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Scientists have been studying autism spectrum disorder for the better part of a century, and yet, there's one thing they can't seem to figure out: why the brains of people with autism develop differently. But because it's more common in boys, some researchers have long suspected that testosterone levels in the womb are the key.

The only problem is, their evidence has come up short. Turns out they might have been looking at the wrong hormones. Just this week, a team of scientists at the University of Cambridge and the State Serum Institute in Denmark announced that they've identified a link between autism and a different sex hormone: estrogen.

And while might sound like the complete opposite of what you'd expect for something more prevalent in boys, it actually lines up with our understanding of autism better than you'd think. Autism spectrum disorder affects about every one in 59 children, but even after correcting for underdiagnosis and misdiagnosis, it's roughly three times more likely in boys than in girls. Girls with autism also generally have fewer autistic traits than boys.

And all that may imply that there's some kind of connection between autism and the physiological differences that generally come with a Y chromosome. Some have even suggested that autism is basically what happens when you take typically male neurological traits and dial them up to 11. This is what's known as the “extreme male brain theory” of autism.

Now, it's important to note that this doesn't mean that autistic people are super masculine overall — it just means that they have more of the traits that you see more frequently, on average, in the brains of men. And the differences we're talking about are very small. Studies consistently show that men and women are more psychologically similar than they are different.

But there are some traits that, again, on average are more common or more pronounced in the brains of people with a Y chromosome or who identify as men. And it does seem like these traits are amplified in people with autism. To give one example, the brains of men tend to have weaker connectivity in the brain's default mode network.

That's a group of brain regions that's most active when you're not focused on the outside world. And it turns out that both men and women with autism have even lower connectivity in this region than the average neurotypical man. Because there does seem to be some merit to this extreme male brain idea, researchers have suggested that the biological pathways involved in the development of typically masculine traits might be at the root of autism.

And that all traces back to fetal sex differentiation: the biological cues that lead to the development of typically masculine or feminine traits. So in recent years, researchers have begun to look for clues to autism in fetal development and the conditions fetuses experience in-utero. And at first, many thought androgens— the hormones involved in typically male traits— might be to blame, which makes intuitive sense.

The thing is, studies on prenatal testosterone levels alone— which is arguably the most important androgen— have found no relationship between it and autistic features. Then, in a study published in 2015,. Cambridge and Danish researchers found elevated levels of several sex hormones in the amniotic fluid of male fetuses that went on to develop autism.

And while that did include testosterone and another androgen, it also included progesterone: which got the researchers thinking maybe they needed to widen their scope. Which brings us to estrogen. Estrogen actually refers to a group of hormones which includes estriol, estradiol, estrone, and estetrol— none of which were tested in that 2015 study.

And these so-called “female” hormones are very important for fetal development regardless of sex. Estradiol, in particular, contributes a lot to brain development. It helps to form and prune neurons and synapses, and it regulates the activity of the neurotransmitter GABA.

In the brains of people with autism, synapse and neuron formation and GABA regulation are all atypical. So it might make sense that estrogen levels in the womb could play a role in the development of autism, too. To find out, those same researchers returned to the amniotic fluid samples they used in their 2015 study.

These initially came from The Danish Historic Birth

Cohort: a set of biological samples from more than a hundred thousand pregnant people collected between 1980 and 2004 who were followed up with to monitor the children's health over time, including whether they were diagnosed with autism. The researchers ended up with amniotic fluid samples from 98 males with autism and 177 neurotypical males. They then analyzed the samples for various forms of estrogen. And lo and behold, they found that elevated levels of estradiol, estriol, and estrone were all associated with an autism diagnosis.

Estradiol had the biggest effect: a rise in this hormone from the 25th to the 75th percentile came with an almost 50% increase in the likelihood of autism. That's a lot more of an effect than has ever been seen with androgens. Now, it may sound strange that estrogen, of all things, could lead to a so-called “extreme male brain.” But remember, estrogens do a lot of different things to a developing fetus, depending on the tissues and the development period.

And they're not exclusively a female thing. In fact, maternal estrogen levels are higher throughout pregnancy no matter what sex the fetus is. What this study suggests is that high levels of estrogen, at least at about 15 weeks gestation, might lead to differences in brain development.

As for why estrogen levels are higher at that time, the researchers suggested the placenta may have something to do with it. It acts as a hormone regulator between mom and fetus, and it's the fetus's main source of estrogen. Plus, placental issues and autism risk often go hand in hand, and they also disproportionately affect male fetuses.

But why that is is unclear— and there's a lot we don't understand about the interplay between mom, baby, and placenta when it comes to hormones. So the researchers want to further untangle what's going on. And all that said, the research didn't find that amniotic fluid hormones perfectly predict autism.

That's probably because both genes and hormones are at play: like, high levels of estrogen might interact with particular gene variants to affect the way the brain forms. Also, the researchers have made it clear they're not interested in making some kind of “screening test” for autism— as the lead researcher said, they want to understand autism, not prevent it. One major drawback to this study is that it was only in male fetuses, so it's unclear whether the findings hold true for everyone.

At the time, the team simply didn't have enough samples to do these tests for female fetuses because the prevalence of autism is so much lower in them, but they hope to get those samples in the future. And the findings are still correlational— there may be some as of yet unidentified factor that impacts amniotic hormone levels and the likelihood of an autism diagnosis. Still, it suggests that researchers may have overlooked key components in the development of autism by focusing on typically “male” things like testosterone.

And they're going to have to look at everything if they want to get to the bottom of this century-old mystery. Thanks for watching this episode of SciShow News! And a special thank you to our channel members.

Those are the people you see in comments or chats with those special badges— they've all committed to supporting this channel, and we couldn't make episodes like this without that support. So if you're already a channel member, thank you so much! And if you're not but might like to be, you can click on the Join button below to learn more. [ outro ].