How Hormones Shape Sexual Development | Huberman Lab Essentials

00:00:00.000 | - Welcome to Huberman Lab Essentials,

00:00:02.320 | where we revisit past episodes

00:00:04.380 | for the most potent and actionable science-based tools

00:00:07.560 | for mental health, physical health, and performance.

00:00:10.340 | I'm Andrew Huberman,

00:00:13.000 | and I'm a professor of neurobiology and ophthalmology

00:00:16.080 | at Stanford School of Medicine.

00:00:18.180 | This podcast is separate

00:00:19.460 | from my teaching and research roles at Stanford.

00:00:21.960 | Today, we're going to explore hormones, what they are,

00:00:24.760 | how they work, what leads to masculinization

00:00:27.720 | or feminization of the brain and body.

00:00:30.700 | What we're trying to do today is really get to the biology,

00:00:34.860 | the physiology, the endocrinology, and the behavior.

00:00:38.800 | Hormones, by definition, are a substance,

00:00:41.800 | a chemical that's released in one area of the body,

00:00:44.600 | typically from something we call a gland,

00:00:46.800 | although they can also be released from neurons,

00:00:50.240 | but they're released often from glands

00:00:52.640 | that travel and have effects both on that gland,

00:00:56.960 | but also on other organs and tissues in the body.

00:01:00.280 | And that differentiates hormones

00:01:01.940 | from things like neurotransmitters,

00:01:03.700 | which tend to act more locally.

00:01:06.040 | Examples of tissues that produce hormones

00:01:09.120 | would be the thyroid, the testes, the ovaries, et cetera.

00:01:13.520 | And then, of course, there are areas of the brain

00:01:15.160 | like the hypothalamus and the pituitary,

00:01:18.280 | which are closely related to one another

00:01:21.000 | and release hormones that cause the release

00:01:23.080 | of yet other hormones out in the body.

00:01:25.040 | So let's start with development.

00:01:28.000 | Sperm meets egg.

00:01:29.280 | Everything that happens before that

00:01:30.480 | is a topic of the next episode.

00:01:32.860 | But sperm meets egg, this is mammalian reproduction,

00:01:36.160 | and that egg starts to duplicate.

00:01:37.840 | It starts to make more of itself.

00:01:39.520 | It makes more cells.

00:01:40.640 | And eventually some of those cells become skin,

00:01:42.440 | some of those cells become brain,

00:01:44.000 | some of those cells become muscle,

00:01:45.400 | some of those cells become fingers,

00:01:47.340 | all the stuff that makes up the brain and body plan.

00:01:52.180 | In addition, there are hormones that come

00:01:55.500 | both from the mother and from the developing baby,

00:01:59.880 | the developing fetus,

00:02:01.140 | that impact whether or not the brain will be

00:02:03.900 | what they call organized masculine or organized feminine.

00:02:07.580 | And as I say this,

00:02:09.260 | I want you to try and discard with the cultural connotations

00:02:12.700 | or your psychological connotations

00:02:14.500 | of what masculinization and feminization are,

00:02:17.540 | because we're only centering on the biology.

00:02:20.900 | So typically people have either two X chromosomes,

00:02:25.900 | and the traditional language around that

00:02:28.980 | is that person is female, right?

00:02:31.780 | Or an X chromosome and a Y chromosome,

00:02:34.400 | and that person will become male.

00:02:36.660 | Now, it's not always the case.

00:02:38.380 | There are cases where it's XXY,

00:02:41.100 | where there are two X chromosomes plus a Y chromosome.

00:02:43.820 | There are also cases where it's XYY,

00:02:46.340 | where there are two Y chromosomes.

00:02:48.060 | And these have important biological

00:02:50.300 | and psychological impacts.

00:02:52.060 | So the first thing we need to establish

00:02:54.860 | is that there is something called chromosomal sex,

00:02:57.900 | whether or not they're two X chromosomes

00:02:59.580 | or an X and Y chromosome is what we call chromosomal sex.

00:03:04.580 | But the next stage of separating out the sexes

00:03:08.900 | is what we call gonadal sex.

00:03:11.020 | Typically, not always,

00:03:12.780 | but typically if somebody has testes for their gonads,

00:03:17.420 | we think of them as male.

00:03:19.800 | And if somebody has ovaries, we think of them as female,

00:03:23.700 | although that's not always the case either.

00:03:26.060 | But let's just explore the transition

00:03:28.740 | from chromosomal sex to gonadal sex,

00:03:30.780 | because it's a fascinating one

00:03:32.580 | that we all went through in some form or another.

00:03:35.900 | So this XY that we typically think of

00:03:39.580 | as promoting masculinization of the fetus,

00:03:43.900 | we say that because on the Y chromosome, there are genes,

00:03:48.900 | and those genes have particular functions

00:03:51.660 | that suppress female reproductive organs.

00:03:56.020 | So on the Y chromosome, there's a gene

00:03:59.160 | which encodes for something called

00:04:01.180 | mullerian inhibiting hormone.

00:04:03.440 | So there's actually a hormone

00:04:05.700 | that's programmed by the Y chromosome

00:04:07.960 | that inhibits the formation of mullerian ducts,

00:04:10.820 | which are an important part

00:04:11.980 | of the female reproductive apparatus.

00:04:14.260 | That's critical because already we're seeing the transition

00:04:18.460 | between chromosome, Y chromosome and gonad.

00:04:21.940 | And other genes on the Y chromosome

00:04:24.960 | promote the formation of testes.

00:04:27.180 | So there are genes like the SRY gene

00:04:29.220 | and other genes that promote the formation of testes

00:04:31.780 | while they also inhibit the formation of the mullerian ducts.

00:04:36.140 | So the transition from chromosomal sex to gonadal sex

00:04:39.740 | is a very important distinction.

00:04:42.100 | It's kind of a fork in the road

00:04:43.700 | that happens very early in development

00:04:45.580 | while fetuses are still in the embryo.

00:04:48.220 | So we have to distinguish between chromosomal sex,

00:04:51.300 | gonadal sex, and then there's what we call hormonal sex,

00:04:55.680 | which is the effects of the steroid hormones,

00:04:59.300 | estrogen and testosterone and their derivatives

00:05:02.100 | on what we call morphological sex

00:05:04.940 | or the shape of the baby and the human and the genitalia

00:05:07.780 | and the jaw and all these other things.

00:05:09.620 | And so it actually is quite complicated.

00:05:11.940 | So it's a long distance from chromosomes to gender identity

00:05:16.140 | and gender identity has a lot of social influences and roles.

00:05:19.700 | This is an area that right now is very dynamic

00:05:21.900 | and in the discussion out there, as you know,

00:05:24.100 | but just getting from chromosomal sex

00:05:26.140 | to what we would call gonadal sex and hormonal sex

00:05:30.100 | and morphological sex involves a number of steps.

00:05:32.900 | So today we're going to talk about those steps.

00:05:35.180 | And there's some fascinating things

00:05:36.980 | that do indeed relate to tools,

00:05:39.640 | do indeed relate to some important behavioral choices,

00:05:43.540 | important choices about things to avoid while pregnant.

00:05:47.320 | And for those of you that are not pregnant,

00:05:49.100 | things to avoid if you're thinking

00:05:50.660 | about eventually having children,

00:05:52.700 | and that is not to drive development

00:05:54.660 | in one direction or another,

00:05:55.940 | but there are examples where there are some deleterious

00:05:58.740 | things in our environment that can actually negatively

00:06:01.460 | impact what we call sexual development overall,

00:06:04.500 | regardless of chromosomal background.

00:06:06.620 | So let's get started with that.

00:06:08.260 | Let's talk a little bit more about what hormones do.

00:06:11.340 | Hormones generally have two categories of effects.

00:06:13.960 | They can either be very fast or they can be very slow.

00:06:16.660 | There are hormones like cortisol and adrenaline,

00:06:19.400 | which act very fast.

00:06:20.880 | And then there are hormones like testosterone and estrogen,

00:06:24.700 | which we refer to as the sex steroid hormones.

00:06:28.340 | These molecules, for those of you that are interested,

00:06:31.180 | are what are called lipophilic,

00:06:32.540 | which just means that they like fatty stuff.

00:06:34.220 | They can actually pass through fatty membranes.

00:06:36.120 | And because the outside of cells,

00:06:38.460 | as well as what's called the nuclear envelope,

00:06:40.540 | where all the DNA contents and stuff are stuffed inside,

00:06:43.700 | are made of lipid, of fat,

00:06:46.620 | these steroid hormones can actually travel into cells

00:06:49.500 | and then interact with the DNA of cells

00:06:51.740 | in order to control gene expression.

00:06:53.380 | So they can change the sorts of things

00:06:56.000 | that cells will become,

00:06:57.340 | and they can change the way that cells function

00:06:59.220 | in a long-term way.

00:07:00.460 | And that's actually how the presence of these genes,

00:07:03.700 | like SRY and Mullerian inhibiting hormone,

00:07:06.480 | lead to reductions or elimination, I should say,

00:07:10.620 | of things like the Mullerian ducts

00:07:12.260 | and promote instead what's called in males,

00:07:14.220 | the Wolfian ducts,

00:07:16.020 | or promote the development of testes rather than ovaries.

00:07:19.340 | So all you need to know is that hormones have short-term

00:07:22.440 | and long-term effects.

00:07:23.420 | And the long-term effects are actually related

00:07:25.840 | to their effects on genes

00:07:27.680 | and how those genes are expressed or repressed,

00:07:30.340 | not in order to prevent them

00:07:32.220 | from having particular proteins made.

00:07:35.100 | So these hormones, these steroid hormones,

00:07:37.880 | are exceedingly powerful.

00:07:40.100 | And if we're going to have a discussion

00:07:41.980 | about masculinization or feminization, et cetera,

00:07:44.800 | you also need to think about the counterpart.

00:07:46.340 | It's not just about masculinizing the body

00:07:48.300 | or feminizing the body and brain,

00:07:49.860 | it's also about demasculinizing the brain in many cases

00:07:54.100 | as a normal biological function,

00:07:56.000 | typically of XX females.

00:07:59.840 | And defeminization, the suppression of certain pathways

00:08:02.780 | that are related to feminization of the body and brain.

00:08:06.260 | So I've just thrown a lot of biology at you,

00:08:08.740 | but this is where it all starts

00:08:10.780 | to get incredibly surprising.

00:08:13.280 | You would think that it's straightforward, right?

00:08:17.900 | You have a Y chromosome,

00:08:20.020 | you suppress the female reproductive pathway,

00:08:24.140 | like the Mullerian ducts,

00:08:26.420 | you promote the development of testes

00:08:29.180 | and then testes make testosterone.

00:08:31.340 | And then it organizes the brain male

00:08:33.460 | and it wants to do male-like things.

00:08:34.940 | And then in females, you get estrogen

00:08:37.480 | and it wants to do a female-like things

00:08:39.580 | and air quotes here for all of this.

00:08:41.880 | And it turns out that isn't how it works at all.

00:08:46.220 | Here's where it's interesting.

00:08:47.220 | We have to understand that there are effects

00:08:49.780 | of these hormones, testosterone and estrogen,

00:08:53.420 | on what are called primary sexual characteristics,

00:08:56.460 | which are the ones that you're born with,

00:08:59.260 | secondary sexual characteristics,

00:09:01.260 | which are the ones that show up in puberty.

00:09:02.940 | And these are happening in the brain

00:09:04.800 | and body and spinal cord.

00:09:06.620 | And so I'm going to disentangle all this for you

00:09:08.260 | by giving you some examples.

00:09:10.220 | First, let's talk about the development

00:09:11.720 | of primary sexual characteristics,

00:09:13.580 | the ones that show up at birth.

00:09:16.780 | And one of the more dramatic examples of this,

00:09:19.980 | it comes from the role of testosterone

00:09:23.620 | in creating the external genitalia.

00:09:27.020 | It turns out that it's not testosterone

00:09:29.940 | that's responsible for the development of the penis

00:09:33.280 | in a baby that has an X chromosome and a Y chromosome.

00:09:37.380 | It's a different androgen.

00:09:40.260 | Androgen is just a category of hormones

00:09:43.380 | that includes testosterone,

00:09:45.620 | but testosterone is converted in the fetus

00:09:50.040 | to something called dihydrotestosterone.

00:09:52.660 | And that's accomplished through an enzyme

00:09:54.900 | called 5-alpha reductase.

00:09:56.660 | Dihydrotestosterone is what we would call

00:09:58.940 | the dominant androgen in males.

00:10:01.420 | It's responsible for aggression.

00:10:02.940 | It's responsible for a lot of muscular strength.

00:10:06.800 | It's involved in beard growth and male pattern baldness.

00:10:10.260 | We're going to talk about all of that,

00:10:11.660 | but dihydrotestosterone has powerful effects

00:10:15.180 | in determining the genitalia

00:10:17.160 | while the baby is still in the embryo.

00:10:19.300 | So there's testosterone that's made

00:10:22.380 | and that testosterone gets converted

00:10:25.900 | by this enzyme 5-alpha reductase

00:10:28.440 | in a little structure called the tubercle.

00:10:30.740 | That tubercle will eventually become the penis.

00:10:33.740 | So you say, okay, straightforward.

00:10:35.480 | This testosterone is converted to dihydrotestosterone.

00:10:38.500 | And then if there's dihydrotestosterone,

00:10:40.780 | it controls penis growth.

00:10:42.380 | And indeed that's the case.

00:10:44.420 | So that's a primary sexual characteristic.

00:10:46.940 | That baby will then grow up.

00:10:49.160 | And later during puberty,

00:10:52.220 | there will be the release of a molecule.

00:10:53.860 | I talked about this last episode called kispeptin,

00:10:56.380 | K-I-S-P-E-P-T-I-N, kispeptin,

00:10:59.980 | which will cause the release of some other hormones,

00:11:01.920 | connatural releasing hormone,

00:11:03.180 | luteinizing hormone will stimulate the testes

00:11:04.820 | to make testosterone.

00:11:05.880 | So in puberty,

00:11:07.000 | testosterone leads to further growth

00:11:09.540 | and development of the penis,

00:11:10.980 | as well as the accumulation of,

00:11:13.300 | or growth of pubic hair, deepening of the voice,

00:11:16.740 | all the secondary sexual characteristics.

00:11:19.100 | There's a very interesting phenomenon

00:11:21.960 | that was published in the journal science in the 1970s,

00:11:25.100 | for which now there's a wealth of scientific data.

00:11:28.500 | And this relates to a genetic mutation

00:11:31.340 | where five alpha reductase,

00:11:33.620 | the enzyme that converts testosterone

00:11:36.060 | to dihydrotestosterone doesn't exist.

00:11:38.900 | It's mutated.

00:11:39.820 | And this actually was first identified

00:11:42.060 | in the Dominican Republic.

00:11:43.680 | What happens is baby is born.

00:11:46.460 | If you were to look at that baby,

00:11:47.940 | it would look female.

00:11:50.060 | There would be very little or no external penis.

00:11:54.500 | And what was observed is that from time to time,

00:11:58.840 | that baby, after being raised as a girl,

00:12:01.940 | would around the age of 11 or 12 or 13,

00:12:06.660 | would start to sprout a penis.

00:12:08.700 | There's actually a name for this.

00:12:09.860 | It's called cuevedosis,

00:12:11.420 | which the translation is more or less penis at 12.

00:12:16.220 | And as strange as this might sound,

00:12:18.780 | it makes sense if you understand the underlying mutation.

00:12:21.700 | What happens in these children,

00:12:24.140 | these cuevedosis is that the child is born.

00:12:28.620 | It has testes, which are not descended.

00:12:31.620 | So up in the body,

00:12:33.220 | they weren't able to convert testosterone

00:12:35.620 | to dihydrotestosterone

00:12:36.820 | because they lack this enzyme five alpha reductase.

00:12:39.520 | As a consequence,

00:12:41.740 | the primary sexual characteristic

00:12:43.560 | of external male genitalia, penis, doesn't develop.

00:12:48.560 | And then what happens is the baby grows up

00:12:51.420 | and then testosterone starts getting secreted

00:12:54.780 | from the testes 'cause cispeptin in the brain

00:12:57.520 | signals through gonadotropin and luteinizing hormone

00:12:59.860 | travels down to the testes.

00:13:01.100 | The testes start churning out testosterone

00:13:03.180 | and there's a secondary growth of the penis.

00:13:05.620 | And all of a sudden there's a penis.

00:13:06.900 | And the point here is that dihydrotestosterone,

00:13:12.040 | not testosterone is responsible

00:13:14.040 | for this primary growth of the penis.

00:13:17.180 | And that testosterone later is involved

00:13:19.420 | in the secondary sexual characteristics,

00:13:21.740 | deepening in the voice, et cetera.

00:13:23.660 | Now, this is where the information

00:13:24.900 | gets even more interesting

00:13:26.900 | and applies to essentially everybody.

00:13:30.660 | You might think that testosterone,

00:13:33.780 | because it masculinizes the body

00:13:37.140 | in the secondary sexual characteristic way,

00:13:40.940 | and because dihydrotestosterone, another androgen,

00:13:45.040 | masculinizes the primary sexual characteristics,

00:13:48.540 | the growth of the penis early on,

00:13:50.160 | that testosterone must masculinize the brain.

00:13:53.520 | But the masculinization of the brain

00:13:56.040 | is not accomplished by testosterone.

00:13:59.000 | It is accomplished by estrogen.

00:14:02.060 | Testosterone can be converted into estrogen

00:14:06.160 | by an enzyme called aromatase.

00:14:08.480 | There are neurons in the brain that make aromatase

00:14:11.820 | and convert testosterone into estrogen.

00:14:14.220 | In other words, it's estrogen

00:14:15.620 | that masculinizes the XY individual

00:14:19.940 | that masculinizes the brain.

00:14:22.020 | And this has profound effects on all sorts of things,

00:14:25.460 | on behavior, on outlook in the world, et cetera.

00:14:29.700 | But I think most people don't realize

00:14:31.060 | that it's estrogen that comes from testosterone

00:14:33.980 | that masculinizes the male brain,

00:14:36.180 | the XY brain, not testosterone nor dihydrotestosterone.

00:14:41.080 | So I just want to mention some tools.

00:14:43.160 | You might be asking yourself,

00:14:44.440 | how could tools possibly come up

00:14:46.340 | at this stage of the conversation

00:14:47.820 | where we're talking about sexual development

00:14:50.040 | and we're talking about the differentiation

00:14:52.260 | of tissues in the body?

00:14:54.360 | Well, this is true both for children and parents and adults.

00:14:57.680 | I want to emphasize that there are things

00:15:01.600 | that are environmental,

00:15:03.640 | and there are things that people use

00:15:05.880 | that actually can impact hormone levels

00:15:08.880 | and can impact sexual development in fairly profound ways.

00:15:12.640 | And I want to be very clear,

00:15:14.480 | this is not me pulling from some rare journal,

00:15:18.360 | I've never heard of it.

00:15:19.480 | This is pulling from textbooks in particular.

00:15:22.240 | Today, I'm guiding a lot of the conversation

00:15:24.240 | on work that on behavioral endocrinology.

00:15:28.400 | This is a book by Randy Nelson and Lance Crigfield,

00:15:32.080 | true experts in the field.

00:15:33.900 | I'm going to talk about some of the work from Tyrone Hayes

00:15:36.360 | from UC Berkeley about environmental toxins

00:15:39.840 | and their impacts on some of these things

00:15:41.600 | like testosterone and estrogen.

00:15:43.660 | I'm going to touch into them.

00:15:45.180 | I'm going to give some anecdotal evidence

00:15:47.180 | that's grounded in studies,

00:15:48.560 | which we will provide in the caption

00:15:50.420 | or that I'll reference here.

00:15:51.700 | You know, again, I'm just going to highlight

00:15:53.740 | when one starts talking about environmental factors

00:15:56.460 | and how they're poisoning us

00:15:57.660 | or disrupting growth or fertility rates,

00:16:00.340 | it can start to sound a little bit crazy,

00:16:02.620 | except when you start to actually look

00:16:04.300 | at some of the real data,

00:16:05.800 | data from quality research labs

00:16:07.860 | funded by federal government,

00:16:09.800 | funded not from companies or other sources

00:16:12.500 | that are really aimed at understanding

00:16:13.820 | what the underlying biology is.

00:16:15.500 | And for that, I really,

00:16:17.420 | we should all be grateful to Tyrone Hayes at UC Berkeley.

00:16:22.020 | I remember way back when I was a graduate student

00:16:24.520 | in the late nineties, goodness, at UC Berkeley.

00:16:28.500 | And I remember him, he was studying frogs.

00:16:30.700 | He was talking about developmental defects

00:16:33.780 | in these frogs that live in different waters around,

00:16:36.620 | it was California, but also elsewhere.

00:16:39.300 | And he identified a substance which is present

00:16:41.980 | in a lot of waterways throughout this country

00:16:44.260 | and other countries, so US and beyond,

00:16:47.100 | certainly not just restricted California,

00:16:49.140 | which is atrazine, this is A-T-R-A-Z-I-N-E.

00:16:53.580 | Again, this is the stuff of textbooks

00:16:55.260 | and it causes severe testicular malformations.

00:16:58.980 | So again, atrazine exposure is serious.

00:17:02.140 | And what's interesting is if you look at the data,

00:17:05.520 | what you find is that at sites in Western

00:17:09.120 | and Midwestern sections of the United States,

00:17:11.220 | 10 to 92% of male frogs, these were frogs, mind you,

00:17:15.860 | had testicular abnormalities.

00:17:17.860 | And the most severe testicular malformations

00:17:21.020 | were in the testes rather than in the sperm.

00:17:23.760 | So it's actually the organ itself, the gonad itself.

00:17:26.680 | Now, it's very well known now

00:17:30.580 | that atrazine is in many herbicides.

00:17:33.100 | And so, whereas I would say in the '80s and '90s,

00:17:36.580 | the discussion around herbicides and their negative effects

00:17:40.060 | was considered kind of like hippie-dippie stuff

00:17:42.020 | or the stuff you hear about at your local community markets

00:17:46.460 | and these kind of new agey communities,

00:17:48.260 | now there's very solid data from federally funded labs

00:17:53.080 | at major universities that have been peer reviewed

00:17:55.580 | and published in excellent journals,

00:17:57.720 | showing that indeed many of these herbicides

00:17:59.940 | can have negative effects primarily by impacting

00:18:04.180 | the ratios of these hormones in either the mothers

00:18:08.540 | or in the testes, altering the testes of the fathers,

00:18:13.540 | or direct effects on developing young animals

00:18:17.980 | and potentially humans.

00:18:19.060 | And so you ask, well, what about humans?

00:18:20.880 | Frogs are wonderful, but what about humans?

00:18:23.860 | So here are the data on what's happening.

00:18:27.500 | And this isn't all going to be scary stuff.

00:18:30.140 | We're also going to talk about tools to ameliorate

00:18:32.440 | and offset some of these effects, depending on your needs.

00:18:35.400 | But across human populations,

00:18:37.540 | sperm counts are indeed declining, okay?

00:18:40.180 | So in 1940, the average density of human sperm

00:18:45.060 | was 113 million per milliliter of semen.

00:18:49.180 | That's how it's measured.

00:18:50.020 | How many sperm per milliliter of semen?

00:18:52.340 | In 1990, this figure has dropped to 66.

00:18:55.540 | It went from 113 million per milliliter

00:18:58.940 | to 66 million per milliliter

00:19:01.000 | in the United States and Western Europe.

00:19:03.100 | So it's not just a US thing.

00:19:04.600 | Researchers also estimated that the volume of semen

00:19:07.380 | produced by men has dropped 20% in that time,

00:19:10.140 | reduced sperm count per ejaculation even further.

00:19:13.100 | So between 1981 and 1991,

00:19:16.380 | the ratio of normal spermatogenesis has decreased

00:19:18.860 | from 56.4% to 26.9%.

00:19:23.860 | So there's a lot that's happening primarily

00:19:28.260 | because of these herbicides that are in widespread use

00:19:31.160 | to reduce sperm counts.

00:19:32.780 | And these are going to have profound effects,

00:19:34.680 | not just on sperm counts, but on development,

00:19:37.620 | sexual development at the level of the gonads and the brain,

00:19:40.620 | because you need testosterone to get dihydrotestosterone

00:19:44.900 | for primary sexual characteristics.

00:19:46.420 | You need estrogen that's come from testosterone

00:19:49.300 | to masculinize the brain.

00:19:50.460 | And of course,

00:19:51.900 | we're not just focusing on sperm and testosterone.

00:19:54.940 | You, of course, also know that many of these herbicides

00:19:58.660 | are disrupting estrogens in a similar way,

00:20:01.900 | which might explain why puberty is happening

00:20:05.540 | so much earlier in young girls these days.

00:20:08.860 | So there are a lot of things that are happening.

00:20:10.660 | Now, does this mean that you have to run around

00:20:12.900 | and neurotically avoid anything that includes things

00:20:16.860 | like atrazine?

00:20:18.040 | And should you be avoiding all kinds of herbicides?

00:20:21.580 | I don't know, that's up to you,

00:20:23.240 | but it does seem that these have pretty marked effects

00:20:26.420 | in both the animal studies and in the human studies.

00:20:29.860 | So let's talk about female sexual development.

00:20:33.120 | And as always, what we'll do

00:20:35.300 | is we'll talk about the normal biology.

00:20:36.800 | Then we'll talk a little bit about a kind of extraordinary

00:20:41.080 | or unusual set of cases,

00:20:42.940 | but we'll talk about them

00:20:45.300 | because they illustrate an important principle

00:20:47.860 | about how things work under typical circumstances.

00:20:51.820 | So there is a mutation

00:20:56.340 | called androgen insensitivity syndrome.

00:20:59.100 | And understanding how androgen insensitivity syndrome works

00:21:03.140 | can help you really understand

00:21:04.860 | how hormones impact sexual development.

00:21:07.940 | So here's how it works.

00:21:09.620 | There are individuals who are X, Y,

00:21:12.200 | so they have a Y chromosome,

00:21:13.600 | that are born, that make testosterone.

00:21:18.420 | They have testes and they don't have mullerian ducts

00:21:22.340 | because on the Y chromosome

00:21:24.360 | is this mullerian inhibiting hormone.

00:21:26.520 | However, these individuals look completely female.

00:21:30.720 | And in general, they report feeling like girls

00:21:34.500 | when they're young, women when they're older.

00:21:37.440 | But there's something unusual that's happening

00:21:40.060 | in these individuals

00:21:41.020 | because they have an X, Y chromosomal type and not XX.

00:21:46.020 | So what's happening?

00:21:47.700 | Well, what's happening is the testes are making testosterone,

00:21:52.100 | but the receptor for testosterone is mutated.

00:21:55.540 | And therefore the testes never descend.

00:21:58.860 | They don't have ovaries, they have testes,

00:22:01.260 | but the testes are internal.

00:22:03.060 | And so typically these individuals find out

00:22:06.100 | that they are actually X, Y chromosomes

00:22:08.060 | so that their chromosomal sex is male, if you will,

00:22:13.020 | and their gonadal sex is male,

00:22:15.740 | but the gonads, the testes are inside the body,

00:22:18.120 | they don't actually develop a scrotum,

00:22:20.100 | they don't make ovaries.

00:22:21.180 | And when they don't menstruate around the time of puberty,

00:22:24.340 | that's a sign that something is different.

00:22:27.340 | And so they never menstruate around puberty.

00:22:29.040 | And if they look into this deeply enough,

00:22:31.460 | what you find is that they are actually X, Y,

00:22:34.500 | they make testosterone,

00:22:35.500 | but their body can't make use of the testosterone

00:22:37.580 | because they don't have the receptors.

00:22:40.060 | And the receptors are vitally important

00:22:42.060 | for most all of the secondary sexual characteristics

00:22:46.300 | that we talked about,

00:22:47.180 | body hair, penis growth during puberty, et cetera.

00:22:50.860 | So again, we're talking about this

00:22:52.620 | in order to illustrate the principle

00:22:53.940 | that in order to have its effects,

00:22:56.060 | a hormone doesn't just have to be present,

00:22:58.460 | that hormone actually has to be able to bind its receptor

00:23:01.740 | and take action on the target cells.

00:23:04.540 | Perhaps the simplest way to understand

00:23:06.980 | how estrogen and testosterone impact masculinization

00:23:11.260 | or feminization of the brain and behavior

00:23:13.700 | is from a statement.

00:23:15.620 | It's actually the closing sentence of an abstract

00:23:18.020 | that my colleague Niral Shah

00:23:19.440 | at Stanford School of Medicine published,

00:23:22.940 | which is that estrogen,

00:23:25.500 | again, it's estrogen that is aromatized from testosterone

00:23:29.860 | by aromatase,

00:23:31.620 | sets up the masculine repertoire of sexual

00:23:35.140 | and in animals and in humans, territorial behaviors.

00:23:38.580 | So it sets up the circuitry in the brain.

00:23:40.900 | Estrogen does that.

00:23:42.380 | Estrogen sets up the masculine circuitry in the brain

00:23:46.580 | and testosterone is then what controls

00:23:50.180 | the display of those behaviors later in life.

00:23:53.860 | And I find that incredibly interesting.

00:23:56.020 | You would think it was just testosterone did one thing

00:23:58.020 | and estrogen did another,

00:23:59.420 | but it turns out that nature

00:24:01.020 | is far more interesting than that.

00:24:03.340 | Okay, so what are some things

00:24:04.700 | that impact sexual development early in life

00:24:08.500 | and later in life?

00:24:09.680 | Let's talk about cannabis.

00:24:14.300 | Let's talk about alcohol.

00:24:16.380 | First of all, cannabis, marijuana, THC.

00:24:20.500 | There are many studies that point to the fact

00:24:23.660 | that THC and other things in cannabis

00:24:27.940 | promote significant increases in aromatase activity.

00:24:32.940 | Now, pot smokers aren't going to like this,

00:24:35.580 | especially male pot smokers aren't going to like this,

00:24:37.740 | but it's the reality.

00:24:38.940 | Here's the deal, that cannabis,

00:24:41.760 | and it's not clear if it's THC itself

00:24:44.300 | or other elements in the marijuana plant

00:24:47.100 | promote aromatase activity.

00:24:50.220 | Now, this has been observed anecdotally

00:24:53.840 | where pot smokers have a higher incidence

00:24:56.380 | of developing something I mentioned before,

00:24:58.260 | gynecomastia, breast bud development,

00:25:00.300 | or full-blown breast development in males.

00:25:03.420 | Now, earlier I said that estrogen

00:25:05.300 | is what masculinizes the male brain.

00:25:07.280 | In utero, that's true,

00:25:08.880 | but the way that cannabis seems to work,

00:25:10.820 | at least from the studies I was able to identify,

00:25:13.340 | is that it promotes circulating estrogen in the body

00:25:17.900 | and therefore can counteract

00:25:19.860 | some of the masculinizing effects

00:25:21.880 | of things like testosterone

00:25:24.900 | and dihydrotestosterone

00:25:26.300 | on primary and secondary sexual characteristics.

00:25:29.060 | So I mentioned this because, you know,

00:25:31.940 | I think nowadays marijuana use is far more widespread

00:25:35.380 | and certainly during puberty,

00:25:37.180 | it can have profound effects on these hormonal systems.

00:25:40.460 | And so we'll do another episode

00:25:42.420 | that goes really deep into this,

00:25:43.580 | but yes, cannabis promotes estrogenic activity

00:25:46.940 | by increasing aromatase.

00:25:48.980 | Most everyone can appreciate

00:25:50.540 | that drinking during pregnancy

00:25:52.380 | is not good for the developing fetus.

00:25:54.240 | Fetal alcohol syndrome

00:25:55.340 | is a well-established negative outcome of pregnancy,

00:26:00.340 | and it's something that there are cognitive effects

00:26:03.220 | that are really bad.

00:26:04.540 | There's actually physical malformation, et cetera.

00:26:08.160 | So drinking during pregnancy, not good.

00:26:10.840 | Probably drinking during puberty, not good either,

00:26:13.020 | because alcohol, in particular,

00:26:15.400 | certain things like beer,

00:26:17.380 | but other grain alcohols can increase estrogenic activity.

00:26:23.260 | Now, this isn't just about protecting young boys

00:26:28.260 | from estrogenic activity.

00:26:30.620 | It's also protecting girls from excessive

00:26:35.120 | or even hypoestrogenic effects of alcohol in puberty.

00:26:40.120 | Now, many teenagers drink, college students drink,

00:26:45.040 | and it's important to point out

00:26:46.320 | that puberty doesn't start on one day

00:26:48.320 | and end on another day.

00:26:50.080 | Puberty has a beginning, a middle, and an end,

00:26:52.400 | but development is really our entire lifespan.

00:26:55.240 | Okay, so we talked about cannabis.

00:26:56.840 | We talked about alcohol.

00:26:58.600 | Let's talk about cell phones.

00:27:00.600 | First of all, I use a cell phone.

00:27:03.600 | I use it very often,

00:27:06.000 | and I do not think they are evil devices.

00:27:08.120 | I think that they require some discipline

00:27:11.680 | in order to make sure

00:27:13.160 | that it does not become a negative force in one's life.

00:27:15.960 | So I personally restrict the number of hours

00:27:17.980 | that I'm on the phone and in particular on social media.

00:27:20.440 | But what about the cell phone itself?

00:27:23.120 | When I was a junior professor,

00:27:26.960 | I was a pre-tenure early professor,

00:27:29.560 | I taught this class on neural circuits

00:27:31.880 | and health and disease.

00:27:33.280 | And one of the students asked me,

00:27:35.440 | "Are cell phones safe for the brain?"

00:27:37.720 | And all the data point to the fact that they were,

00:27:42.440 | or at least there were no data showing that it wasn't.

00:27:45.560 | I still don't have the answer on that, frankly.

00:27:47.360 | I'm not personally aware of any evidence

00:27:49.640 | in quality peer-reviewed studies

00:27:51.400 | showing that cell phones are bad for the brain,

00:27:53.700 | or that holding the phone to the ear is bad,

00:27:55.700 | or that Bluetooth is bad, or any of that.

00:27:57.540 | I'm just not aware of any quality studies.

00:27:59.440 | However, I was very interested in a particular study

00:28:04.440 | that was published back in 2013 on rats.

00:28:09.440 | It was basically took a cell phone

00:28:11.960 | and put it under a cage of rats,

00:28:13.580 | and looked at basically testicular

00:28:15.940 | and ovarian development in rats,

00:28:17.360 | and saw minor, but still statistically significant defects

00:28:22.360 | in ovarian and testicular development.

00:28:25.420 | Since then, and now returning to the literature,

00:28:28.840 | I've seen a absolute explosion of studies,

00:28:34.800 | some of which are in quality journals,

00:28:37.040 | some of which are in what I would call

00:28:38.720 | not blue ribbon journals,

00:28:41.160 | identifying defects in testicular

00:28:44.880 | and/or ovarian development by mere exposure

00:28:48.260 | to cell phone emitted waves, let's just call that.

00:28:52.560 | We don't know what they are.

00:28:53.760 | And this sounds almost crazy, right?

00:28:56.300 | Anytime somebody starts talking about EMFs

00:28:58.200 | and things like that, you kind of worry,

00:28:59.280 | like, is this person okay?

00:29:00.660 | But look, the literature are pointing in a direction

00:29:04.020 | where chronic exposure of the gonads to cell phones

00:29:09.020 | could be creating serious issues

00:29:11.200 | in terms of the health at the cellular level,

00:29:14.280 | and in terms of the output.

00:29:15.680 | So the output for the testes would be sperm production,

00:29:19.680 | swimming speed in sperm is an important feature

00:29:22.340 | of sperm health.

00:29:23.560 | In the ovaries, it would be estrogenic output,

00:29:26.420 | how regular the cycles are.

00:29:29.820 | I think that it's fair to say, based on the literature,

00:29:33.200 | that there are effects of cell phone emitted waves

00:29:37.760 | on gonadal development.

00:29:39.360 | The question is, what is the proximity of the cell phone

00:29:42.760 | to the gonads?

00:29:43.600 | So you have to take these sorts of studies

00:29:45.140 | with a grain of salt.

00:29:46.300 | There's some interesting effects of hormones

00:29:48.080 | that actually you can observe on the outside of people

00:29:51.520 | that tell you something about,

00:29:53.860 | not just their level of hormones,

00:29:55.800 | but also about their underlying genetics.

00:29:58.240 | And these relate to beard growth and baldness.

00:30:00.800 | And it's fascinating.

00:30:02.280 | The molecule, the hormone, dihydrotestosterone,

00:30:05.680 | made from testosterone,

00:30:07.000 | is the hormone primarily responsible for facial hair,

00:30:11.680 | for beard growth.

00:30:13.640 | As well, it's the molecule, the hormone,

00:30:17.200 | primarily responsible for lack of hair on the head,

00:30:21.560 | for hair loss.

00:30:23.020 | Not incidentally, the drugs that are designed

00:30:27.160 | to prevent hair loss are 5-alpha-reductase inhibitors.

00:30:32.160 | So remember 5-alpha-reductase from the huevidosis?

00:30:35.880 | Well, the people that discovered the huevidosis

00:30:38.280 | went on to do a lot of research

00:30:40.000 | on the underlying biochemistry

00:30:41.840 | of this really interesting molecule, dihydrotestosterone,

00:30:45.280 | the identified 5-alpha-reductase.

00:30:47.500 | And 5-alpha-reductase inhibitors

00:30:51.080 | are the basis of most of the anti-hair loss treatments

00:30:54.880 | that are out there.

00:30:56.440 | And so there are some interesting things here.

00:30:58.040 | First of all, the side effect profiles

00:31:00.780 | of those treatments for hair loss

00:31:03.840 | are quite severe in many individuals.

00:31:06.000 | Remember, DHT is the primary androgen for libido,

00:31:09.560 | for strength and connective tissue repair,

00:31:13.280 | for aggression, even if that aggression,

00:31:16.800 | of course, is held in check,

00:31:18.340 | but just sort of ambition and aggression

00:31:20.280 | is related to dopamine,

00:31:21.360 | but within the testosterone pathway,

00:31:23.720 | less so pure testosterone,

00:31:25.840 | although pure testosterone has its effects,

00:31:27.600 | but DHT is, at least in primate species, including humans,

00:31:32.120 | is the dominant androgen

00:31:33.820 | for most of those sorts of effects.

00:31:36.360 | And if you look at somebody,

00:31:39.280 | everyone can predict whether or not they're going to go bald

00:31:42.720 | based on looking at their,

00:31:44.040 | we're always taught, our mother's father.

00:31:46.000 | So if your mother's father was bald,

00:31:48.360 | there's a higher probability that you're going to go bald.

00:31:51.200 | The pattern of DHT receptors on the scalp

00:31:54.700 | will dictate whether or not

00:31:55.600 | you're going to go bald everywhere,

00:31:57.280 | or just in the front, or so-called crown-type baldness.

00:32:00.940 | And the density of the beard

00:32:02.520 | tells you about the density of DHT receptors.

00:32:04.640 | Now, this varies by background, by genetic background.

00:32:08.880 | There are areas of the world

00:32:11.000 | where all the men seem to be,

00:32:13.680 | have the same pattern of baldness,

00:32:14.960 | like a strip of baldness down the center,

00:32:16.680 | with hair still on the sides and full beards.

00:32:19.000 | That's because these patterns of DHT receptors

00:32:22.120 | are genetically determined.

00:32:23.960 | Elsewhere, testosterone levels can still be very high.

00:32:27.680 | DHT levels in the blood can be very high,

00:32:30.480 | and yet people will have very light beards or no beards,

00:32:33.240 | and that's because they don't have

00:32:34.860 | a lot of DHT receptors in the face.

00:32:37.360 | There are a lot of effects of DHT

00:32:39.360 | that you can just see in male phenotypes.

00:32:42.440 | And it's interesting that these hair loss drugs

00:32:45.360 | that are, or to prevent hair loss drugs,

00:32:49.000 | are directly aimed at preventing

00:32:52.360 | the conversion of testosterone into dihydrotestosterone,

00:32:56.000 | and that's why they, to some extent, prevent hair loss,

00:32:59.040 | but also, to some extent, have a bunch of side effects

00:33:02.480 | that are associated with low DHT.

00:33:04.220 | I want to tell you a story about hyenas

00:33:09.020 | and clitorises the size of penises.

00:33:12.440 | So when I was a graduate student at UC Berkeley,

00:33:16.900 | we had a professor in our department,

00:33:19.220 | phenomenal scientist named Steve Glickman.

00:33:23.000 | Steve Glickman had a colony of hyenas, spotted hyenas,

00:33:28.000 | that lived within caged enclosures, of course,

00:33:32.040 | in Tilden Park, behind the UC Berkeley campus.

00:33:34.700 | The hyenas are no longer there.

00:33:36.340 | Hyenas exhibit an incredible feature to their body,

00:33:40.540 | their hormones, and their social structure.

00:33:42.860 | Hyenas, unlike many species,

00:33:47.900 | have a situation with their genitalia

00:33:50.260 | where the male penis is actually smaller

00:33:54.700 | than the female clitoris.

00:33:57.180 | And I should say that the male penis itself,

00:33:59.460 | having seen a fair number of hyena penises,

00:34:03.080 | is not particularly small,

00:34:04.960 | which means that the hyena clitorises are extremely large.

00:34:08.960 | This was well-known for some time.

00:34:12.480 | It turns out that in the spotted hyenas,

00:34:16.020 | the females are dominant.

00:34:19.280 | So after a kill, the females will eat,

00:34:21.800 | then their young will eat,

00:34:23.480 | and then the male hyenas will eat.

00:34:27.080 | As well, when the female hyena gives birth,

00:34:31.300 | she gives birth not through the vaginal canal

00:34:35.340 | that we're accustomed to seeing,

00:34:38.700 | but through a very enlarged clitoris-like phallus,

00:34:43.700 | although it's not a phallus, it's a clitoris,

00:34:47.940 | and it literally splits open.

00:34:49.900 | So many fetuses die

00:34:51.620 | during the course of hyena development and birth.

00:34:55.380 | The baby hyena actually comes through the tissue,

00:34:59.240 | and it's a very traumatic birth.

00:35:01.960 | It was a mystery as to how the female hyenas have this,

00:35:06.960 | we'll call it masculinization,

00:35:08.380 | but it's really a androgenization

00:35:11.440 | of the periphery of the genitalia.

00:35:14.960 | And it turns out, through a lot of careful research

00:35:17.920 | done by Steve Glickman, Christine Dre, and others,

00:35:22.480 | that it's androstenedione,

00:35:26.200 | what is essentially a pro-hormone to testosterone,

00:35:29.100 | it's androstenedione at very high levels

00:35:33.020 | that's produced in female hyenas

00:35:36.080 | that creates this enlargement of their genitalia.

00:35:39.140 | So if you want to read up on androstenedione,

00:35:41.780 | androstenedione is made into testosterone

00:35:44.500 | through this enzyme 17-beta-hydroxysteroid dehydrogenase.

00:35:51.820 | It's a complicated pathway to pronounce,

00:35:54.800 | it's a fairly straightforward pathway biochemically.

00:35:58.080 | You may recall during the '90s and 2000s,

00:36:01.720 | there were a lot of performance-enhancing drug scandals,

00:36:05.080 | in particular in Major League Baseball,

00:36:07.520 | and it was purported,

00:36:10.160 | although I don't know that it was ever verified,

00:36:12.160 | but it was purported that the major

00:36:14.360 | performance-enhancing drug of abuse at that time,

00:36:18.440 | in particular players whose names we won't mention,

00:36:20.520 | but you can Google it if you want to find out,

00:36:22.860 | was androstenedione.

00:36:24.240 | And the last little anecdote about this,

00:36:26.300 | which is also published in the scientific literature,

00:36:29.460 | which is weird, but I do find interesting,

00:36:31.680 | hormones are so fascinating,

00:36:33.020 | they're just incredible to me,

00:36:34.820 | is going back to the marijuana plant.

00:36:39.020 | You know, the marijuana plant has these estrogenic properties

00:36:42.020 | and I asked a plant biologist

00:36:46.060 | whether or not this was unusual,

00:36:48.140 | but this plant biologist told me,

00:36:49.380 | oh yeah, there are plants that make

00:36:52.740 | what is essentially the equivalent of testosterone,

00:36:56.120 | like pine pollen, it looks a lot like testosterone,

00:36:58.620 | and there are other plants that make

00:37:00.460 | what is essentially estrogen.

00:37:03.100 | And I said, well, why would they do that?

00:37:04.420 | He said that one of the reasons why some plants

00:37:08.260 | have evolved this capacity to increase estrogen levels

00:37:13.260 | in animals that smoke, not smoke it,

00:37:16.260 | but then animals that consume them,

00:37:17.860 | I'm guessing that animals aren't smoking marijuana,

00:37:19.700 | although I don't know, send me the paper

00:37:21.340 | if you've heard of this,

00:37:23.180 | is that plants have figured out ways,

00:37:26.020 | they've adapted ways to push back on populations of rodents

00:37:29.980 | and other species of animals that eat them.

00:37:32.240 | So plants are engaged in a kind of plant to animal warfare

00:37:36.820 | where they increase the estrogen

00:37:38.500 | of the males in that population to lower the sperm counts,

00:37:41.340 | to keep those populations clamped at certain levels

00:37:44.580 | so that those plants can continue to flourish.

00:37:47.540 | And I find this just fascinating.

00:37:49.460 | And hormones, therefore, aren't just impacting tissue growth

00:37:54.460 | and development within the individual

00:37:57.220 | and between the mother,

00:37:58.660 | remember the placenta is an endocrine organ,

00:38:00.680 | and the offspring,

00:38:01.660 | but plants and animals are in this communication.

00:38:04.220 | So it's a fascinating area of biology.

00:38:06.420 | And as you've noticed today,

00:38:07.860 | none of this deals with the current controversies

00:38:11.020 | around gender and how many genders and sex, et cetera.

00:38:14.340 | That's a separate conversation that is by definition,

00:38:17.820 | grounded in the kind of concepts

00:38:19.620 | we've been talking about today

00:38:21.060 | and needs to take place,

00:38:22.760 | taking into consideration all of the aspects of sex

00:38:26.340 | and the effects of hormones,

00:38:27.560 | both on the body, on the brain.

00:38:29.940 | We didn't talk a lot about spinal cord,

00:38:31.340 | but we will in the next episode on,

00:38:33.480 | but we can just say on the brain and the periphery,

00:38:36.080 | early effects, late effects, acute effects,

00:38:39.440 | meaning effects that are very fast

00:38:41.500 | of levels of hormones going up or down,

00:38:43.580 | something that absolutely happens

00:38:45.040 | during and across the menstrual cycle,

00:38:47.700 | as well as long-term effects,

00:38:49.280 | like the effects of these hormones on gene expression.

00:38:53.060 | So today, as always,

00:38:55.180 | we weren't able to cover all things related to sex

00:38:59.980 | and hormones and sexual differentiation or development.

00:39:04.180 | There's no way we could,

00:39:05.460 | but we have covered a lot of material.

00:39:07.660 | So once again,

00:39:08.500 | I want to thank you for embarking on this journey

00:39:10.740 | through neuroscience.

00:39:11.900 | And today, neuroendocrinology with me.

00:39:14.900 | And as always, thank you for your interest in science.

00:39:17.600 | [upbeat music]

00:39:20.180 | (upbeat music)

How Hormones Shape Sexual Development | Huberman Lab Essentials

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