Essentials: How Hormones Shape Sexual Development

0:00:05 Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent
0:00:11 and actionable science-based tools for mental health, physical health, and performance.
0:00:16 I’m Andrew Huberman, and I’m a professor of neurobiology and ophthalmology at Stanford
0:00:18 School of Medicine.
0:00:21 This podcast is separate from my teaching and research roles at Stanford.
0:00:27 Today, we’re going to explore hormones, what they are, how they work, what leads to masculinization
0:00:30 or feminization of the brain and body.
0:00:37 What we’re trying to do today is really get to the biology, the physiology, the endocrinology,
0:00:39 and the behavior.
0:00:44 Hormones, by definition, are a substance, a chemical that’s released in one area of
0:00:48 the body, typically from something we call a gland, although they can also be released
0:00:55 from neurons, but they’re released often from glands that travel and have effects both
0:01:00 on that gland, but also on other organs and tissues in the body.
0:01:04 That differentiates hormones from things like neurotransmitters, which tend to act more
0:01:06 locally.
0:01:12 Examples of tissues that produce hormones would be the thyroid, the testes, the ovaries,
0:01:13 et cetera.
0:01:19 Then, of course, there are areas of the brain like the hypothalamus and the pituitary, which
0:01:23 are closely related to one another and release hormones that cause the release of yet other
0:01:25 hormones out in the body.
0:01:28 Let’s start with development.
0:01:29 Sperm meets egg.
0:01:34 Everything that happens before that is a topic of the next episode, but sperm meets egg.
0:01:37 This is mammalian reproduction, and that egg starts to duplicate.
0:01:39 It starts to make more of itself.
0:01:43 It makes more cells, and eventually some of those cells become skin, some of those cells
0:01:47 become brain, some of those cells become muscle, some of those cells become fingers, all the
0:01:52 stuff that makes up the brain and body plan.
0:01:58 In addition, there are hormones that come both from the mother and from the developing
0:02:05 baby, the developing fetus, that impact whether or not the brain will be what they call organized
0:02:07 masculine or organized feminine.
0:02:13 As I say this, I want you to try and discard with the cultural connotations or your psychological
0:02:21 connotations of what masculinization and feminization are because we’re only centering on the biology.
0:02:29 Typically, people have either two X chromosomes, and the traditional language around that is
0:02:35 that person is female, right, or an X chromosome and a Y chromosome, and that person will become
0:02:36 male.
0:02:38 Now, it’s not always the case.
0:02:43 There are cases where it’s X, XY, where there are two X chromosomes plus a Y chromosome.
0:02:48 There are also cases where it’s XYY, where there are two Y chromosomes, and these have
0:02:52 important biological and psychological impacts.
0:02:57 So, the first thing we need to establish is that there is something called chromosomal
0:02:58 sex.
0:03:02 Whether or not there are two X chromosomes or an X and Y chromosome is what we call
0:03:04 chromosomal sex.
0:03:11 But the next stage of separating out the sexes is what we call gonadal sex.
0:03:18 Typically, not always, but typically, if somebody has testes for their gonads, we think of them
0:03:20 as male.
0:03:25 And if somebody has ovaries, we think of them as female, although that’s not always the
0:03:26 case either.
0:03:31 But let’s just explore the transition from chromosomal sex to gonadal sex, because it’s
0:03:36 a fascinating one that we all went through in some form or another.
0:03:44 So, this XY that we typically think of as promoting masculinization of the fetus.
0:03:50 We say that because on the Y chromosome, there are genes, and those genes have particular
0:03:55 functions that suppress female reproductive organs.
0:04:02 So, on the Y chromosome, there’s a gene which encodes for something called Mulerian inhibiting
0:04:03 hormone.
0:04:09 So, there’s actually a hormone that’s programmed by the Y chromosome that inhibits the formation
0:04:15 of Mulerian ducts, which are an important part of the female reproductive apparatus.
0:04:20 That’s critical because already, we’re seeing the transition between chromosome, Y chromosome,
0:04:22 and gonad.
0:04:27 And other genes on the Y chromosome promote the formation of testes.
0:04:32 So, there are genes like the SRY gene and other genes that promote the formation of testes,
0:04:35 while they also inhibit the formation of the Mulerian ducts.
0:04:42 So, the transition from chromosomal sex to gonadal sex is a very important distinction.
0:04:46 It’s kind of a fork in the road that happens very early in development while fetuses are
0:04:48 still in the embryo.
0:04:54 So, we have to distinguish between chromosomal sex, gonadal sex, and then there’s what we
0:05:00 call hormonal sex, which is the effects of the steroid hormones, estrogen and testosterone
0:05:06 in their derivatives, on what we call morphological sex or the shape of the baby in the human
0:05:09 and the genitalia and the jaw and all these other things.
0:05:12 And so, it actually is quite complicated.
0:05:17 So, you know, it’s a long distance from chromosomes to gender identity, and gender identity has
0:05:19 a lot of social influences and roles.
0:05:24 This is an area that right now is very dynamic and in the discussion out there, as you know.
0:05:30 But just getting from chromosomal sex to what we would call gonadal sex and hormonal sex
0:05:32 and morphological sex involves a number of steps.
0:05:36 So, today we’re going to talk about those steps and there’s some fascinating things
0:05:44 that do indeed relate to tools, do indeed relate to some important behavioral choices.
0:05:47 Important choices about things to avoid while pregnant.
0:05:51 And for those of you that are not pregnant, things to avoid if you’re thinking about eventually
0:05:52 having children.
0:05:57 And that is not to drive development in one direction or another, but there are examples
0:06:01 where there are some deleterious things in our environment that can actually negatively
0:06:06 impact what we call sexual development overall regardless of chromosomal background.
0:06:08 So let’s get started with that.
0:06:12 I’d like to take a quick break and acknowledge one of our sponsors, Function.
0:06:16 Last year I became a Function member after searching for the most comprehensive approach
0:06:17 to lab testing.
0:06:22 Function provides over 100 advanced lab tests that give you a key snapshot of your entire
0:06:24 bodily health.
0:06:27 This snapshot offers you with insights on your heart health, hormone health, immune
0:06:30 functioning, nutrient levels, and much more.
0:06:35 They’ve also recently added tests for toxins such as BPA exposure from harmful plastics
0:06:38 and tests for PFASs or forever chemicals.
0:06:42 Function not only provides testing of over 100 biomarkers key to your physical and mental
0:06:47 health, but it also analyzes these results and provides insights from top doctors who
0:06:49 are expert in the relevant areas.
0:06:53 For example, in one of my first tests with Function, I learned that I had elevated levels
0:06:55 of mercury in my blood.
0:06:58 Function not only helped me detect that, but offered insights into how best to reduce my
0:07:02 mercury levels, which included limiting my tuna consumption – I’ve been eating a lot
0:07:06 of tuna – while also making an effort to eat more leafy greens and supplementing with
0:07:11 NAC and acetylcysteine, both of which can support glutathione production and detoxification.
0:07:15 And I should say, by taking a second Function test, that approach worked.
0:07:17 Comprehensive blood testing is vitally important.
0:07:22 There’s so many things related to your mental and physical health that can only be detected
0:07:23 in a blood test.
0:07:26 The problem is, blood testing has always been very expensive and complicated.
0:07:31 In contrast, I’ve been super impressed by Function’s simplicity and at the level of
0:07:32 cost.
0:07:33 It is very affordable.
0:07:36 As a consequence, I decided to join their scientific advisory board, and I’m thrilled
0:07:38 that they’re sponsoring the podcast.
0:07:43 If you’d like to try Function, you can go to functionhealth.com/huberman.
0:07:47 Function currently has a waitlist of over 250,000 people, but they’re offering early
0:07:50 access to Huberman podcast listeners.
0:07:55 Again, that’s functionhealth.com/huberman to get early access to Function.
0:07:59 Let’s talk a little bit more about what hormones do.
0:08:01 Hormones generally have two categories of effects.
0:08:04 They can either be very fast or they can be very slow.
0:08:08 There are hormones like cortisol and adrenaline, which act very fast.
0:08:12 And then there are hormones like what we like testosterone and estrogen, which we refer
0:08:15 to as the sex steroid hormones.
0:08:19 These molecules, for those of you that are interested, are what it’s called lipophilic,
0:08:21 which just means that they like fatty stuff.
0:08:23 They can actually pass through fatty membranes.
0:08:27 And because the outside of cells, as well as what’s called the nuclear envelope, where
0:08:34 all the DNA contents and stuff are stuffed inside, are made of lipid, of fat, these steroid
0:08:39 hormones can actually travel into cells and then interact with the DNA of cells in order
0:08:40 to control gene expression.
0:08:45 So they can change the sorts of things that cells will become, and they can change the
0:08:47 way that cells function in a long-term way.
0:08:53 And that’s actually how the presence of these genes like SRY and Mulerian inhibiting hormone
0:08:59 lead to reductions or elimination, I should say, of things like the Mulerian ducts and
0:09:05 promote instead what’s called in males, the Wolfian ducts, or promote the development
0:09:06 of testes rather than ovaries.
0:09:10 So all you need to know is that hormones have short-term and long-term effects, and the
0:09:15 long-term effects are actually related to their effects on genes and how those genes
0:09:22 are expressed or repressed, to prevent them from having particular proteins made.
0:09:27 So these hormones, these steroid hormones, are exceedingly powerful.
0:09:32 And if we’re going to have a discussion about masculinization or feminization, et cetera,
0:09:33 you also need to think about the counterpart.
0:09:37 It’s not just about masculinizing the body or feminizing the body and brain.
0:09:45 It’s also about demasculinizing the brain in many cases as a normal biological function,
0:09:50 typically of XX females, and de-feminization, the suppression of certain pathways that are
0:09:53 related to feminization of the body and brain.
0:09:56 So I’ve just thrown a lot of biology at you.
0:10:01 But this is where it all starts to get incredibly surprising.
0:10:05 You would think that it’s straightforward, right?
0:10:07 You have a Y chromosome.
0:10:13 You suppress the female reproductive pathway like the malaria index.
0:10:18 You promote the development of testes, and then testes make testosterone.
0:10:22 And then it organizes the brain male, and it wants to do male-like things.
0:10:27 And then in females, you get estrogen, and it wants to do female-like things, and air
0:10:29 quotes here for all of this.
0:10:33 And it turns out that isn’t how it works at all.
0:10:34 Here’s where it’s interesting.
0:10:40 You have to understand that there are effects of these hormones, testosterone and estrogen,
0:10:46 on what are called primary sexual characteristics, which are the ones that you’re born with,
0:10:50 secondary sexual characteristics, which are the ones that show up in puberty, and these
0:10:54 are happening in the brain, and body, and spinal cord.
0:10:57 And so I’m going to disentangle all this for you by giving you some examples.
0:11:01 First let’s talk about the development of primary sexual characteristics, the ones that
0:11:04 show up at birth.
0:11:12 And one of the more dramatic examples of this comes from the role of testosterone in creating
0:11:14 the external genitalia.
0:11:20 It turns out that it’s not testosterone that’s responsible for the development of the penis
0:11:25 in a baby that has an X chromosome and a Y chromosome.
0:11:28 It’s a different androgen.
0:11:33 Testosterone is just a category of hormones that includes testosterone, but testosterone
0:11:40 is converted in the fetus to something called dihydrotestosterone.
0:11:44 And that’s accomplished through an enzyme called 5-alpha reductase.
0:11:48 Dihydrotestosterone is what we would call the dominant androgen in males.
0:11:50 It’s responsible for aggression.
0:11:54 It’s responsible for a lot of muscular strength.
0:11:57 It’s involved in beard growth and male pattern baldness.
0:11:59 You’re going to talk about all of that.
0:12:05 But dihydrotestosterone has powerful effects in determining the genitalia while the baby
0:12:06 is still in the embryo.
0:12:13 So there’s testosterone that’s made and that testosterone gets converted by this enzyme
0:12:18 5-alpha reductase in a little structure called the tubercle.
0:12:21 That tubercle will eventually become the penis.
0:12:23 So you say, “Okay, straightforward.
0:12:28 This testosterone is converted to dihydrotestosterone and then if there’s dihydrotestosterone,
0:12:30 it controls penis growth.”
0:12:31 And indeed, that’s the case.
0:12:34 So that’s a primary sexual characteristic.
0:12:41 That baby will then grow up and later during puberty, there will be the release of a molecule.
0:12:47 I talked about this last episode called Kispeptin, K-I-S-S-P-E-P-T-I-N, Kispeptin, which will
0:12:49 cause the release of some other hormones.
0:12:53 Releasing hormone, luteinizing hormone will stimulate the testes to make testosterone.
0:12:58 So in puberty, testosterone leads to further growth and development of the penis as well
0:13:05 as the accumulation of or growth of pubic hair, deepening in the voice, all the secondary
0:13:07 sexual characteristics.
0:13:11 There’s a very interesting phenomenon that was published in the journal Science in the
0:13:16 1970s, for which now there’s a wealth of scientific data.
0:13:22 And this relates to a genetic mutation where 5-alpha reductase, the enzyme that converts
0:13:26 testosterone to dihydrotestosterone, doesn’t exist.
0:13:31 It’s mutated and this actually was first identified in the Dominican Republic.
0:13:37 What happens is, baby is born, if you were to look at that baby, it would look female.
0:13:42 There would be very little or no external penis.
0:13:49 And what was observed is that from time to time, that baby, after being raised as a girl,
0:13:56 would around the age of 11 or 12 or 13, would start to sprout a penis.
0:13:57 There’s actually a name for this.
0:14:03 It’s called Juevedosis, which the translation is more or less penis at 12.
0:14:09 And as strange as this might sound, it makes sense if you understand the underlying mutation.
0:14:17 What happens in these children, these Juevedosis, is that the child is born, it has testes which
0:14:24 are not descended, so up in the body, they weren’t able to convert testosterone to dihydrotestosterone
0:14:27 because they lack this enzyme, 5-alpha reductase.
0:14:36 As a consequence, the primary sexual characteristic of external male genitalia, penis, doesn’t develop.
0:14:42 And then what happens is, the baby grows up, and then testosterone starts getting secreted
0:14:46 from the testes because chispeptin in the brain signals through gonadotropin and luteinizing
0:14:48 hormone, travels down to the testes.
0:14:53 The testes start churning out testosterone, and there’s a secondary growth of the penis,
0:14:54 and all of a sudden, there’s a penis.
0:15:02 And the point here is that dihydrotestosterone, not testosterone, is responsible for this primary
0:15:08 growth of the penis, and that testosterone later is involved in the secondary sexual
0:15:11 characteristics, deepening in the voice, et cetera.
0:15:16 Now this is where the information gets even more interesting, and applies to essentially
0:15:18 everybody.
0:15:25 You might think that testosterone, because it masculinizes the body in the secondary
0:15:34 sexual characteristic way, and because dihydrotestosterone, another androgen, masculinizes the primary
0:15:39 sexual characteristics, the growth of the penis early on, that testosterone must masculinize
0:15:41 the brain.
0:15:46 But the masculinization of the brain is not accomplished by testosterone.
0:15:51 It is accomplished by estrogen.
0:15:56 Testosterone can be converted into estrogen by an enzyme called aromatase.
0:16:01 There are neurons in the brain that make aromatase and convert testosterone into estrogen.
0:16:09 In other words, it’s estrogen that masculinizes the XY individual that masculinizes the brain.
0:16:15 And this has profound effects on all sorts of things, on behavior, on outlook in the
0:16:17 world, et cetera.
0:16:21 But I think most people don’t realize that it’s estrogen that comes from testosterone
0:16:28 that masculinizes the male brain, the XY brain, not testosterone, nor dihydrotestosterone.
0:16:32 I’d like to take a quick break and then acknowledge one of our sponsors, Our Place.
0:16:36 Our Place makes my favorite pots, pans, and other cookware.
0:16:41 Surprisingly, toxic compounds such as PFASs or forever chemicals are still found in 80%
0:16:46 of nonstick pans, as well as utensils, appliances, and countless other kitchen products.
0:16:51 I’ve discussed on this podcast before that the PFASs or forever chemicals like Teflon
0:16:55 have been linked to major health issues such as endocrine disruption, that means hormone
0:17:00 disruption, gut microbiome disruption, fertility issues, and many other health problems.
0:17:01 So it’s really important to avoid them.
0:17:05 This is why I recently fell in love with Our Place products, especially one of their
0:17:08 cooking pans, the Titanium Always Pan Pro.
0:17:13 Our Place products are made with the highest quality materials and are all PFAS and toxin-free.
0:17:18 They’re beautifully designed and function extremely well for all your cooking needs.
0:17:22 Most mornings I cook eggs in it, I cook ground beef in it, ground venison, and the Titanium
0:17:26 Pan is also designed in a way that allows eggs and meat to cook perfectly without sticking
0:17:27 to the pan.
0:17:32 It’s extremely easy to clean and like all Our Place products, it’s nice to look at
0:17:34 when sitting on the counter or on the stove.
0:17:39 For a limited time, Our Place is offering an exclusive 20% discount on their innovative
0:17:44 Titanium Always Pan Pro, designed to last a lifetime and completely toxin-free.
0:17:50 Visit FromOurPlace.com/Huberman and use the code SAVEHuberman20 to claim the offer.
0:17:54 With a 100-day risk-free trial, free shipping, and free returns, you can experience this
0:17:57 terrific cookware with zero risk.
0:18:00 Today’s episode is also brought to us by BetterHelp.
0:18:04 BetterHelp offers professional therapy with a licensed therapist carried out entirely
0:18:05 online.
0:18:08 I’ve been doing weekly therapy for well over 30 years.
0:18:13 Initially I didn’t have a choice, it was a condition of being allowed to stay in school,
0:18:16 but pretty soon I realized that therapy is an extremely important component to overall
0:18:17 health.
0:18:21 In fact, I consider doing regular therapy just as important as getting regular exercise,
0:18:26 including cardiovascular exercise and resistance training, which of course I also do every week.
0:18:30 There are essentially three things that great therapy provides.
0:18:33 First of all, it provides a good rapport with somebody that you can trust and talk to about
0:18:35 all issues that you’re concerned about.
0:18:41 Second of all, it can provide support in the form of emotional support or directed guidance.
0:18:44 And third, expert therapy can provide useful insights.
0:18:48 With BetterHelp, they make it very easy to find an expert therapist with whom you resonate
0:18:51 with and can provide those benefits that come through effective therapy.
0:18:57 Also, because BetterHelp allows therapy to be done entirely online, it’s very time-efficient.
0:19:00 It’s easy to fit into a busy schedule, there’s no commuting to a therapist’s office or
0:19:02 sitting in a waiting room or anything like that.
0:19:05 You simply go online and hold your appointment.
0:19:10 If you would like to try BetterHelp, go to betterhelp.com/huberman to get 10% off your
0:19:11 first month.
0:19:15 Again, that’s betterhelp.com/huberman.
0:19:17 So I just want to mention some tools.
0:19:21 You might be asking yourself, how could tools possibly come up at this stage of the conversation
0:19:26 where we’re talking about sexual development and we’re talking about the differentiation
0:19:27 of tissues in the body?
0:19:31 Well, this is true both for children and parents and adults.
0:19:38 I want to emphasize that there are things that are environmental and there are things
0:19:45 that people use that actually can impact hormone levels and can impact sexual development
0:19:46 in fairly profound ways.
0:19:52 And I want to be very clear, this is not me pulling from some rare journal I’ve never
0:19:53 heard of it.
0:19:57 This is pulling from textbooks in particular, today I’m guiding a lot of the conversation
0:20:06 on work that on behavioral endocrinology was a book by Randy Nelson and Lance Crickfield,
0:20:07 true experts in the field.
0:20:13 I’m going to talk about some of the work from Tyrone Hayes from UC Berkeley about environmental
0:20:17 toxins and their impacts on some of these things like testosterone and estrogen.
0:20:18 I’m going to touch into them.
0:20:22 I’m going to give some anecdotal evidence that’s grounded in studies, which we will
0:20:25 provide in the caption or that I’ll reference here.
0:20:29 You know, again, I’m just going to highlight when one starts talking about environmental
0:20:34 factors and how they’re poisoning us or disrupting growth or fertility rates, it can start to
0:20:39 sound a little bit crazy except when you start to actually look at some of the real data.
0:20:45 Data from quality research labs funded by federal government, funded not from companies
0:20:49 or other sources that are really aimed at understanding what the underlying biology is.
0:20:55 And for that, I really, we should all be grateful to Tyrone Hayes at UC Berkeley.
0:21:02 I remember way back when I was a graduate student in the late 90s, goodness, at UC Berkeley,
0:21:07 and I remember him, he was studying frogs, he was talking about developmental defects
0:21:13 in these frogs that live in different waters around, it was California, but also elsewhere.
0:21:18 And he identified a substance which is present in a lot of waterways throughout this country
0:21:23 and other countries, so US and beyond, certainly not just restricted to California, which is
0:21:29 atrazine, this is A-T-R-A-Z-I-N-E, again, this is the stuff of textbooks.
0:21:32 And it causes severe testicular malformations.
0:21:36 So again, atrazine exposure is serious.
0:21:42 And what’s interesting is if you look at the data, what you find is that at sites in western
0:21:48 and midwestern sections of the United States, 10 to 92% of male frogs, these were frogs,
0:21:51 mind you, had testicular abnormalities.
0:21:57 And the most severe testicular malformations were in the testes rather than in the sperm.
0:22:00 So it’s actually the organ itself, the gonad itself.
0:22:07 Now, it’s very well known now that atrazine is in many herbicides.
0:22:12 And so whereas, I would say, in the ’80s and ’90s, the discussion around herbicides and
0:22:16 their negative effects was considered kind of like hippie-dippy stuff or the stuff you
0:22:22 hear about it, your local community markets and these kind of new-agey communities.
0:22:28 Now, there’s very solid data from federally funded labs at major universities that have
0:22:33 been peer reviewed and published in excellent journals showing that, indeed, many of these
0:22:40 herbicides can have negative effects primarily by impacting the ratios of these hormones
0:22:49 in either the mothers or in the testes, altering the testes of the fathers or direct effects
0:22:52 on developing young animals and potentially humans.
0:22:54 And so you ask, well, what about humans?
0:22:57 Frogs are wonderful, but what about humans?
0:23:03 So here are the data on what’s happening, and this isn’t all going to be scary stuff.
0:23:08 We’re also going to talk about tools to ameliorate and offset some of these effects, depending
0:23:09 on your needs.
0:23:14 But across human populations, sperm counts are indeed declining, okay?
0:23:22 So in 1940, the average, the average density of human sperm was 113 million per milliliter
0:23:23 of semen.
0:23:24 That’s how it’s measured.
0:23:26 How many sperm per milliliter of semen?
0:23:33 In 1990, this figure has dropped to 66, so went from 113 million per milliliter to 66
0:23:36 million per milliliter in the United States and Western Europe.
0:23:38 So it’s not just a U.S. thing.
0:23:43 Researchers also estimated that the volume of semen produced by men has dropped 20% in
0:23:47 that time, reduced sperm count per ejaculation even further.
0:23:55 So between 1981 and 1991, the ratio of normal spermatogenesis has decreased from 56.4% to
0:23:58 66.9%.
0:24:04 So there’s a lot that’s happening primarily because of these herbicides that are in widespread
0:24:06 use to reduce sperm counts.
0:24:12 And these are going to have profound effects, not just on sperm counts, but on sexual development
0:24:18 at the level of the gonads and the brain, because you need testosterone to get dihydrotestosterone
0:24:20 for primary sexual characteristics.
0:24:25 You need estrogen that’s come from testosterone to masculinize the brain, and of course, we’re
0:24:28 not just focusing on sperm and testosterone.
0:24:35 You of course also know that many of these herbicides are disrupting estrogens in a similar
0:24:42 way, which might explain why puberty is happening so much earlier in young girls these days.
0:24:44 So there are a lot of things that are happening.
0:24:50 Now does this mean that you have to run around and neurotically avoid anything that includes
0:24:55 things like atrazine and should you be avoiding all kinds of herbicides?
0:25:00 I don’t know that’s up to you, but it does seem that these have pretty market effects
0:25:03 in both the animal studies and in the in the human studies.
0:25:07 So let’s talk about female sexual development.
0:25:11 And as always, what we’ll do is we’ll talk about the normal biology, then we’ll talk
0:25:16 a little bit about a kind of extraordinary or unusual set of cases.
0:25:23 But we’ll talk about them because they illustrate an important principle about how things work
0:25:25 under typical circumstances.
0:25:33 So there is a mutation called androgen insensitivity syndrome.
0:25:38 And understanding how androgen insensitivity syndrome works can help you really understand
0:25:41 how hormones impact sexual development.
0:25:43 So here’s how it works.
0:25:49 There are individuals who are XY, so they have a Y chromosome, that are born that make
0:25:52 testosterone.
0:25:58 They have testes and they don’t have malaria index because they because on the Y chromosome
0:26:00 is this malaria inhibiting hormone.
0:26:04 However, these individuals look completely female.
0:26:11 And in general, they report feeling like girls when they’re young, women when they’re older.
0:26:17 But there’s something unusual that’s happening in these individuals because they have an XY
0:26:20 chromosomal type and not XX.
0:26:21 So what’s happening?
0:26:28 Well, what’s happening is the testes are making testosterone, but the receptor for testosterone
0:26:29 is mutated.
0:26:32 And therefore, the testes never descend.
0:26:37 They don’t have ovaries, they have testes, but the testes are internal.
0:26:42 And so typically these individuals find out that they are actually XY chromosomes so that,
0:26:46 you know, their chromosomal sex is male, if you will.
0:26:49 And their gonadal sex is male.
0:26:54 But the gonads, the testes are inside the body, they don’t actually develop a scrotum,
0:26:55 they don’t make ovaries.
0:27:00 And when they don’t menstruate around the time of puberty, that’s a sign that something
0:27:01 is different.
0:27:02 And so they never menstruate around puberty.
0:27:08 And if they look into this deeply enough, what you find is that they are actually XY.
0:27:11 They make testosterone, but their body can’t make use of the testosterone because they
0:27:13 don’t have the receptors.
0:27:20 And the receptors are vitally important for most all of the secondary sexual characteristics
0:27:24 that we talked about, body hair, penis growth during puberty, etc.
0:27:28 So again, we’re talking about this in order to illustrate the principle that in order to
0:27:34 have its effects, a hormone doesn’t just have to be present, that hormone actually has to
0:27:38 be able to bind its receptor and take action on the target cells.
0:27:45 That’s the simplest way to understand how estrogen and testosterone impact, masculinization
0:27:50 or feminization of the brain and behavior is from a statement, it’s actually the closing
0:27:55 sentence of an abstract that my colleague, Narao Shah at Stanford School of Medicine
0:28:03 published, which is that estrogen, again, it’s estrogen that is aromatized from testosterone
0:28:11 by aromatase sets up the masculine repertoire of sexual and in animals and in humans territorial
0:28:12 behaviors.
0:28:16 So it sets up the circuitry in the brain, estrogen does that.
0:28:23 Estrogen sets up the masculine circuitry in the brain and testosterone is then what controls
0:28:27 the display of those behaviors later in life.
0:28:29 And I find that incredibly interesting.
0:28:33 You would think it was just testosterone did one thing and estrogen did another, but it
0:28:36 turns out that nature is far more interesting than that.
0:28:40 I’d like to take a quick break and acknowledge our sponsor, AG1.
0:28:46 AG1 is a vitamin mineral probiotic drink that also includes prebiotics and adaptogens.
0:28:50 As somebody who’s been involved in research science for almost three decades and in health
0:28:54 and fitness for equally as long, I’m constantly looking for the best tools to improve my mental
0:28:56 health, physical health and performance.
0:29:02 I discovered AG1 way back in 2012, long before I ever had a podcast or even knew what a podcast
0:29:03 was.
0:29:07 And I’ve been taking it every day since I find that AG1 greatly improves all aspects
0:29:08 of my health.
0:29:11 I simply feel much better when I take it.
0:29:15 AG1 uses the highest quality ingredients in the right combinations and they’re constantly
0:29:18 improving their formulas without increasing the cost.
0:29:22 Whenever I’m asked if I could take just one supplement, what would that supplement be?
0:29:23 I always say AG1.
0:29:30 If you’d like to try AG1, you can go to drinkag1.com/huberman to claim a special offer.
0:29:34 Right now, they’re giving away five free travel packs plus a year supply of vitamin
0:29:35 D3K2.
0:29:40 Again, that’s drinkag1.com/huberman to claim that special offer.
0:29:41 Okay.
0:29:48 So what are some things that impact sexual development early in life and later in life?
0:29:51 Let’s talk about cannabis.
0:29:53 Let’s talk about alcohol.
0:29:57 First of all, cannabis, marijuana, THC.
0:30:06 There are many studies that point to the fact that THC and other things in cannabis promote
0:30:11 significant increases in aromatase activity.
0:30:15 Pot smokers aren’t going to like this, especially male pot smokers aren’t going to like this,
0:30:16 but it’s the reality.
0:30:17 Here’s the deal.
0:30:23 That cannabis and it’s not clear if it’s THC itself or other elements in the marijuana
0:30:27 plant promote aromatase activity.
0:30:34 Now this has been observed anecdotally where pot smokers have a higher incidence of developing
0:30:39 something I mentioned before, gynecomastia, breast bud development or full blown breast
0:30:40 development in males.
0:30:45 Now earlier I said that estrogen is what masculinizes the male brain in utero.
0:30:49 That’s true, but the way that cannabis seems to work, at least from the studies I was able
0:30:57 to identify, is that it promotes circulating estrogen in the body and therefore can counteract
0:31:03 some of the masculinizing effects of things like testosterone and dihydrotestosterone on
0:31:06 primary and secondary sexual characteristics.
0:31:12 So I mentioned this because I think nowadays marijuana use is far more widespread and
0:31:18 certainly during puberty, it can have profound effects on these hormonal systems.
0:31:22 And so we’ll do another episode that goes really deep into this, but yes, cannabis promotes
0:31:26 estrogenic activity by increasing aromatase.
0:31:31 Most everyone can appreciate that drinking during pregnancy is not good for the developing
0:31:32 fetus.
0:31:38 Fetal alcohol syndrome is a well-established negative outcome of pregnancy and it’s something
0:31:42 that there are cognitive effects that are really bad.
0:31:45 There’s actually physical malformation, et cetera.
0:31:48 So drinking during pregnancy, not good.
0:31:53 Probably drinking during puberty, not good either because alcohol, in particular, certain
0:32:00 things like beer, but other grain alcohols can increase estrogenic activity.
0:32:08 Now this isn’t just about protecting young boys from estrogenic activity.
0:32:17 It’s also protecting girls from excessive or even hypoestrogenic effects of alcohol
0:32:18 in puberty.
0:32:23 Now many teenagers drink, college students drink, and it’s important to point out that
0:32:27 puberty doesn’t start on one day and end on another day.
0:32:32 Puberty has a beginning, a middle and an end, but development is really our entire lifespan.
0:32:34 Okay, so we talked about cannabis.
0:32:36 We talked about alcohol.
0:32:38 Let’s talk about cell phones.
0:32:40 First of all, I use a cell phone.
0:32:45 I use it very often and I do not think they are evil devices.
0:32:51 I think that they require some discipline in order to make sure that it does not become
0:32:53 a negative force in one’s life.
0:32:56 So I personally restrict the number of hours that I’m on the phone and in particular on
0:33:01 social media, but what about the cell phone itself?
0:33:08 When I was a junior professor, I was a pre-tenure, early professor, I taught this class on neural
0:33:14 circuits and health and disease and one of the students asked me, “Are cell phones safe
0:33:16 for the brain?”
0:33:21 All the data point to the fact that they were, or at least there were no data showing that
0:33:22 it wasn’t.
0:33:24 I still don’t have the answer on that, frankly.
0:33:29 I’m not personally aware of any evidence in quality peer-reviewed studies showing that
0:33:33 cell phones are bad for the brain or that holding the phone to the ear is bad or that
0:33:34 Bluetooth is bad or any of that.
0:33:37 I’m just not aware of any quality studies.
0:33:47 However, I was very interested in a particular study that was published back in 2013 on rats.
0:33:52 It was basically took a cell phone and put it under a cage of rats and looked at basically
0:33:59 testicular novarian development in rats and saw minor but still statistically significant
0:34:03 defects in ovarian and testicular development.
0:34:12 Since then, and now returning to the literature, I’ve seen an absolute explosion of studies,
0:34:16 some of which are in quality journals, some of which are in what I would call not a blue
0:34:25 ribbon journals, identifying defects in testicular and/or ovarian development by mere exposure
0:34:29 to cell phone emitted waves.
0:34:30 Let’s just call that.
0:34:33 We don’t know what they are and this sounds almost crazy, right?
0:34:36 Anytime somebody starts talking about EMFs and things like that, you kind of worry like,
0:34:38 is this person okay?
0:34:45 But look, the literature pointing in a direction where chronic exposure of the of the gonads
0:34:51 to cell phones could be creating serious issues in terms of the health at the cellular level
0:34:53 and in terms of the output.
0:34:58 So the output for the testes would be sperm production, swimming speed and sperm is an
0:35:00 important feature of sperm health.
0:35:07 In the ovaries, it would be estrogenic output, how regular the cycles are.
0:35:13 I think that it’s fair to say, based on the literature, that there are effects of cell
0:35:16 phone emitted waves on gonadal development.
0:35:20 The question is, what is the proximity of the cell phone to the gonads?
0:35:23 So you have to take these sorts of studies with a grain of salt.
0:35:27 There’s some interesting effects of hormones that actually you can observe on the outside
0:35:34 of people that tell you something about not just their level of hormones, but also about
0:35:35 their underlying genetics.
0:35:39 And these relate to beard growth and baldness and it’s fascinating.
0:35:47 The molecule, the hormone, dihydrotestosterone made from testosterone, is the hormone primarily
0:35:51 responsible for facial hair, for beard growth.
0:35:58 As well, it’s the molecule, the hormone primarily responsible for lack of hair on the head,
0:36:00 for hair loss.
0:36:08 Not incidentally, the drugs that are designed to prevent hair loss are five alpha reductase
0:36:10 inhibitors.
0:36:13 So remember five alpha reductase from the hovedosis?
0:36:18 Well, the people that discovered the hovedosis went on to do a lot of research on the underlying
0:36:23 biochemistry of this really interesting molecule, dihydrotestosterone, the identified five alpha
0:36:31 reductase and five alpha reductase inhibitors are the basis of most of the anti hair loss
0:36:33 treatments that are out there.
0:36:35 And so there’s some interesting things here.
0:36:42 First of all, the side effect profiles of those treatments for hair loss are quite severe
0:36:43 in many individuals.
0:36:50 Remember DHT is the primary androgen for libido, for strength and connective tissue repair,
0:36:56 for aggression, even if that aggression, of course, is held in check, but just sort of
0:36:58 ambition and aggression is related to dopamine.
0:37:04 But within the testosterone pathway, less so pure testosterone, although pure testosterone
0:37:10 has its effects, but DHT is at least in primate species, including humans, is the dominant
0:37:13 androgen for most of those sorts of effects.
0:37:19 And if you look at somebody, everyone can predict whether or not they’re going to go
0:37:23 bald based on looking at their, we’re always taught our mother’s father.
0:37:27 So if your mother’s father was bald, there’s a higher probability that you’re going to
0:37:29 go bald.
0:37:33 The pattern of DHT receptors on the scalp will dictate whether or not you’re going to go
0:37:38 bald everywhere or just in the front or so crown type baldness.
0:37:42 And the density of the beard tells you about the density of DHT receptors.
0:37:46 Now this varies by background, by genetic background.
0:37:52 There are areas of the world where all the men seem to have the same pattern of baldness
0:37:56 like a strip of baldness down the center with hair still on the sides and in full beards.
0:38:01 That’s because these patterns of DHT receptors are genetically determined.
0:38:07 Elsewhere, testosterone levels can still be very high, DHT levels in the blood can be
0:38:11 very high and yet people will have very light beards or no beards and that’s because they
0:38:14 don’t have a lot of DHT receptors in the face.
0:38:20 There are a lot of effects of DHT that you can just see in male phenotypes.
0:38:26 And it’s interesting that these hair loss drugs that are or to prevent hair loss drugs
0:38:33 are directly aimed at preventing the conversion of testosterone into dihydrotestosterone.
0:38:39 And that’s why they to some extent prevent hair loss but also to some extent have a bunch
0:38:41 of side effects that are associated with low DHT.
0:38:49 I want to tell you a story about hyenas and clitoris is the size of penises.
0:38:57 So when I was a graduate student at UC Berkeley, we had a professor in our department, phenomenal
0:39:00 scientist named Steve Glickman.
0:39:08 Steve Glickman had a colony of hyenas, spotted hyenas that lived with in caged enclosures
0:39:12 of course in Tilden Park behind the UC Berkeley campus.
0:39:14 The hyenas are no longer there.
0:39:22 Hyenas exhibit an incredible feature to their body, their hormones and their social structure.
0:39:29 Hyenas, unlike many species, have a situation with their genitalia where the male penis is
0:39:34 actually smaller than the female clitoris.
0:39:40 And I should say that the male penis itself, having seen a fair number of hyena penises,
0:39:47 is not particularly small, which means that the hyena clitorises are extremely large.
0:39:49 This was well known for some time.
0:39:56 It turns out that in the spotted hyenas, the females are dominant.
0:40:02 So after a kill, the females will eat, then their young will eat, and then the male hyenas
0:40:04 will eat.
0:40:12 As well, when the female hyena gives birth, she gives birth not through the vaginal canal
0:40:22 that we’re accustomed to seeing, but through a very enlarged clitoris like phallus, although
0:40:27 it’s not a phallus, it’s a clitoris, and it literally splits open.
0:40:32 So the many fetuses died during the course of hyena development and birth.
0:40:39 The baby hyena actually comes through the tissue and it’s a very traumatic birth.
0:40:45 It was a mystery as to how the female hyenas have this, we’ll call it masculinization,
0:40:52 but it’s really a androgenization of the periphery of the genitalia.
0:40:56 And it turns out, through a lot of careful research done by Steve Glickman, Christine
0:41:07 Dre, and others, that it’s interesting dione, what is essentially a prohormone to testosterone.
0:41:14 It’s interesting dione at very high levels that’s produced in female hyenas that creates
0:41:16 this enlargement of their genitalia.
0:41:21 So if you want to read up on enderstein dione, enderstein dione is made into testosterone
0:41:29 through this enzyme 17 beta hydro hydroxy steroid dehydrogenase.
0:41:35 It’s a complicated pathway to pronounce, it’s a fairly straightforward pathway biochemically.
0:41:42 You may recall during the 90s and 2000s, there were a lot of performance enhancing drug scandals
0:41:48 in particular in Major League Baseball, and it was purported, although I don’t know that
0:41:53 it was ever verified, but it was purported that the major performance enhancing drug
0:41:58 of abuse at that time, in particular players whose names we won’t mention, but you can
0:42:01 Google it if you want to find out, was enderstein dione.
0:42:06 And the last little anecdote about this, which is also published in the scientific literature,
0:42:10 which is weird, but I do find interesting, hormones are so fascinating, they’re just
0:42:17 incredible to me, is going back to the marijuana plant, you know, the marijuana plant has these
0:42:20 estrogenic properties.
0:42:26 And I asked a plant biologist whether or not this was unusual, but this plant biologist
0:42:33 told me, oh yeah, there are plants that make what is essentially the equivalent of testosterone,
0:42:38 like pine pollen, it looks a lot like testosterone, and there are other plants that make what is
0:42:41 essentially estrogen, and I said, well, why would they do that?
0:42:49 He said that one of the reasons why some plants have evolved this capacity to increase estrogen
0:42:55 levels in animals that smoke, not smoke it, but then animals that consume them, I’m guessing
0:42:58 that animals aren’t smoking marijuana, although, I don’t know, send me the paper if you’ve
0:43:05 heard of this, is that plants have figured out ways, they’ve adapted ways to push back
0:43:09 on populations of rodents and other species of animals that eat them.
0:43:15 So plants are engaged in a kind of plant to animal warfare, where they increase the estrogen
0:43:20 of the males in that population to lower the sperm counts to keep those populations clamped
0:43:24 at certain levels, so that those plants can continue to flourish.
0:43:32 And I find this just fascinating, and hormones, therefore, aren’t just impacting tissue growth
0:43:36 and development within the individual, and between the mother, remember the placentas
0:43:41 and endocrine organ and the offspring, but plants and animals are in this communication.
0:43:46 So it’s a fascinating area of biology, and as you’ve noticed today, none of this deals
0:43:51 with the current controversies around gender and how many genders and sex, etc.
0:43:56 That’s a separate conversation that is, by definition, grounded in the kind of concepts
0:44:01 we’ve been talking about today, and needs to take place taking into consideration all
0:44:07 of the aspects of sex and the effects of hormones both on the body, on the brain.
0:44:11 We didn’t talk a lot about spinal cord, but we will in the next episode, but we can just
0:44:16 say on the brain and the periphery, early effects, late effects, acute effects, meaning
0:44:21 effects that are very fast of levels of hormones going up or down, something that absolutely
0:44:27 happens during and across the menstrual cycle, as well as long-term effects like the effects
0:44:30 of these hormones on gene expression.
0:44:38 So today, as always, we weren’t able to cover all things related to sex and hormones and
0:44:41 sexual differentiation or development.
0:44:45 There’s no way we could, but we have covered a lot of material.
0:44:49 So once again, I want to thank you for embarking on this journey through neuroscience, and
0:44:54 today, neuroendocrinology with me, and as always, thank you for your interest in science.
0:44:57 (upbeat music)
0:44:59 (guitar music)