The Unexpected Connection Between Estrogen and Autism

Science has been studying autism spectrum disorder for better part of a century, and yet there’s one thing they can’t seem to figure out: why the brain 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 become up short. Turns out they might have been looking at the wrong hormones. Just this week, a team of scientist 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.

While it 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 on of 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 autism traits than boys. And all that may imply that there’s some kind of connection between autism and the physiological difference that generally come with Y chromosome.

Some 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 the autistic people are super masculine overall–it just mean that they have more of the traits that you see more frequently on average, in the brains of men. And the difference is very small.

Studies consistently show that men and women are more psychologically similar that they are different. But there are some traits that, again, on average more common or more pronounced in the brains of people with Y chromosome or who identify as me. And it does seem like the traits are amplified in people with autism. To give one example, the brains of men tend to have weaker connectivity in the brains default mode network.

There’s a group of brain region 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 on 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 all traces back to fetal sex differentation:

The biological cues that lead to the development of typically masculine or feminine traits So in recent years, researchers begin to look for clues to autism in fetal development and conditions fetuses experience in-utero. And at first, many thought androgens- the hormones involved in typically male traits- might be to blaim, 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 the 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 the group of hormones which includes estriol, estradiol, estrone, and estetrol–none of which tested in the 2015 study. And these so called “female” hormones are very important for fetal development regardless of sex. Estradiol, in particular, contributes a lot development. It helps to form and prune neurons and synapses, and it regulates the activity of neurotransmitter GABA. In the brains of people with autism, synapses and neuron formation and GABA regulation are all typical.

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 amiotic fluid samples they used in their 2015 study. These initially came from the Danish Historic Birth Cohort: a set of biological samples are more than a hundred thousand pregnant people collected between 1980 and 2004 who were followed up with the monitor the children’s health overtime, 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.

They found that elevated levels of estradiol and estriol, and estrone were all associated with an autism diagnosis. Estradiol has 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. What this study suggests is that high level of estrogen, at least at about 15 weeks gestation, it might lead to differences in the 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 fetus’ main source of estrogen.

And all that said, the researchers didn’t find that amniotic fluid hormones perfectly predict autism.

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