How Hormones Shape Sexual Development

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. 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. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is 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'm a big believer in blood tests and DNA tests for the simple reason that many of the factors that are important for your short-term and long-term health and overall well-being can only be analyzed from blood and DNA tests. 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It's a new month, which means it's a new topic here at the Huberman Lab Podcast. For the next four or so episodes, we're going to be talking all about hormone effects on the brain and body. So that's a huge number of different topics. We're going to talk about sex. We're going to talk about reproduction. We're going to talk about puberty a little bit more. We talked about that in the previous episode. We're going to talk about menopause. We're going to talk about birth control. We are going to talk about aggression, competition, winning, losing. Basically, we're going to cover as much about hormones as we possibly can in this month.And in doing so, we are going to go deep into tools and protocols. We are also going to talk about a lot of tools that relate to things that you might not want to do in order to optimize hormone health, regardless of stage of life or your goals, et cetera. So it's sure to be a month rich with discussion, rich with tools, and you're going to learn a lot of neuroscience and endocrinology. There's actually a field of neuroendocrinology. It's actually where I started my graduate work. I did a master's in it, which is only to say that I love the topic. I have a lot of friends that work on this topic, many of whom I've consulted for these episodes, and I'm really excited to share the information with you. Before we dive into today's episode all about emotions and sex, I want to just have a few announcements that are designed to point you to some useful resources. Last episode, talking about the science of emotions and relationships, I mentioned the Mood Meter app. The Mood Meter app was developed by, um, people out at Yale University who study the biology and psychology of emotions. It's a really wonderful app. However, many of you quickly told me that the Mood Meter app isn't available in your area. You went to the link we posted, and it just was saying not available in your area. The situation was actually a lot worse than that. The situation was that when we recorded the episode, the Mood Meter app was working. I know because I downloaded a, a fresh copy of it to my phone, and then in the ensuing weekend they took the Mood Meter app down for some repairs. The Mood Meter app is now up. It is available. I want to be really clear. It's not an app I'm affiliated with. I'm just mentioning it to you. They don't know me. I know them, but they don't know me, so we don't have any kind of business relationship. They do charge 99 cents for the app. Uh, I think the free version has disappeared in, in the last year or so. So that's Mood Meter app. We'll provide the link again, and it, the link should be working. Hopefully they won't take it (laughs) down again in between this announcement and the release of this episode. Also just want to take a step back for a moment and talk a little bit about the logic of how to make the most of the information on the Huberman Lab Podcast. I tend to throw out a lot of information about a given topic. Many of you have pointed out however that I don't cover certain things, and once again I'll just say the goal is always to be accurate, but there's no way I can be exhaustive. There's no way I can cover everything for a particular topic. The good news is we have time. My goal at least in the first year of the Huberman Lab Podcast is to give you a basis, a foundation in these different topics of neuroplasticity, focus, sleep, hormones, et cetera, and of course to provide tools along the way. We are going to host guests. I've actually started recording with some of these guests already, and even those episodes will include a little what we call primer, a little description of the basics of a given topic so that you can get more information from those topics. My goal really is to educate you in these topics, give you a foundation in these topics, and allow you to start exploring them here in the episodes with our future guests but also in other podcasts and books and other sources of information. So for those of you that are saying it's too much information, I just encourage, uh, you to remind yourself that you have a pause button. You can return to it. Everything's timestamped. For those of you that feel it's not enough information, I'm not covering enough, just know that this is just the beginning. We d- intend to do this for a very long time, and we will be thorough over time. So thanks for your patience, and please be patient with yourselves. There's no reason why you have to digest all the information in one swoop. The other thing is that I've been told both that I speak too fast and speak too slow, so there's a wonderful solution to this. If I speak too fast or too slow, you can adjust the speed in YouTube. If you're listening in a different format, I think you also can adjust the speed of playback. So that's, uh, something that wouldn't be possible in the classroom, um, but you may find useful. And then last but not least, I want to point people again to this NSDR, non-sleep deep rest protocol that the folks over at Madefor have put out as a free resource. It does, as many of you pointed out, bear resemblance to things like yoga nidra, other forms of meditation, but what we've done is we've stripped out intentions or any kind of the, the, uh, verbiage related to, um, what some people might perceive as kind of related to the yoga community or, um, specific to kind of new agey type techniques, not because we don't like yoga nidra. In fact, I've done yoga nidra daily for almost the last, uh, goodness, um, eight years of my life. I love yoga nidra, but sometimes the complicated language can be a separator and can discourage people from taking on these protocols that are extremely useful. So NSDR is, is intentionally generic. It's designed to bring you into a state of deep relaxation through a combination of breathing and body scan. There's the YouTube script over at you- uh, at Madefor, which is linked in the caption, and many people find that they prefer that to scripts like yoga nidra scripts where they're doing intentions and they're hearing a lot of, um, kind of, uh, unusual language around the process. This is just very basic, and, uh, I hope you'll enjoy it, and if you prefer the more typical yoga nidra scripts, then, um, go with those. There are many of them available on the internet and elsewhere. And last but not least, I want to point out that all our episodes now are subtitled both in English and in Spanish, so for those of you that prefer to digest this information in Spanish, that's now available to you in the subtitles. Today we're going to talk about the science of sex, in particular sexual differentiation. Now, that's a complicated topic because sex is both a adjective, a noun, and a verb depending on the context. Today we're going to talk about the hormonal effects and the neural effects of particular events that happen during development and how those guide adolescent and adult behavior, including sexual preference. It's an area that's fascinating and for which t-There are actually very solid textbook findings. So textbook findings means that there are many studies that have been aggregated over decades that point to what we now know to be absolute truths in terms of how hormones affect brain development, how the brain impacts hormonal development, and how those interact to control behavior, for instance. We are also going to talk about reproduction, the verb sex. And of course, sex, the verb, can also be carried out independent of reproduction. It's not always, in particular in humans, just to produce offspring. So that's going to be covered in the next episode, but you absolutely need to understand the information in this episode in order to make sense of the information in the next episode. So today we're going to explore hormones, what they are, how they work, what leads to masculinization or feminization of the brain and body. I'll just throw out one really interesting fact that perhaps most of you didn't realize, that hormones have direct effects on the body. Most people know that because there are hormone differences and sex differences in bodies in terms of genitalia and body hair, distribution of body hair, et cetera, but there are also effects of hormones on the brain directly, and believe it or not, there are also effects on the spinal cord, on the neurons and structures within the spinal cord that impact in a very direct way what sorts of behaviors are possible. So it's a fascinating area. You might notice I'm going to go a little bit more slowly through this topic than I normally do. I want to be extremely careful with my language. Some of these topics some of you may be thinking are extremely sensitive, right? And of course, any discussion about sex and reproduction is a sensitive one, but today we're just talking about the biology. We're not getting into the cultural constraints or the cultural dialogue. What we're trying to do today is really get to the biology, the physiology, the endocrinology, and the behavior. So let's start by talking about what hormones are, just to remind you, and what they do. Hormones, by definition, are a substance, a chemical that's released in one area of the body, typically from something we call a gland, although they can also be released from neurons, but they're released often from glands that travel and have effects both on that gland, but also on other organs and tissues in the body, and that differentiates hormones from things like neurotransmitters, which tend to act more locally. So that's important. A hormone is a substance secreted at one location in the body that travels and has impact on things elsewhere in the body. Examples of tissues that produce hormones would be the thyroid, the testes, the ovaries, et cetera, and then of course, there are areas of the brain like the hypothalamus and the pituitary, which are closely related to one another and release hormones that cause the release of yet other hormones out in the body. So we're going to cover all this. If you don't know anything about endocrinology, you're still going to be able to understand today's discussion, and we're going to start with a discussion about what hormones actually do to create this thing that we call masculinization or feminization. So let's start with development. Sperm meets egg. Everything that happens before that is a topic of the next episode, but sperm meets egg. This is mammalian reproduction, and that egg starts to duplicate. It starts to make more of itself. It makes more cells, and eventually some of those cells become skin, some of those cells become brain, some of those cells become muscle, some of those cells become fingers. All the stuff that makes up the brain and body plan. In addition, there are hormones that come both from the mother and from the developing baby, the developing fetus, that impact whether or not the brain will be what they call organized masculine or organized feminine, and as I say this, I want you to try and discard what the cultural connotations or your psychological connotations of what masculinization and feminization are because we're only centering on the biology. So typically, people have either two X chromosomes, and the traditional language around that is that person is female, right? Or an X chromosome and a Y chromosome, and that person will become male. Now, it's not always the case. There are cases where it's XXY, where there are two X chromosomes plus a Y chromosome. There are also cases where it's XYY, where there are two Y chromosomes, and these have important biological and psychological impacts. So the first thing we need to establish is that there is something called chromosomal sex. Whether or not there are two X chromosomes or an X and Y chromosome is what we call chromosomal sex, but the next stage of separating out the sexes is what we call gonadal sex. Typically, not always, but typically, if somebody has testes for their gonads, we think of them as male, and if somebody has ovaries, we think of them as female, although that's not always the case either, but let's just explore the transition from chromosomal sex to gonadal sex because it's a fascinating one that we all went through in some form or another. So this XY that we typically think of as promoting masculinization of the fetus, we say that because on the Y chromosome there are genes, and those genes have particular functions that suppress female reproductive organs. So on the Y chromosome there's a gene which encodes for something called Müllerian-inhibiting hormone. So there's actually a hormone that's programmed by the Y chromosome that inhibits the formation of Müllerian ducts, which are an important part of the female reproductive apparatus.That's critical because already we're seeing the transition between chromosome, Y chromosome, and gonad. And other genes on the Y chromosome promote the formation of testes. So there are genes like the SRY gene and other genes that promote the formation of testes while they also inhibit the formation of the Müllerian ducts. So the transition from chromosomal sex to gonadal sex is a very important distinction, it's kind of a fork in the road that happens very early in development while fetuses are still in the embryo. Now, what's interesting as well is that just because there's a Y chromosome that can suppress Müllerian duct formation and there are other genes on the Y chromosome that promote teste development, the placenta itself is an endocrine organ. I think most people don't know this, but the placenta is an endocrine organ. As well, the mother, which of course is carrying the fetus, has an adrenal gland which can produce testosterone. There are instances, for example, where a mother has either a tumor or for some other reason is secreting large levels of testosterone while carrying a fetus that is XX, and that leads to what we would call masculinization of certain aspects of the fetus. Typically, um, that would be enlarged clitoris. There are also some examples of other phenotypes on the body that are created even though it's a purely XX chromosomal baby. So we have to distinguish between chromosomal sex, gonadal sex, and then there's what we call hormonal sex, which is the effects of the, of the steroid hormones, estrogen and testosterone and their, and their derivatives, on what we call morphological sex or the shape of the baby and the human and the genitalia and the jaw and all these other things. And so it actually is quite complicated. So l- you know, it's a long distance from chromosomes to gender identity, and gender identity has a lot of social, uh, influences and roles. This is an area that right now is very dynamic and in the discussion out there, as you know. But just getting from chromosomal sex to what we would call gonadal sex or ho- and hormonal sex and morphological sex involves a number of steps. So today we're going to talk about those steps, and there's some fascinating things that do indeed relate to tools, do indeed relate to some important behavioral choices, important choices about things to avoid while pregnant, and for those of you that are not pregnant, things to avoid if you're thinking about eventually having children, and that is not to drive development in one direction or another, but there are examples where there are some del- deleterious things in our environment that can actually negatively impact what we call sexual development overall, regardless of chromosomal background. So let's get started with that. Let's talk a little bit more about what hormones do. Hormones generally have two categories of effects. They can either be very fast or they can be very slow. There are hormones like cortisol and adrenaline which act very fast. Adrenaline can increase your heart rate, um, very fast once secreted into the body. Cortisol can be a little bit slower, but it also can have some very fast effects. And then there are hormones like what we ... like testosterone and estrogen, which we refer to as the sex steroid hormones. The sex steroid hormones can have quick effects through signaling, meaning they can attach to cells and make those cells do different things, they can have a ... actually quite quick effects on the brain. A lot of people don't know this, but there are some very fast effects of estrogen and testosterone, as well as long-term effects. These molecules, for those of you that are interested, are what are called lipophilic, which just means that they like fatty stuff. They can actually pass through fatty membranes, and because the outside of cells as well as the what's called the nuclear envelope where all the DNA contents and stuff are- are stuffed inside, are made of a- of a- of lipid, of fat. These steroid hormones can actually travel into cells and then get into the D- basically interact with the DNA of cells in order to control gene expression. So they can change the sorts of things that cells will become, and they can change the way that cells function in a long-term way, and that's actually how the presence of these genes like SRY and Müllerian-inhibiting hormone lead to reductions or elimination, I should say, of things like the Müllerian ducts and promote instead what's called in males the Wolffian ducts, or promote the, uh, the development of testes rather than ovaries. So all you need to know is that hormones have short-term and long-term effects, and the long-term effects are actually related to their effects on genes and how those genes are expressed or repressed, not, uh, in order to prevent them from having particular proteins made. So these ho- hormones, these steroid hormones, are exceedingly powerful, and if we're going to have a discussion about masculinization or feminization, et cetera, you also need to think about the counterpart. It's not just about masculinizing the body or feminizing the body and brain, it's also about demasculinizing the brain in many cases, as a normal biological function of- of, uh, typically of XX females, and defeminization, the suppression of certain pathways that are related to feminization of the body and brain. But there are some really fascinating twists in this story. So I've just thrown a lot of biology at you, but this is where it all starts to get incredibly surprising. You would think that it's straightforward, right? You have a Y chromosome. You suppress the female reproductive pathway like the Mu- like the Müllerian ducts. You promote this, the development of testes, and then testes make testosterone, and then it organizes the brain male, and it wants to do male-like things, and then, um, in females you get estrogen and it wants to do, uh, female-like things, and air quotes here, uh, for all of this, and it turns out (laughs) that isn't how it works at all. Here's where it's interesting. We have to understand that there are effects of these hormones, testosterone and estrogen-... on what are called primary sexual characteristics, which are the ones that you're born with, secondary sexual ch- characteristics, which are the ones that show up in puberty, and these are happening in the brain and body and spinal cord. And so I'm going to disentangle all this for you by giving you some examples. First, let's talk about the development of primary sexual characteristics, the ones that show up at birth, and one of the more dramatic examples of this comes from the role of testosterone in creating the external genitalia. Now, you might think it's just straightforward. If there's testes 'cause there's a Y chromosome, you know, you've got a gene that codes for the, uh, the development of testes, you get testosterone, and the penis grows and the baby is born with a penis. You know, one of the first things that happens when the baby comes out is they look at the genitalia and they try and make an assessment on whether or not it's a "boy" or it's a "girl," right? That's been done for a very, very long time in, in, uh, throughout human, uh, history. (smacks lips) It turns out that it's not testosterone that's responsible for the development of the penis in a baby that has an X chromosome and a Y chromosome. It's a different androgen. Androgen is just a category of hormones that includes testosterone, but testosterone is converted in the fetus to something called dihydrotestosterone, and that's accomplished through an enzyme called 5-alpha-reductase. Now, dihydrotestosterone has important effects later in life too. We will talk about those. In fact, if you just want to know, dihydrotestosterone is what we would call the dominant androgen in males. It's responsible for aggression, it's responsible for a lot of muscular strength, it's involved in beard growth and male pattern baldness. We're going to talk about all of that. But dihydrotestosterone has powerful, powerful effects in determining the genitalia while the baby is still in the embryo. So this enz- there's testosterone that's made, and that testosterone gets converted by this enzyme 5-alpha-reductase in a little structure called the tubercle. That tubercle will eventually become the penis. So you say, "Okay, straightforward. This testosterone is converted to dihydrotestosterone, and then if there's dihydrotestosterone, it controls penis growth." And indeed that's the case. So that's a primary sexual characteristic. That baby will then grow up and later, during puberty, there will be the release of a molecule I talked about this last episode called kisspeptin, K-I-S-S-P-E-P-T-I-N, kisspeptin, which will cause the release of some other hormones, gonadotropin-releasing hormone, luteinizing hormone, will stimulate the testes to make testosterone. So in puberty, testosterone leads to further growth and development of the penis, as well as the accumulation of or growth of pubic hair, uh, deepening of the voice, all the secondary sexual characteristics. Okay? So t- dihydrotestosterone def- creates what we would call the, the typical masculine phenotype for primary sexual characteristics and produces, uh, testosterone, excuse me, produces secondary sexual characteristics during puberty. There's a very interesting phenomenon that was published in the journal Science in the 1970s, for which now there's a wealth of scientific data, and this relates to a genetic mutation where 5-alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone, doesn't exist. It's mutated in a way in a genome that it doesn't exist. And this actually was first identified in the Dominican Republic. It has shown up elsewhere. It's quite rare, but where it shows up, it's robust. What happens is baby is born. Typically, when a baby is born they don't measure chromosomes, they don't look at chromosomal sex, XX or XY. That's not typically done nowadays. Baby is born. If you were to look at that baby, it would look female. There would be very little or no external penis, and so people would say, "It's a girl!" And they might s- you know, have the celebration, "It's a girl." And I guess now they call them gender reveal parties or something like that. I don't know about this. But, um, uh, anyway, they would reveal the, the, the baby would reveal its, um, its external genitalia simply by being there and being naked when it's born. Has nothing to do with gender. It has to do with genitalia and sex. That baby would be born, and what was observed is that from time to time, that baby, after being raised as a girl, perfectly happy as a girl, would around the age of 11 or 12 or 13 would suddenly start to sprout a penis. There's actually a name for this. It's called guevedoces, which the translation is more or less penis at 12. And as strange as this might sound, it makes sense if you understand the underlying mutation. What happens in these children, these guevedoces, is that the child is born, it m- has testes which are not descended, so up in the body. They're not making a lot of testosterone early on. They weren't able to convert testosterone to dihydrotestosterone because they lack this enzyme 5-alpha-reductase. As a consequence, the primary sexual characteristic of external male genitalia, penis, doesn't develop, and then what happens is the baby grows up as a young child essentially as, is treated as a girl. Uh, generally they report being pretty comfortable as, as, as girls, although not always, and then...... testosterone starts getting secreted from the testes 'cause kisspeptin in the brain signals through gonadotropin and luteinizing hormone, travels down to the testes. The testes start churning out testosterone, and there's a secondary growth of the penis, and all of a sudden there's a penis. And this leads to some very (laughs) complicated situations in families and culturally, and actually the outcomes, in terms of whether or not these children decide to self-identify as males or females and how people treat them, actually varies quite a lot. There's actually been a kind of an, um, adopting of a third category of sex and gender in these Guevedoces for, in order to just offer them, uh, the opportunity to, um, explore not just what would be a typical kind of g- girl or woman or boy or man phenotype, but something in between, something that some people call intersex. Although intersex and pseudohermaphrodism is actually a separate thing altogether. So it's fascinating, and the point here is that dihydrotestosterone, not testosterone, is responsible for this primary growth of the penis, and that testosterone later is involved in the secondary sexual characteristics, deepening of the voice, et cetera. Now, this is where the information gets even more interesting and applies to essentially everybody. You might think that testosterone, because it masculinizes the body in these, in the secondary sexual characteristic way and because dihydrotestosterone, another androgen, masculinizes the primary sexual characteristics, the growth of the penis early on, that testosterone must masculinize the brain. And there are in fact aspects of masculinization of the, of the brain and body that are independent of genitalia. That might be obvious to some of you, but some people probably don't realize that. Yes, indeed, the brain has receptors for testosterone. It also has receptors for estrogen. But the fascinating thing is that if you look at the brains of people that have Y chromosomes and that have testes and that make testosterone, and you look at the brains of people that don't have Y chromosomes or testes and therefore make far less testosterone in general, what you realize is that the cells in the brain that differ between what I'll call males and females, but between XY and XX, have receptors for testosterone, but the masculinization of the brain is not accomplished by testosterone. I want to repeat this. The masculinization of the brain is not accomplished by testosterone. It is accomplished by estrogen. Testosterone can be converted into estrogen by an enzyme called aromatase. This is vitally important to understand. Testosterone can be converted into estrogen by something called aromatase. I'll give an example of where this happens later in life to just illustrate the principle and really embed it in your mind. During puberty in boys, XY chromosome individuals, it's not uncommon for there to be transient or sometimes long-lasting breast bud development. Testosterone goes up during puberty for the reasons we d- talked about before, and some of that testosterone gets converted into estrogen by an enzyme called aromatase. Aromatase is made by several sources in the body. One of the main sources is body fat. So it can make a lot of aromatase. Sometimes you'll even see a fairly dramatic breast development in males during puberty. Sometimes it's transient, sometimes it's not. The other place where you see this is in athletes and bodybuilders that take a lot of anabolic steroids, that take high levels of androgens. So they'll be taking testosterone at super physiological doses. Sometimes, not always, they will convert some of that testosterone into estrogen, and they'll get what's called gynecomastia, which is the development of male breast tissue. Sometimes they'll get it cut out surgically. Other times they'll start trying to take estrogen blockers in order to try and suppress it or they'll try and block, block prolactin. It's a topic that we're going to get into in more detail, but what's important here is to understand that testosterone can be converted into estrogen by aromatase. Aromatase is not just made in body fat. There are neurons in the brain that make aromatase and convert testosterone into estrogen, and it is testosterone converted into estrogen. In other words, it's estrogen that masculinizes the XY individual, that masculinizes the brain. And this has profound effects on all sorts of things, on behavior, on outlook in the world, et cetera, but I think most people don't realize that it's estrogen that comes from testosterone that masculinizes the male brain, the XY brain, not testosterone nor dihydrotestosterone. So I just want to mention some tools. You might be asking (laughs) yourself, "How could tools possibly come up at this stage of the conversation where we're talking about sexual development and we're talking about the differentiation of tissues in the body?" Well, this is true both for children and parents and adults. I want to emphasize that there are things that are environmental and there are things that people use that, in their homes sometimes, that actually can impact hormone levels and can impact s- sexual development in fairly profound ways, and I want to be very clear, this is not, uh, me pulling from some rare journal, I've never heard of it. This is pulling from textbooks. In particular, today I'm guiding a lot of the conversation on, uh, work that, uh, on Behavioral Endocrinology. This is a book by, um, Randy Nelson and, and Lance Kriegfield, ex- true experts in the field. I'm going to talk about some of the work from Tyrone Hayes, uh, from UC Berkeley.... about environmental toxins and their impacts on some of these things like testosterone and estrogen. I'm going to touch into them. They're, I'm going to give some anecdotal evidence that's grounded in studies, which we will, uh, provide in the caption or that I'll reference here. One of those that's actually really, uh, interesting but helps illustrate the principle that we've been talking about is a few years ago, there was a lot of excitement about evening primrose oil. Evening primrose oil is in a lot of products that typically are associated with skin beauty and skin health, and so I'm generalizing here, but, um, typically it was mothers or sisters that were using it. And there were actually examples starting to crop up of young boys getting accelerated breast bud development from con- skin contact with women who were using evening primrose oil. So evening primrose oil is chemically a lot like estrogen, and it has a lot of estrogenic compounds. There are a number of things out there like this, so believe it or not, things like pine pollen look very much like testosterone structurally. They are, more or less are testosterone. Their bioavailability in humans isn't as clear. Evening primrose oil has a lot of estrogenic elements to it, just structurally how it's built. And so there were cases where boys were understandably, you know, being hugged by their mom or maybe even like showering and, and taking a, um, you know, using the eve- evening primrose oil solution. Those solu- things will actually change levels of estrogens in boys and girls, and so this wasn't just an issue for young boys. This was also an issue for young girls. So, um, it's not that evening primrose oil is bad, it's just that, uh, many of you have probably heard about the dangers of soys and isoflavones and things like that. The impact of soy on estrogen levels is, are, um, there are some decent evidence to support that. However, it, there's a lot of other factors that are more severe, and one of those is this evening primrose oil. So regardless of age, if, uh, let's just put it this way, because people might be wanting to drive their hormones more estrogenic or more androgenic, which, uh, how could I know which, what your preference is? I don't know. But in any case, things like pre- evening primrose oil can actually promote estrogenic pathways in the body, and some of it can go transdermal. Likewise, because testosterone replacement therapy is fairly widespread nowadays and some people accomplish that through cream, it's pretty well-understood that if someone's taking that, that they want to avoid contact with anyone, uh, skin contact with anyone that is trying to promote, uh, more estrogenic, uh, activity in their body, uh, and, and especially in children. So that's one. The other is this issue of environmental factors. Now this, you know, again, I'm just going to highlight when one starts talking about environmental factors and how they're poisoning us or disrupting growth or fertility rates, it can start to sound a little bit crazy, except when you start to actually look at some of the real data, data from quality research labs funded by federal government, funded not from companies or other sources, that are really aimed at understanding what the underlying biology is. And for that I, I really, we, we should all be grateful to Tyrone Hayes, um, at UC Berkeley. I remember way back when I was a graduate student in the l- uh, late '90s, goodness, um, at UC Berkeley, and I remember him. He was studying frogs. He was talking about developmental, um, defects in these frogs that live in different waters around, it was California but also elsewhere. Um, and he identified a substance which is present in a lot of waterways throughout this country and other countries, so US and, and, and beyond, certainly not just restricted to California, which is m- atrazine. This is A-T-R-A-Z-I-N-E. Again, this is the stuff of textbooks and it causes severe testicular malformations. So again, atrazine exposure is serious. And what's interesting is if you look at the data, what you find is that at sites in Western and Midwestern sections of the United States, 10 to 92% of male frogs, these were frogs mind you, had testicular abnormalities. And the most severe testicular malformations, uh, were in the testes rather than in the sperm. So it's actually the organ itself, the gonad itself. Now, it's very well-known now that atrazine is in many herbicides, and so, you know, whereas I would say in the '80s and '90s, the discussion around, you know, herbicides and their negative effects was considered kind of like hippie dippy stuff or the stuff you hear about at, um, you know, at the, your local community markets and the- these kind of new agey communities. Now there's y- very solid data from federally-funded labs at major universities that have been peer-reviewed and published in excellent journals showing that indeed many of these herbicides can have n- negative effects primarily by impacting the ratios of these hormones in either the mothers or in the f- the, the testes, altering the testes of the fathers or direct effects on developing young animals and potentially humans. And so you ask, "Well, what about humans? I mean, frogs are, are wonderful, but what about, you know, what about humans?" So here are the data on what's happening, um, and I, this isn't all going to be scary stuff. We're also going to talk about, uh, tools to ameliorate and offset some of these effects. One would be, be cautious with evening primrose as well as testosterone creams depending on whether or not you want to be more androgenic or estrogenic, um, depending on your needs. But across human populations, sperm counts are indeed declining, okay? So in 1940, the average, um, the average density of human sperm was 113 m- million per milliliter of semen. That's how it's measured, how many sperm per milliliter of semen. In 1990, this figure has dropped to 66, so it went from 113 (laughs) million per milliliter to 66 million per milliliter in the United States and Western Europe. This is not just a US thing. Researchers al- also estimate that the volume of semen produced by men has dropped 20% in that time, reduced sperm count per ejaculation even further. So between 1981 and 1991, the ratio of normal spermatogenesis has decreased from 56.4% to 26.9%. So...There's a lot that's happening primarily because of these herbicides that are in widespread use to reduce sperm counts, and these are going to have profound effects not just on sperm counts but on development, sexual development at the level of the gonads and the brain because you need testosterone to get vous t-, uh, dihydrotestosterone for primary sexual characteristics. You need estrogen that's come from testosterone to masculinize the brain, and of course, we're not just focusing on sperm and testosterones. You, of course, also know that many of these herbicides are disrupting estrogens in a similar way or are leading to hyper estrogenetic, uh, estrogenic, excuse me, states, which might explain why puberty is happening so much earlier in young girls these days. So there are a lot of things that are happening. Now, does this mean that you have to run around and neurotically, um, avoid anything that includes things like atrazine, and should you be avoiding all kinds of herbicides? I don't know. That's up to you, but it does seem that these have pretty marked effects in both the animal studies and in the, in the human studies. Uh, you know, you can open up a textbook like the endocrinology textbook and thi-, and find things like vinclozolin, this is V-I-N-C-L-O-Z-O-L-I-N, which is a fungicide and it's an anti-androgen. You give it to animals, to rats, and instead of forming a penis, they don't form a penis. They basically, it's not that they form a, um, a clitoris, they just don't form a penis. So let's talk about female sexual development, and as always, what we'll do is we'll talk about the normal biology, then we'll talk a little bit about a kind of s-, of extraordinary or unusual set of cases, but we'll talk about them because they illustrate an important principle about how things work under typical circumstances. So there is a mutation called androgen insensitivity syndrome, and understanding how androgen insensitivity syndrome works can help you really understand how hormones impact sexual development. So here's how it works. There are individuals who are XY, so they have a Y chromosome, that are born that make testosterone, they have testes, and they don't have Müllerian ducts because they, because on the Y chromosome is this Müllerian-inhibiting hormone. However, these individuals look completely female, and in general, they report feeling like girls when they're young, women when they're older, but there's something unusual that's happening in these individuals because they have an XY chromosomal type and not XX, so what's happening? Well, what's happening is the testes are making testosterone but the receptor for testosterone is mutated, and therefore, the testes never descend, they don't have ovaries, they have testes, but the testes are internal, and so typically, these individuals find out that they are actually XY chromosomes so that, you know, their chromosomal sex is male, if you will, and their gonadal sex is male, but the gonads, the testes, are inside the body. They don't actually develop a scrotum. They don't make ovaries. And when they don't menstruate around the time of puberty, that's a sign that something is different. And so they never menstruate around puberty, and if they look into this deeply enough, what you find is that they are actually XY, they make testosterone, but their body can't make use of the testosterone because they don't have the receptors, and the receptors are vitally important for some, for most all of the secondary sexual characteristics that we talked about, body hair, penis growth at, during puberty, et cetera. They live fairly happy lives as females, although of course they can't conceive, right? They don't have a uterus. They don't have ovaries. Um, they also in general don't produce sperm at, in quantities enough that they could actually, um, reproduce with somebody else, although sometimes they can. And believe it or not, uh, and I'm not going to name names, but there are actually reports of several, um, people, uh, fairly prominent people throughout history who have had this androgen insensitivity syndrome or people suspected they did. And the reason to not name names is that it gets right to the heart of whether or not they are male or female. Wha-, how, how could you say, right? They have XY chromosomes, but gonadally they have testes that are inside, and yet if you looked at their bodies, if you looked at their, their faces, you would say w- almost with certainty that they were, that they appeared female. And that ex-, uh, naturally-occurring experiment points to the fact that testosterone that shows up in the body and impacts the things at the levels of the receptor has a profound effect on phenotype, on the external or, um, body plan. So again, we're talking about this bec-, in order to illustrate the principle that in order to have its effects, a hormone doesn't just have to be present. That hormone actually has to be able to bind its receptor and take action on the target cells, and once again, I'll just throw out the example of where people are, are using performance-enhancing drugs, although that's a pretty broad statement. Nowadays there's a lot of excitement about the co-, so-called SARMs, which is modif-, which are more on the receptor side, and so we'll talk about this in a future episode, um, and I just say that as a teaser because the SARMs and what's happening right now in augmenting sports performance both with testosterone directly but also testosterone derivatives and then also altering things at the level of the receptor is exceedingly interesting and is, um, ill-, revealing to us the many ways in which hormones can impact brain and body in ways that we didn't suspect. Perhaps the simplest way to understand how estrogen and testosterone impact masculinization or feminization of the brain and behavior is from a, uh, statement. It's actually the closing sentence of an abstract that my colleague Niral Shah at Stanford School of Medicine, uh, published, which is that estrogen...Again, it's estrogen that is aromatized from testosterone by aromatase. Sets up the masculine repertoire of sexual and, in animals and in humans, territorial behaviors. So it sets up the circuitry in the brain. Estrogen does that. Estrogen sets up the masculine circuitry in the brain. And testosterone is then what controls the display of those behaviors later in life, and I find that incredibly interesting. You would think it was just testosterone did one thing and estrogen did another, but it turns out that nature is far more interesting than that. Okay, so what are some things that impact sexual development early in life and later in life? Let's talk about cannabis, let's talk about alcohol, and dare I say let's talk about cellphones, something that I never thought I would ever do either in this podcast or in the classroom, but these days there are really interesting data and I think you should be aware of them. First of all, cannabis, marijuana, THC. I realize that there are now a lot of different variants on this, there are a lot of different strains of cannabis. Um, I personally am not a pot smoker. I, it's just not, not for me. I am not talking about the moral or legal implications. You know, in some states it's decriminalized. In other places it's really illegal. In other places it's basically legal. You have to check, uh, you know, where you live and understand the laws. That's not what this is about. What we do know, however, is that, with the exception of one study, there are many studies that point to the fact that THC and other things in cannabis promote significant increases in aromatase activity. Now, pot smokers aren't going to like this, especially male pot smokers aren't going to like this, but it's the reality. Remember...