Scientists in the U.K. and Denmark have identified a link between fetal exposure to high levels of estrogen hormones during pregnancy, and the likelihood of autism. Reporting in Molecular Psychiatry, the researchers say their analysis of samples held within the Danish Historic Birth Cohort offers up “the first evidence that prenatal amniotic estradiol, estriol, and estrone are each associated with autism.”

The study was headed by Simon Baron-Cohen, PhD, director of the Autism Research Centre at the University of Cambridge, who first proposed a link between prenatal sex steroid exposure and autism. Baron-Cohen commented, “This new finding supports the idea that increased prenatal sex steroid hormones are one of the potential causes for the condition. Genetics is well established as another, and these hormones likely interact with genetic factors to affect the developing fetal brain.”

The team, including scientists at the University of Cambridge, the University of Edinburgh, the Statens Serum Institute, and the Hospital of Southern Jutland, report their results in a paper titled “Fetal estrogens and autism”.

Males are more than three times more likely to develop autism than are females, which implicates mechanisms of sexual differentiation in the development of the disorder, the authors wrote. Supporting this hypothesis, back in 2015, the team at the University of Cambridge and the Statens Serum Institute reported on a study in which they measured levels of four steroid hormones, including two androgens, in amniotic fluid samples held within the Danish Historic Birth Cohort, and showed that levels were higher in male fetuses who later developed autism.

The androgens are generally produced in higher quantities in male fetuses than they are in female fetuses, and are also known to masculinize part of the brain, and to impact on brain cell connections, which might also explain why autism occurs more often in boys than it does in girls. Interestingly, three large epidemiological studies have also linked autism with maternal polycystic ovarian syndrome, a condition that is also associated with excess androgen production, the authors pointed out. While prenatal androgens are responsible for masculinization in humans, “prenatal estrogens also contribute to fetal and neonatal brain development,” they noted, “and yet these have not been thoroughly investigated for their potential role in autism likelihood.” Estrogens and estrogen receptors are widespread in the developing male and female brain, and regulate many neurodevelopmental processes, including the development of synapses and neuronal differentiation, the authors pointed out. “Estradiol, in particular, supports synapse formation in the cortex by enhancing excitatory GABA activity. In autism, synapse formation, neuronal differentiation, as well as the GABAergic system are all atypical. These provide clues that prenatal estrogens may be involved in autism.” What’s been lacking, the team commented, is any direct evidence.

To assess any potential link between prenatal estrogens and autism, the researchers turned again to the Danish Historic Birth Cohort, a biobank that has collected amniotic samples from more than 100,000 pregnancies. They measured prenatal levels of estriol, estradiol, estrone, and estrone sulphate in the same samples of amniotic fluid from the pregnancies of 98 boys who developed autism, and 177 boys who did not, which they had analyzed for androgen levels in their 2015-reported study. Some of the androgen hormones are directly converted into estrogens. “We revisited the previously assayed concentrations of androgens and cortisol in the same subset of samples in which we assayed estrogens, to understand whether the relationship between estrogens and autism likelihood was similar to the relationship between androgens and autism likelihood,” the authors stated.

The new analyses showed that levels of all four estrogens were much higher, on average, in the 98 amniotic fluid samples from fetuses who later developed autism, when compared with the 177 control samples. In fact, high levels of prenatal estrogens were even more predictive of autism than were high levels of prenatal androgens, including testosterone. “This study reports the first evidence that elevated levels of prenatal amniotic estradiol, estriol, and estrone are each associated with autism, with estradiol levels being the most significant predictor of autism likelihood,” they stated. “We found that estradiol had the strongest positive effect size on autism likelihood, followed by estrone, estriol, and progesterone.” The investigators had to limit their analyses to male fetuses because there were too few diagnosed females in the HBC in the time window (between 1993 and 1999) of pregnancies assessed.

What isn’t yet known is what causes the higher levels of estrogens in some pregnancies. “These elevated hormones could be coming from the mother, the baby, or the placenta,” noted University of Cambridge co-author Alex Tsompanidis, PhD. “Our next step should be to study all these possible sources and how they interact during pregnancy.”

The authors highlight the placenta as one potential source of altered hormone levels. “A discrepancy in estrogen levels between the mother and child could potentially be attributed to the placenta, which acts as an endocrine regulator of the maternal–fetal interface and the main source of estrogen production for the fetus via the aromatization of androgens,” they noted. “Several lines of evidence suggest a contributory role for the placenta in the aetiology of autism.” The scientists further suggested that cases of autism have been linked with increased placental inflammation, atypical placental morphology and size, and placenta-related complications in pregnancy. “As with autism, placental dysfunction also disproportionately affects males more than females.”

The authors acknowledged that their study does have some limitations. Nevertheless, commented co-author Alexa Pohl, a PhD student at the University of Cambridge, “this finding is exciting because the role of estrogens in autism has hardly been studied, and we hope that we can learn more about how they contribute to fetal brain development in further experiments. We still need to see whether the same result holds true in autistic females.”

 

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