How to Optimize Fertility in Males & Females

Andrew Huberman 0:00 (music plays) 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. Today, we are discussing fertility. We will discuss male fertility and female fertility, and I should mention that today's discussion is not just for people who are seeking to conceive children or who want to know how their children were conceived, but it's really for everybody, and I say that because it is the story of all of us. All of us are here because a specialized set of cells called germ cells, that is the sperm and the egg, and I'll make it very clear why they're called germ cells a little bit later. It has nothing to do with infection. But it's because a sperm cell and an egg cell arrived at one another either in vivo, inside of our mother, or in vitro, so-called in vitro fertilization, and then were implanted into our mother and became us. And so understanding the process of how the egg cell and the sperm cell came to be is really the key to understanding how that fertilization process came to be. Now, I know everyone's thinking, "I know how fertilization occurs. It occurs through sexual intercourse," and so on, and we'll talk a little bit about that. But I promise you that if you understand the menstrual cycle... And the menstrual cycle in today's conversation can best be thought of as a biological cycle that occurs in females that allows the potential for fertilization by the sperm, because that's really what it is, and it's a beautifully orchestrated process that I'll describe to you. And I should say all people, males and females, should really understand how the menstrual cycle works, how it impacts fertilization, but also how it impacts the brain and body, behavior, psychology, et cetera. And we will also talk about spermatogenesis, how sperm cells come to be and how they arrive, that is how they swim to the egg, and the incredible interplay between the biology of the sperm and the biology of the egg leads to this incredible thing that we call embryogenesis and the birth of the child and, of course, the development of that child into an infant, a toddler, an adolescent, a teen, and an adult. Today's discussion, again, is not just for those of you that are seeking to have children, and I say that because when you look at the data, you look at the literature on longevity and vitality, two themes in biology that oftentimes people lump together but aren't always the same. For instance, there are a lot of things that we can do to increase our vitality that actually can harm our longevity. But there are a subset of biological rules and mechanisms that, when aligned, allow us to maximize both our vitality and our longevity, and I think it's fair to say that all of those mechanisms and tools are housed in the discussion around maximizing fertility. And that's true whether or not you're male or female. In other words, if you want children or if you don't, if you already have children or if you don't, understanding how fertility and fertilization occurs in the brain and body will allow you to maximize your vitality and longevity. And of course, today's discussion will provide an understanding of the biology and many actionable tools that will also help you conceive children if that's your wish. So of course, as is characteristic of this podcast, we will discuss science-based tools, including behavioral tools, both the dos and the don'ts, and we will discuss nutrition-based tools and supplementation-based tools and some other practices, including things like acupuncture, which have quite good data to support them in terms of improving fertility, and we will discuss why those certain practices can work. And we will discuss prescription drugs that your doctor can prescribe to you if, for instance, you have a deficit at the level of hormone production or neurotransmitter production at the level of the brain or the pituitary gland, I'll explain what all of those things are soon, or the gonads, the ovary and the testes in females and males respectively. Again, by the end of today's episode, you will have a lot of knowledge and actionable tools related to maximizing fertility, and you will have a lot of knowledge and actionable tools related to maximizing vitality and longevity.

Andrew Huberman 4:24 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. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Maui Nui Meats. Maui Nui Meats, I can confidently say, are the most nutrient-dense and delicious red meat available. Maui Nui spent nearly a decade building a USDA-certified wild harvesting system to help balance invasive deer populations on the island of Maui. The solution they built turns the proliferation of an invasive species into a wide range of nutrient-dense products, from fresh butcher cuts and organ meats to bone broth, jerky, and even pet treats. Their bone broth has an unmatched 25 grams of protein per 100 calories. I've talked before on this podcast, and I've had several expert guests come on this podcast to talk about the fact that most people should aim to get one gram of quality protein per pound of body weight per day in order to maximize their health, tissue repair, which includes brain tissue repair, and if you're an active exerciser, to support recovery from exercise. Maui Nui Meats have an incredible quality protein-to-calorie ratio, and I mentioned the bone broth. I should also mention that their ground meats and their venison steaks are absolutely delicious and their jerky is absolutely terrific. In fact, it's the only jerky that I've eaten consistently that I happen to like consistently over time. If you'd like to try Maui Nui venison, go to mauinuivenison.com/huberman to get 20% off your first order. Again, that's mauinuivenison.com/huberman to get 20% off your first order.Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. I've talked many times before on this podcast about the fact that sleep is the fundamental layer of mental health, physical health, and performance. Now, one of the key things for getting a great night's sleep every single night is to optimize the temperature of your sleeping environment. Put simply, in order to fall asleep and stay deeply asleep, your body temperature needs to drop by about one to three degrees, and waking up, on the other hand, involves a heating of your body by about one to three degrees. With Eight Sleep, you can tune the temperature of your mattress cover or mattress to be cooler or hotter, depending on whether or not you tend to run too hot or too cold, and you can even vary it across the night so that you can access the best deep sleep early in the night, the so-called REM sleep, rapid eye movement sleep, that's more pronounced in the later half of the night, and in doing so, really get your sleep optimized, not just in terms of duration, but in terms of quality and the overall architecture of your sleep. This has a profound influence on your alertness, focus, mood, and many other important factors throughout the day. If you'd like to try Eight Sleep, you can go to eightsleep.com/huberman to save up to $150 off their Pod 3 cover. Today's episode is also brought to us by Momentous supplements. I want to acknowledge that not everybody needs supplements, and yet many, many people derive tremendous benefit from proper supplementation. I would count myself in that group. There are excellent supplements for improving the depth and quality of sleep, for improving focus, and for improving energy, and for hormone optimization, and many other factors related to our mental health, physical health, and performance. We've partnered with Momentous supplements for three important reasons. First of all, Momentous supplements are of the very highest quality. Second of all, they ship internationally, and we know that many of you reside outside of the United States. And third, they focus on single-ingredient formulations. This is very important. There is a place for blends, but in most cases, if you're going to develop a supplement protocol, you want it to be single-ingredient formulations so that you can adjust the dosages of different things according to what works and doesn't work for you, which is essentially impossible to do if you are using multi-ingredient formulations. If you'd like to see the supplements that I take and that we've discussed here on the Huberman Lab Podcast, you can go to livemomentous, spelled O-U-S, so livemomentous.com/huberman and get 20% off any supplements. Again, that's livemomentous.com/huberman to get 20%

Andrew Huberman 8:20 off. Let's talk about fertility, and in doing so, let's take a step back from this word fertility and ask, what is fertility and fertilization really all about? Well, the obvious answer is that it's about producing offspring. But more importantly, it's about producing offspring that contain the genetic components of both parents, and indeed contain half of the genes from one parent and half of the genes from another parent. Now, there are two general types of cells in the body. The most common types of cells in the body are called somatic cells. So this would be all the cells in your body except the egg in females and the sperm in males. The egg in females and the sperm in males are part of what's called the germline. And again, it has nothing to do with infection. It's just that the cells of the germline have genes that cannot be modified by the behavior of the individual that houses those genes. What do I mean by that? Well, if I were to tell you that by exercising you can improve mitochondrial function, you can change hormones, um, by reducing stress you can reduce cortisol, by, um, hitting puberty, for instance, uh, you will have the secretion of hormones that then change gene expression in other cells, leading to development of body hair, facial hair, deepening the voice, breast growth, et cetera, you'd say, "Okay, great. Yeah, that all makes perfect sense." But that's all occurring in the so-called somatic cells. The germ cells or the germline cells, that is, the egg and the sperm, are a very unique and protected set of cells that are generated in a particular way and whose genetic components are not modifiable by experience. And when you take a step back and you think about it, you say, "Oh, that's right." There's no reason to think that exercising will make the children that you have not yet had stronger. (...) of course not. Well, why is that? Well, that's because there is a barrier between the genes of the germline cells and behaviors. They cannot be modified by behaviors and the various things that you do in your lifetime. Now, I suppose there's an exception in the negative direction. And what I'm referring to here is if you were to, say, be exposed to a chemical that could mutate the DNA of your egg or sperm, or if you were to fertilize an embryo at a- in a certain way or at a certain stage of life that it got an extra chromosome, for instance, we'll talk about this a little bit later, well then of course you could end up with offspring that have modified DNA that don't faithfully represent half of the genes from mom and half of the genes from dad, but that's not the same as specific behaviors modifying the genes of those cells, the sperm and the egg cells, in a way that improves the offspring. Okay? So the key first thing to understand today is that there's a distinction between somatic cells, which is the vast majority of cells in your body, and the so-called germline cells, which are the egg and the sperm. The egg and the sperm are these highly protected populations of cells that in females actually come to be during embryogenesis. Okay? So for all females out there, you generate what today I'm going to refer to as a vault of cells, you have a vault of, of eggs that are your germline. Those eggs all contain all the chromosomes of your DNA. So it's going to be, as most of you know, there are 23 chromosomes, and chromosomes exist in pairs. So the way to think about this is each pair is one strand and you have 22 so-called autosomes and then you have one sex chromosome. The sex chromosome will be either X or Y. So in a female, they have two X chromosomes. So when each one of the eggs that a woman has and that she's had since she was an embryo and that's contained in this vault, those eggs are of course going to be very immature at birth, right? She hasn't undergone puberty yet, and certainly as an embryo, she hasn't undergone puberty. And those cells are going to contain 23 pairs of chromosomes. Okay. This is very important. 23 pairs of chromosomes. The chromosomes are essentially the...... wrapped up DNA that contains all the genetic information to create any cell type in the body, and actually, to create an entirely new individual. Now, there are 23 pairs of chromosomes, 22 of which are called autosomes. Okay? If that doesn't make sense to you, just remember, autosome, okay, there's 22 of them, and then there's one so-called sex chromosome. The sex chromosomes are either X or Y, but this is a female, so she's gonna have 23 pairs of chromosomes, and she's gonna have two X chromosomes for the sex chromosomes. Okay? If this is already confusing to you, don't worry. I'll make it very clear how this all relates to fertility and how it rel- relates to chromosomal segregation and a bunch of things that I think maybe you've heard of and that perhaps, um, were opaque to you, but I promise to make them clear. But just understand that within each of those eggs, they have 23 pairs of chromosomes. And for those of you that like nomenclature, I'll tell you that those cells are considered diploid. They're called the diploid, and that means that they have 23 pairs of chromosomes, as distinguished from cells that are haploid, where there's only one set of those 23 chromosomes. So instead of 23 pairs, there's only 23 chromosomes. We'll t- we'll come back to haploid cells a little bit later. Okay, so when a female is born, she has all these eggs in the reserve, in this vault, that she'll have for her entire life. She's not going to make any more, but they are very, very immature. So when a woman is in embryogenesis, she develops these very immature eggs, okay? Today, we're also gonna talk about follicles, and, um, we will be careful to distinguish follicles from eggs. They're often talked about interchangeably (laughs) online and elsewhere and even by fertility docs and OBGYNs. But we'll t- right now, we're just talking about the egg cells, okay? The eggs themselves, which are cells. Now, the goal of fertilization is to bring that egg cell into close enough proximity that it can be fertilized by a single sperm cell, and that sperm cell will bring 23 chromosomes as well that include, just as in the female egg, it'll have 22 autosomes and one sex chromosome. And in the male, that sex chromosome can either be an X chromosome, which then would give rise to female offspring, or a Y chromosome, which would give rise to male offspring. And today, we're not talking about sexual differentiation. That's a topic of a previous and yet another future episode. But just to give you a sense of how X chromosomes and Y chromosomes can actually accomplish that sexual differentiation, both of body and brain, I'll just mention in two sentences that, for instance, if there's a Y chromosome as opposed to an X chromosome, that Y chromosome contains genes that suppress, for instance, the development of female genitalia and thereby give rise to male genitalia. So rather than the formation of a clitoris, it's the formation of a penis, and rather than the formation of ovaries, the formation of a testis. Okay? So that's more directed towards sexual differentiation. We're not gonna get into that right now. We'll get into that in a future episode. But even if you're only f- tracking about 10% of what I'm saying right now, I promise you're doing great. If you're tracking more than 10%, well, then you're doing terrifically well, because the essence of fertility and fertilization is to bring together that haploid cell that is the sperm, that only has 23 chromosomes, but not pairs of chromosomes, right? 'Cause that's the DNA from dad, together with the egg, which as I told you already, has 23 pairs of chromosomes. So part of the fertilization process has to be to get rid of one half of those 23 pairs in the female. You gotta get rid of it, and you have to get the egg and the sperm in proximity so that the egg can potentially be fertilized by the sperm, bringing the DNA, the 23 single strands of chromosomes from dad into a cell that has 23 single strands from mom. Okay? So I'm, I realize I'm probably being a little bit repetitive here, but I want everyone to understand this 'cause it really frames up fertility and reproduction in the proper way. We've got a cell from mom, the egg, which has 23 pairs of chromosomes. We need to get rid of one set of those pairs so that there's only 23 chromosomes. We need to get rid of half of those chromosomes, and then we need to bring that cell together physically with the sperm cell that contains the 23 chromosomal strands from dad, and we need to bring those together so that you get 23 chromosomal pairs from dad and 23 chromosomal pairs from mom. And in doing so, you create a cell which then becomes multiple cells, that's going to be the developing embryo, that has half the genes from mom and half the genes from dad. So I hope that's clear. That is the biological logic, which I realize is a bit of a tongue twister, but, um, forgive me. It is the, uh, most accurate way to describe this process. We're trying to bring together the 23 single strands of chromosomes from dad and the 23 single strands of chromosomes from mom into the same cell. Now, that requires a literal physical contact and pairing of the two cells, but as I mentioned before, all these eggs in mom are sitting in a vault, and they're very, very immature. So the ovulatory cycle and the menstrual cycle are really about first eliminating half of the chromosomal pairs in that 23 sets of chromosomes and not getting rid of, for instance, half, you know, just going one to, uh, you know, 1 to 11 or, and then, or 12 to 23. That's not the goal. The goal is to have chromosomes one, two, three, four, five, six, all the way up to 23, but only to have half of the chromosomes there and to bring that cell together with the sperm cell physically, then allow them to fuse and allow the chromosomes from dad and the chromosomes from mom to fuse within a single cell and duplicate into cells that contain-... half of the chromosomes from dad and half of the chromosomes from mom. That's what the ovulatory and menstrual cycle are really all about.

Andrew Huberman 18:28 So when thinking about it that way, I'd like to just initiate the discussion by focusing first on the female component or the egg component of fertility and fertilization. (smacks lips) As I mentioned before, a female has all the eggs, albeit very immature eggs, that she's going to have at the time that she's born. Now, puberty will happen at some point and will allow the ovulatory and the menstrual cycle to commence. Now, one question that you perhaps are asking is, "What controls the onset of puberty?" And there, there are a number of different results, (clicks tongue) each of which could be an entire episode of a podcast on its own. But I'll just highlight a few things that we know about the onset of menses or menstruation, or it's sometimes also called menarche. All right. One thing that you'll notice about today's discussion is that if you were to take any number of your notes online and put them into a, a search function, that you would see a lot of different language used for the same thing. So for instance, some people will talk about the egg and the follicle as the same thing, even though they are not. I'll explain the difference soon. Some people will talk about menses or menstruation or menarche as the exact same thing. And in fact, they are not the exact same thing, but oftentimes these, uh, words are used interchangeably. I'll do my best today to not overload you with nomenclature, but rather to use the most commonly used terms for the different aspects of fertility and fertilization. (smacks lips) But when it comes to the onset of puberty, first of all, most of you have probably heard that the onset of puberty is happening much earlier in females now than it was some years ago. And in fact, that is the case. And I'll talk about some statistics related to this, um, which are pretty striking, but don't necessarily point to anything detrimental. It doesn't necessarily mean that something bad is happening. What do we know for sure? Well, we know that there are a number of signals that come both through the brain and through the body, and more likely both, in order to control the onset of puberty in females. A couple of examples. The first is a mechanistic one. We know, for instance, that the entire process of the ovulatory and menstrual cycle is initiated from the brain. We're gonna get into this in a lot more detail in a few minutes. But there's a certain number of hormones and neurotransmitters that are communicated from the brain, a structure called the hypothalamus, which s- roughly sits above the roof of your mouth and that communicates with a gland, an endocrine or hormone-releasing gland called the pituitary gland. Uh, the pituitary gland looks like a, a stalk, um, that essentially extends out of the brain, it's also located not far from, uh, your, the roof of your mouth, and that has two sort of, um, small marble or grape-sized, um, uh, protrusions, the, the anterior pituitary and the posterior pituitary. And they release different hormones into the bloodstream. Puberty is in part controlled by the fact that up until puberty, there are neurons in the hypothalamus that release a neurotransmitter called GABA, which is inhibitory, and that prevents the neurons in the hypothalamus from releasing a very important hormone called gonadotropin-releasing hormone, or GNRH. So the first thing that I'd really like everyone to know and commit to memory today is very easy. GNRH stands for gonadotropin-releasing hormone. This comes from the brain and will communicate to the pituitary to release certain hormones. Prior to puberty, in both males and females, there are neurons in the brain that are actively suppressing the neurons that release GNRH. It's like, "No puberty, no puberty, no puberty, can't have puberty, can't have puberty." And in fact, those cells are releasing this neurotransmitter called GABA because it's inhibitory, it prevents the firing of those neurons. Okay? So puberty is actively suppressed up until a certain point. It's also actively suppressed, at least in some species and we think at least partially in humans, by the tonic release, that means the ongoing release around the clock, of a hormone called melatonin. Later in life, in fact, after puberty, melatonin will be secreted only in the dark phase of each night and around the time that one goes to sleep. But in children, and in particular in children prior to puberty, melatonin is released more or less constantly. Now, melatonin isn't the only source of suppression of puberty, it's also these neural mechanisms involving GABA, but it is certainly a great candidate for one of the reasons why puberty doesn't generally tend to happen at, say, age four or age five. That would be very unusual. (smacks lips) Another component of suppression of puberty is that typically in children, they have relatively low body fat stores. Why is this important? Well, we know that one of the things that can trigger the onset of puberty, in particular in females, is that when enough body fat accumulates, that body fat releases a hormone called leptin. And that hormone, leptin, travels in the bloodstream across the blood-brain barrier and goes to the hypothalamus and can trigger the onset of puberty by activating the neurons that release gonadotropin-releasing hormone. So many

Andrew Huberman 23:38 people believe that one of the reasons that puberty is happening earlier and earlier in females is because of the accumulation of more body fat at younger ages than was observed 30 or 40 and certainly 100 years ago. Now, I can already imagine a number of people are thinking, "Oh, this must re- relate to the obesity crisis." And indeed, there is a crisis of obesity. Obesity, uh, is something that is causing all sorts of, um, problems with people's health at various levels, brain and body, and that is far more frequent today than it was even 20 years ago. So it is indeed a crisis, because it has enormous detrimental effects for so many aspects of, of, uh, brain and body health and longevity. But this whole process of thinking about body fat signaling leptin into the hypothalamus and the onset of puberty doesn't necessarily have to do with the obesity crisis. It might relate, but it could also relate f- to, for instance, improved nutrition, which is allowing body fat stores to accumulate maybe not to the level of obesity, but to accumulate earlier...... and at younger ages in females, which is then causing earlier puberty in females. To just highlight how that might be possible, wan- I want to review some data that talk about the onset of menses, menstruation, that is puberty, in females according to country and according to age over the last 100 or more years. So, what are the general trends in terms of the onset of puberty in females? Well, that's an easy one to answer. Over the last 100 years or so, the onset of puberty has been occurring much earlier with each passing decade. It's really a- an incredible set of statistics. Um, I'll pro- I will provide a link to these data, since I know a number of you are listening and not just, uh, watching on YouTube. Um, this is from a study in which the onset of puberty has been analyzed from as early as the 1850s, right? In certain countries, there are data on that, out to the 1970s, and in other countries starting at about 1900, um, extending out to about 1990. These are ongoing collections of data, but just to give you a sense to how the data are falling out in a couple of different countries, just to give you a, a flavor. But for those of you listening and for those of you watching, the essence of all of these findings is that puberty is happening much, much earlier with each passing decade. So for instance, in the United States around 1900 or 1903, the average age of menarche, the onset of puberty, in females was about 14 years old. Whereas in 1990, the average age is 11. So that's a pretty significant, um, we can say acceleration of the onset of puberty. Now, of course, these are averages, so there will be exceptions. There's a distribution of data. Today still there will be, uh, young females who will undergo puberty at age 11 or 10 or maybe even 9, and others who will undergo puberty at age 13, 14, maybe even 16 or 17. However, if we look at, for instance, the data from Norway, which dates back, uh, quite far, they have excellent record keeping (laughs) to 1850, what we see is that the average age of the onset of female puberty in 1850 in Norway was 17 years old. Whereas in 1970, it's 13 years old. So this is a dramatic acceleration of the onset of puberty. And you see a similar trend in other countries as well. So if we were to look in, uh, for instance, in the UK, um, they have a, a smaller data set, um, meaning it only extends back to about 1940, but the average age of the onset of puberty in the UK, uh, in 1940 was 13 and a half years old. Again, this is just, uh, for females. And in 1970, it was closer to 13, with, uh, a trend towards declining even further. Unfortunately, they didn't continue to collect data out to, uh, 2022. And as a final point, if we were to look at, for instance, in, uh, Germany and Finland, uh, the average, uh, onset of puberty in 1870 was 16 and a half years old. Uh, by 1940, it was down to 13 and a half years old. So all of these data have borne out over and over again, regardless of location in the world, which is important because when you start to think about the obesity crisis, you could say, "Well, that's mainly in developed countries," believe it or not, or perhaps not surprisingly, and maybe it has to do with the obesity crisis. And yet, I don't think we can conclude that at all. Something is happening, however. It could be increased body fat stores due to overeating and obesity. However, it could also be unrelated to obesity. It could be, for instance, improved nutrition and the availabi- availability of quality nutrition, which can signal the maturation of the brain and body mechanisms that trigger the onset of puberty, ovulatory cycle, and menstruation. So we want to be very careful about leaping to conclusions about what these trends mean, but the trends themselves are very, very apparent. And as a final point, I should also mention that there are a number of different behavioral and psychosocial, as they're called, interactions that can influence puberty as well. This has been most strikingly observed in animals, and so I don't want anyone to be alarmed or to leap to any great conclusions about the onset of timing of puberty in humans, but I'd be remiss if I didn't tell you about a certain result which shows that if a young female is exposed to the odor, not necessarily the pheromones, right? There's a distinction between odors that we perceive and pheromones which are subconscious, right? The, that we don't actively perceive but that can impact our biology, and pheromone effects in humans are very controversial. But we know, for instance, that if you take a female animal, and there's some evidence from humans that if you take a young pre-pubertal female and you expose her to the scent of a reproductively competent male for a series of days, but maybe even as short as a few hours, and she is also not regularly being exposed to the scent of her father, that she can undergo puberty earlier. That's right. There is something about the odor and/or pheromones or perhaps something else that occurs when a young pre-pubertal female is in the, has a father that she's in regular contact with, he wouldn't necessarily have to live at home but that is around a lot, that her, his smell, excuse me, is registered by her biological systems, that, I don't want to say protects because it kind of skews the, uh, (laughs) the valence of the conversation, but that, that offsets or buffers the otherwise observed effect, which is that the scent of a reproductively competent male, if it's present often enough or perhaps intensely enough, that it can trigger the onset of puberty in that female. In other words, the scent of a, of a male that is not the father, and we think also that is not biologically related to her, can trigger earlier onset of puberty, and that effect can at least be partially buffered by her being in the presence of the scent from her biological father. Now, some of you (laughs) are probably already leaping to conclusions about what this means. You know, should you, uh, not allow your daughter to be exposed to any males who are of reproductive age, et cetera?... and that's- it's certainly not what I'm saying. There's a huge number of considerations that, um, that go into that calculation for everybody and circumstances, et cetera. But the point is that the odors of individuals, both related, in particular closely related, and non-related individuals, can shape the neural systems and the hormone systems that can trigger the onset of puberty or suppress the onset of puberty. So whether or not we're talking about onset of puberty at this age or that age and whether or not biologically related male or non-biologically related male scents around, et cetera, the thing I

Andrew Huberman 31:24 want everyone to know is that at some point during development, typically nowadays between the ages of 11 and 15 or so, again, there's variability there, the suppression of gonadotropin-releasing hormone released from the hypothalamus is removed. And then gonadotropin-releasing hormone can activate cells within the pituitary, and if you really want to know, it's the anterior pituitary in particular. And then the anterior pituitary gland, which sits a- and kind of bridges the brain and the body, because it allows the release of hormones into the bloodstream, that anterior pituitary is going to release two key hormones that everyone should know the name of and what they do. And when I say everyone, I mean males and females need to know about these hormones, because they have an active role in both males and females. And of course, you should want to know and should know about the biology of everyone on the planet, in my opinion, because it tells you a lot more about humans than if you just focus on your own biology. But those two hormones are called luteinizing hormone, which is abbreviated LH, and follicle-stimulating hormone, which is abbreviated FSH. Okay? So the, the simple picture that you need to have in your mind is gonadotropin-releasing hormone from the brain, from the hypothalamus in particular, is causing the release of luteinizing hormone and follicle-stimulating hormone. GnRH stimulates LH, luteinizing hormone, and follicle-stimulating hormone, FSH. LH and FSH travel in the blood and can access all the cells and tissues of the body. This is one of the incredible things about hormones, is that many hormones, and LH and FSH are included in this group, can travel into cells and they can actually change the genetic expression of those cells. They can change which genes are turned on and which genes are turned off, and they can also attach to the surface of those cells and make those cells take on different properties. So they can mature those cells. So for instance, a good example of this outside of the context we've been talking about, is the hormone testosterone can travel to the hair follicle and can stimulate changes in the genes of the cells of the hair follicle that can make hair grow. A different hormone, estrogen, can travel to the cells of the breast tissue and activate genes that control enlargement of the cells of the breast tissue. Prolactin, a different hormone, can travel to the mammary ducts and control the production and the secretion of milk. And in males, that can actually happen in certain cases, although it's rare, but prolactin can also travel to areas of the brain that control libido, for instance, and, uh, just so you'll never forget it, males, um, elevated levels of prolactin are actually what set the refractory period after ejaculation and prevent erection for some period of time. So you'll never forget prolactin. Um, the point being that different hormones have different effects on different cells depending on what cells those are, right? Estrogen or estradiol is going to have different effects on the breast tissue than it would on skin, although it has effects on both. Similarly, when LH and FSH, luteinizing hormone and follicle-stimulating hormone, travel in the blood to the gonad and the gonad is an ovary, it will have a certain set of consequences. And when luteinizing hormone and follicle-stimulating hormone travel in the blood to a gonad and that gonad happens to be a testie, then it will have a different set of biological implications. So let's focus now on what happens when LH and FSH arrive at the ovary, and let's assume now that we're talking about a female who has already undergone puberty or perhaps we could even frame this in the context of a female who is about to undergo puberty. FSH and LH are now able to be released because she's undergoing puberty, but the same set of processes essentially would occur for any point from puberty onward until menopause, which is the depletion of that vault, that ovarian reserve of all those immature

Andrew Huberman 35:25 eggs. I'd like to take a brief break and acknowledge our sponsor, Athletic Greens. Athletic Greens is an all-in-one vitamin mineral probiotic drink that also contains digestive enzymes and adaptogens. I started taking Athletic Greens way back in 2012, so that's 10 years now of taking Athletic Greens every single day. So I'm delighted that they're sponsoring this podcast. The reason I started taking Athletic Greens and the reason I still take Athletic Greens is that it covers all of my foundational nutritional needs. So whether or not I'm eating well or enough or not, I'm sure that I'm covering all of my needs for vitamins, minerals, probiotics, adaptogens to combat stress, and the digestive enzymes really help my digestion. I just feel much better when I'm drinking Athletic Greens. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman and for the month of January, they have a special offer where they'll give you 10 free travel packs plus a year's supply of vitamin D3 K2. Vitamin D3 and K2 are vital for immune function, metabolic function, hormone health, but also calcium regulation and heart health. Again, that's athleticgreens.com/huberman to claim their special offer in the month of January of 10 free travel packs plus a year's supply of vitamin D3 K2.

Andrew Huberman 36:34 Okay, so we're now going to talk about ovulation and menstruation, and let's just remember what this is all about. This is all about creating the potential for an egg to be fertilized and that egg needs to have half of the chromosomal pair. So no pairs, but it's got to have 23 chromosomes just from mom, and we need to position that egg so that the egg can...... be met by the sperm, and that sperm can penetrate that egg and donate its 23 individual strands of chromosomes to that egg so that you can bring together the DNA of Dad and the DNA of Mom. So the ovulatory and menstrual cycle occurs when luteinizing hormone and follicle-stimulating hormone have been released and the ovulatory/menstrual cycle... And here I have to kind of pick what I want to call it. Um, I guess to be really accurate, we would just call it the female reproductive cycle, but that includes underneath it, but the menstrual cycle as it's sometimes called, and the ovulatory cycle. (laughs) So you decide. I'm going to interchangeably discuss the ovulatory cycle and the menstrual cycle. The problem is when you say menstruation, people often think about just the period, the shedding of the uterine lining when fertilization has not occurred. So if I start saying ovulatory cycle, just keep in mind I'm referring to the entire thing. Now, this is probably also a good opportunity to say that if you heard that the ovulatory/menstrual cycle is 28 days long, that's true in some cases, but that's not always true. It's on average 28 days long. There are some females for which the ovulatory cycle will be shorter, it can be as short as 21 days, and other females for which it will be 35 days long. Shorter than 21 days and longer than 35 days is rare, although it does occur. One of the key things when thinking about fertility is if you talk to OB-GYNs who are focused on fertility, which I have in anticipation of this episode, they'll tell you that whether or not your cycle is 21 days long or 35 days long is not as much of an issue necessarily, unless it's happening to become much shorter or much longer in a kind of erratic way. So if you're somebody who's consistently had 23-day-long cycles and all of a sudden you're having 30-day-long cycles, that's not necessarily an indication of anything bad. But if it's 21 days one month and it's 30 days the next month and then it's 17 days the next month, or even if it's always falling within that 21 to 35-day-long cycle but it's very variable from each month or every other month or so, you probably want to talk to your OB-GYN, because that could indicate a number of different things. Which things could it indicate? Well, that will become clear as I spell out the biology in a bit more detail. Okay? But this idea that the menstrual cycle, ovulatory cycle is always 28 days, that's just false. That's just not true. I should also mention that there is a common misconception that because the average menstrual cycle is 28 days, indeed the average is 28 days, and the lunar cycle is 28 days, and of course there is real biology to support the fact that the lunar cycle can in fact impact certain aspects of human behavior. It does, and we'll talk about lunar cycles in a future episode. But there is zero data to support the idea that the menstrual cycle and the lunar cycle are linked in any kind of causal way. I'm sorry to break it to you. The lunar cycle and the tidal cycles at the ocean are definitely linked in ways that are super interesting related to the tilt of the earth and the pull of gravity of different planets, and it's an incredible story unto itself, but the lunar cycle and the menstrual cycle, despite having some weak correlation in terms of their, their gen- their duration, or their so-called periodicity, no pun intended, well, there's no causal relationship whatsoever between the lunar cycle and the menstrual cycle. If any of you are aware of any real data that conflict with what I just said, please put that in the comment section on YouTube. Um, but this is pretty well-established as, as far as I know.

Andrew Huberman 40:36 Okay, so we need to bring together the so-called haploid cont- contents, the 23 individual strands of, of chromosomes from the egg, to a place and a position where it could potentially be fertilized by the male. So what happens? Luteinizing hormone and follicle-stimulating hormone travel to the ovary. These hormones are able to access the ovary. There's a lot of blood supply to the ovary. And FSH and LH arrive at the ovary. The ovary has this vault, this ovarian reserve of immature cells. They reside within what are called follicles. The follicles are little spherical packages that can potentially provide a nice environment for those eggs to mature. And when FSH in particular arrives at the ovary, a small number of those follicles will split off from the reserve. They will exit the vault, and they will undergo maturation. And the key player here is follicle-stimulating hormone, and the first 14 days of the menstrual ovulatory cycle is referred to as the follicular phase because of this relationship between FSH triggering the maturation of a subset of follicles. Now, typically in the context of a 28-day or so ovulatory menstrual cycle, day one is designated as the first day of the period, of the shedding of the uterine lining from the previous ovulatory menstrual cycle in which fertilization did not occur. Okay? So day one is when the period initiates. It is days one through 14 approximately, right? 'Cause here we're just considering the average of a 28-day cycle, but it could be longer, could be shorter, but the first half of that cycle is the so-called follicular phase. FSH has triggered the departure of a subset of these follicles that contain immature eggs, and it is triggering the maturation of those eggs. Luteinizing hormone is also present, but also at relatively low levels. And it's during the first half of this ovulatory menstrual cycle that the main goal is to get those follicles to mature. So inside of those follicles, the egg is developing, it's growing, it's maturing, and in doing so, it's also making its own hormones. This, I think, is one of the most elegant aspects of the ovulatory menstrual cycle, that in a few minutes you'll learn (laughs) about something which still to this day, even though I've known about this stuff for, for decades now because of my training, still just blows my mind that you have s- one hormone, follicle-stimulating hormone, triggering the maturation of some eggs inside of some follicles, and then those follicles themselves making another hormone...... that furthers the process and then soon, as you'll learn, create a hormone to trigger the second half of the process, just a beautiful symphony of expression of different genes and different hormones to make everything work as optimally as possible. So as these different follicles mature, somehow, and we still don't know exactly how, one of those follicles containing an egg gets selected. It's either because it matures the fastest or there's something about it that is still not completely understood that allows it to be selected, and all the other follicles that are maturing degenerate and die. And they're gone. They don't go back into the ovarian reserve. They are now depleted from that bank account that is the ovarian reserve. They die off, but that single egg, that keep in mind contains 23 pairs of chromosomes, right? We haven't gotten rid of, uh, one half of those 23 sets of chromosomes yet. But that one will continue to mature, and then at some point, that egg will start to in- undergo a process in which those chromosomes are pulled apart by little components within the egg called spindles. They literally have a physical pulling of the chromosomes apart. So now those 23 pairs are no longer attached to one another at the middle like they were before, like two beads o- of, of strings, or I should say 23 short strands of beads that were at once connected to one another now are pulled apart so that you have 23 chromosomes on each side, but they're pulled apart from one another. All right? So that diploid cell is now starting to become a cell in which half of the chromosomes, half of those 23 pairs are physically pulled away from the others, and then the egg actually starts to form its own what we call an involution of membrane around those 23 pairs, one set of them, and encapsulates them. So you've sort of got an egg with two parts, where the two sets of chromosomes, two sets of 23 chromosomes are now separate from one another inside of the egg, and then one of those actually gets ejected from the egg, and i- th- the name of that thing that gets ejected is sort of like the little hoverpod, is how I imagine it, um, you know, from, from Star Wars, you know, or from any kind of, uh, Space Odyssey movie where something is ready to happen, you know, the little hoverpod shoots out of the ship. Well, that 23 pairs is now ejected from the egg. It's called the polar body, and that's going to degenerate. It's going to go away, and in doing so, take it, the egg cell which was once diploid, it had 23 pairs of chromosomes, and making it haploid. And now what you've got, in ideal circumstances, is a beautifully pristine egg that was selected for and has 23 single strands of chromosomes, 22 autosomes and one sex chromosome, and that sex chromosome is going to be an X chromosome, almost with certainty, because f- female, mother is creating that egg. So then the egg that contains just the appropriate 23 single-stranded chromosomes is going to fuse with the wall of the ovary, and that egg will be released and will travel into the fallopian tube. Now, we'll get back to that egg in a few moments, but that process which represents the first half of the ovulatory menstrual cycle, again, was triggered by FSH and to some extent luteinizing hormone, but it is the ongoing maturation of that egg which also causes the production of estrogen, which allows that whole process to occur. And you could say, "Why?" Well, the answer to the why is a very important biological principle that we are going to return to in a number of different contexts today, both, a- as reference to female and male fertility, and the principle is a so-called negative feedback. So when estrogen is present at relatively low levels in females, in the ovary, as it is during the development of these eggs, some of that estrogen, of course, is going to exit the ovary. It's going to go into the bloodstream, and it's going to travel back to the pituitary. Now, the pituitary can release things like follicle-stimulating hormone and luteinizing hormone, but the way I'd like you to think about the pituitary for sake of feedback loops is that it's sort of like a thermometer that you would put into a pool, like a backyard pool, that is attached to the heater. And for instance, if you were to put a thermometer into a pool that you would like to keep at 70 degrees and the temperature of that pool is 60 degrees, well then that thermometer ought to trigger some sort of mechanism where the pool would heat up until the temperature of the pool hit 70 degrees, and then it should trigger that thermometer to turn off the heating system. Okay? That's kind of a negative feedback system that would keep the temperature more or less correct. That's a lot of the way that the systems related to estrogen and also testosterone and these different things like luteinizing hormone and follicle-stimulating hormone work as well. Typically h- when the level of a hormone is too high, then it shuts down the production of the hormones that would trigger further production of that hormone. I know that's a mouthful. It's a lot to think about, and some of you are probably thinking, whoa, I'm getting dizzy now with biology, but I promise you can understand this. In females, when estrogen is relatively low, but not zero, but is relatively low during that first follicular half of the ovulatory cycle, it actually triggers negative feedback on LH and FSH so that not too much is produced. But then just prior to ovulation, the levels of estrogen and the levels of some other hormones from those eggs, right? You have the eggs producing estrogen themselves, gets high enough that it actually triggers a positive feedback loop on the pituitary. So the pituitary is, is essentially observing the amount of estrogen in the bloodstream produced by the ovary and the amount of estrogen towards the end of the second half of the menstrual cycle has increased and triggers a positive feedback loop. It triggers the pituitary to release more FSH and LH, and that helps trigger ovulation, okay? That-... d- deployment or the release of that one mature, proper, selected egg with, that's haploid, with the 23 individual pairs of chromosomes into the fallopian tube. So let's just back up really quickly and just kind of summarize what's happened. Gonadotropin-releasing hormone from the hypothalamus triggers the release of follicle-stimulating hormone and luteinizing hormone. That travels to the ovary, triggers the release of a subset of immature follicles with immature eggs. Those immature follicles and immature eggs start to mature, start to grow because of the presence of follicle-stimulating hormone. The growth of those eggs themselves increases estrogen. As the estrogen starts to accumulate in the environment, some of that travels back to the pituitary, and when levels of estrogen arriving at the pituitary are relatively low, the pituitary says, "Oh, we don't need to release any more follicle-stimulating and luteinizing hormone." However, at some point just prior to ovulation, enough estrogen has been produced by that one single selected mature egg and some of the other follicles around it that were maturing but then since died off, that the estrogen triggers a positive feedback loop. The pituitary says okay and releases more follicle-stimulating hormone and luteinizing hormone, and bam, the egg which has the proper genetic components sets off out of the ovary and into the fallopian tube. So-called ovulation has begun. Okay? N- that itself, what I just described, constitutes the first half of the ovulatory menstrual cycle, which we call the follicular phase, and it's marked by the presence of FSH and some other things, but we can really think about it as marked by FSH from the pituitary and by estrogen or estradiol made within

Andrew Huberman 51:09 the ovary. Okay, then comes the second half of the ovulatory menstrual cycle, which I personally think is one of the coolest mechanisms in all of biology, which is that, remember the follicle that housed that one egg that was the selected egg that became the mature egg? And that follicle, which no longer contains the egg because the egg took off and ovulated, is called the corpus luteum. And the corpus luteum starts making three hormones, which include estradiol, a thing called inhibin, but the most important hormone, the one that you really need to know about, is that it starts producing very high levels of progesterone. Progesterone levels start to increase about the time of ovulation, although just prior to ovulation, and over the next s- second half of the ovulatory cycle, so about 14 days if it's a 28-day cycle, a little bit longer or a little bit shorter depending on the length of the cycle, levels of progesterone in the second half of the ovulatory cycle are going to increase by 1,400-fold compared to what they were in the first half of the ovulatory cycle. So again, if we were to characterize the menstrual ovulatory cycle wi- in broad strokes, what we would say is that FSH and estrogen mark the initial part, the first half, so-called follicular phase, and that the estrogen and FSH set in motion ovulation and they prime the system for the production of a corpus luteum, which p- produces progesterone and the second half of all of this is called the luteal phase. The second half of the ovulatory menstrual cycle is the luteal phase because of corpus luteum, this otherwise discarded tissue that produces progesterone. What does progesterone do? Well, progesterone impacts the uterine lining, so-called endometrium or the lining, the mucus lining of the uterus, where that egg that's ovulated is potentially going to implant if it's fertilized. And so, in a kind of perfect way, or I should say in a, um, seemingly perfect way, the egg is off on its way. It might get fertilized. The remnants of the compartment that let go of that egg produce a hormone that then prepares the endometrial lining of the uterus for the potential implantation of that egg. It's basically making the bed for the fertilized egg to potentially embed in, to implant in, and then achieve all the nourishment that it needs to grow eventually into a healthy embryo and child. Just an amazing set of biological mechanisms, if you ask me, because what you're observing here is an incredible economy of function, whereby the same cellular components that are producing the egg, well, some of them are being discarded, but they're not being discarded without purpose. They're being discarded in a way that triggers the onset of hormonal expression that then prepares the fertilized egg to be in an enriched environment in which it can thrive. Now, I realize that was a lot of detail, but we have a couple of key themes. We've got the hypothalamus, GnRH. We've got the pituitary with LH and FSH, and those hormones travel to the ovary. The ovary has eggs in a vault, basically immature eggs in a vault. Some of those are activated by the presence of FSH and LH each month, and one of those eggs will be selected and will ovulate. The remnants of the follicle and egg that are not selected, the chromosomes that you don't need are, disappear in the polar body and the corpus luteum gives rise to progesterone and sets in motion the second half of the ovulatory menstrual cycle, which is the luteal phase, which is essentially the potential for that fertilized egg to embed in a nice nourishing environment. And of course, we should all be thinking if the egg is fertilized and then it lays down in the, uh, nice comfy uterine lining that's been prepared by, um, progesterone and the corpus luteum, well, then everything's fine and good. But what if fertilization doesn't occur? Well, we all know what happens if fertilization doesn't occur. If fertilization does not occur for whatever reason, that uterine lining is going to shed, and that's actually what's referred to as the period. It's the actual removal or the departure, rather, of the thickened endometrium lining of the uterus when fertilization has not occurred.And of course, if that happens, we need another ovulatory menstrual cycle. So how does that happen? Well, the hormone inhibin is also made by the corpus luteum and doesn't go quite as high as the hormone progesterone, but it kind of tracks that increase in progesterone that occurs in the second half of the ovulatory cycle. But then if fertilization does not occur, inhibin levels start to drop. And what I haven't told you is what inhibin does. Inhibin, in concert with other hormones like estrogen, feed back to the hypothalamus and prevent the further release of follicle-stimulating hormone and luteinizing hormone, right? If you're- have an egg that gets fertilized and can implant, well then, you don't want more eggs to mature, right? You want to hold onto the ones in the vault. You don't want them to mature. And hormones like inhibin, and again, working with other hormones, are going to prevent the secretion of things like FSH and LH. Now, typically, people are not getting pregnant every month. In fact, that's not possible, and part of the reason it's not possible is that if the fertilized egg implants, there are a number of different hormone cascades that shut down the production of things like GNRH, FSH, and LH in ways that prevent further maturation of follicles in a follicular phase. But in the instance where fertilization doesn't occur and menstruation occurs... And I should mention that the, the duration of menstruation, the actual bleeding, typically is anywhere from one to five days. The, quote-unquote, heaviness, the lightness or heaviness of that bleeding will depend on, you guessed it, the amount of progesterone that is secreted from the corpus luteum. That's one of the key players there. And if menstruation occurs, well then, inhibin levels also drop, progesterone levels also drop, and when that occurs, there's a positive feedback signal up at the level of the pituitary. The pituitary literally can register how much inhibin and progesterone and estrogen is present in the bloodstream, and if those levels are sufficiently low, well then GNRH gets secreted again, FSH gets secreted again, and LH s- gets secreted again, and the first half, the follicular phase of the menstrual cycle initiates all over again. It's hard to overstate how beautifully orchestrated this entire system is, the number of feedback loops and feedforward loops. I think if you can just generally understand that the first half of the menstrual ovulatory cycle is marked by the maturation of the follicles and FSH and that the second half is marked by the accumulation of progesterone and the thickening of the uterine lining should fertilization and imp- implantation occur, I think that you will certainly understand the female reproductive cycle better than most people out there. It will also

Andrew Huberman 58:14 help you understand a number of things that are sometimes associated with the female reproductive cycle. For instance, there are data showing that in many, not all, but in many women, in the four to five days prior to ovulation, there is a dramatic increase in libido. That dramatic increase in libido is triggered by a number of things, but some of those things include the spike in FSH that occurs, the spike in LH that occurs, and some associated increases in androgens, things like DHEA and testosterone, which, just as in males can be related to libido, in females trigger libido. You can imagine why this would be an effective mechanism to have in place in females if the goal, as it were, um, certainly of the egg, um, perhaps not of the, the woman as a whole, but if the goal is to fertilize the egg. So increases in libido just prior to the onset of ovulation. There's also been a lot of discussion and interest, and frankly data, exploring the malaise that e- can occur at certain portions of the, of the menstrual cycle, and there's a lot of misconception about this. A lot of people have focused on the malaise that can occur around the time of bleeding, but there are actually stronger data to support the fact that some, again, some, not all women experience a kind of malaise, sometimes associated with anxiety, sometimes not, that's associated with the mid to second half of the luteal phase of the ovulatory menstrual cycle. And that, despite what people commonly think, is not associated with elevated levels of estrogen. It's actually associated with the depletion in estrogen levels that can occur during certain portions of that second half of the luteal phase of the menstrual cycle. So, um, again, this is highly variable. Um, you know, for some people, they might not experience any malaise at any point during their menstrual cycle. Other individuals also, for instance, might not experience any variation in their libido at any point during their menstrual cycle. Again, highly variable, and yet there are some statistically significant trends that have been observed that track to very specific hormonal components within the menstrual cycle. Again, this will all be very contextual, and of course, this can play out in a number of different ways. So for instance, some women experience very heightened levels of sensitivity to caffeine at certain p- portions of their menstrual cycle. Other women experience, uh, more cramping than others, uh, different portions of their menstrual cycle. Tremendous variation from individual to individual. Um, one of the, uh, I view it as an advantage, but one of the th- um, things that many females can really do and experience because they have cycles that occur every month that are fairly dramatic in terms of their levels of hormones, so for instance, a more than thousand-fold increase in progesterone during the lead- luteal phase of the menstrual cycle, and I should also mention, a 200-fold increase in estrogen during the period just prior to ovulation. That's why they always say estrogen primes progesterone. That's, uh, what you learn in kind of basic endocrinology when you're learning the menstrual cycle. Estrogen in the first half of the menstrual cycle primes progesterone in the second half of the, of the ovulatory menstrual cycle. Well, that, those estrogen increases just prior to ovulation are in part responsible for the increases in libido.... but it's also the presence of increased androgen just prior to ovulation. So, there's a lot of complex interplay. I think what we will do is we will reserve the discussion about libido per se and some of the other aspects related to sexual differentiation that we were talking about earlier for a future episode. But hopefully, now you have in mind what the ovulatory menstrual cycle is. It is a signal from the brain, from the hypothalamus, which then triggers a signal from the pituitary, an endocrine gland, which then signals the release of hormones that travel to the ovary and that control two things: maturation of eggs and the identification of one egg in particular, and then preparation of the milieu, the environment in which that fertilized egg could potentially land and mature into a healthy embryo and child. So if you have that framed up in your mind, and even if you just extracted maybe 10% to 15% of the hormones and different aspects that I described up until now, I would consider you far more knowledgeable about this entire process than 99% of people out there. Uh, certainly not the OB-GYNs and urologists, but than 99% of individuals out there. It also frames up for us the second half of this whole story about fertility and fertilization, which is the generation of sperm and how the sperm eventually arrive at the egg and how certain sperm are selected to potentially fertilize that egg, whereas others never really stand a chance. So next, we're gonna talk about sperm. We're gonna talk about what sperm are, where they are generated and how they are generated, and how they need to travel both within the male and within the female in order to allow fertilization to potentially occur.

Andrew Huberman 1:03:14 I'd like to take a brief break and thank our sponsor, InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done for the simple reason that many of the factors that impact your immediate and long-term health can only be analyzed from a quality blood test. The problem with a lot of blood and DNA tests out there, however, is that you get data back about metabolic factors, lipids and hormones and so forth, but you don't know what to do with those data. InsideTracker solves that problem and makes it very easy for you to understand what sorts of nutritional, behavioral, maybe even supplementation-based interventions you might want to take on in order to adjust the numbers of those metabolic factors, hormones, lipids, and other things that impact your immediate and long-term health, to bring those numbers into the ranges that are appropriate and indeed optimal for you. If you'd like to try InsideTracker, you can visit insidetracker.com/huberman and get 20% off any of InsideTracker's plans. That's insidetracker.com/huberman to get 20%

Andrew Huberman 1:04:18 off. So we've covered the ovulatory cycle in females, and I confess it was a lot of information with a lot of biological nomenclature. But I promise you that many of those same themes and indeed the same names and nomenclature will show up in the discussion that we're going to have now, which is about the generation of sperm. Now, sperm are similar to eggs in the sense that they are part of the germline. They are these protected cells, protected in the sense that the activities of an individual are not going to change the genetic makeup of those cells. Now, again, there are instances in which mutagens, such as, uh, chemicals, could disrupt the genomes of the germ cells in males just as it could in females. But in general, the activities, the things that we do, the experiences we have, doesn't tend to change the genome of those cells. However, there are a lot of lifestyle factors, do's and don'ts, nutrition and supplements and prescription drugs, et cetera, that can indeed modify the quality of the sperm. And we'll talk about what sperm quality means. But the point is that the sperm cell, much like the egg cell, are both germline cells. They are not like somatic cells. They are unique populations. And let's just remember what the job of the sperm cell is. The job of the sperm cell is to deliver the genetic material from the father and to do that in the form of a haploid cell. So that means 23 chromosomes, 22 autosomes, one so-called sex chromosome. Again, not sex the verb, at least not in this case. Sex the verb is a discussion we're gonna have in a few minutes. But sex the noun. The sex chromosome can either be an X chromosome or a Y chromosome. Okay, so 22 autosomes and then one sex chromosome is going to be contained within the sperm, because it's a haploid cell, not a diploid cell. Remember the egg was diploid, then it became haploid. The sperm cells are cells that are created through the division of other cells, but after that division occurs, through a process called meiosis, the sperm cell is going to contain 23 chromosomes consisting of 22 autosomes and one sex chromosome. And the sperm that manages to deposit its DNA contents into the egg to fertilize the egg will either have an X sex chromosome or a Y sex chromosome. And the Y sex chromosome has a number of different genes on that chromosome that will suppress, for instance, the development of the female reproductive axis. Uh, one, uh, good example would be the Müllerian-inhibiting hormone, or MIH. The gene for Müllerian-inhibiting hormone, which is a hormone that prevents the formation of the Müllerian ducts, which is part of the female reproductive structure, well, that gene controls the i- prevention of the development of the female genitalia, and in doing so, promotes the development of male genitalia. And there are other examples of genes that are on the Y chromosome that give you a what we call male phenotype, right? You have genotype and phenotype. By the way, in case you haven't, um, heard this in a while from your high school biology or if you never heard it, no big deal, karyotype is the complement of chromosome, XX or XY. And there are individuals out there that are XXY or XYY, a discussion for our episode on sex differentiation. That's karyotype with a K. Then there's genotype, which are the genes that you have, and then there's phenotype, spelled P-H, pheno, P-H-E-N-O-T-Y-P-E, phenotype. And the phenotype is...... how the genes, which then code for RNA, which code for protein, how those are expressed in terms of things like eye color. So, eye color's a phenotype, height is a phenotype, hair color's a phenotype. Okay, so you have karyotype, genotype, and phenotype. Well, what we need to do is we need to bring together that sperm, which is haploid, contains those 23 chromosomal strands with either an X or a Y, sex chromosome is the 23rd chromosome, we need to get that cell to the egg. And so, when we talk about spermatogenesis, of course we are talking about the generation of sperm cells, but what we're really talking about is the generation of cells whose job is to deliver the genetic material from dad to the egg within the female in a way that increases the probability that not only will that egg be fertilized, but that it will progress in a healthy way with each set of chromosomes from mom and from dad, each set of 23 chromosomes, that is, will progress in a healthy way, will implant in a healthy way, and will maintain and grow in a healthy way to a healthy embryo and child, and eventually adult. That's the job of the sperm, okay? So, as we talk about spermatogenesis, let's just remember that and why they're there in the first place. Now, a few things about sperm that are interesting besides the fact that they're haploid and besides the fact that, as you all know, they swim, they have a head and a tail. They actually have a head, a mid-region, and a tail, and that mid-region turns out to be very important, it's something we'll come back to again and again. That mid-region is really key for the ability for sperm to engage in forward progression, to swim forward. Um, it involves the activity of mitochondria, which are involved in generation of ATP, which is involved in als- aspects of energy in all cells. But let's just remember that the sperm are swimming cells, and in order to create a really good swimmer or set of swimmers, (laughs) you need a- a couple of things. First of all, within the testes is where the sperm develop, and unlike in females and unlike in the ovary, there's no vault of sperm. The sperm are continually being generated. It takes about 60 days for sperm to be born from their parent cells, because cells actually give rise to other cells, that's the way it works, to be born from their parent cells and then mature to the point where they can be a really good swimmer. Now, that doesn't mean that a bunch of sperm are made on day one and then 60 days later all those sperm are deployed in the form of ejaculate and then it, the cycle starts over again, so it's a little different than the ovulatory menstrual cycle. Rather, at any given point in time, like right now, if you have testes, you have some sperm in your testes that are immature and cannot swim, cannot deliver those contents, uh, to, those genetic contents, rather, to the female egg, and you have some sperm in there mature, and you very likely have some sperm that are so mature that they are dying off or that they're dead. Almost certainly, also, regardless of your age, you have sp- some sperm that are healthier than others, they're better swimmers than others. This is just, uh, the way the system works. Now, the process of spermatogenesis involves a couple of things, but a lot of the players are the same as the process of developing the so-called oocyte, the immature egg. We've got GnRH from the hypothalamus, that's gonna be a player. We have FSH, follicle stimulating hormone, although the name's a little bit of a misnomer in the context of spermatogenesis, because in the context of spermatogenesis, there is no follicle. What we're really talking about is FSH for stimulating the maturation of the sperm cell, so not egg follicle but sperm cell. But we still have GnRH, FSH, LH, and rather than the ovary being the target of those hormones, it's going to be the testes. So, most everybody should know that the testes and the

Andrew Huberman 1:11:40 ovaries are the so-called gonads. The testes, of course, reside outside of the body. There are instances where the testes fail to descend during development. Certainly if the testes don't descend on time, that's something that doctors need to be m- made aware of, the pediatrician should be made aware of, because that can prevent fertility. Why would that be? Well, turns out that the testes reside outside the body in the scrotum because the temperature conditions under which spermatogenesis can occur and under which healthy sperm can be maintained are very restricted and is, uh, approximately two degrees cooler than the rest of the body. This is very important. You know, I think this is something that used to be discussed a lot more but isn't discussed so much these days, but keeping the testes cool enough doesn't necessarily mean keeping them cold, although there is a place for using cold exposure, deliberate cold exposure, to improve sperm quality and number and perhaps even testosterone levels, we'll talk about that a little bit later. But keeping the testes about two degrees cooler than the rest of the body is absolutely key. If sperm get too hot, they die. And a spermatocyte, the cells get, that give rise to sperm get too warm, well then oftentimes the sperm that develop are not healthy, not healthy in a number of ways. Either they can't engage in fast-forward progression and sw- that is, swimming, or they will lack the ability to deposit their DNA contents within the egg. So again, whatever is contained in the ejaculate is going to be a mixture of different sperm qualities, and sperm of different ages will impact the quality, but also the temperature under which those sperm developed is going to impact their quality. And so, uh, we're going to get into tools a little bit later, as I mentioned, but just to give you a, a simple takeaway, if you are hoping to conceive in the next 90 days, right? The spermatogenesis cycle takes 60 days, but then the sperm actually have to migrate from the testicle into the so-called epididymis, which is, uh, a related structure, and then into the vas deferens and then into the urethra where it can be part of the ejaculate. In order for sperm to do all that properly, undergo that maturation and then exit and ejaculate in a way that's healthy, or that the sperm is healthy...... if you plan to conceive children or to try and conceive children in the next 90 days, you definitely want to avoid exposing your testicles, that is your scrotum, to elevated temperatures. So that means definitely avoiding hot tubs, definitely avoiding hot baths. Now, a brief hot bath or hot tub or hot shower isn't going to be a problem, although if you're really interested in conceiving, I would avoid hot tubs and- and hot baths as much as possible. Hot showers are probably fine. But if you're going to go into a sauna, for instance, you might want to rethink that decision, and if you do decide to, you almost certainly would want to bring a cold pack in that you could, um, well, hopefully put some material between the cold pack and, uh, and the scrotum so you don't get a cold burn. But put something there, but keep the scrotal tissue cool, keep it cold to cool, because heat exposure can really mutate and disrupt the developing sperm and it can kill sperm. And so again, that would be for an entire 90 days leading up to your attempts to- to conceive. Again, we'll get into more tools later, but a number of people also, uh, have probably heard of the boxers versus briefs, um, controversy (laughs) I guess, uh, it is, um, or whether or not, uh, people call it, uh, going commando with no, um, with no underwear of any kind, boxers, briefers- briefs, or otherwise, rather. Turns out that the date on that point to the fact that there isn't really a big difference in terms of sperm quality if people wear boxers or briefs or don't wear anything under their, um, jeans or shorts at all. Um, the scrotum has the ability to move the testicles far enough away from the body in order to achieve lower temperatures if it needs to. It- it achieves that through a muscle called the cremaster muscle, which is a really interesting muscle, believe it or not. I was reading up on the biology of the cremaster muscle, something I never thought I'd spend, uh, too much time on but that I ended up spending far too much time, uh, reading up about, and it's really fascinating. What you have is a- is a- a muscle that's a smooth muscle tissue, unlike skeletal muscle, which is striated muscle, that is temperature dependent. So it has certain nerve endings and it has certain, uh, receptors on it that allow it to respond to local temperature and then to relax in order to, um, essentially let the testicles to descend further from the body or to contract and bring the testicles closer to the body in order to try and maintain the optimal temperature range. And it turns out the cremaster muscle can achieve that whether or not people are wearing boxers or briefs, although it stands to reason that any kind of, um ... there's no other name for it, undergarments, you know, I don't know why that word is- is- just seems kind of antiquated, but undergarment that allows some movement of the- of the scrotum and the testicles should be sufficient to allow these, um, temperature, uh, variations to occur and keep- keep things in range. Um, that said, wh- a little bit later, we'll go into some detail really, because it's important as to why, for instance, if you are somebody who has big thighs, believe it or not (laughs) , that it actually can lower sperm count substantially. Whether or not the big thighs occur because you're very muscular or the big thighs occur because you, um, are overweight, it can increase the temperature. Uh, if you're sitting a lot, increases scrotal temperature for sure, and there are some other things that can increase scrotal temperature. Um, seat heaters in cars, for instance, terrible idea if you ... (laughs) just terrible idea if you're hoping to conceive in the near future. Um, and again, hot tub, things of that sort. Okay, so temperature modulation

Andrew Huberman 1:17:22 of spermatogenesis and sperm quality and function is key. That relates a little bit more to tools, but what happens? How does the actual sperm develop? Well, contained within the testicle, you have the cells, the so-called spermatogonia, which differentiate into so-called spermatocytes. You don't have to remember all this. And the spermatocytes undergo this process of meiosis. Meiosis is a form of cell division which reduces the chromosome number to those 23 individual strands as opposed to pairs, right? So it makes them haploid as opposed to diploid. Very, very important for reasons that we talked about earlier. And the meiosis process in these primordial sperm cells, these immature sperm cells is similar to the meiosis process that occurs in eggs when the chromosomes segregate in that it involves these spindle-like, um, structures within the cell. Now, why do I keep bringing up the spindles? Well, it turns out that the function of the spindle in the egg and the sperm is heavily dependent on mitochondrial function, and later when we get into tools for improving egg and sperm quality, you're going to hear about a lot of tools for improving mitochondria. And it's not just because the mitochondria are involved in- in energy demanding aspects of cell biology, but it's also because the mitochondria in this context are very, very important for the removal of or the separation of one set of chromosomes to give you these two sets of haploid cells, the egg and the sperm. And this is so important because many failures at fertilization, many failures at implantation, many, many miscarriages and many birth defects that do survive after birth that are very detrimental such as trisomies and things like that occur because the spindles don't effectively pull apart the chromosomes in the- typically the egg, but it can also occur in the sperm. Okay, so the spindles and the fact that mitochondria are rich on the spindle are very important for generating these haploid sperm, again, 23 individual strands of chromosomes. That's occurring inside of the testes, okay? So there's not as much long distance migration of the spermatos- of the spermatocytes and the sperm cells as there is the egg, just when you think about the overall architecture of the uterus and the fallopian tubes compared to the testicles, but there's still a lot of movement. So within the testicle, if you were to look at the testicle in cross-section, and I prefer to call it that rather than cut the testicle in half. Any time you talk about anatomy, you actually talk about slicing things, that's what you would do in- with a cadaver, is what, um, I teach and we do, um, in my laboratory and frankly in biological laboratories all over the place. But when you talk about this, you have to talk about if you were to take a visual cross-section (laughs) through the testicle, what you would find is that there are a lot of different little tubes, a lot of ducts, D-U-C-T...... T-S, ducts. Those are pathways. And the main ducts that are important for this discussion are s- called the seminiferous tubules. Okay? So it's a b- it's a, uh, mesh-like or network structure of tubes in the testicle, and the immature sperm sit on a little compartment, um, along the edge of those tubes. And as they mature, they move towards the center of those tubes, and then when they are mature enough, those sperm cells actually drop into the hollow of the tube and then can travel through those tubes to a structure that's n- along the side of the testicle called the epididymis. The epididymis, again, is a series of ducts, and then the epididymis converges with something called the vas deferens, okay? I think in high school, we all remember this by thinking about it's the vast difference. I don't know. Va- I don't know who came up with that. Maybe... I think it was a, a young girl sitting to the left of me that was like, "Oh, it's like the vast difference." I never forgot that. I don't know. Maybe it was the topic matter. Maybe it was her. Maybe it was some combination of the two. But in any case, the sperm go from the seminiferous tubules to the epididymis, and then to the vas deferens, and then are contained in the ejaculate along with seminal fluid. Now, the seminal fluid is the carrier fluid for the sperm themselves. This is important because it turns out that a lot of the things that can both negatively or positively impact the quality of the sperm relates not just to the sperm cells themselves and the temperature of the environment that they were, uh, matured in, but also to the semen quality. For instance, if you are a heavy drinker, if you are a smoker, or if you are a regular user of cannabis, especially if you smoke cannabis or, or vape cannabis, you create a lot of reactive oxygen species that disrupt the chemistry of the seminal fluid, which disrupts the sperm cell. So it's not a direct action always on the sperm cell itself, although it can be. So for instance, in the form of, of smoked tobacco or cannabis, there are a lot of carcinogens and mutagens that actually mutate the DNA, can cause DNA fragmentation and debilitate sperm. But there are also a lot of things created by smoking in particular, whether regardless of what's being smoked, that can create elevated reactive oxygen species and disrupt the seminal fluid that the sperm are contained in in the so-called ejaculate, the semen. Now, this will also become a relevant conversation later when we briefly talk about vasectomies. Vasectomies i- are literally a, a cutting of the vas deferens, which leads to a situation, provided the surgery was done correctly, where men can still achieve all the other aspects of intercourse. They can still, uh, achieve erection. They can still achieve orgasm. They can still ejaculate, but when they ejaculate, the seminal fluid is released, but there are no sperm contained within the seminal fluid. And it turns out that, um, vasectomies are a very effective form of birth control, and they always check to see if zero sperm and confirm that zero sperm are being, uh, released in the ejaculate. They are reversible. That is, vasectomies are reversible, but not always. There are a subset of cases where it's not reversible, in which case if people still want to have children, you have to go in and actually surgically extract, uh, sperm from the testicles. But it's a process in which the vas deferens is altered or severed in a way that the sperm can't actually exit the testicle. They can get into the epididymis usually, but not into the vas deferens and so on and so forth. Um, so if you've ever wondered what a vasectomy is, that's what a vasectomy is. And I mention vasectomy now because it illustrates the difference between the seminal fluid, the semen, and the sperm that the semen contain. Okay? So 60 days to generate these, the sperm, another, um, two weeks or so for the sperm to travel through the various ducts to the point where