124 Male Gender Bias and Levels of Male Hormones During Fetal Development
there are only limited numbers of progenitor neurons that express oxytocin‐
and arginine vasopressin‐receptor positive neurons. Elimination or a signifi-
cant variation in neurotoxicity most likely is due to timing of exposure to
testosterone or similar acting chemicals found in fragrances and food flavors
and our environment. We maintain that exposure of the human population to
an increasingly diverse set of synthetic chemicals may provide the basis for the
alarming 10‐fold increase in autism in recent years. It is possible that use of
certain fragrances may be neuromodulatory to fetal brains, especially early in
gestation. It is also probable that the neuromodulatory effects initiated during
gestation may persist after birth. We are most intrigued by the observations
that certain fragrances at fentomolar concentrations can be neuromodulatory
considering the amount of fragrance that will reach a developing fetal brain
during weeks 8–24 of gestation [the most vulnerable time of fetal brain devel-
opment related to autism spectrum disorder (ASD)] [2,3].
One hypothesis that has been advanced, to account for the cognitive style in
autism, suggests that it is best described as an extreme variant of male intelli-
gence. Proponents of the “extreme male brain” theory or EMB theory, Baron‐
Cohen and colleagues [3,4] have also suggested that increased exposure to
male hormones (i.e., androgen or testosterone) in utero may contribute to the
development of ASD in both genders [3,4]. This is supported by an association
between higher testosterone levels in amniotic fluid, poorer social skills at 3 years
old, and higher scores on autism rating scales. Hormonal studies of children
with ASD have shown elevated level of androgens, especially in girls. In fact,
females with ASD often report androgen‐related conditions in adulthood.
It has been suggested that fetal or perinatal exposure to elevated levels of
male hormones may increase autism susceptibility [3–10]. In animal [11–16]
and human [3–10,17–30] studies, variations in testosterone levels were associ-
ated with differences in behavior, cognition, and brain structure between males
and females (reviewed in Ref. [3]). An association between prenatal testoster-
one levels and cognitive development has also been observed in recent studies
looking at amniotic androgen [4,21,24,28]. The EMB theory of ASD suggests
that fetal testosterone (testosterone) exposure may underlie sex differences in
autistic traits [3–6]. Since it is difficult to directly measure prenatal testoster-
one due to cost and health risks, proxy measures such as maternal circulating
testosterone levels during pregnancy and digit radio (second‐to‐fourth digit
ratio, 2D:4D) have been utilized. In fact, a link has been drawn between the
organizational effects of testosterone on the brain and ASD based on research
using 2D:4D [3–6,31]. The EMB theory is the most popular hypothesis put
forward to explain the sex difference in ASD [6]. This theory postulates that
children with ASD exhibit an enhanced form of the male cognitive profile, and
proposes that gestation exposure to testosterone causes biological effects asso-
ciated with autism. Some evidence from animal studies suggests that testoster-
one may mediate cognitive differences between the sexes via organizational