Sex-related variation in human behavior and the brain

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1 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. (mh504@cam.ac.uk). 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 /$ see front matter ß 2010 Elsevier Ltd. All rights reserved. doi: /j.tics Trends in Cognitive Sciences, October 2010, Vol. 14, No. 10

2 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. 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. 449

3 Box 2. What human behaviors show sex differences and how large are these differences? 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]. 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 Approximate size in standard deviation units (d) Core gender identity [23,74] Sexual orientation [24,75] Childhood play Play with girls toys [8] 1.8 Play with boys toys [8] 2.1 Feminine preschool games [76] 1.1 Masculine preschool games [76] Playmate preferences [76] Composite of sex-typed play (PSAI) [77,78] 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] 0.4 Computational skills [86] 0.0 Math concepts [86] 0.0 Verbal fluency [87,88] 0.5 Perceptual speed [89] Vocabulary [90] 0.0 SAT Verbal [90] 0.0 Personality (assessed with questionnaires) Tendencies to physical aggression [35,91] Empathy [34,92] Dominance/assertiveness [92] 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 Box 3. How can early hormone influences on human development be assessed? 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. 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 450

4 [(Figure_1)TD$FIG] Review Trends in Cognitive Sciences Vol.14 No.10 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 451

5 [(Figure_2)TD$FIG] Review Trends in Cognitive Sciences Vol.14 No.10 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 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]. 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, 452

6 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 testosteroneexposurehasbeen 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]. ForASC[34,46,47], andforeatingdisorders [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]. Inaddition,forASCandfor 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 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

7 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. 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