Autism's Testosterone Question

graphical representation of a head shaped by puzzle pieces and one of the top puzzle pieces at the top back of the head is red
February 16, 2011

By Danny Freedman

A gene that is suppressed in some people with autism may explain evidence of high testosterone levels, and could shed light on why autism affects males at four times the rate of females, according to a new study by GW researchers.

Some researchers have suggested there may be a link between autism and exposure of a fetus to elevated levels of testosterone, however “there’s been no explanation for why or how fetal testosterone gets elevated,” says lead author Valerie Hu, a professor in GW’s Department of Biochemistry and Molecular Biology.

In the study, published late Wednesday in the online journal PLoS One, Dr. Hu and her colleagues identified a downward spiral that, in some people with autism, leaves the body with a glut of testosterone, the primary male sex hormone.

The affected gene is called RORA (short for retinoic acid-related orphan receptor-alpha), which Dr. Hu’s research previously has shown to be suppressed in brain tissue and lab-grown blood cells from some autistic males and females.

A deficiency in RORA aligns with several processes known to be lacking in autism, such as development of the brain’s cerebellum and the protection of brain cells against physiological stress.

In the current study, the team found that RORA levels are decreased by testosterone, and that creates a self-perpetuating loop: RORA controls an enzyme called aromatase—which the body uses to convert testosterone into estrogen (the primary female sex hormone)—so that enzyme also decreases in the brain when RORA is suppressed. The body then is left with an excess of testosterone that even further stifles RORA.

It’s the first time that a gene tied to autism has been shown to be sensitive to hormones, according to Dr. Hu.

The study “can both explain the higher level of testosterone in at least some individuals with autism, which no one has ever explained before,” she says, “and it gives us some insight into a possible mechanism for the sex bias.”

The researchers found that estrogen has the opposite impact, boosting RORA, and as a result raising the enzyme that converts testosterone to estrogen. If high testosterone is found to be a cause of autism, estrogen may be protecting females from developing the disorder, says Dr. Hu.

“This male/female ratio, heavily slanted towards males, has always been a puzzle,” says Dr. Hu. “No one has been able to explain that. So I think if there is any sort of molecular mechanism that can help point in that direction, it’s really getting at one of the core pieces of the biology of autism.”

Along with Dr. Hu, the other authors of the study were GW Ph.D. and master’s students Tewarit Sarachana and Minyi Xu, respectively, and Ray-Chang Wu, an assistant professor in the Department of Biochemistry and Molecular Biology.

Further research aimed at understanding precisely how RORA is regulated could yield an avenue for treating aspects of autism in some people, says Dr. Hu. “If one of the key problems is that RORA is decreased in autism, how do you increase it? How do you keep it up?”

This therapeutic approach—hunting for and isolating deficiencies on a genetic level—is the overarching work of Dr. Hu’s lab (which was chronicled in the summer issue of GW Magazine).

Her studies have been inching closer to a blood test that could detect not just autism, but specific subtypes of autism. In addition to raising hopes for earlier detection, a genetics-based diagnostic test may also point to better targets for drug treatments.

The work of Dr. Hu is in addition to the efforts of some-two dozen other faculty members at the university who are chasing autism from myriad angles. To that end, Dr. Hu and other researchers last year began laying the groundwork for unifying these efforts within a new autism institute, to be created in partnership with Children’s National Medical Center, in D.C.

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