Male vs. Female Brain Differences & How They Arise From Genes & Hormones | Dr. Nirao Shah

One gene determines biological sex: the SRY story

Dr. Nirao Shah explains that a single gene -- SRY on the Y chromosome -- determines biological sex. It encodes a transcription factor that converts the bipotential gonad into testes, which then secrete testosterone and anti-Mullerian hormone. Without SRY, the default pathway produces a female, even with XY chromosomes.

"Are there male-female differences in terms of brain structure and function? Yes."

Organizing vs activating effects: hormones shape the brain in two waves

Shah describes the two-phase action of sex hormones. During an early critical period (in utero for humans, perinatal for mice), hormones irreversibly organize brain circuits along male or female pathways. Then after puberty, the same hormones return to activate those pre-laid circuits for adult behavior.

"Okay, so just to step back for people that aren't so familiar with how chromosomes and genes work upstream of hormones. So what you're telling us is 22 sets of autosomes. Then we have the sex chromosomes. In females, it's XX. In males, it's XY. On the Y chromosome, there's this SRY gene. There's a single gene, SRY. And the presence of that gene means that there will be RNA and then protein made. That's correct. And some of those proteins will cause the development of the testes. And then the testes will secrete testosterone in utero and shape the brain for its potential to be male when puberty happens later on, right? Yes. Let me qualify that. Okay. So SRY is a transcription factor, which means it is a gene that encodes a protein from RNA. You know, it gets transcribed into RNA, and then RNA gets made into protein. And the protein is a transcription factor, the SRY protein. And what that means is it sort of can regulate expression of other genes. So it can sort of switch on or silence suites of genes that take the bipotential gonad. So the gonad, before it becomes testes or ovaries, is a bipotential gonad. It can go either way. At what stage of embryonic development in human is the gonad bipotential? It could become male or female. It's thought that it's early, late first or early second trimester. So as late as the second trimester, the gonads are equal potential. They could become male or female. And which direction they go depends entirely on the presence of this SRY transcription factor. That's right. And the same is true in the mouse as well. So in the mouse, the gonads are by potential until day 12 of gestation. Mouse gestation is about 20 days. So does this mean that prior to the beginning of the second trimester, because the SRY transcription factor isn't active yet, that the brain of the fetus is essentially identical between males and females? That's the thinking, yes. And that same is true in the mouse. In fact, in the mouse, which is our model organism in the laboratory, the brain is thought to be by potential right almost until birth. Really? Yes. And I'm sure you'll get into this, but the organizing effect of testosterone, as we sort of talked about, can in fact be detected even as late as after birth in the mouse. So you can take a female mouse at birth and give it testosterone, and you can masternize her behaviors down the road. But she doesn't have testes. That's right. So the simple act of giving testosterone will do that. So that's the organizing action of testosterone, irreversible differentiation of a bipotential brain along a male pathway with testosterone. Okay, but in humans, as early as the second trimester beginning, the SRY transcription factor kicks on. My understanding based on my training from some years ago, hopefully this is still true. You'll correct me if it's not, is that some of the genes downstream of SRY start to suppress the Mullerian ducts, the fallopian tubes, and instead you get testes and the vasodeferins and basically all the structure for delivering sperm out of the penis for copulation later in life. That's right. So SRY sort of takes the gonad, makes it into a testes. The testes secretes at least two hormones that we know about that are very important for sexual differentiation. One is testosterone, which people have heard about, and the other is an anti-malarian hormone. And this hormone from the testes sort of suppresses differentiation of the uterus and the vaginal tract and the fallopian tubes and the ovaries. So you get a testes that suppresses female gonadal development, genitalia development, and you have testosterone that takes the bipredential genitalia and then masculinize them and you get a penis and a scortal sac. And what about the role of dihydrotestosterone? My understanding is that the development of the male brain and the development of male genitalia was strongly dictated also by dihydrotestosterone. So the action of dihydrotestosterone, which is a derivative of testosterone from a single enzyme, you know, 5-alpha reductase, converts testosterone and makes it into dihydrotestosterone or DHT. The action of DHT is best understood on the external genitalia. So DHT acts on the same receptor as testosterone does, the androgen receptor, except it binds at much higher affinities. So it's a much more potent activator of the receptor. And this activation of the receptor in the external genitalia tissue really is what gives you masculinization of the penis and the scotal sac. So what I'm taking from this is that the hormones themselves shape circuitries in the brain. We'll talk about how that happens. They shape the external genitalia. But unless you have the SRY transcription factor, you won't get the suppression of the ovaries and the Mullerian ducts and all of that stuff. So it's not as if the presence of androgens, testosterone and DHT, to a female XX chromosomal fetus will make that female fetus male. It's really the presence of that SRY gene. You need suppression of femaleness plus you need amplification of maleness, so to speak. That's exactly right. Yeah. Okay. So the reason I'm asking all of this and the reason we're painting this tapestry of hormones and genes, et cetera, is because as you know, these days it's very controversial out there as to when sex versus gender is established. And some of that I think is born of political leanings, but it's also born of this understanding that there's perhaps a continuum between masculinity and femininity. That you can find males that are kind of in the extreme stereotype of maleness. You can find females that are at the extreme stereotype of femaleness in terms of behavior and external morphology, right? Presence of breasts, et cetera. But that there seems to be a continuum of phenotypes. But when it comes down to the genetic biology, it really is about the presence of this SRY gene. That seems to be the deterministic factor. That's right. So you can even have SRY sort of hop chromosomes from a Y chromosome onto an autosome. That's happened? That's happened. In humans? In humans and in mice. And if that happens, you can have a full complement of XX chromosomes. It can be female, but SRY is sitting on an autosome. And then that animal becomes a male. So you can have XX males as well. So it's not the Y chromosome per se. It's a gene, SRY. So one gene, SRY, determines maleness or femaleness. That's right. And if you take away SRY, if you mutate it, for example, genetically with experiments in the mouse or naturally occurring mutations in humans, SRY, you know, loss of function of SRY, you will have XY females. Wow. It's really all about SRY. Like the entire political debate, you know, not sociological debate, but the entire political debate as to whether or not someone is male or female, if you wanted to boil it down to a biological factor, it's one factor, it's SRY. Yes, to make a female or a male, yes. A chromosomal genetic female or male would be SRY. I'd like to take a quick break and acknowledge our sponsor, Maui Nui Venison. Maui Nui venison is the most nutrient-dense and delicious red meat available. It's also ethically sourced. Maui Nui hunts and harvest wild access deer on the island of Maui. This solves the problem of managing an invasive species while also creating an extraordinary source of protein. 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Penis at 12 syndrome: when sex changes at puberty

People born without the enzyme converting testosterone to DHT appear female at birth but develop male genitalia at puberty when testosterone levels rise high enough. Called "penis at 12 syndrome" in medical textbooks, this is more common in communities with consanguineous marriages.

"And then my understanding is there's also a mutation where people lack the enzyme that converts testosterone to dihydrotestosterone. So they're born appearing female. They have SRY, that gene, this deterministic gene. They make testosterone. It doesn't convert to dihydrotestosterone. Then puberty rolls around and they go from having what the parents and they thought was a vagina and a clitoris and they sprout a penis. That's right. How common is that? It's not that common. I think it's more common in places where there's consanguinous marriages. So, you know, in some villages in some countries, it's fairly common. And they even have sort of local dialect names for this condition. I forget what it's called in those languages. But there's definitely... So it's called a penis at 12 syndrome in sort of medical textbooks. Because as you said, there's part of penis at 12 because the orally penile development and the squirrel sac development depends on DHT, which is a much more potent activator of the androgen receptors. If you can't have DHT, then testosterone alone cannot masculinize the external genitalia. It's feminized early on, but after puberty, when the testosterone levels go up again, that level of testosterone is now sufficient to differentiate the external genitalia into a penis. So in the strictest sense, the presence of the SRY gene is deterministic for maleness. Yes. It's not even just the Y chromosome. It's really SRY gene on the Y chromosome. Because as you point out, if the SRY gene is on a different chromosome, because it got translocated there, then you still get a male fetus. Is it also fair to say that the absence of the SRY gene is what determines femaleness, or are there a separate set of deterministic genes that designate femaleness? Some people might be confused by this question only because what I'm not being clear about is you could imagine that it's the presence, yes, of SRY that creates maleness, and in its absence, you just get a female by default. Or it could be that there's a deterministic female gene that makes the brain and body of females female. Right. So that's not known in mammals, at least. There's no single gene that's been identified in mammals, in mouse or humans, that determines femaleness. So no gene that, if placed onto a Y chromosome, would drive the differentiation of that fetus to female. That's right. Okay. What does that tell us about human evolution? I don't know what it says about evolution. It says that there's a genetically programmed pathway that in the fetus in the absence of SRY will give you a female body and a brain. So that pathway, the genetic program exists, and that SRY sort of temps it down and boosts maleness. Okay. I want to get back to sex differentiation and behavior in a moment, but I want you to tell me if the news report from a few years ago, the California condors can reproduce from two females. Is that true? I've not seen that report. I don't know."