Sex Steroids and Human Behavior: Implications for Developmental Psychopathology

Sex Steroids and Human Behavior: Implications for Developmental Psychopathology
By Gerianne M. Alexander, PhD, and Bradley S. Peterson, MD

CNS Spectrums 2001;6(1):75-88

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Abstract

In a variety of mammalian species, prenatal androgens organize brain structures and functions that are later activated by steroid hormones in postnatal life. In humans, studies of individuals with typical and atypical development suggest that sex differences in reproductive and nonreproductive behavior derive in part from similar prenatal and postnatal steroid effects on brain development. This paper provides a summary of research investigating hormonal influences on human behavior and describes how sex differences in the prevalences and natural histories of developmental psychopathologies may be consistent with these steroid effects. An association between patterns of sexual differentiation and specific forms of psychopathology suggests novel avenues for assessing the effects of sex steroids on brain structure and function, which may in turn improve our understanding of typical and atypical development in women and men.

Introduction

Sex differences in both the prevalences and natural histories of psychiatric disorders are well-documented. Although core features of psychiatric disorders do not systematically vary between the sexes, females are more likely to have higher lifetime prevalences of dysthymia, depression,1 simple phobias, agoraphobia, social phobia, panic disorders, posttraumatic stress disorder,2 and obsessive-compulsive disorder (OCD).3 In contrast, males are more likely to present with conduct disorders, attention-deficit/hyperactivity disorder (ADHD), substance abuse,4 learning disorders,5 and chronic motor tics.6 Furthermore, the onset of male-typed disorders and other psychiatric disorders, such as schizophrenia7,8 and OCD,9,10 occurs earlier in boys than in girls. Consequently, the prevalence of childhood psychopathologies differs greatly between sexes, with boys much more likely than girls to present for the treatment of a psychiatric disorder. However, this overall sex-specific prevalence difference reverses following puberty, as the rate of psychologic disorders increases in girls to overtake the prevalence in boys.11 Gender, in fact, is one of the most robust and well-replicated risk factors in all of developmental psychopathology.

Sex differences in psychiatric disease prevalence may derive from sex differences in socialization.12 This hypothesis is supported by considerable research showing that socially conferred gender labels pervade multiple levels of social experience. First, such labels influence a child’s environment (eg, girls’ environments are more often made pastel colors and boys’ environments are more often made primary colors; girls are given more verbal stimulation) and bias how adults view a child’s temperament (eg, boys get angry, girls become afraid) and appearance (eg, boys are big and strong; girls are delicate).13 Gender identification predicts interactions with the outer world, as indicated by the child’s toy preferences, activity levels, and playmate choices.14-17 Gender labels also influence a child’s inner world–his or her self-representations and self-identifications18-20 (schemas that include social scripts that may define gender-appropriate levels or expressions of sexual interest).21 These social processes may explain sex-specific personality traits22 and assumptions about social relations (eg, girls typically report feeling greater dependency on others)23 and may influence abilities to process cognitive-emotional stimuli that may impact response to stress.24,25 In other words, the differential treatment of males and females may result in behavioral sex differences that alter thresholds for vulnerability to psychopathology, possibly by increasing the potential for specific psychiatric symptoms that are viewed by society as compatible with one’s gender role.12

Sex differences in the frequency or intensity of some behaviors (eg, rough-and-tumble play and aggression) also derive from sex differences in steroid levels. From this perspective of biologic influences on behavioral sex differences, the differing prevalence and natural histories of developmental disorders between the sexes suggest that steroid hormones may contribute to sex differences in psychopathology.26-28 Gender socialization typically conforms to gender labels that describe external genitalia–the sexual differentiation of which is hormonally determined. By initiating a process of gender socialization, sex steroids may indirectly contribute to behavioral sex differences that influence psychopathology. However, animal and human research also indicates that sex steroids may have more direct effects on the development of psychopathology, either by producing structural dimorphisms in brain regions integral to mood and behavioral regulation (eg, in the hypothalamus and amygdala)24 or by increasing the potential for sexually dimorphic behaviors (eg, childhood play, aggression, and sexual interest) that may facilitate the acquisition of a masculine or feminine gender role in society. If sexual differentiation of the central nervous system (CNS) and the development of gender role behavior are indeed variables that alter thresholds for vulnerability to psychopathology, then, in addition to social factors, biologic factors that contribute to their development may warrant closer consideration in studies of psychopathology. This paper provides a brief overview of the sexual differentiation of the CNS and gender-role behavior, and it describes how the methodology used in human research of hormone/behavior associations may help improve our understanding of the biologic basis of sex differences in psychopathology.

SEX STEROIDS AND SEXUAL DIFFERENTIATION

Perinatal Development

In the classic theory of hormone effects, masculinization and defeminization of the structure and function of structures in the brain and periphery are thought to be a consequence of the permanent organizational effects of testicular androgens,29,30 although the role of ovarian hormones in this process is a topic of both theoretical and research debate.31,32 In other species, high levels of androgens alter structural and functional properties of the hypothalamus (eg, so that the hypothalamus of the male, in contrast to that of the female, is forever unable to induce cyclic gonadotropin secretion).33,34 In the periphery, testosterone and its metabolites suppress the development of the female reproductive tract and promote a masculine phenotype.35 In the nonhuman brain, testosterone crosses the blood-brain barrier and is metabolized to estrogen in brain cells expressing the enzyme aromatase.36 Through estrogen’s actions on genomic transcription and protein synthesis in brain areas expressing aromatase, testicular testosterone organizes brain structures and functions that characterize the male pattern of development in these species.37 Across animal species, females may escape the masculinizing effects of ovarian estrogens through a variety of mechanisms that render the steroid less biologically active. Hypothesized protective mechanisms, for example, include estrogen binding to a-fetoprotein in the rat,38 and placental actions on estradiol in primates.39

In other animals, hormonally dependent, sex-specific changes in the ultrastructure of the CNS include effects on cell proliferation and cell death, patterns of cell migration, dendritic branching, and density of dendritic spines.37 These ultrastructural effects of sex hormones on the nonhuman brain during critical periods of development produce permanent sex differences in brain morphology. Aromatase is expressed in especially high concentrations in the hypothalamus, cortex, hippocampus, midbrain, and amygdala.40 Sex differences in testosterone levels, therefore, affect volumes of the hypothalamus, amygdala, and hippocampus–regions that are the neural substrates of sexual behavior, aggression, learning, and memory.38,41 High levels of testosterone may also produce a masculine pattern of brain asymmetry, in which the cortex of the right hemisphere is thicker than that of the left.42 In fact, it has been observed that all known sexual dimorphisms in the nonhuman nervous system can be altered by manipulation of steroid hormones during critical periods of development.30

In humans, testicular-androgen production begins during the 6th week of gestation, resulting in higher testosterone levels in males than in females from weeks 8—24. During this period of development, organizational effects of sex steroids promote the sexual differentiation of the human reproductive system.35 This continuity of hormone effects on the reproductive system across species suggests that hormone-dependent effects on human brain development may also occur during this time. Studies that would establish a causal relationship between sex differences in the human brain and prenatal hormone levels (eg, manipulation of steroids during prenatal life) are clearly unethical; therefore, tests of prenatal hormone effects on brain structure and function depend on converging evidence from experimental research in animals and from descriptive studies in humans who have typical or atypical prenatal development.

In studies of women and men with typical development, sex differences in brain development include findings that females have smaller brain weights, smaller brain volumes,43,44 and reduced hemispheric asymmetries than do males (B. S. Peterson, H. Mohlberg, L. H. Staib, et al, unpublished data, November 2000). Males and females also differ in the size and shape of interhemispheric commissures (eg, the corpus callosum in women may have a more bulbous splenium and larger isthmus),45-47 and the size of some subcortical structures (the interstitial nucleus of the anterior hypothalamus and the bed nucleus of the stria terminalis) may be smaller in women.48,49 Recent imaging data show sex differences in neocortical regions, including the inferior parietal lobule, where right volumes are larger in men than in women.50 The existence of these sex differences in the human brain is apparently consistent with animal research of perinatal hormone effects on development. Yet, in addition to the brain size differences that are apparent at birth, sex differences in human brain morphology appear to occur in later life–well beyond the times of peak estrogen synthesis in the brain.29,43,45,51 In other mammals, most brain sexual dimorphisms are a result of differential maturational processes that are initiated by estrogen synthesis at an earlier time.52 In this model of hormonal influences on brain development, the effects of social or hormonal variables on postnatal CNS development depend both on the sex of the individual and the course of brain development that was programmed or organized by hormones in perinatal life. The spinal nucleus of the bulbocavernosus (SNB) in the rat undergoes organizational changes in response to hormonal manipulation in adult life30–a recent finding that suggests that organizational processes bearing on brain/behavior associations in humans may occur beyond the perinatal period. However, for the most part, animal research suggests that the postnatal hormonal milieu may support or constrain, but not radically alter, the fundamental sexual differentiation of the mammalian brain that is established in the perinatal period.

Postnatal Development

Sexual differentiation during postnatal life is controlled primarily by the activational effects of sex steroids on development. In contrast to their organizational effects, activational effects of sex steroids are the reversible and transient effects on systems that are hypothesized to be organized by sex steroids in earlier development. Maturation of the reproductive system, for example, involves activational effects on the brain and peripheral organ systems (eg, the hypothalamus and genitalia) that were permanently differentiated as male or female by sex steroids in perinatal development.53 In other words, structural or behavioral sensitivity to sex steroids in postnatal life is viewed as a consequence of earlier organizational effects of steroids on some aspect of a particular structure or function.31 Activational effects of sex steroids in postnatal life may include receptor-mediated changes in areas associated with both reproductive function (eg, the hypothalamus) and nonreproductive functions (eg, learning and memory systems in the amygdala, hippocampus, and cortex). In addition, evidence increasingly indicates that these genomic effects may be complemented by earlier rapid actions of sex steroids on the function of brain cells through nongenomic mechanisms.54-56

Androgen production by the human testes and adrenal glands changes during the course of postnatal development. For several months following birth, males experience higher androgen levels due to a dramatic increase in androgen production by the testes.57 At this same time in both sexes, levels of adrenal androgens exceed those in adulthood, but then fall rapidly over the next 4—6 months to low levels. Androgens remain at low levels until the adrenal gland begins to mature around 6—8 years of age.58 Following adrenarche, adrenal androgens in both sexes continue to increase with age until the third decade of life. Adrenal androgen levels then fall progressively over the next two decades; by the eighth decade, they are nearly undetectable.57

The outcome of the relatively unsex-typed process of adrenal development in childhood is modified by the sex of the individual. Adrenarche appears to support, or in some way trigger, the onset of puberty–after which, gonadal maturation produces large sex differences in both the level and pattern of gonadal hormone secretion. For example, although androgen levels in men vary diurnally and seasonally,59-61 activity of the central control mechanism of androgen production (ie, the GnRH pulse frequencies) is relatively constant.62 In addition, until menopause, near the age of 50 years, women show complex cyclic changes in ovarian steroid production that include ovulatory increases in levels of estrogen and androgen.63 With the onset of natural menopause, however, the ovaries atrophy, resulting in low levels of estrogen. Although ovarian production of androgens typically continues after menopause,64 the cyclic changes in ovarian androgens that are associated with ovulation65 then subside.

Sexual Differentiation of Behavior

In other species, experimental manipulation of gonadal hormones during development (eg, by physical or chemical castration or by injecting exogenous androgens) shows unequivocally that hormone-dependent masculinization of the CNS in early development masculinizes sexual behavior.66 It also increases subsequent rough-and-tumble play67,68 and aggression,66 and may enhance spatial learning.69 Sex steroids in postnatal life further activate most of these sexually dimorphic behaviors. In some cases, however, prenatal androgens may affect behavior independently of postnatal steroid levels. For example, prenatal exposure to androgens increases rough-and-tumble play, but the subsequent experimental manipulation of androgens in later life (eg, castration in males or androgen injection in females) does not alter the frequency of this behavior.68 Sex steroids may also affect sexual differentiation in the periphery without any apparent influence on brain/behavior associations. In other primates, for example, increased androgens during the first few months of life contribute to penile growth and penile development, but do not appear to alter subsequent male gender role development or male socialization.70

Prenatal Steroids and Human Behavioral Sex Differences

In human research, sexually dimorphic behavior can be categorized according to whether the behaviors reflect sexual orientation, gender identity, or gender role behavior. Gender role behaviors include certain personality characteristics, cognitive abilities, play styles, and aspects of sexual behavior that show sex differences independent of sexual orientation (eg, levels of sexual interest). Sex steroids are hypothesized to influence all three classes of behavior, but different critical periods or different hormonal mechanisms are suggested by their apparent dissociability. For example, women who identify themselves as women (ie, female-typical gender identity) may be sexually aroused by women and not by men (ie, male-typical sexual orientation). Similarly, men who are sexually aroused by women and not by men (ie, male-typical sexual orientation) may be feminine in their interests or personality style (ie, female-typical gender role). The existence of different critical periods for the development of gender role behaviors is consistent with animal research showing that changes in the timing and duration of testosterone exposure during perinatal development can produce a genetic male or a genetic female who exhibits high frequencies of female-typical behavior or male-typical behavior or even high frequencies of both.31,38,41 Different critical periods of hormone contributions to behavior may also explain why, to date, the role of sex steroids in the development of gender identity and sexual orientation has been elusive or equivocal.71

In contrast, there is a more consistent role of sex steroids in the development of male-typical or female-typical gender role behavior. In children and adults assumed to have normal reproductive development, sex differences in brain function and in related behavioral domains exist that are known to be androgen dependent in other species. Sex differences in recovery from brain injury, for instance, and hemispheric activation during performance of right- or left-hemisphere tasks72-74 suggest that functional laterality is greater in men than in women. Consistent with the known organizational effects on brain/behavior associations, human males are more active than human females,16,17 show preferences for rough-and-tumble play,75,76 are more physically aggressive,77 and generally excel on visuospatial tasks.78-80 Females, in contrast, show preferences for doll play15,81 and are more affiliative socially.23 Females also generally excel at verbal-fluency tasks,82 measures of perceptual speed,72,83 and perhaps specialized forms of spatial memory, such as memory for object locations.84,85

Similarly, studies of individuals with atypical reproductive development during prenatal life suggest that these behavioral sexual dimorphisms in postnatal life are the consequence of sex differences in prenatal androgen levels.31,86 Functional brain asymmetry is masculinized (ie, increased), for example, in women exposed prenatally to high levels of a synthetic estrogen (diethylstilbestrol) or to high adrenal androgen levels, consistent with the hypothesized organizational effects of sex steroids on cerebral laterality.87-89 Girls with congenital adrenal hyperplasia (CAH), moreover, are exposed to high levels of adrenal androgens prenatally. Postnatally, they show more masculinized play preferences,90,91 greater aggression,92 enhanced (ie, masculine) visuospatial abilities,93,94 and more masculine occupational preferences.95

Although prenatal androgen levels seem to influence the development of these sex-typed behaviors, the gender roles of girls exposed prenatally to high androgen levels are typically less masculine than those of normal boys. This observation suggests that gender socialization can substantially constrain a hormonally based predisposition when that predisposition is inconsistent with a socially conferred gender label.95 However, the onset or duration of prenatal androgen exposure in girls with CAH may also contribute to variable degrees of masculine gender role behavior, as suggested by reports of increasing gender-role dysphoria in a genetic male castrated at birth and socialized as female.96 Gender-role behaviors like brain sexual dimorphisms, therefore, seem to be determined by the effects of complex interactions between steroid hormones and societal influences during critical phases of human development.

Postnatal Steroids and Human Sex-Typed Behavior

Activational effects of steroid hormones on the expression of sexually dimorphic behaviors are consistent with the developmental trajectories of these behaviors in childhood. The behavioral manifestations of sexual interest emerge, for example, several years before puberty, in temporal proximity to the increase in androgen levels during adrenarche.97 Similarly, increased androgen levels during puberty are associated with increased sexual interest,98 the emergence of sexual social interactions,99 and increased male aggression.100 Individual changes in androgen levels across the menstrual cycle in women (or possibly across seasons in men101) appear to modify the degree and direction of cerebral functional asymmetries (G. M. Alexander, B. S. Peterson, B. S. Wexler, unpublished data, October 2000),102,103 sexual interest,104,105 mood,106,107 and sexually dimorphic cognitive abilities.108,109 In addition, some research suggests that sex-steroid levels in blood or saliva predict gender-role behaviors, such as levels of aggression100 and spatial abilities.101

Studies of individuals with atypical postnatal reproductive development further support the importance of activational effects of sex steroids on gender-role behaviors. Androgen administration to women and men with androgen deficiencies, for example, may enhance mood110-112 and verbal abilities.113 In well-controlled studies of these individuals, testosterone replacement increases sexual interest, sexual thoughts, sexual daydreams, spontaneous erections, and episodes of nocturnal penile tumescence (NPT).114-117 These findings are consistent with observations of a similar positive association of androgen levels with behavior in studies of women who have androgen deficiencies due to the suppression (with oral contraceptives)118 or elimination (with surgery) of ovarian androgen production.119 Androgens in humans, therefore, seem to enhance behaviors that indicate a desire to engage in sexual activities–the so-called appetitive sexual behaviors. In contrast, abundant evidence in humans suggests that androgens have relatively little effect on consummatory sexual behaviors or those behaviors that are required for engagement in sexual activities.120,121

Brain/Behavior Associations

Sexually dimorphic brain areas and sexually dimorphic behaviors may both be consequences of the developmental effects of androgens on the human brain. In some instances, however, brain sexual dimorphisms appear to have little or no functional significance in terms of sexually dimorphic behaviors. The sexually dimorphic nucleus of the preoptic area (SDN-POA) of the hypothalamus in rodents, for example, has little or no apparent role in sexual behavior. The functional significance of findings in humans that the size of a similar hypothalamic structure–the interstitial nucleus of the anterior hypothalamus–may vary according to sex and sexual orientation122 is, therefore, unclear. In other cases, the assumed brain/behavior relationship has yet to be evaluated. Sex differences in the size of the inferior parietal lobule,50 for example, are consistent with sex differences in spatial abilities. However, no studies have yet demonstrated that the volume of this structure is associated with performance measures on sex-typed spatial tasks. Moreover, behaviors that are not sexually dimorphic (eg, working memory) may show sexually dimorphic patterns of brain activation,123 further obscuring the nature and behavioral significance of observed sexual dimorphisms in the CNS.

It seems obvious that the expression of sexually dimorphic behavior depends on the successful recruitment of a network of brain structures–not all of which are themselves necessarily sexually dimorphic. For example, the neuroanatomic basis of social play includes limbic forebrain structures (the nucleus accumbens, the caudate, and the amygdala), the hypothalamus, and sensory systems.124 However, the sexual differentiation of play occurs as a consequence of testosterone’s prenatal organizational effects on the amygdala.67 In addition, only some aspects of a given behavior might be sensitive to sex or hormone effects. Sexual behavior is illustrative of this last possibility. Although not without controversy,125 different neural systems are known to subserve appetitive (ie, reward areas, including the basolateral amygdala and the nucleus accumbens) and consummatory sexual behaviors (ie, hypothalamic areas).121 Although in animals both of these systems are androgen-sensitive, the preferential effects of androgens on appetitive sexual behavior in humans strongly suggest that these dual brain systems are differentially responsive to androgens postnatally. Better understanding of the effects of hormones on human behavior may, therefore, depend on careful deconstruction of brain networks and the behavioral systems they subserve.

Androgens And Psychopathology

Prenatal Steroid Effects

Converging evidence from both animal and human research indicates that sex differences in human brain function, including the incidence of psychopathologies, may be associated with early sex steroid effects on sexual differentiation of brain and behavior. An association between the organizational effects of prenatal androgens and psychopathology is further suggested by research on prenatal stress. In humans, prenatal stress produces attentional deficits and excess anxiety, and has been implicated in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and a subsequent impaired stress response.126,127 These effects of prenatal stress on the HPA axis are also implicated in the pathogenesis of sex-typed psychiatric disorders, such as depression.128 In rodents, maternal stressors, such as physical restraint and social crowding, also demasculinize and feminize sexual behavior and social play in male offspring.129,130 In addition, sexually dimorphic brain structures (ie, SDN-POA) in these male offspring are more similar to those in females.131 In humans, prenatal stress effects on gender role development are not firmly established.132,133 However, this animal research suggests that it may be informative to consider whether shifts in male-typical gender-role behavior are associated with shifts in the frequency of male-typical psychiatric disorders. Individuals displaying decreased frequencies of male-typical gender-role behaviors (eg, decreased frequencies of rough-and-tumble play, aggression, or decreased spatial ability) may not be at increased or decreased risk for psychopathology in general, but they may be less likely to present with male-typical disorders, such as conduct disorders or substance abuse, and perhaps more likely to present with female-typical disorders, such as depression.

The possibility that the organizational effects of androgens exert a major influence on the expression of psychopathology is made explicit in pathophysiologic models of Tourette syndrome (TS),134 a disorder that affects males 4—10 times more frequently than females.135-137 Twin and family genetic studies provide strong evidence for the importance of genes of major effect in the pathophysiology of TS. To date, however, studies that have screened large multigenerational families have not identified linkage of a particular chromosomal region with the vertical transmission of the syndrome. One hypothesis consistent with sex differences in the prevalence of TS is that variability in prenatal androgen levels may affect expression of the TS vulnerability genes, either by regulating transcription of those genes during critical periods of development or by organizing brain structures that influence the expression and natural history of TS symptoms.134 Consistent with this possibility is magnetic resonance imaging evidence that TS patients have a reduction in normal brain asymmetries138-140 and altered sex differences in regional brain volumes, particularly in parietooccipital cortices.141

Noninvasive neuroimaging techniques make it possible to adapt methodologies used in animal research (ie, brain morphometry) to human studies of sexual differentiation of the CNS and sexually dimorphic psychopathologies. In women with TS, for example, masculinization of sexually dimorphic brain structures141 is consistent with prenatal steroid effects on the development of psychopathology. However, in rats, postnatal steroid levels and gender socialization (ie, greater maternal stimulation of the anogenital region of male than female pups) can regulate some sexually dimorphic structures (ie, the size of the SNB motor neurons).142 The possibility that gender socialization and sex steroids in postnatal development influence CNS organization suggests that in future biologic research of psychopathology it may be useful to consider typical and atypical development of these structures along with gender socialization and postnatal reproductive development. Excluding atypical gender socialization or atypical adrenal or gonadal functioning in girls or women with TS who show shifts in brain asymmetry, for example, would strengthen the hypothesis that altered sex differences in regional brain volumes derive from perinatal steroid effects on CNS development. Similarly, recent imaging data suggest that amygdala activation during the processing of negative affect is greater in men than in women,143 but the etiology of this sex difference in brain function is unknown. Including measures of gender-role behavior and reproductive status in future studies of age-related changes in amygdala structure and function may address whether these differences derive primarily from early brain organization, gender-role socialization (eg, differential reinforcement of emotional processing in girls and boys), or sex differences in concurrent steroid levels.

A widely used strategy to evaluate the organizational effects of prenatal steroids on human development can be applied to the study of sexually dimorphic psychopathology. This strategy involves measuring the postnatal behavioral correlates of early steroid effects on brain development. The hypothesis that prenatal androgens predispose vulnerable males to ADHD, for example, has been explored using animal models of ADHD. Testosterone is known to affect both dopamine activity in the mesolimbic system and the development of dopamine systems in the frontal cortex144–a brain region repeatedly implicated in the pathogenesis of ADHD.145 In spontaneously hypertensive rat pups (an animal model of ADHD), high levels of perinatal testosterone exaggerate deficits in spatial learning, increase adrenocorticotropic hormone levels, and slow development of catecholamine neurons in the frontal cortex.146 Although levels of rough-and-tumble play were not evaluated in that study, observations that ADHD children have heightened aggressive play tendencies suggest that measuring frequencies of androgen-dependent behaviors, such as rough-and-tumble play, in animal models of this disorder may prove informative.

In humans, similar behavioral markers of early steroid effects (eg, play and spatial ability) may provide additional converging evidence for the importance of androgens in the pathophysiology of sex differences in psychopathology. For example, in future tests of prenatal androgen effects on the development of TS, it may be useful to measure sexually dimorphic behaviors that are associated with known androgenizing syndromes in humans, such as CAH. Sexually dimorphic play, in particular, may be a useful measure of early androgen effects because, unlike most androgen-dependent behaviors, it seems unaffected by changes in postnatal steroid levels. Similarly, other markers of early brain sexual differentiation–such as the lengths of the second and fourth fingers (which are more discrepant in males than females147), human otoacoustic emissions (sounds produced in the cochlea that are stronger and more frequent in females of all ages148), or other sexually dimorphic physical characteristics–may be useful to consider in relation to sex-typed psychopathology.

Postnatal Steroid Effects

Sensitivity to sex steroids in postnatal life is a general characteristic of behaviors that show sex differences, but it is not a characteristic of behaviors that do not show sex differences.31 Therefore, the developmental trajectories and natural histories of psychopathologies in males and females suggest that the postnatal hormonal milieu modifies the expression of psychiatric disorders, as it does with other sexually dimorphic behaviors. Activational effects of androgens, for example, are implicated in the expression of chronic vocal and motor tics. Briefly, periods of increased adrenal- and gonadal-steroid production (eg, adrenarche, puberty, pregnancy, and across the luteal phase of the menstrual cycle) coincide with the onset or expression of chronic motor and vocal tics.134,149 For example, the modal age of onset of tics (7 years of age for motor tics and 9 years of age for phonic tics) occurs in temporal proximity to the known increase in adrenal androgens. Tic severity also increases during the prepubertal period, when gonadal androgen production markedly increases. Significantly, the hypothesis that androgen levels in adulthood influence symptom severity is also supported by reports that androgen administration produces symptom exacerbation150 and that androgen receptor blockade attenuates TS symptoms in some individuals.151

In general, despite the associations between endogenous steroid levels and symptom onset or severity152-154 and evidence that steroids modulate neurotransmitter systems implicated in the etiology and treatment of psychiatric disorders,155 there is considerable variability across patient groups in the magnitude and direction of any steroid effects on behavior. In men who have androgen deficiencies, for example, androgen replacement generally improves mood and decreases anger.110,111 In healthy men who have normal hormonal profiles, however, supraphysiologic doses of androgens can increase sexual arousal to erotic stimuli,112,156 as well as induce mania and aggressive behavior.157 Similarly, although menstrual cycle changes can affect cognitive performance,108,109 sudden decreased estrogen levels associated with the postpartum period158 or following administration of leuprolide acetate159 are associated with considerable impairment in memory, attention, and concentration in only a small percentage of women. Considerable individual variability in behavioral responsiveness to hormone levels is also supported by reports that manipulating androgen availability in the treatment of symptoms in sex-specific disorders has variable degrees of effectiveness.152,160,161

Characteristics of individuals who are behaviorally sensitive to changing sex steroids levels are not well-established.162 In studies of male rats, individual variability in hormone sensitivity is associated with a variety of behavioral indicators of general arousal, including habituation measures and pain thresholds.163 A similar association has been observed between pain sensitivity and sexual interest in women and men,164 suggesting that levels of sex-typed behaviors may be associated with indicators of central arousal, similar to the associations reported in animals. Other research suggests that the association of androgens with behavioral measures is stronger in right-handed individuals than in left-handed individuals,165-168 perhaps because the degree or direction of brain lateralization may derive from early sensitivity to steroid hormone effects. Consistent with these findings, one favored explanation for the inconsistent effects of sex steroids on the brain and behavior in postnatal life is that they depend on hormone effects that are established early in perinatal brain development. Activational effects of steroid hormones on psychopathology and human behavior may, therefore, be evaluated more fully when there is a concurrent consideration of the early organizational effects of steroids on behavior. By adopting methodologies used successfully in other research of prenatal steroids and human sex-typed behavior, it may be possible to identify patient groups who have been exposed to altered prenatal steroid levels and have an altered behavioral sensitivity to postnatal steroids.

Conclusion

Not long ago, observations that castrates could engage in sexual intercourse were thought to herald the emancipation of human behavior from hormonal control.171 More recent, careful behavioral deconstruction in studies of individuals who have typical and atypical reproductive development, however, has deepened our understanding of the biologic basis of human behavior. It suggests that in humans, as in other species, the actions of androgens during prenatal and postnatal life profoundly influence the development of sex-typed behaviors through their organizational and activational effects on CNS development. Gender roles and gender socialization have long been implicated in the development of sex differences in psychopathology. Increasing evidence suggests that sexual differentiation of the CNS may also have an important influence on the rates and expression of various forms of psychopathology. It is possible that by studying psychopathology in the broader construct of sex-typed behaviors, the influence of androgens in both the normal and abnormal expression of human behavior will be more fully understood.

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Dr. Alexander is a postdoctoral associate and Dr. Peterson is the House Jameson Associate Professor of Child Psychiatry and Diagnostic Radiology, both in the Child Study Center at Yale University in New Haven, CT.
Disclosure: This work was supported by National Institutes of Health Grants MH01232 and MH59139 (to Dr. Peterson).

Males are more likely to present with conduct disorders, attention-deficit/hyperactivity disorder (ADHD), substance abuse, learning disorders, and chronic motor tics. Furthermore, the onset of male-typed disorders and other psychiatric disorders, such as schizophrenia and OCD

This paper provides a summary of research investigating hormonal influences on human behavior and describes how sex differences in the prevalences and natural histories of developmental psychopathologies may be consistent with these steroid effects