Sex-related variation in human behavior and the brain Melissa Hines

Review
Sex-related variation in human
behavior and the brain
Melissa Hines
Department of Social and Developmental Psychology, University of Cambridge, Free School Lane, Cambridge, CB2 3RQ, UK
Male and female fetuses differ in testosterone concentrations beginning as early as week 8 of gestation. This
early hormone difference exerts permanent influences
on brain development and behavior. Contemporary
research shows that hormones are particularly important for the development of sex-typical childhood behavior, including toy choices, which until recently were
thought to result solely from sociocultural influences.
Prenatal testosterone exposure also appears to influence
sexual orientation and gender identity, as well as some,
but not all, sex-related cognitive, motor and personality
characteristics. Neural mechanisms responsible for
these hormone-induced behavioral outcomes are beginning to be identified, and current evidence suggests
involvement of the hypothalamus and amygdala, as well
as interhemispheric connectivity, and cortical areas
involved in visual processing.
Human sexual differentiation
Why do males and females differ behaviorally? Certainly,
there is much differential socialization of the sexes, but is
there an inborn element as well? Darwin’s sexual selection
theory [1] suggests that competition for mates and discriminative mate choices have shaped the evolution of sex
differences [2]. Efforts to apply this theory to understanding sex differences in human behavior have been controversial [3], and because they are distal explanations of
behavior, evolutionary theories can be difficult to subject to
direct scientific scrutiny. However, whatever distal genetic
forces have shaped the evolution of human sex differences,
they appear to act through proximal mechanisms that can
be evaluated more directly. Prominent among these mechanisms are differences in the amount of testosterone to
which male and female fetuses are exposed.
The hypothesis that prenatal testosterone influences
human neural and behavioral development derives from
thousands of experimental studies in non-human mammals. In these studies, animals are assigned at random to
various hormonal manipulations during critical periods of
early development and influences on brain and behavior
are observed (Box 1). These studies show that prenatal or
neonatal levels of gonadal hormones are a major determinant of sex differences in brain development and in subsequent behavior, with direct genetic effects playing a
smaller role. The hypothesis that hormones exert similar
influences on human neurobehavioral development has
been debated, but recent studies provide convincing
evidence that prenatal androgen exposure influences
Corresponding author: Hines, M. ([email protected]).
448
children’s sex-typed play behavior. In addition, there is
growing evidence that other behaviors that show sex
differences, including sexual orientation, core gender identity, personality characteristics and motor performance are
similarly influenced, and the neural underpinnings of
these hormonal influences on behavior are being identified.
This article reviews evidence substantiating the role of
testosterone in the development of children’s sex-typed
behavior, discusses other behaviors that appear to be
similarly influenced by prenatal testosterone exposure,
and considers neural mechanisms that could mediate these
effects.
Toy story
Why study sex differences in children’s play? First, children spend the majority of their waking life playing,
producing interest in the causes and consequences of individual differences in play preferences. Second, there are
large sex differences in children’s play, including in preferences for toys, such as dolls and trucks (Box 2). Third,
children’s play behavior can be assessed readily and
reliably. Fourth, sex differences in children’s play are
evident early in life, providing scope for influence on
subsequent behavior, and during a period of hormonal
quiescence, allowing examination of the permanent, organizational influences of hormones on brain development
before the transient, activational influences of hormones
in adulthood have begun (Box 1).
Traditional developmental psychological theories posit
that children acquire sex-typical behavior through social
learning, and through cognitive developmental processes
that lead to gender identification and valuing of behaviors
associated with one’s gender [4,5]. In support of these
theories, boys and girls receive different responses when
they play with sex-typed toys, such as dolls [6–8], and they
tend to choose objects that have been labeled as for their
own sex or that they have seen others of their own sex
choose [9,10]. Perhaps more surprising than this evidence
of sociocultural influence, however, is evidence that sextyped toy preferences, and other sex-typed aspects of children’s play, also are influenced by testosterone prenatally.
Hormones and sexual differentiation
Before birth, boys and girls already differ hormonally. At
about week 7 of human gestation, the testes begin to
produce hormones, resulting in a substantial sex difference
in testosterone concentrations [11]. This sex difference
appears to be maximal between approximately weeks 8
and 24 of gestation, with testosterone in males tapering off
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Review
Glossary
2D:4D: the ratio of the length of the second digit of the hand to the length of the
fourth digit. It is higher in females than in males and is thought to reflect the
amount of prenatal androgen exposure. 2D:4D is easily obtained and has been
used in hundreds of studies attempting to link the prenatal hormone
environment to subsequent human behavior. To date, results of these studies
have been inconsistent, perhaps because the relation of 2D:4D to prenatal
androgen levels is weak.
Androgens: substances that promote masculinization. Androgens are produced by the testes, the adrenal gland and the ovary, but the testes are the
largest source. Therefore, androgens are present in higher concentrations in
males at many life stages, including before birth, shortly after birth and from
puberty onwards. Testosterone is one of the most potent androgens.
Androgenic progestins (anti-androgenic progestins): androgenic progestins
are synthetic hormones made to mimic the action of progesterone, a naturally
occurring hormone, typically produced by the ovaries, but also interacting with
androgen receptors, and so mimicking the action of androgens as well. Antiandrogenic progestins also were synthesized to mimic the action of
progesterone, but in this case they also interfere with the ability of androgen
to act.
Complete androgen insensitivity syndrome (CAIS): an X-linked, genetic
disorder that results in the inability of receptors in cells to respond to
androgen. Because the disorder is X-linked, it occurs almost exclusively in XY
(genetically male) individuals. XY individuals with CAIS are born with
feminine-appearing external genitalia and are typically assigned and reared
as girls. At puberty, their breasts develop in response to estrogens produced
from the androgens from their undescended testes. Female internal genitalia
are absent, however, and so menstruation does not occur. The absence of
menstruation typically leads to diagnosis. XY individuals with CAIS typically
show behavior similar to that of other females.
Congenital adrenal hyperplasia (CAH): a group of autosomal recessive, genetic
disorders involving deficiencies of enzymes in the cortisol pathway. CAH causes
reduced cortisol production, and increased androgen production, from the
adrenal gland, beginning prenatally. Girls with CAH are born with ambiguous
(partially virilized) genitalia. This usually leads to prompt diagnosis, and early
postnatal treatment to regulate the hormonal imbalance and feminize the
external genitalia. Although socialized as girls, females with CAH show increased
male-typical behavior and decreased female-typical behavior.
Core gender identity: an individual’s fundamental sense of self as male or
female.
Disorder of sex development (DSD): (formerly called Intersex Conditions)
conditions where the dimensions of sex (e.g. genetic, hormonal, genital) are
not consistent. Often there is ambiguity of the external genitalia at birth, so that
the preferred sex of assignment is not immediately clear. Many DSDs involve
prenatal hormone abnormality.
Gender identity: a person’s concept of himself or herself as male or female.
Gender dysphoria: dissatisfaction with one’s apparent sex or its usual gender
role, with the desire for the body and role of the other sex.
Gender identity disorder: a strong and persistent identification with the
opposite sex, coupled with persistent discomfort with one’s own sex or gender
role, causing significant distress or impairment in social, occupational, or other
important areas of functioning.
Gonad: a gamete (oocyte or spermatozoon), producing gland; usually an
ovary, or testis, but rarely an ovotestis (combined ovary and testis).
Gonadal hormones: hormones produced by the gonads (testes in males,
ovaries in females), particularly androgens, including testosterone, and
estrogens and progesterone.
Homologous: having a related, similar, or corresponding position, structure or
origin.
Ovaries: the female gonads; the sexual glands in which the ova are formed.
Typically there are two ovaries, one on each side of the body. Each is a flat oval
body along the lateral wall of the pelvic cavity, attached to the posterior surface
of the broad ligament. The ovaries produces estrogens and progesterone, as
well as a smaller amount of androgens.
Preoptic area: a brain region in front of the hypothalamus, sometimes
regarded as being apart from the hypothalamus proper. It contains subregions
with dense concentrations of receptors for gonadal hormones and is
implicated in sexual behavior, aggression, maternal behavior, and thirst.
Rough-and-tumble play: a juvenile behavior characterized by overall body
contact or playful aggression. It is more common in males than in females
across a wide range of mammals, including humans.
Sex chromosomes: chromosomes associated with the determination of sex. In
mammals, XX is female and XY is male.
Sex difference: an average difference between males and females.
Sexual differentiation: the process by which male or female characteristics
develop.
Sexually dimorphic nucleus of the preoptic area (SDN-POA): a cell-dense
region of the preoptic area of the brain that is larger in males than in females,
and is influenced by levels of testosterone, and hormones produced from
testosterone, during early critical periods of development.
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Testes (testicles): the male gonads. Paired, egg-shaped glands normally
situated in the scrotum. The testes contain the seminiferous tubules in which
the spermatozoa are produced, as well as specialized interstitial cells (Leydig’s
cells) that secrete testosterone.
Testosterone: the major androgenic hormone produced by the interstitial cells
of the testes. It, and dihydrotestosterone which is produced from testosterone,
regulate development of the internal and external genitalia in the male pattern.
It also influences other tissues, including the brain, where androgen receptors
are present.
Transsexual: an adult with a severe manifestation of gender identity disorder.
Transsexualism is characterized by a prolonged, persistent desire to relinquish
one’s primary and secondary sex characteristics and acquire those of the other
sex. It particularly describes individuals who live as members of the other sex,
typically having undergone hormonal and surgical treatment for sex reassignment.
Virilized genitalia: masculinized genitalia. Prenatal exposure of female fetuses
to androgens can result in partial virilization of the external genitalia, so that
the genitalia are ambiguous at birth, typically involving an enlarged clitoris and
partially fused labia.
before birth. There are androgen receptors in some brain
regions, and, in non-human mammals at comparable
stages of early development, testosterone acts through
neural receptors to influence cell survival, anatomical
connectivity and neurochemical specification, producing
sex differences in brain structure and function [12]. These
developmental effects of testosterone provide powerful
mechanisms for influencing behavior across the lifespan
(Box 1).
Hormones cannot be manipulated during early development in humans solely for research purposes, but situations where hormone exposure has been unusual for other
reasons (e.g. because of genetic disorders) have been
studied. In addition, some studies have related normal
Box 1. Gonadal hormones organize the mammalian brain
during early development; after puberty, they activate
previously organized neural systems
Thousands of studies have manipulated hormones during early
development in non-human mammals and assessed the impact of
these manipulations on brain structure and behavior later in life.
These studies have included species ranging from rodents, such as
rats, mice and guinea pigs, to non-human primates, such as rhesus
monkeys. Across all these species, early levels of testosterone and
hormones produced from testosterone, shape brain development in
regions with receptors for these hormones. Because these hormonal influences are written into the structure of the brain, they
manifest in behavior across the lifespan.
For instance, the female offspring of rhesus monkeys treated with
testosterone during pregnancy show increased male-typical, roughand-tumble play as juveniles, and increased male-typical and
reduced female-typical sexual behavior as adults [73]. Similar
effects are seen in rats, both for play behavior and for sexual
behavior. These hormone treatments also influence neural structure, enlarging brain regions that are larger in males, and reducing
those that are larger in females [12]. In rodents, structures thought
to be involved in sexual behavior, such as the sexually-dimorphic
nucleus of the preoptic area (SDN-POA) and the bed nucleus of the
stria terminalis (BNST), are affected, as is the medial amygdala, a
region linked to rough-and-tumble play [12,23]. In research in nonhuman mammals, experimental techniques, such as castration and
hormone replacement, are used to control the adult hormone
environment, allowing separation of the early and permanent,
organizational effects of hormones on brain and behavior from the
later and transient, activational effects of hormones that occur after
puberty [23,73]. Similar adult manipulations are not possible in
humans, making pre-pubertal behaviors, such as childhood toy
preferences, particularly attractive for studying organizational
influences of hormones on human behavior.
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Box 2. What human behaviors show sex differences and
how large are these differences?
Box 3. How can early hormone influences on human
development be assessed?
Sex differences in core gender identity, sexual orientation and
childhood play are larger than those in cognition or personality, and
are larger than the familiar sex difference in height (Table I).
In addition, the sizes of gender differences in cognition and
personality can vary across different measures of the same
construct. In the realm of personality, sex differences assessed with
the NEO, a measure of what are called the big five personality traits,
tend to be smaller than those assessed with Cattell’s 16 PF, a
measure of 16 primary personality factors. These differences
between tests can make sex differences seem smaller in metaanalyses that combine tests than they are on some individual tests
[23,35]. Sex differences in some cognitive abilities seem to have
declined over time [89]. For the SAT Mathematics, the sex ratio
among those scoring at the upper extreme has declined from 13
boys to one girl in 1982 to 2.8 boys to one girl more recently [93].
Sex differences in some areas also grow larger or smaller with age.
For instance the sex difference in childhood play increases from
ages 2.5 to 5 years [77], whereas the sex difference in physical
aggression appears to be larger in children than in adults [91].
In non-human species, hormones can be manipulated experimentally with random assignment. Because of ethical considerations,
researchers have used alternative approaches to study humans. One
involves studying the behavior of individuals with disorders of sex
development (DSD) that cause early hormone abnormality. The best
studied of these DSD in terms of behavioral outcomes is CAH.
Another is complete androgen insensitivity syndrome (CAIS). Girls
with CAH are exposed to testosterone levels prenatally that
resemble those of healthy male fetuses. Consequently, they are
born with partially masculinized external genitalia. Although treated
to correct the hormone abnormality and typically surgically
femininized early in life, females with CAH show increased maletypical behavior across the lifespan. CAIS almost exclusively affects
XY individuals, who have normal testes that produce testosterone,
but lack functional androgen receptors. Because their cells cannot
respond to androgen, they are born with feminine-appearing
external genitalia, and reared as girls. Sex-typed behavior in XY
females with CAIS is usually indistinguishable from that of girls and
women in general, despite their Y chromosome. (These and other
DSDs and gender-related behavior are reviewed by [13,23,94].)
Researchers also have studied the offspring of mothers who were
prescribed hormones during pregnancy for medical reasons. Offspring exposed to androgenic progestins show increased maletypical, or decreased female-typical, behavior, and those exposed to
anti-androgenic progestins show the opposite effects [36,95,96]. Yet
another approach involves measuring androgens in substances,
such as amniotic fluid or maternal blood during pregnancy.
Testosterone measured in maternal blood and in amniotic fluid
have each been related to sex-typed behavior in childhood [17,18],
providing additional support for early hormone influences. Opposite- and same-sex twins also have been compared, on the rationale
that there could be transfer of androgens from male to female cotwins, but these studies have not found differences for childhood
play [97] (A.C. Iervolino, PhD thesis, University of London, 2003),
and outcomes for other sex-linked behaviors have been inconsistent. Finally, researchers have measured physical characteristics
that show sex differences, and are thought to reflect prenatal
androgen action, particularly 2D:4D. So far, results using 2D:4D, as
with those for studies of opposite- versus same-sex twins, have
been inconsistent.
Table I. The sizes of sex differences in human behavior/
psychological characteristics that have been studied in
relation to the early hormone environment
Behavior/psychological characteristic
Core gender identity [23,74]
Sexual orientation [24,75]
Childhood play
Play with girls’ toys [8]
Play with boys’ toys [8]
Feminine preschool games [76]
Masculine preschool games [76]
Playmate preferences [76]
Composite of sex-typed play
(PSAI) [77,78]
Approximate size
in standard
deviation units (d)
11.0–13.2
6.0–7.0
1.8
2.1
1.1
0.7–1.8
2.3–5.6
2.7–3.2
Cognitive and motor abilities
(adolescents/adults)
Targeting [37,38,79–81]
Fine motor skill [38,82,83]
Mental rotations [84,85]
Spatial perception [84,85]
Spatial visualization [84,85]
SAT mathematics [86]
Computational skills [86]
Math concepts [86]
Verbal fluency [87,88]
Perceptual speed [89]
Vocabulary [90]
SAT Verbal [90]
1.1–2.0
0.5–0.6
0.3–0.9
0.3–0.6
0.0–0.6
0.4
0.0
0.0
0.5
0.3–0.7
0.0
0.0
Personality (assessed with questionnaires)
Tendencies to physical aggression [35,91]
Empathy [34,92]
Dominance/assertiveness [92]
0.4–1.3
0.3–1.3
0.2–0.8
variability in the early hormone environment to normal
variability in subsequent behavior. Each of these
approaches has advantages and disadvantages, but
taken together they can provide convergent evidence of
hormonal influences on human neurobehavioral development (Box 3).
In regard to children’s play, evidence from studies of
genetic disorders, of maternal treatment with hormones,
and of normal variability in hormones all point to the
same conclusion: testosterone concentrations prenatally
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influence children’s subsequent sex-typed toy, playmate
and activity preferences (reviewed by [13]). A consistent
finding is that girls exposed to unusually high levels
of androgens prenatally, owing to congenital adrenal
hyperplasia (CAH) (Box 3), show increased male-typical
play and reduced female-typical play (Figure 1). Similarly, children whose mothers took androgenic progestins during pregnancy show increased male-typical toy
and activity preferences, whereas the opposite is the
case for children whose mothers took anti-androgenic
progestins.
Addressing the counter arguments
There are receptors for androgens in the external genitalia,
as well as in the brain. Consequently, girls with CAH, as well
as those whose mothers took androgenic progestins, are
born with virilized genitalia. It has been suggested that
the abnormal external genitalia of these girls at birth, rather
than the action of androgens on their brain, could masculinize their behavior [14,15]. For instance, parents might
treat their daughters differently because of the girls’ external virilization at birth. Recent studies observing the girls
with their parents, however, suggest that this is not the
case [8,16]; if anything, parents encourage female-typical
(Figure_1)TD$IG][ Review
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behavior. Testosterone concentrations in maternal blood
samples taken during pregnancy, or in amniotic fluid of
normally developing fetuses, relate to subsequent sextyped behavior as would be predicted; higher levels of
testosterone are associated with more male-typical and
less female-typical childhood play [17,18]. Because these
children have normal appearing genitalia, and their
parents have no knowledge of their testosterone levels,
it is unlikely that socialization accounts for the relation
between prenatal hormones and postnatal behavior.
It is impossible to completely rule out the social environment, or potential alterations in the child’s cognitive understanding of gender, as explanations of behavioral
change in androgen-exposed girls, however. Therefore,
researchers also have looked at species where children’s
toys are novel objects, and so not subject to the social and
cognitive mechanisms thought to explain sex-typed toy
preferences in children. Studies of non-human primates
have found sex-typed toy preferences similar to those seen
in children. Male vervet monkeys [19] spend more time
than females contacting toys that are typically preferred by
boys (e.g. a car) and less time contacting toys that are
typically preferred by girls (e.g. a doll). (Figure 2). Similarly, male rhesus monkeys prefer toys normally preferred
by boys (wheeled toys) to plush toys [20].
Figure 1. Influences of prenatal androgen exposure in females, caused by CAH, on
preferences for sex-typed toys and on a broad measure of sex-typical activity and
interest preferences. Girls with CAH are exposed to high levels of androgens
prenatally, similar to levels experienced by unaffected boys and boys with CAH.
For toy preferences, values are the mean (+SD) percentages of time spent playing
with girls’ toys (a) or boys’ toys (b) in a playroom setting where a variety of girls’
toys (e.g. dolls, tea set, cosmetics) and boys’ toys (e.g. cars, trucks, guns) are
available, along with neutral toys (e.g. books, puzzles, crayons and paper). For sextyped activities and interests, values are mean (+SD) scores on the Pre-School
Activites Inventory (PSAI), a 24-item, standardized measure [72]. Scoring of the
PSAI involves subtracting scores on girl-typical items from scores on boy-typical
items. Consequently, higher scores represent more male-typical behavior. In all
three panels (a–c), means for girls and boys differ significantly, as do means for
girls with and without CAH. Data in panels a and b are adapted from [8] and data in
panel c are adapted from [24].
behavior more in their daughters with CAH than in other
girls [8].
Another approach to addressing these concerns involves
relating normal variability in early hormones to later
Why a truck? A new perspective on children’s toys
The traditional perspective on children’s sex-typical toy
preferences is that they result from socialization and provide rehearsals for adult sex-typed social roles. Evidence of
inborn influences has led to re-evaluation of these toys, and
investigation of the object features that make certain toys
appeal differentially to brains exposed prenatally to different amounts of testosterone. Perhaps shape or color is
important, because boys’ toys tend to be angular and blue,
whereas girls’ toys tend to be rounded and pink. One
investigation of these possibilities looked at infants’ interest in different toys, colors and shapes using a visual
preference paradigm [21]. Twelve- to 24-month-old infants
showed the anticipated sex differences in visual preferences; girls looked longer than boys at dolls and boys looked
longer than girls at cars. However, there were no sex
differences in preferences for pink or blue. Thus, sex-typed
color preferences do not appear to underlie sex-typed toy
preferences, because the toy preferences are present before
the color preferences. Interest in the shape stimuli, as for
the color stimuli, also did not differ by sex. Another possibility is that boys like toys that can be moved in space, and
prenatal androgen exposure might increase interest in
watching things move in space [19,22,23], perhaps by
altering development of the visual system [22].
Early hormone influences on sexual orientation and
core gender identity
Adult behaviors that show sex differences, including
sexual orientation and core gender identity, also appear
to be influenced by prenatal testosterone exposure. Women
with CAH not only recall more male-typical childhood
behavior, but also show reduced heterosexual orientation
as adults, and these two outcomes correlate [24]
(additional studies of CAH and sexual orientation are
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(Figure_2)TD$IG][ Review
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Figure 2. Examples of a male and a female vervet monkey contacting human children’s sex-typed toys. The female animal (left) appears to be inspecting the doll, in a
manner similar to that in which vervet monkeys inspect infant vervets. The male animal (right) appears to be moving the car along the ground as a child might do.
Reproduced with permission from [19].
reviewed by [25]). Normal variability in testosterone prenatally, e.g. from maternal blood or amniotic fluid, has not
yet been related to sexual orientation, but a characteristic
that is thought to provide an indirect measure of the early
hormone environment (2D:4D), has been. A study of over
200 000 individuals, who measured their own 2D:4D and
reported their sexual orientation on-line, found that 2D:4D
related as predicted to sexual orientation in males, but not
females [26]. A meta-analysis, that did not include this large
study, reached a somewhat different conclusion, however,
finding that 2D:4D related as predicted to sexual orientation
in females, but not males [27]. Finger ratios are probably a
weak correlate of prenatal testosterone exposure, perhaps
accounting for the somewhat inconsistent results.
Evidence linking core gender identity to early hormone
exposure also has come from studies of women with CAH
(reviewed by [28]), who are many hundred times as likely
as women in general to be gender dysphoric. Approximately 3% of women with CAH, despite being reared as
girls, express a wish to live as men in adulthood, in contrast
to approximately 0.005% of women in general [29]. Girls
with other disorders involving exposure to elevated androgens prenatally also show increased gender dysphoria [30].
Additionally, even when not gender dysphoric or wishing to
change sex, girls and women exposed to elevated androgen,
because of CAH or other disorders, show somewhat
reduced satisfaction with the female sex of assignment
[24,31,32].
452
Early hormone influences on personality, cognition and
motor performance
The effects of the early hormone environment also extend
to personality characteristics that show sex differences.
Probably the best-established links in this area involve
empathy, which is typically higher in females, and physical
aggression, which is typically higher in males. Females
with CAH show reduced empathy [33], and testosterone
measured in amniotic fluid relates negatively to empathy
in both boys and girls [34]. Tendencies to physical aggression also relate to prenatal testosterone exposure. Girls
and women with CAH show increased physical aggression
[33,35], as do children exposed prenatally to androgenic
progestins [36]. Not all personality dimensions that vary
by sex relate to prenatal testosterone, however. For
instance, the study that found increased aggression and
reduced empathy in females with CAH found no difference
in dominance/assertiveness, despite the existence of a sex
difference on this personality dimension.
Cognitive and motor abilities that show sex differences
also have been related to prenatal testosterone exposure
(reviewed by [28]). One study found that females with CAH
showed more male-typical behavior in the form of accuracy
in throwing balls and darts at targets [37], a result that
was not accounted for by increased muscle strength [38].
Some studies also have found that females with CAH
resemble males in showing enhanced mental rotations
performance, but others have not [37]. Paradoxically,
Review
two studies have found that males with CAH show reduced
mental rotations or other visuo-spatial performance [37,39]
and several studies have found that both males and females
with CAH show impaired performance on arithmetic and
mathematical tests [40–42]. Most studies have found no
alterations for tasks such as verbal fluency or perceptual
speed, at which females excel, in individuals with CAH,
although one study suggests that they show reduced femaletypical behavior in the form of impaired fine motor performance [38]. Perhaps prenatal testosterone exposure has a
clearer impact on motor abilities that show sex differences
(targeting, fine motor performance) than on cognitive abilities assessed with paper-and-pencil tests.
Sex-related psychiatric disorders
Some psychiatric disorders are more common in one sex or
the other and prenatal testosterone exposure has been
suggested to contribute here also. For example, testosterone has been suggested to contribute to autistic spectrum
conditions (ASC) [43], obsessive compulsive disorder
(OCD), and Tourette syndrome [44], and to protect against
eating disorders [45]. For OCD and Tourette syndrome,
evidence that individuals with these disorders are more
male-typical in other respects, such as childhood play
behavior, has been interpreted to support a link to testosterone [44]. For ASC [34,46,47], and for eating disorders
[45], behaviors in the normal range that are similar to
those seen in the disorders (e.g. empathy for ASC, and
disordered eating for eating disorders) have been linked to
prenatal androgens, although for disordered eating, there
are failures to replicate [48]. In addition, for ASC and for
eating disorders, it has not been shown that variability in
the early hormone environment leads to the disorder
itself, as opposed to behaviors in the normal range that
resemble those that characterize the disorder. For
instance, although a study of females with CAH found
increased scores on an inventory of traits related to ASC,
none scored high enough to suggest a clinical diagnosis
[47]. The proposed link between prenatal testosterone and
ASC has also been called into question by evidence that
both males and females with gender identity disorder,
rather than females only, are at increased risk of ASC
[49]. One possibility is that prenatal androgen exposure
contributes to individual differences within the normal
range in behaviors that show sex differences, but that
developmental disorders that are more common in males,
such as ASC, are more susceptible to direct genetic effects
[50], perhaps particularly those of genes encoded in the X
and Y chromosomes [50–52].
Sex differences in the brain
Behavior depends on the brain, and so sex differences in
behavior imply sex differences in brain structure or function.
Numerous sex differences in human brain structure have
been described, and are too numerous for a comprehensive
list here (reviewed by [13,53]). For instance, total brain
volume, as with body size, is larger in males than females.
In addition, the amygdala is larger in males, whereas the
hippocampus is larger in females [54], and men and women
appear to use these brain regions somewhat differently
when completing memory tasks [53]. Women show greater
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cortical thickness than men in many regions too [55].
Perhaps in compensation for their smaller brain, women
also show greater gyrification in parts of frontal and parietal
cortex, and perhaps more efficient use of white matter [56].
Although many neural sex differences have been
described, few have been linked to behavioral sex differences. The best established link involves the Third Interstitial Nucleus of the Anterior Hypothalamus (INAH-3).
INAH-3 is larger in males than in females [57–59], and is
thought to be homologous to the rodent SDN-POA, which
shows a similar sex difference [57], and is influenced by
early testosterone exposure. INAH-3 is smaller (i.e. more
female-typical) in homosexual than heterosexual men
[58,59], although the number of neurons in the nucleus
appears similar for these two groups [58].
Heterosexual and homosexual men also have been
reported to differ in corpus callosum anatomy, with the
isthmus in particular being significantly larger in righthanded homosexual than right-handed heterosexual men
[60]. Patterns of cerebral asymmetry and functional cortical connectivity also have been linked to sexual orientation in both men and women [61].
Researchers searching for neural correlates of gender
identity have reported that a subregion of the bed nucleus
of the stria terminalis (BNSTc) is smaller in women and in
male to female transsexuals than in non-transsexual men
[62]. Interpretation of this finding is complicated, however,
because the sex difference in BNSTc does not appear until
after puberty [63], whereas most transsexual individuals
recall feeling strongly cross-gendered from early childhood.
Thus, the difference in BNSTc might be the result of
experience, or of the adult hormone treatment associated
with changing sex [64].
In the realm of cognitive and motor sex differences, the
midsagittal area of posterior callosal regions, particularly
the splenium, has been found to relate negatively to
language lateralization and positively to verbal fluency
in women, a pattern representing correspondence between
female-typical brain structure and female-typical cognitive
function [65]. In addition, structural sex differences have
been described in areas of human visual cortex related to
the detection of motion, perhaps giving males more
capacity to process information related to spatial or targeting abilities [66].
Experience can change the mammalian brain throughout the lifespan, and neurogenesis continues into adulthood [67–69]. Hence, the existence of a neural sex
difference, even one that relates to a behavior known to
be influenced by early androgen exposure, does not prove
that the hormone exposure caused the neural difference. A
more direct strategy for identifying links between early
hormones and the brain is to look at neural structure or
function in individuals with early hormone abnormality.
Some neural differences have been described in individuals
with CAH (reviewed by [13]). For instance, both males and
females with CAH show decreased amygdala volume [70]
and females with CAH show increased amygdala activation to negative facial emotions, and in this respect
resemble healthy males [71]. These findings fit well with
expectations based on experimental work in other species,
because the amygdala contains receptors for androgen, and
453
Review
Box 4. Outstanding questions
What is the complete behavioral phenotype associated with
prenatal androgen exposure?
What neural changes underlie the effects of early androgen
exposure on human behavior?
How does the prenatal environment interact with postnatal
experience to shape sex-related behavior? Or brain structure
and function?
What are the different roles of prenatal hormones and direct
genetic effects on sex-linked psychopathologies?
What aspects of sex-typical toys make them more or less
appealing to individuals with different histories of testosterone
exposure?
What are the links between prenatal testosterone, development of
the visual system, preferences for toys and later spatial and
targeting abilities?
How can we measure the prenatal hormone environment more
readily and reliably in representative samples of healthy individuals?
is involved in behaviors that show sex differences, including rough-and-tumble play and aggression.
Concluding remarks
The prenatal hormone environment clearly contributes to
the development of sex-related variation in human behavior, and plays a role in the development of individual
differences in behavior within each sex, as well as differences between the sexes. Thus, early hormone differences
appear to be part of the answer to questions such as why
some children are more sex-typical than others, why some
adults are more aggressive or better at targeting than
others and why some people are heterosexual whereas
others are not. In other species, the early hormone environment exerts its enduring effects on behavior by altering
neural development. Similar neural changes are thought
to underlie associations between the early hormone
environment and human behavior, but the specific neural
changes involved are just beginning to be identified. Many
sex differences have been described in the human brain,
but only a subset of these have been related to behavioral
sex differences and still fewer to the early hormone
environment. Steroid-sensitive regions, including regions
of the hypothalamus and amygdala are implicated, as are
interhemispheric connections, but establishing firm links
between early hormones, brain development and behavior
is a primary area for future research (Box 4).
Research documenting the influence of prenatal androgen on children’s sex-typical toy preferences has provided
surprising new clues regarding neural sexual differentiation. This research has led to the realization that toys
have non-obvious properties that make them more or less
attractive to an androgen-exposed brain. This realization,
in turn, has led to suggestions that watching objects move
in space might be more attractive to a testosterone-exposed
brain and that androgen might exert its effects on children’s toy preferences by acting on the developing visual
system. Recent evidence of sex differences in visual cortex
fit well with these suggestions.
References
1 Darwin, C. (1871) The Descent of Man and Selection in Relation to Sex,
John Murray
454
Trends in Cognitive Sciences Vol.14 No.10
2 Geary, D.C. (2010) Male, Female: the Evolution of Human Sex
Differences, APA Press
3 Laland, K.N. and Brown, G. (2002) Sense and Nonsense: Evolutionary
Perspectives on Human Behavior, Oxford University Press
4 Bussey, K. and Bandura, A. (1999) Social cognitive theory of gender
development and differentiation. Psychol. Rev. 106, 676–713
5 Martin, C.L. et al. (2002) Cognitive theories of early gender
development. Psychol. Bull. 128, 903–933
6 Fagot, B.I. (1978) The influence of sex of child on parental reactions to
toddler children. Child Dev. 49, 459–465
7 Langlois, J.H. and Downs, A.C. (1980) Mothers, fathers and peers as
socialization agents of sex-typed play behaviors in young children.
Child Dev. 51, 1217–1247
8 Pasterski, V.L. et al. (2005) Prenatal hormones and postnatal
socialization by parents as determinants of male-typical toy play in
girls with congenital adrenal hyperplasia. Child Dev. 76, 264–278
9 Masters, J.C. et al. (1979) Modeling and labeling as integrated
determinants of children’s sex-typed imitative behavior. Child Dev.
50, 364–371
10 Perry, D.G. and Bussey, K. (1979) The social learning theory of sex
difference: imitation is alive and well. J. Pers. Soc. Psychol. 37, 1699–
1712
11 Wilson, J.D. et al. (1981) The hormonal control of sexual development.
Science 211, 1278–1284
12 McCarthy, M.M. et al. (2009) Sexual differentiation of the brain: mode,
mechanisms, and meaning, In Hormones, Brain and Behavior (2nd
edn) (Pfaff, D.W. et al., eds), pp. 1707–1744, Academic Press
13 Hines, M. (2009) Gonadal hormones and sexual differentiation of
human brain and behavior, In Hormones, Brain and Behavior (2nd
edn) (Pfaff, D.W. et al., eds), pp. 1869–1909, Academic Press
14 Fausto-Sterling, A. (1992) Myths of Gender, Basic Books
15 Jordan-Young, R.M. (2010) Brainstorm: The Flaws in the Science of Sex
Differences, Harvard University Press
16 Servin, A. et al. (2003) Prenatal androgens and gender-typed behavior:
a study of girls with mild and severe forms of congenital adrenal
hyperplasia. Dev. Psychol. 39, 440–450
17 Auyeung, B. et al. (2009) Fetal testosterone predicts sexually
differentiated childhood behavior in girls and in boys. Psychol. Sci.
20, 144–148
18 Hines, M. et al. (2002) Testosterone during pregnancy and childhood
gender role behavior: a longitudinal population study. Child Dev. 73,
1678–1687
19 Alexander, G.M. and Hines, M. (2002) Sex differences in response to
children’s toys in nonhuman primates (Cercopithecus aethiops
sabaeus). Evol. Human Behav. 23, 467–479
20 Hassett, J.M. et al. (2008) Sex differences in rhesus monkey toy
preferences parallel those of children. Horm. Behav. 54, 359–364
21 Jadva, V. et al. (2010) Infants’ preferences for toys, colors and shapes.
Arch. Sex. Behav. 39, DOI: 10.1007/s10508-010-9618-z
22 Alexander, G.M. (2003) An evolutionary perspective of sex-typed toy
preferences: pink, blue, and the brain. Arch. Sex Behav. 32, 7–14
23 Hines, M. (2004) Brain Gender, Oxford University Press
24 Hines, M. et al. (2004) Androgen and psychosexual development: core
gender identity, sexual orientation and recalled childhood gender role
behavior in women and men with congenital adrenal hyperplasia
(CAH). J. Sex Res. 41, 75–81
25 Meyer-Bahlburg, H.F.L. et al. (2008) Sexual orientation in women with
classical or non-classical congenital adrenal hyperplasia as a function
of degree of prenatal androgen excess. Arch. Sex Behav. 37, 85–99
26 Collaer, M.L. et al. (2007) Visuospatial performance on an internet line
judgment task and potential hormonal markers: sex, sexual
orientation, and 2D:4D. Arch. Sex Behav. 36, 177–192
27 Grimbos, T. et al. (2010) Sexual orientation and the second to fourth
finger length ratio: a meta-analysis in men and women. Behav.
Neurosci. 124, 278–287
28 Hines, M. (2009) Gendered and sex-stereotyped behavior across the
lifespan. In Life-span Development (Vol. 2) (Lerner, R.M. et al., eds), In
John Wiley and Sons
29 Dessens, A.B. et al. (2005) Gender dysphoria and gender change in
chromosomal females with congenital adrenal hyperplasia. Arch. Sex
Behav. 34, 389–397
30 Slijper, F.M.E. et al. (1998) Long-term psychological evaluation of
intersex children. Arch. Sex Behav. 27, 125–144
Review
31 Ehrhardt, A.A. et al. (1968) Fetal androgens and female gender identity
in the early-treated adrenogenital syndrome. Johns Hopkins Med. J.
122, 160–167
32 Ehrhardt, A.A. and Baker, S.W. (1974) Fetal androgens, human central
nervous system differentiation, and behavior sex differences. In Sex
Differences in Behavior (Friedman, R.C. et al., eds), pp. 33–52, Wiley
33 Mathews, G.A. et al. (2009) Personality and congenital adrenal
hyperplasia: Possible effects of prenatal androgen exposure. Horm.
Behav. 55, 285–291
34 Chapman, E. et al. (2006) Fetal testosterone and empathy: Evidence
from the Empathy Quotient (EQ) and the ‘Reading the mind in the eyes’
test. Soc. Neurosci. 1, 135–148
35 Pasterski, V.L. et al. (2007) Increased aggression and activity level in 3to 11-year-old girls with congenital adrenal hyperplasia (CAH). Horm.
Behav. 52, 368–374
36 Reinisch, J.M. (1981) Prenatal exposure to synthetic progestins
increases potential for aggression in humans. Science 211, 1171–
1173
37 Hines, M. et al. (2003) Spatial abilities following prenatal androgen
abnormality: Targeting and mental rotations performance in
individuals
with
congenital
adrenal
hyperplasia
(CAH).
Psychoneuroendocrinology 28, 1010–1026
38 Collaer, M.L. et al. (2009) Motor development in individuals with
congenital adrenal hyperplasia: Strength, targeting, and fine motor
skill. Psychoneuroendocrinology 34, 249–258
39 Hampson, E. et al. (1998) Spatial reasoning in children with congenital
adrenal hyperplasia due to 21-hydroxylase deficiency. Dev.
Neuropsychol. 14, 299–320
40 Baker, S.W. and Ehrhardt, A.A. (1974) Prenatal androgen, intelligence
and cognitive sex differences. In Sex Differences in Behavior (Friedman,
R.C. et al., eds), pp. 53–76, Wiley
41 Perlman, S.M. (1973) Cognitive abilities of children with hormone
abnormalities: Screening by psychoeducational tests. J. Learning
Disabilities 6, 21–29
42 Sinforiani, E. et al. (1994) Cognitive and neuroradiological findings in
congenital adrenal hyperplasia. Psychoneuroendocrinology 19, 55–64
43 Baron-Cohen, S. (2002) The extreme male brain theory of autism.
Trends Cogn. Sci. 6, 248–254
44 Alexander, G.M. and Peterson, B.S. (2004) Testing the prenatal
hormone hypothesis of tic-related disorders: gender identity and
gender role behavior. Dev. Psychopathol. 16, 407–420
45 Culbert, K.M. et al. (2008) Prenatal hormone exposure and risk for
eating disorders. Arch. Gen. Psychiatry 65, 329–336
46 Auyeung, B. et al. (2009) Fetal testosterone and autistic traits. Br. J.
Psychol. 100, 1–22
47 Knickmeyer, R. et al. (2006) Androgens and autistic traits: a study of
individuals with congenital adrenal hyperplasia. Horm. Behav. 50,
148–153
48 Raevuori, A. et al. (2008) Anorexia and bulimia nervosa in same-sex
and opposite-sex twins: lack of an association with twin type in a
nationwide study of Finnish twins. Am. J. Psychiatry 165, 1604–1610
49 de Vries, A.L.C. et al. (2010) Autism spectrum disorders in gender
dysphoric children and adolescents. J. Autism Dev. Disord. 40, 930–936
50 Skuse, D.H. (2006) Sexual dimorphism in cognition and behaviour: the
role of X-linked genes. Eur. J. Endocrinol. 155, S99–S106
51 Reinius, B. et al. (2008) An evolutionarily conserved sexual signature in
the primate brain. PLoS Genet. 4, e1000100
52 Reinius, B. and Jazin, E. (2009) Prenatal sex differences in the human
brain. Mol. Psychiatry 14, 988–989
53 Cahill, L. (2009) Sex differences in human brain structure and
function: relevance to learning and memory, In Hormones, Brain
and Behavior (2nd edn) (Pfaff, D.W. et al., eds), pp. 2307–2315,
Academic Press
54 Goldstein, J.M. et al. (2001) Normal sexual dimorphism of the adult
human brain assessed by in vivo magnetic resonance imaging. Cerebral
Cortex 11, 490–497
55 Luders, E. et al. (2006) Gender effects on cortical thickness and the
influence of scaling. Human Brain Mapping 27, 314–324
56 Gur, R.C. et al. (1999) Sex differences in gray and white matter in
healthy young adults: correlations with cognitive performance. J.
Neurosci. 19, 4065–4072
57 Allen, L.S. et al. (1989) Two sexually dimorphic cell groups in the
human brain. J. Neurosci. 9, 497–506
Trends in Cognitive Sciences
Vol.14 No.10
58 Byne, W. et al. (2001) The interstitial nuclei of the human anterior
hypothalamus: An investigation of variation with sex, sexual
orientation, and HIV status. Horm. Behav. 40, 86–92
59 LeVay, S. (1991) A difference in hypothalamic structure between
heterosexual and homosexual men. Science 253, 1034–1037
60 Witelson, S.F. et al. (2008) Corpus callosum anatomy in righthanded homosexual and heterosexual men. Arch. Sex Behav. 37,
857–863
61 Savic, I. and Lindstrom, P. (2008) PET and MRI show differences in
cerebral asymmetry and functional connectivity between homo- and
heterosexual subjects. Proc. Natl. Acad. Sci. U. S. A. 105, 9403–
9408
62 Zhou, J. et al. (1995) A sex difference in the human brain and its
relation to transsexuality. Nature 378, 68–70
63 Chung, W.C.J. et al. (2002) Sexual differentiation of the bed nucleus of
the stria terminalis in humans may extend into adulthood. J. Neurosci.
22, 1027–1033
64 Lawrence, A.A. (2009) Parallels between gender identity disorder and
body integrity identity disorder: A review and update. In Body Integrity
Identity Disorder; Psychological, Neurobiological, Ethical, and Legal
Aspects (Stirn, A. et al., eds), pp. 154–172
65 Hines, M. et al. (1992) Cognition and the corpus callosum: Verbal
fluency, visuospatial ability and language lateralization related to
midsagittal surface areas of callosal subregions. Behav. Neurosci.
106, 3–14
66 Amunts, K. et al. (2007) Gender-specific left-right asymmetries in
human visual cortex. J. Neurosci. 27, 1356–1364
67 Juraska, J.M. (1998) Neural plasticity and the development of sex
differences. Annu. Rev. Sex Res. 9, 20–38
68 Maguire, E.A. et al. (2006) London taxi drivers and bus drivers: a
structural MRI and neuropsychological analysis. Hippocampus 16,
1091–1101
69 Ming, G. and Song, H. (2005) Adult neurogenesis in the mammalian
central nervous system. Annu. Rev. Neurosci. 28, 223–250
70 Merke, D.P. et al. (2003) Children with classic congenital adrenal
hyperplasia have decreased amygdala volume: potential prenatal
and postnatal hormonal effects. J. Clin. Endocrinol. Metab. 88,
1760–1765
71 Ernst, M. et al. (2007) Amygdala function in adolescents with
congenital adrenal hyperplasia: a model for the study of early
steroid abnormalities. Neuropsychologia 45, 2104–2113
72 Golombok, S. and Rust, J. (2009) The Handbook of the Pre-School
Activities Inventory, Pearson Assessment
73 Goy, R.W. and McEwen, B.S. (1980) Sexual Differentiation of the Brain,
MIT Press
74 Deogracias, J.J. et al. (2007) The gender identity/gender dysphoria
questionnaire for adolescents and adults. J. Sex Res. 44, 370–379
75 Meyer-Bahlburg, H.F.L. et al. (2006) Gender development in women
with Congenital Adrenal Hyperplasia as a function of disorder severity.
Arch. Sex Behav. 35, 667–684
76 Zucker, K.J. (2005) Measurement of psychosexual differentiation.
Arch. Sex Behav. 34, 375–388
77 Golombok, S. et al. (2008) Developmental trajectories of sex-typed
behavior in boys and girls: a longitudinal general population study
of children aged 2.5-8 years. Child Dev. 79, 1583–1593
78 Hines, M. et al. (2002) Prenatal stress and gender role behavior in girls
and boys: a longitudinal, population study. Horm. Behav. 42, 126–134
79 Jardine, R. and Martin, N.G. (1983) Spatial ability and throwing
accuracy. Behav. Genet. 13, 331–340
80 Watson, N.V. and Kimura, D. (1989) Right-hand superiority for
throwing but not for intercepting. Neuropsychologia 27, 1399–
1414
81 Watson, N.V. and Kimura, D. (1991) Nontrivial sex differences
in throwing and intercepting: relation to psychometricallydefined spatial functions. Personality Individual Differences 12, 375–
385
82 Strauss, E. et al. (2006) A Compendium of Neuropsychological Tests,
Oxford University Press
83 Yeudall, L.T. et al. (1986) Normative data stratified by age and sex for
12 neuropsychological tests. J. Clin. Psychol. 42, 918–946
84 Linn, M.C. and Petersen, A.C. (1985) Emergence and characterization
of sex differences in spatial ability: a meta-analysis. Child Dev. 56,
1479–1498
455
Review
85 Voyer, D. et al. (1995) Magnitude of sex differences in spatial abilities: a
meta-analysis and consideration of critical variables. Psychol. Bull.
117, 250–270
86 Hyde, J.S. et al. (1990) Gender differences in mathematics
performance: a meta-analysis. Psychol. Bull. 107, 139–155
87 Kolb, B. and Whishaw, I.Q. (1985) Fundamentals of Human
Neuropsychology, W.H. Freeman and Co
88 Spreen, O. and Strauss, E. (1991) A Compendium of
Neuropsychological Tests, Oxford University Press
89 Feingold, A. (1988) Cognitive gender differences are disappearing. Am.
Psychologist. 43, 95–103
90 Hyde, J.S. and Linn, M.C. (1988) Gender differences in verbal ability: a
meta-analysis. Psychol. Bull. 104, 53–69
91 Hyde, J.S. (1984) How large are gender differences in aggression? A
developmental meta-analysis. Dev. Psychol. 20, 722–736
456
Trends in Cognitive Sciences Vol.14 No.10
92 Feingold, A. (1994) Gender differences in personality: a meta-analysis.
Psychol. Bull. 116, 429–456
93 Halpern, D.F. et al. (2007) The science of sex differences in science and
mathematics. Psychol. Sci. Public Interest 8, 1–51
94 Hughes, I.A. et al. (2006) Consensus statement on management of
intersex disorders. Arch. Disease Childhood 91, 554–563
95 Ehrhardt, A.A. and Money, J. (1967) Progestin-induced
hermaphroditism: IQ and psychosexual identity in a study of ten
girls. J. Sex Res. 3, 83–100
96 Ehrhardt, A.A. et al. (1977) Prenatal exposure to medroxyprogesterone
acetate (MPA) in girls. Psychoneuroendocrinology 2, 391–398
97 Henderson, B.A. and Berenbaum, S.A. (1997) Sex-typed play in
opposite-sex twins. Dev. Psychobiol. 31, 115–123