Dysregulated Oxytocin Not Unique to Autism

Megan Brooks

August 06, 2014

A new study casts doubt on the theory that low oxytocin may be an underlying cause of social impairments in children with autism spectrum disorder (ASD).

Dr. Karen Parker. Photo: Norbert von der Groeben/Stanford School of Medicine.

The study by researchers at Stanford University School of Medicine in California shows that plasma oxytocin concentrations and polymorphisms in the oxytocin receptor (OXTR) predict social impairments in children with and without autism.

"Our findings provide the first evidence that low blood oxytocin concentrations are not specifically linked to autism," lead author Karen J. Parker, PhD, assistant professor of psychiatry and behavioral sciences at Stanford, told Medscape Medical News.

"Rather, blood oxytocin concentrations are a biomarker of human functioning in a universal sense, with low oxytocin concentrations associated with diminished social functioning and high oxytocin concentrations associated with enhanced social functioning across all children," she said.

"Our findings also demonstrate that oxytocin concentrations are as heritable as height in the general population," Dr. Parker added.

The study was published online August 4 in the Proceedings of the National Academy of Sciences.

Universal Regulator of Social Ability

Autism affects roughly 1 in every 68 children in the United States. Altered biology of the neuropeptide oxytocin, which regulates social functioning, is thought to play a role in ASD. But it has been unclear whether oxytocin dysregulation is unique to ASD or whether oxytocin biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes, the authors note.

To investigate, they measured plasma oxytocin levels and determined OXTR variants in 79 children with autism, 52 of their unaffected siblings, and 62 unrelated children who were without autism. All of the children were between 3 and 12 years old.

They found no evidence to support the oxytocin deficit hypothesis of ASD, inasmuch as oxytocin concentrations correlated "strongly and positively" with social functioning in all 3 groups of children.

Higher oxytocin levels correlated with better social functioning in all groups. In the children with autism, social deficits were worst in those with the lowest blood oxytocin levels and mildest in those with the highest oxytocin levels. In the comparison groups, children's social skills also fell across a range that correlated with their oxytocin levels, the researchers say. "Oxytocin appears to be a universal regulator of social functioning in humans," Dr. Parker said in a statement.

"It didn't matter if you were a typically developing child, a sibling, or an individual with autism: Your social ability was related to a certain extent to your oxytocin levels, which is very different from what people have speculated," added Antonio Hardan, MD, professor of psychiatry and behavioral sciences at Stanford and the study's senior author.

The hypothesis that low oxytocin is linked to autism may be "a little bit simplistic," Dr. Hardan said. "It's much more complex: Oxytocin is a vulnerability factor that has to be accounted for, but it's not the only thing leading to the development of autism."

The investigators also found that blood levels of oxytocin are highly heritable, with a rate of around 85%, which is on par with that of height, suggesting that social function may be inherited within families.

In addition, there was no evidence that single nucleotide polymorphisms in OXTR are uniquely associated with ASD. Among all 3 groups of children, carriers of the G allele of rs53576 showed impaired affect recognition performance, and carriers of the A allele of rs22554298 showed greater global social impairments.

Dr. Parker said that ongoing oxytocin treatment trials in patients with autism have reported robust treatment responders and nonresponders.

"Our findings," she said, "indicate that measures of pretreatment oxytocin biology may provide important information about how patients will respond or not respond to oxytocin treatment."

The researchers are currently testing this hypothesis in an ongoing oxytocin treatment trial.

The investigators caution that oxytocin concentrations in blood may be different from cerebrospinal fluid (CSF) concentrations, which they did not measure.

Therefore, the current findings "do not rule out a role for oxytocin biology in autism," Dr. Parker said. "We are currently testing whether CSF concentrations of oxytocin are a better biomarker of disease status, as CSF measures are typically better indicators of brain activity than blood ones."

"Major Shortcoming"

Angela Sirigu, PhD, of the Institute of Cognitive Science, Centre de Neuroscience Cognitive, Lyon, France, told Medscape Medical News these new findings are "interesting" and are in line with findings her team published in 2012 in Cerebral Cortex.

The study in 30 healthy adults showed a correlation between the level of plasma oxytocin and the level of sociability, measured with a score of extraversion. "That is, subjects with higher levels of plasma oxytocin were more sociable and enjoyed being with others compared to those having a low level of oxytocin and poor social skills," Dr. Sirigu said.

However, she added that in her view, a "major problem" with the article in Proceedings is use of enzyme immunoassay to measure oxytocin levels. This method, "even with extraction, has been highly criticized because of low sensitivity to detect OXT. In other words, what they measured is OXT but also other multiple immunoreactive products present in addition to oxytocin. This is a major shortcoming we need to consider," said Dr. Sirigu.

The study was supported by grants from the Simons Foundation Autism Research Initiative, the Mosbacher Family Fund for Autism Research, the Escher Fund at the Silicon Valley Community Foundation, Stanford's Child Health Research Institute, and the National Institutes of Health. The authors and Dr. Sirigu report no relevant financial relationships.

Proc Natl Acad Sci. Published online August 4, 2014. Abstract


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