly every 28 days. Manarchy. But let's talk about this 28 days thing, because I think a lot of people think that, quote unquote, normal menstruation is always 28 days, and we know that's not true. So what is the range of normal durations between menstruation cycles or duration of the menstruation cycle? And let's also define when the menstruation cycle starts, probably for the males, mostly in the audience.

B

Sure, sure. So let's think through the cycle. We'll do a quick one over and then answer the questions. So what we think of as cycle day one or when you're going to say this starts is going to be the day that you start bleeding. So that's actually shedding the endometrial lining from what grew the last time.

A

So any spotting even, would be considered day one.

B

Okay, so it is. We can get back to it, but there's problematic if you have a lot of spotting before that full flow starts a day or so can be really normal, just as the body's adjusting to the drop in progesterone. But let's just start at the beginning. Day one, you have a period immense. This is when you're actually bleeding. At this time period, we like to think about all of those new eggs being out of the vault, being susceptible to that FSH, which, of course, is that well named hormone because it stimulates a follicle to grow. And each egg is in a follicle. That egg starts to grow and makes estrogen. That estrogen stimulates the proliferation of the lining of the uterus and preparation for potentially that pregnancy that may come. And also that estrogen makes you feel really great, right? That's the follicular phase named so because that follicle is growing and it's an FSH dominant phase where you have a lot of estrogen and people feel great.

A

When they have a lot of estrogen.

B

Women feel good with estrogen because of.

A

The relationship between estrogen and other neuromodulators, like dopamine, serotonin. And is that happening in parallel, or are they somehow related? Like, is estrogen controlling the release of serotonin somehow and vice versa? Or are they just kind of coincidentally happening in parallel?

B

We definitely think that there's more of a correlation causation than just coincidence, because we know there's time periods where people are more depressed within your cycle, correlating with those low estrogen levels. And we know that when you go into menopause or you run out of eggs and you're now in a low estrogen phase, we see a lot more of a depressed mood. And, you know, anhedonia, lack of response to things which would normally give you pleasure happens more frequently. The female brain loves estrogen, and it's protective against things like dementia. So this is a time period where women are going to be more energetic, they're going to have more energy, more focus. This is the estrogen dominant phase of the cycle. And when you have seen that estrogen at its high levels, which it's only made from a mature follicle and it's very specific, 200 picograms per milliliter for 50 hours, that's the brain's clue. Okay, we must have a mature egg, and it can send out that surge of lh or luteinizing hormone. And now you ovulate, and when you ovulate, the follicle opens up, releases, closes back, and then it's the corpus luteum, and we've entered the luteal phase and.

A

The corpus luteum, as the name suggests, a corpus. It's like a body that's basically the. It's basically the corpse of what unsheathed the egg before. And what I find so amazing, I mean, biology is so beautiful. Instead of just taking that tissue and saying, okay, let's just discard this, or that becomes the trigger for the next phase of the.

B

It is essential for life, right? The corpus luteum, which makes progesterone, opens and closes the implantation window. It is what allows somebody to get pregnant and for our species to continue. And so it's extremely fascinating. And that corpus luteum gets stimulated to produce progesterone impulses throughout the entire luteal phase because it's still controlled by the brain unless you get pregnant. And then in that luteal phase, progesterone is fascinating. It's trying to protect you from things which could potentially harm your baby. So suddenly now you have less energy, you want to sleep more, you want to eat more, you maybe do not want to have sex as much because your body is suddenly saying, let's just protect this potential implantation that you're going to have if that pregnancy doesn't come. The corpus luteum can only live twelve to 14 days. It has a very distinct lifespan, and then it dies. Your estrogen and progesterone both drop. You bleed, starting over the next cycle, and a new group of follicles comes out to be released. And the reason why walking through that very succinctly, but is important when you're asking how long is the normal cycle? Because the luteal phase is pretty set at twelve to 14 days, the follicular phase can vary in person to person. And what we know, though, is, for one individual, if your menstrual cycle, your reproductive hormones are working right, it should be relatively constant for you. And so if your periods are every 24 days, but they've always been every 24 to 25 days, then that's not concerning. And if your periods are every 33 days, but they've always been every 33 days, then that's not concerning. But we do get concerned when there's a change in your period, or we get concerned when people have, what I like to say is irregularly regular periods. Because what you'll see textbooks tell you is that your periods could be as short as 21 days, as long as 35 days, and that can all be normal. But people will hop between them and they'll have one cycle that is 24 days in length from day one to the last day before the next day one, then the next cycle is 32 and then it's 26 and then it's 34. And that's not normal, that's too irregular. And that can be a sign that something is not communicating correctly within your reproductive hormone. So what I tell patients is, in general, your period should be less than 35 days apart, and you should be able to look at a calendar and with your finger, put a finger on the date and within a couple days of accuracy, be able to predict when your period is coming. And if you can't, there could likely be something that is interfering with the hormonal signals between the brain and the ovary. And one of the biggest, really one of the only things we see as women start to have fewer eggs in the vault is a shortening of their cycles. So you have a regular period and suddenly now you have less eggs in the vault, so less are coming out each month. And when the brain sends out that fsh signal, now there's fewer eggs, so it's not getting as dilute. And you have one starting to respond sooner. So suddenly you're ovulating shorter, faster in your cycle. You're ovulating on cycle date nine instead of 14. Your luteal phase is still set, but the person who comes to see me and says, my periods have always been 28 to 30 days, but now they're every 24, I just figure it's no big deal. I have red flags going off everywhere because I'm now really concerned that potentially their ovarian reserve has dropped to a point where we are starting to see clinical changes. Now, of course, things like thyroid and prolactin and other hormones can also cause such changes. But that's why you'll hear most reproductive endocrinologists say your period's a vital sign. And what we really mean is the regularity at which it comes and the predictability of it is telling us if your hormones are all communicating in a normal fashion or if something could potentially be off.

A

I'd like to take a quick break and acknowledge one of our sponsors, athletic greens. Athletic greens, now called ag one, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking athletic greens, and the reason I still take athletic greens once or usually twice a day, is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics and athletic greens are optimal and vital for microbiotic health. In addition, athletic greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met. And it tastes great. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greenshouse while you're on the road, in the car, on the plane, etcetera. And they'll give you a year's supply of vitamin D. Three, k, two. Again, that's athleticgreens.com Huberman to get the five free travel packs and the year's supply of vitamin D. Three, k, two. Let me see if I have this correct. We've got this thing that we call the menstrual cycle or the ovulatory cycle. There's two phases, follicular phase and a luteal phase. Follicular precedes the luteal phase. The luteal phase tends to be, if I heard correctly, fairly fixed, about 14 days. The follicular phase can vary in duration, maybe ten to 14 days, maybe even ten to 18 days, depending on the person. Something about their brain to overeat communication. For those that aren't familiar with this, I always learned that estrogen primes. Progesterone is kind of the really basic top contour description of the ovulatory cycle. That estrogen is going to slowly climb toward the point of ovulation, and then there's a peak and then a drop, and then progesterone is going to dominate in the luteal phase. The second half you said that estrogen is associated with a psychological level and a physiological level, more energy, feelings of vitality. And some of that estrogen increase is actually coming from the one egg that got stimulated the most, the one that got selected. So it picked for the team, potentially for the team, but got picked potentially for fertilization. And that egg sheds its corpus luteum, which is this piece of the egg that then triggers the progesterone that dominates the luteal phase. Do I have that right?

B

Mostly.

A

Mostly, yeah. Please correct me.

B

Where I'm from, the follicle in which the egg grows, when you ovulate ruptures, the cyst bursts. A follicle is a cyst. A cyst is a fluid filled structure. Follicle is a fluid filled structure that holds an egg. So when you ovulate and you get that LH surge, the cyst bursts, it opens up and the egg comes out of it and then it reheals and becomes the corpus luteum.

A

Got it.

B

So just a little bit different in timing. And you're right with estrogen primes progesterone, but really we think about it, the layer of the uterus, because estrogen stimulates the growth of that lining and then progesterone stabilizes it and allows implantation to occur. But the sequence of events of when you're estrogen dominant and progesterone deficient, which is the follicular phase, and people will come in having labs drawn randomly and they're all concerned that they don't have progesterone. And when you talk to them about where they are in their cycle, you say you're not supposed to have progesterone. That's your follicular phase. This is perfectly normal.

A

Okay, great. Thanks for that clarification. I get a lot of questions about birth control, but on my social media handles.

B

Don't we all? Don't we all?

A

To be clear, it's a vast topic for exploration, but along the lines of what we're talking about now, I've heard, and I suspect it may not be true. But tell me, is there any evidence that taking birth control can disrupt the process that you just described? And when we talk about birth control, we should probably define what we're talking about. So there are hormone based birth controls, aka the pill. There are also hormone based birth controls that are not in pill form. There are IUD's that are copper IUd's. There are other Iud's. Let's talk about hormone based contraception in females, which many of them, as I understand, are estrogen mimics or estrogen themselves, that suppress ovulation? Do they diminish or increase the number of eggs that are taken from the vault?

B

Fantastic question. Let's talk about what people say is the pill. So let's specifically talk about combined oral contraception, the pill which has ethanyl estradiol and some type of progestin. No, contraception does not change the release of eggs out of the vault. They are occurring at the same process and the same pathway. You're not ovulating because that estrogen does prevent FSh from coming from the brain. So you have the group of eggs still come out of the vault. There's no FSH. They just all die, the next group comes out. So when you are saying, are you going to run out of eggs faster, is it going to harm your fertility? Does birth control impair the process? The answer is no. But there's a couple important caveats. One is that the birth control pills, especially if you take them continuously or for a prolonged period of time, the body's smart and the ovaries start to say, well, we're not really doing anything. And one of those markers of ovarian reserve we have is amh, and that's anti mullerian hormone. And amh is made from the granulosa cells or the cells that surround every follicle. So in the shortest way possible, more eggs in the vault, more come out every month. Higher amhemental, fewer eggs in the vault, fewer come out, lower amh. If your amh is being suppressed because of the birth control pill, because it's decreasing the activity of those granulosa cells, you might get a low amh value. When you've been on the birth control pill for a long time, that is completely reversible, but it can be significant. So if somebody is wanting to get an amh level, let's say somebody comes to my clinic, they're not trying to get pregnant, and they're on the pill and they're considering freezing their eggs. So we're going to check their ovarian reserve. If we draw it, I always say this, amh may be up to 30% lower in somebody who is on the birth control pill. So we can still draw it, and if it comes back in the normal range, we feel good. But if it does come back low, we're going to have to make a decision. Are we going to stop the birth control pill for a period of some months? Use alternative contraception if you don't want to be pregnant, and then repeat this test to see if this is a true low, because we do see that young women do have low ovarian reserve sometimes, or was this just suppressed because you were on the birth control pill? So we see it impact some of the hormone testing that we can do, and I think that's an important distinction. And we can see that the longer you take it, that potentially it might actually improve your fertility if you had underlying endometriosis or some medical conditions that we see associated with infertility. So prolonged pill users can potentially improve their fertility versus people who are trying to get pregnant that same age who were not on the pill. Those studies are complicated, right? Because of selection bias. Because if you've been on the pill for ten years. You're a little bit older. So is it that they were preventing pregnancy and the other group potentially had some exposures, so they were inherently more infertile than the group that was on the pill. But we do know that the pill doesn't cause infertility. And I use it all the time. All the time. In IVF cycles, we put people on the birth control pill because we can actually synchronize that group of eggs that comes out of the vault to grow together. Because your body doesn't want to have 20 babies at one time. Right. And what we're trying to do with IVF, get 20 eggs to grow if that's what's out of the vault, really goes against the check and balance of the human body to not have 20 babies at once.

A

Why is it that males who take testosterone, synthetic testosterone, it shuts down their own testosterone production and sperm production, but females who take estrogen in the form of birth control pills, it doesn't shut down estrogen production by the ovaries?

B

So I love this question. You know the answer. So I like it extra, because I know you're asking. Spermatogenesis is a constant and ongoing process. Right? So, in women, you're born with all the eggs you're ever going to have. And what we're talking about is, if we stop FSH at that moment, we're just impacting the ability to ovulate at that time. But we're not changing this constant loss throughout the vault. Spermatogenesis, right? The sperm is made every single day. You're making brand new sperm. So 72 days for the sperm to be created in the testes and 18 days to find their way out the ejaculatory system. And so, exposures that you have that stop the production of FSH and LH inhibit the development, the creation of new sperm. So somebody who's been on testosterone will tell the brain. The brain doesn't know it's from your taking it. It says, hey, we have plenty of sperm, we're good. We don't need anymore. So the brain then gets suppressed and doesn't make that FSH and LH, therefore not stimulating both further testosterone production, because you don't need that. But testosterone production and sperm production go hand in hand. So therefore, you're no longer making new sperm. And in fact, the longer you're on testosterone, the harder it may be to get sperm production to come back. And in 25% of people, they may not get it back if they've been on prolonged testosterone exposure. So it's really because of what women will sometimes say is unfair, which is the fact that you're born with all these eggs and you run out of them. They accumulate the wear and tear of your life. Right. We see egg quality being a huge issue in female reproduction, yet men get to have new sperm every 90 days. They get to wash away whatever bad deeds they did and can change their lifestyle and their exposures and have very different sperm. But because of that same process, things that shut off the production of FsHLH really impact sperm quite significantly.

A

You mentioned bad deeds for sperm. Not by sperm. I said for sperm. And we know that heat is a pretty dramatic insult to the spermatogenesis cycle. Saunas and hot tubs and whatnot. I did receive the question as to whether or not heat exposure, saunas, hot tubs, et cetera, are they detrimental to ovulation or egg production in any way? I mean, obviously things are more internal in females. The ovaries are internal, but is there any evidence for that? I mean, the body does heat up.

B

Yeah, there's no. It doesn't harm the ovulatory period or the ovaries. And just like we know, the reason why the testes are so susceptible is because they're supposed to be at a cooler temperature. That's why they're in the scrotum outside the body. That's why the testes are so susceptible to heat changes. But the ovaries being inside the body, they're not in the same way now, when somebody's pregnant. Important distinction, right? We know that the development, especially organ development of an embryo, can be more sensitive to certain things, and that heat exposure at that time, whether it's hot tub use or extreme fevers, even, can make a difference in development of a fetus. But when it's coming to the ovulatory cycle or hormone production, heat in the female doesn't make any difference.

A

I want to be clear before I ask the next question, that I don't want to be responsible for any unwanted pregnancies. But when I was in high school, they told us that women can get pregnant even while they have their period. Is that true? It seems like a lie based on everything you're saying, but I don't want anyone to run out and test that hypothesis without having the facts first.

B

So, in general, if somebody has extremely regular cycles, then that's a complete lie. You can't get pregnant on your period. The reason why they tell us this is one. Especially when you're younger, your period cycles tend to be irregular your body hasn't fully matured to have that regularity. And that we know that sperm do live in the reproductive tract for much longer than the egg does. So sperm can live there for up to five days. So if somebody did have a shorter period window, let's say their normal periods are going to be 24 days. They're ovulating on cycle day ten. If they have a regular period, that's five or six days, they could potentially have intercourse that end part of that period. The sperm could live for five days and be right there when you have the egg en route. So it's not the most fertile time for sure. And in most people, that is considered a time when you're not going to get pregnant, but especially when you're younger and you have more irregularity or in people who have a short cycle window, that might not be the case.

A

So by extension, can we conclude then that the most fertile time is going to be when sperm meets egg, let's say timing of intercourse for the time being? Cause there can be a delay there when sperm meets egg. On obviously, day of ovulation or day, day after day of day of, the.

B

Egg lives for 24 hours. So the egg can only be fertilized for 24 hours while it's in the fallopian tube. Once the egg has entered the uterus, it can't be fertilized anymore. So it has this very short window of time where it will allow sperm to enter it. Now, sperm can live for five days. So we'll say the fertile window is this five day period ending on the day of ovulation. You will hear a lot of us, a lot of doctors say the day after ovulation, because do you really know exactly what time you ovulated on? And if the egg has 24 hours, then that extra day could potentially be helpful. But really, it's five days ending on the day of ovulation. And people with very regular cycles or who can track them and they know when that ovulation is happening. The day before and the day of ovulation, those are the two top hitting days. So if you're kind of not in the mood to have lots of sex, those are going to be the days you target to have the highest chance of conceiving.

A

And what is the relationship between estrogen libido and ovulation in females?

B

The higher your estrogen is, the increased libido that you're going to have. And of course, you see those peak estrogen levels which are going to trigger that LH surge. So the body is made to get pregnant. You're going to have that peak estrogen, that peak libido right before and right at that ovulatory time period, so that hopefully you also want to have intercourse and get pregnant.

A

I've heard before, let's just say that some people, to be careful here, can sense, literally, the deployment of the egg, the ovulation. They report that they can feel, let's just say, the departure of the egg. Is that an imaginary thing?

B

No, no, that's real.

A

I always liked that image that people can know when that happens.

B

It's so real. It has.

A

I mean, after all, men generally know when they're. When their sperm are leaving their body. Let's hope they do. But why wouldn't there be an internal sense for women also, of what's going on? I mean, we have interoception. There's a ton of nerve innervation of.

B

That area doesn't communicate to the brain. Excellent as far as tracking to where that sensation is. But you're right. I already said ovulation is the rupture of a cyst. Right. It is rupturing and the egg is being released, and those follicular fluid is also exiting and going into the peritoneal cavity. And so there is a group of women who can feel that, especially people who are very in tune with their body. And it has a name. It's called middleschmirtz. The pain almost feels like a crampy pain that happens in the middle of the cycle, and that is your ovulatory pain.

A

Oh, interesting. What is it called?

B

Middleschmirtz.

A

Okay, we'll put that in the show. Note captions, and whoever does it is going to have to get the spelling right. Mendelschmirtz. Amazing. Amazing. Amazing and foreign to me, but for obvious reasons, but amazing. I'm always astonished in how incredibly well orchestrated this whole process is. It's just such an incredible feat of biology. I mean, the number of things that have to be timed correctly and the use, and I don't want to say reuse, but the repurposing of tissues for different things and, like, it's. What an incredible dance. That's just amazing.

B

It's beautiful. I mean, I'm so nerdy because I just love how everything has to communicate just perfectly. It makes you in awe of all the pregnancies that just happen just all the time. Because really, things have to synchronize, really, at the wonderful time period. And even though this isn't what we're talking about, I've heard you say this, so I want to say this. People always ask every single day, well, how much sex should you have? When should you have sex? Is there too much sex? And what we know is that you definitely should not decrease your sexual intercourse interval. So if you are in a relationship and you are sex everyday people have sex every day, you will 100% hit intercourse throughout your entire fertile window. On the day that you ovulate, you're depositing the same sperm there because you're not generating new sperm. It's whether the load went half and half and half and half, or if it went in one big group. But if you're constantly putting more sperm out there, you have a higher chance. And so studies go back and always say daily intercourse associated with the highest chance of fecundability, especially during the fertile window. However, for couples who are not sex everyday people, that idea can cause a lot of stress. Stress, of course, impacts the system in a lot of different ways. It can also cause sexual burnout where they no longer feel like being intimate or having sex on the day they're actually ovulating because they've been doing it this whole time leading up. And that's where the time period of saying have sex every other day throughout the fertile window. So starting five or six days before, you think you're going to ovulate and then try to target having intercourse on the day before and the day of ovulation. And the reason why people said every other day or a few days prior to kind of get some sperm exposure there in case you ovulated early. But really to try to prevent some of that increased stress that can happen when you're trying to conceive, especially if you have programmed or timed intercourse, that needs to happen on an everyday interval. But the odds of getting pregnant by saving up sperm for two or three days, that's not higher.

A

I'm curious then, why, if, let's just say hypothetically, someone is donating or freezing sperm or doing ivf, why they instruct the male to not ejaculate for 48 to 72 hours prior to, let's just say, depositing sperm. It's such a funny word. It is, but it works.

B

Two points. One, if we're doing a semen analysis now, we're trying to evaluate this sperm. And any test has certain normal parameters. And these are all based on a 48 to 72 hours abstinence period. So, yes, if you ejaculate more frequently, you're going to have less sperm, and that can be very normal. But if we're looking at a test with set normal parameters that are based on two to three days of not having intercourse. That's why we want you to do it for that. If we're doing, let's say, iUI or intrauterine insemination, also known as artificial insemination, or where we take the sperm and put it in a catheter and put it in the uterus, we're trying to get more players further down the field. And in that case, I know when you ovulate, because I'm timing it perfectly, and I am trying to get as many possible in this process, because we're not just having them deposited in the vagina, we're trying to get them further. So we want more because that's part of that treatment process. And similarly with IVF, I want to have as many sperm as possible to sort through and pick out the best looking, the most modal, the most normally shaped ones. So we're trying to get just a better sample. And by having these normal guidelines, we're able to judge this is low for what it should be, which can also be a clue to other problems.

A

I definitely want to talk about chemistry, both sort of interpersonal chemistry and literally ejaculate and vaginal chemistry. But before we do that, I'm curious whether or not we can just touch on a few of the things that a lot of people wonder about in terms of egg quality. And if they touch on sperm quality, maybe we can also just mention that. But, for instance, does cannabis, either by edible or by smoking cannabis, impact egg quality in either direction? Alcohol would be the next. And then I'm going to assume, and I have to do this strictly because of what I understand about drugs of abuse, like cocaine and amphetamine, methamphetamine. But none of those can be good for systems of the body because they create so much stress for the body. But let's just say alcohol and cannabis. I read a statistic when researching the episode on cannabis that shocked me, which is that 15%, one 5%, not 1.515 percent of american women, at least in this one study survey, reported having consumed or smoked cannabis during known pregnancy, which is wild.

B

Wild.

A

Unless, of course, I'm just naive and THC is not harmful to the fetus, but I have a hard time believing that. So what gives? I mean, here we and there, I actually just threw in fetal development. So is cannabis, is alcohol bad for egg quality?

B

So they're different things and they're the same thing in one. So let's answer them. Each individually. So we'll go with the one that everybody knows and has accepted now that they wouldn't have accepted 40 years ago. Right. Smoking cigarettes, so that's obviously bad, decreases the number of eggs you have in the vault. Smoking cigarettes actually gets into your vault, decreases the number that you have, you have a higher chance of going into menopause earlier, and it increases the risk of having abnormal chromosomes, which is what we really think about when we think about egg quality, right. Impacting those meiotic spindles inside the eggs, which hold the chromosomes in their perfect position, they are associated. They get wear and tear from things that cause inflammation or are toxic. So cigarette smoke, we know, decreases egg quality, egg quantity increases miscarriage, and then, of course, has fetal impacts.

A

Could I just ask you, because when we talk about there's nicotine, which itself is not carcinogenic, and then there's the smoking process, which brings in a bunch of other things, the question I know is burning in everybody's mind is vaping, right? Because vaping is. I'm very bullish on this. I mean, it's very clear that the chemicals associated with vaping are just oh, so bad for everybody's health. But it's distinctly different from saying that nicotine is bad for one's health. And it can be, but without doing too much of a deep dive, are there any data that show that vaping is bad for egg quality?

B

Of course, there's not as much data because it just hasn't been around as long. But yes, vaping definitely has chemicals that looks like it's associated with poor success rates and IVF cycles. And that's really kind of one of the most finite measures of egg quality we can see, because we're really testing the egg at a level in a lab versus just, are you getting pregnant naturally?

A

And sorry to interject again, but anytime a conversation like this comes up, especially between two people in the health science space, there are these shout, because I hear them literally, where people say, well, listen, I vaped every day and I've had three healthy babies, and I think my response is always, okay, there's going to be a distribution of responses. And then, of course, how much healthier could your babies have been had you not vaped during pregnancy or vaped prior to pregnancy? I mean, I think these are the key issues that, like, you can't rewind the clock, as far as I know. Right. In the absence of a time machine, you can't rewind the clock. I mean, basically everything you're saying is that smoking cigarettes or vaping nicotine just can't be good for egg quality.

B

We know that. We know that it's not good for getting pregnant. We know that it's not good for sperm, and therefore, we also know it's going to impact pregnancy rates. You know, things like cannabis. Right. Decreases sperm production, decreases sperm motility, changes sperm morphology, the shape of it changes the DNA, increases the fragmentation of the DNA. If your partner uses cannabis and you get pregnant, you have a higher chance of miscarriage because of the sperm association with the cannabis.

A

Now, edible cannabis, as well as smoking.

B

Right. Because you can't study something that's illegal. So a lot of this data is just more new, and a lot of it's going to be observational.