A female sex hormone that protects women from stroke may also lower their risk of autism, new research suggests.
A study by researchers at the Medical College of Georgia at Georgia Regents University reports significantly reduced expression of estrogen receptor beta (ERβ) in the brains of children with autism spectrum disorder. ERβ mediates many of estrogen’s neuroprotective effects and influences locomotion and behaviors related to anxiety, depression, memory, and learning.
“Clinicians who treat autistic patients consistently report a striking gender imbalance: far more males than females,” said Dr. Anilkumar Pillai, MCG neuroscientist and corresponding author of the study published in the journal Molecular Autism. That male predominance—about five males for every female diagnosed—has long prompted researchers to investigate sex hormones as factors in autism risk.
Estrogen offers measurable protection to premenopausal women against conditions such as stroke and cognitive decline. Conversely, exposure to elevated levels of testosterone during early development has been associated with an increased risk of autism. The new findings, showing lower levels of ERβ and of aromatase—the enzyme that converts testosterone into estrogen—may help explain both higher testosterone measurements in some autistic individuals and the greater prevalence of autism among males.
“While the testosterone hypothesis has been explored, the role of estrogen in the autistic brain had not been closely examined,” Pillai said. “Estrogen is known to be neuroprotective, but our analysis shows that many children with autism had insufficient ERβ expression to receive estrogen’s full protective benefit.”
The research compared postmortem prefrontal cortex tissue from 13 children with autism and 13 matched controls. The team observed a roughly 35 percent decrease in ERβ expression in autistic samples and a 38 percent reduction in aromatase (CYP19A1). Protein levels of ERβ—the active molecules that enable estrogen’s effects—were also notably lower. Expression of estrogen receptor alpha (ERα), which is more closely linked to sexual behavior, did not show a measurable difference.
All brain tissue was obtained from a national brain and tissue repository for developmental disorders. The samples were predominantly from male children; only one control sample came from a female. The children in the study died at an average age of about 11 years from causes such as drowning, other accidents, or suicide. The team focused on the middle frontal gyrus, a prefrontal cortex subregion important for social cognition and executive function.
Although these findings are preliminary, they point to new directions for understanding sex differences in autism and for potential therapeutics. Estrogen receptor beta agonists—compounds that boost ERβ activity—already improve brain plasticity and memory in animal models and are being tested in clinical trials for other psychiatric disorders. Pillai and colleagues suggest that ERβ agonists could one day be evaluated for their ability to reduce core behavioral features of autism, such as social withdrawal and repetitive behaviors.
The research team is already initiating animal studies to test causality and therapeutic potential. Planned experiments include reducing ERβ expression in mice to observe behavioral and physiological effects, and administering ERβ agonists to mouse models with generalized inflammation and autism-like signs to determine whether enhanced ERβ function can mitigate those symptoms. Inflammation is a common contributor to disorders of the brain and body, and ERβ-targeting agents may change inflammatory responses as well as synaptic plasticity.
Future human studies should expand sample sizes and investigate related mechanisms, including the role of androgen and testosterone receptor levels in autistic versus neurotypical brains. The researchers also want to identify the biological and molecular reasons for reduced ERβ expression in affected individuals.
Complementary work published in Molecular Psychiatry earlier this year reported that male children who went on to develop autism were exposed during development to higher prenatal concentrations of steroid hormones, including testosterone and progesterone, compared with peers who did not develop autism. Together, these lines of evidence underscore the importance of sex hormone signaling—both androgens and estrogens—in neurodevelopment and autism risk.
Public health data indicate that the diagnosed prevalence of autism has risen in recent years; estimates from the Centers for Disease Control and Prevention report approximately 1 in 68 children in the United States, with most diagnoses made around age 4 though evaluations can begin as early as age 2. Diagnostic assessment relies on extensive behavioral and psychological testing.
GRU graduate student Amanda Crider is first author on the study. Correspondence and press inquiries were handled through the Medical College of Georgia at Georgia Regents University. The study titled “Dysregulation of estrogen receptor beta (ERβ), aromatase (CYP19A1), and ER co-activators in the middle frontal gyrus of autism spectrum disorder subjects” was published in Molecular Autism (Amanda Crider, Roshni Thakkar, Anthony O. Ahmed, Anilkumar Pillai). The research was released as an open-access article in 2014.