**2. Evidence for a correlation between elevated androgens and ASD traits/ symptoms**

Investigators have systematically evaluated measurements of androgens and their relation‐ ship with the clinical symptoms or traits defining or observed in individuals diagnosed with an ASD [6, 7]. Fetal testosterone levels were observed to be significantly inversely related to eye contact, quality of social relationships, vocabulary size, and empathy among typically developing children. By contrast, fetal testosterone levels were observed to significantly positively correlate with autistic traits, restricted interests, and systemizing behaviors.

It was also determined on a psychological testing basis that were significant differences among individuals diagnosed with an ASD in comparison to neurotypical males and females [6, 7]. The tests revealed that autism quotient (AQ), systemizing quotient (SQ), child autism spectrum test (CAST), embedded figures test, intuitive physics test, social responsiveness scale, quanti‐ tative checklist for autism in toddlers (Q-CHAT) scores revealed a pattern of ASDs > males > females. By contrast, empathy quotient (EQ), faux pas test, friendship and relationship questionnaire (FQ), reading the mind in the eyes, and social stories questionnaire (SSQ) scores revealed a pattern of females > males > ASDs.

Other investigators examined brain structure for evidence of an extreme male brain among individuals diagnosed with an ASD in comparison to neurotypical males and females [6, 7]. A pattern of extreme male brain structure with ASD > males > females for total brain volume and amgydala size was observed. By contrast, it was observed that the brain size was females > males > ASD for the perisylvian language areas, left > right asymmetry in planum temporale, and lateral fronto-parietal cortex. Furthermore, brain function patterns revealed females > males > ASD for default mode network connectivity, embedded figures functional magnetic resonance imaging (fMRI), and reading the mind in the eyes task fMRI.

Still other investigators examined the relationship between various diseases known to be associated with elevated androgen levels and ASD traits and symptoms [6, 7]. For example, individuals diagnosed with congenital adrenal hyperplasia (CAH) were found to have increased problem behaviors and increases in AQ scores relative to unaffected controls. It was even observed that some individuals diagnosed with DNA-confirmed CAH mutations and associated clinical and laboratory findings had a concurrent diagnosis of an ASD. As another example, individuals diagnosed with polycystic ovarian syndrome (PCOS) were observed to have significantly increased AQ scores, significantly impaired communication, socialization, and attention relative to unaffected controls. Finally, investigators examined bio-physiological and cognitive differences in children diagnosed with premature adrenarche (with elevated blood androgen levels) in comparison to on-time adrenarche [8]. Children diagnosed with premature adrenarche in comparison to on-time adrenarche had significantly increased problem behaviors and attention problems, as well as significantly decreased skills in social‐ ization, information processing, language/communication.

ASD would result in a significant amelioration of their clinical symptoms [5]. The purpose of this critical review is to examine evidence supporting the role of androgens in mediating ASD traits/symptoms, elevated androgens among individuals diagnosed with an ASD, and the observed important role for anti-androgen medications in treatment of ASD traits/symptoms.

**2. Evidence for a correlation between elevated androgens and ASD traits/**

Investigators have systematically evaluated measurements of androgens and their relation‐ ship with the clinical symptoms or traits defining or observed in individuals diagnosed with an ASD [6, 7]. Fetal testosterone levels were observed to be significantly inversely related to eye contact, quality of social relationships, vocabulary size, and empathy among typically developing children. By contrast, fetal testosterone levels were observed to significantly positively correlate with autistic traits, restricted interests, and systemizing behaviors.

It was also determined on a psychological testing basis that were significant differences among individuals diagnosed with an ASD in comparison to neurotypical males and females [6, 7]. The tests revealed that autism quotient (AQ), systemizing quotient (SQ), child autism spectrum test (CAST), embedded figures test, intuitive physics test, social responsiveness scale, quanti‐ tative checklist for autism in toddlers (Q-CHAT) scores revealed a pattern of ASDs > males > females. By contrast, empathy quotient (EQ), faux pas test, friendship and relationship questionnaire (FQ), reading the mind in the eyes, and social stories questionnaire (SSQ) scores

Other investigators examined brain structure for evidence of an extreme male brain among individuals diagnosed with an ASD in comparison to neurotypical males and females [6, 7]. A pattern of extreme male brain structure with ASD > males > females for total brain volume and amgydala size was observed. By contrast, it was observed that the brain size was females > males > ASD for the perisylvian language areas, left > right asymmetry in planum temporale, and lateral fronto-parietal cortex. Furthermore, brain function patterns revealed females > males > ASD for default mode network connectivity, embedded figures functional magnetic

Still other investigators examined the relationship between various diseases known to be associated with elevated androgen levels and ASD traits and symptoms [6, 7]. For example, individuals diagnosed with congenital adrenal hyperplasia (CAH) were found to have increased problem behaviors and increases in AQ scores relative to unaffected controls. It was even observed that some individuals diagnosed with DNA-confirmed CAH mutations and associated clinical and laboratory findings had a concurrent diagnosis of an ASD. As another example, individuals diagnosed with polycystic ovarian syndrome (PCOS) were observed to have significantly increased AQ scores, significantly impaired communication, socialization, and attention relative to unaffected controls. Finally, investigators examined bio-physiological and cognitive differences in children diagnosed with premature adrenarche (with elevated blood androgen levels) in comparison to on-time adrenarche [8]. Children diagnosed with

resonance imaging (fMRI), and reading the mind in the eyes task fMRI.

**symptoms**

270 Autism Spectrum Disorder - Recent Advances

revealed a pattern of females > males > ASDs.

Other investigators have more specifically examined the direct relationship between hormonal treatment status and ASD traits/symptoms by examining various groups of transsexual individuals [9] and among individuals injected with testosterone in a double-blind study [10]. It was observed among various groups of transsexual individuals that compared ASD traits/ symptoms using AQ scores derived from five groups: (1) n = 61 transmen (female-to-male transsexual individuals); (2) n = 198 transwomen (male-to-female transsexual individuals); (3) n = 76 typical males; (4) n = 98 typical females; and (5) n = 125 individuals diagnosed with an ASD [9]. Higher AQ scores were seen in transmen than in typical females, typical males, or trans women, but transmen had lower SQ scores than those individuals diagnosed with an ASD. Transmen displayed ASD-like symptoms/traits and were more comfortable socializing with male peers than female peers. Thus androgen treatment in transmen correlated directly with development of ASD symptoms/traits. Transmen had a higher mean AQ than typical females, typical males and transwomen, but lower than individuals diagnosed with an ASD. Transmen have more ASD traits/symptoms and may have had difficulty socializing with female peers and thus found it easier to identify with male peer groups. The importance of these findings being that direct hormonal treatment with androgen therapy in transmen directly correlated with their development of ASD traits/symptoms. It was also observed, among individuals injected with testosterone in a double-blind study, that these individuals manifested a significant increase in ASD traits/symptoms with impairment in their cognitive ability to infer emotions, intentions, feelings, and other mental states from observing the eye region of another's face [10].
