References 5.a: Causes – Hormone exposure – Human studies

An endocrine disrupting chemical, bisphenol A: could it be associated with sex differentiation in brain regarding to transsexuality?

Transsexuality is characterised by a belief of having been born in a wrong body. Sexual differentiation of genitals take place in the first 2 months of pregnancy. Sexual differentiation of brain takes place in the second half of pregnancy. It is found that there is structural sex differences in the central nucleus of the bed nucleus of the stria terminalis (BSTc). Structural differences were found to be reversed in transsexual people. In humans main mechanism appears to involve a direct effect of testosterone on the developing brain. Direct effect of testosterone on developing brain in boys and lack of this effect in girls are crucial factors in the development of male and female gender identity. The origin of transsexuality is based on the fact that the differentiation of sexual organs takes place before the sexual differentiation of the brain. It was found a reversal in BSTc. In men this area is twice the size of that in women. In male-to-female transsexuals they found female BSTc. They had shown that sex reversal of the differences in the BSTc were independent of changing hormone levels in adulthood. The size of BSTc and the number of neurons match the gender that transsexuals feel they belong to, not the sex of their sexual organs. An endocrine disrupting chemical (EDC), bisphenol A (BPA), acts as oestrogen mimic compund. BPA may affect sexual differentiation of brain and cause reversal of differentiation in male to female transsexual as female brain. Brain expresses the oestrogen receptors and other hormone receptors making it a potential target for EDC. Transsexuality presume a combination of a genetic background and an early effect on interaction of sex hormones with developing brain during critical foetal period. We hypothesize that exposure to BPA may be a cause for transsexualism.

Author/-s:       Banu Sarer Yurekli; Nilufer Ozdemir Kutbay; Fusun Saygili

Publication:     Endocrine Abstracts, 2015

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Early androgen exposure and human gender development

During early development, testosterone plays an important role in sexual differentiation of the mammalian brain and has enduring influences on behavior. Testosterone exerts these influences at times when the testes are active, as evidenced by higher concentrations of testosterone in developing male than in developing female animals. This article critically reviews the available evidence regarding influences of testosterone on human gender-related development. In humans, testosterone is elevated in males from about weeks 8 to 24 of gestation and then again during early postnatal development. Individuals exposed to atypical concentrations of testosterone or other androgenic hormones prenatally, for example, because of genetic conditions or because their mothers were prescribed hormones during pregnancy, have been consistently found to show increased male-typical juvenile play behavior, alterations in sexual orientation and gender identity (the sense of self as male or female), and increased tendencies to engage in physically aggressive behavior. Studies of other behavioral outcomes following dramatic androgen abnormality prenatally are either too small in their numbers or too inconsistent in their results, to provide similarly conclusive evidence. Studies relating normal variability in testosterone prenatally to subsequent gender-related behavior have produced largely inconsistent results or have yet to be independently replicated. For studies of prenatal exposures in typically developing individuals, testosterone has been measured in single samples of maternal blood or amniotic fluid. These techniques may not be sufficiently powerful to consistently detect influences of testosterone on behavior, particularly in the relatively small samples that have generally been studied. The postnatal surge in testosterone in male infants, sometimes called mini-puberty, may provide a more accessible opportunity for measuring early androgen exposure during typical development. This approach has recently begun to be used, with some promising results relating testosterone during the first few months of postnatal life to later gender-typical play behavior. In replicating and extending these findings, it may be important to assess testosterone when it is maximal (months 1 to 2 postnatal) and to take advantage of the increased reliability afforded by repeated sampling.

Author/-s:       Melissa Hines; Mihaela Constantinescu; Debra Spencer

Publication:     Biology of Sex Differences, 2015

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Gender identity development in children with heightened prenatal androgen exposure

Understanding how gender identity develops has important theoretical implications for typically developing populations and clinical implications for those with gender variability or dysphoria (e.g. low contentment with one’s assigned gender) and practical implications for the assignment and management of gender in children born with ambiguous sex/genitalia. While chromosomal females exposed to heightened levels of androgens prenatally consistently express later masculinised/defeminised gendered behaviour, the relationship between prenatal androgen exposure and gender identity development (masculinisation/defeminisation and feelings associated with this) is less consistent. Between-group differences in gender identity, gendered behaviour, gender typicality, gender contentedness, and felt pressure for gender conformity were examined in a sample of children (age 7 – 11) with congenital adrenal hyperplasia (CAH; 23 males, 26 females) together with unaffected siblings (19 males, 29 females). Analyses reveal reduced gender typicality and gender contentedness in girls with CAH together with reduced female gender identity and increased cross-sex gendered behaviour. Bootstrapping mediation analysis examining gender typicality, gender contentedness, and gendered behaviour as mediators between prenatal androgen exposure typicality and gender identity revealed two important relationships: (1) gendered behaviour mediated the relationship between prenatal androgen exposure typicality and gender identity and, (2) this mediation was moderated by gender typicality and gender contentedness. These findings suggest that, for girls with CAH, the increased expression of cross-sex gendered behaviour contributes to the development of desires to be the other sex and that this relationship may depend upon feelings of gender typicality and contentedness.

Author/-s:       Miranda L. Abild

Publication:     Dissertation, Department of Psychology, University of Cambridge, 2015

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Gendered Development

How does human behavior come to be gendered, and how do gendered behaviors change or remain stable over time? Although men and women, as well as girls and boys, are largely similar psychologically and behaviorally, there are some areas of gender difference. These include gender identity; sexual orientation; childhood play behaviors, such as toy, playmate, and activity preferences; personality characteristics, such as aggression and empathy; and some specific spatial, mathematical, and verbal abilities. The incidence of many psychiatric disorders also differs by sex. These gender differences appear to result from numerous factors and their interactions. These include genetic information on the sex chromosomes; concentrations of gonadal steroids, particularly testosterone, before and shortly after birth; socialization by parents, peers, teachers, and strangers; and cognitive developmental processes. Gender identity also is a mechanism for acquiring gendered behavior; based on this identity, children self-socialize gendered behavior. These factors have been shown to act individually to influence gendered outcomes. They are also likely to interact with one another to shape gender development, but little research has investigated these interactions. An understanding of gendered development is important for addressing differences between the sexes in social roles and economic status, and should also be relevant to understanding and ameliorating psychiatric disorders that differ by gender. A complete understanding will probably require developmental systems approaches to understanding change and stability over time, but, thus far, such approaches have been uncommon.

Author/-s:       Melissa Hines

Publication:     Handbook of Child Psychology and Developmental Science, 2015

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Postnatal penile growth concurrent with mini-puberty predicts later sex-typed play behavior: Evidence for neurobehavioral effects of the postnatal androgen surge in typically developing boys

The masculinizing effects of prenatal androgens on human neurobehavioral development are well established. Also, the early postnatal surge of androgens in male infants, or mini-puberty, has been well documented and is known to influence physiological development, including penile growth. However, neurobehavioral effects of androgen exposure during mini-puberty are largely unknown. The main aim of the current study was to evaluate possible neurobehavioral consequences of mini-puberty by relating penile growth in the early postnatal period to subsequent behavior. Using multiple linear regression, we demonstrated that penile growth between birth and three months postnatal, concurrent with mini-puberty, significantly predicted increased masculine/decreased feminine behavior assessed using the Pre-school Activities Inventory (PSAI) in 81 healthy boys at 3 to 4 years of age. When we controlled for other potential influences on masculine/feminine behavior and/or penile growth, including variance in androgen exposure prenatally and body growth postnally, the predictive value of penile growth in the early postnatal period persisted. More specifically, prenatal androgen exposure, reflected in the measurement of anogenital distance (AGD), and early postnatal androgen exposure, reflected in penile growth from birth to 3 months, were significant predictors of increased masculine/decreased feminine behavior, with each accounting for unique variance. Our findings suggest that independent associations of PSAI with AGD at birth and with penile growth during mini-puberty reflect prenatal and early postnatal androgen exposures respectively. Thus, we provide a novel and readily available approach for assessing effects of early androgen exposures, as well as novel evidence that early postnatal aes human neurobehavioral development.

Author/-s:       Vickie Pasterski; Carlo L. Acerini; David B. Dunger; Ken K. Ong; Ieuan A. Hughes; Ajay Thankamony; Melissa Hines

Publication:     Hormones and Behavior, 2015

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Psychomedical care in gender identity dysphoria during adolescence

Introduction: In the clinical literature, the term gender dysphoria is used to define the perception of rejection that a person has to the fact of being male or female. In children and adolescents, gender identity dysphoria is a complex clinical entity. The result of entity is variable and uncertain, but in the end only a few will be transsexuals in adulthood.


  • To review the current status of the etiology and prevalence, Spanish health care protocols, DSM-V, ICD-10 and international standards.

  • Psychomedical intervention in under 18 year-olds.


  • A review of PubMed and UpToDate databases.

  • Presentation of a clinical case in adolescence woman > man.

Results and conclusions

  • There is evidence of a hormonal impact on the etiology of gender identity dysphoria and an underestimation of its prevalence.

  • Relevance to DSM-V, including the replacement of the term «gender identity disorder» by «dysphoria gender identity», and thus the partial removal of the previous disease connotation.

  • The seventh edition of the international standards World Professional Association for Transgender Health highlight the role of the therapist for advice on the way to the transition.

  • The Spanish 2012 guide stands out for its wealth of details and explanations, with a language targeted at different professionals.

  • Dysphoria gender identity must be studied by a multidisciplinary team, in which the psychotherapist must be expert in developmental psychopathology and evaluate emotional and behavioral problems.

Author/-s:       Isabel Sánchez Lorenzo; Juan José Mora Mesa; Olga Oviedo de Lúcas

Publication:     Revista de Psiquiatría y Salud Mental, 2015

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Brain responses to sexual images in 46,XY women with complete androgen insensitivity syndrome are female-typical

Androgens, estrogens, and sex chromosomes are the major influences guiding sex differences in brain development, yet their relative roles and importance remain unclear. Individuals with complete androgen insensitivity syndrome (CAIS) offer a unique opportunity to address these issues. Although women with CAIS have a Y chromosome, testes, and produce male-typical levels of androgens, they lack functional androgen receptors preventing responding to their androgens. Thus, they develop a female physical phenotype, are reared as girls, and develop into women. Because sexually differentiated brain development in primates is determined primarily by androgens, but may be affected by sex chromosome complement, it is currently unknown whether brain structure and function in women with CAIS is more like that of women or men. In the first functional neuroimaging study of (46,XY) women with CAIS, typical (46,XX) women, and typical (46, XY) men, we found that men showed greater amygdala activation to sexual images than did either typical women or women with CAIS. Typical women and women with CAIS had highly similar patterns of brain activation, indicating that a Y chromosome is insufficient for male-typical human brain responses. Because women with CAIS produce male-typical or elevated levels of testosterone which is aromatized to estradiol these results rule out aromatization of testosterone to estradiol as a determinate of sex differences in patterns of brain activation to sexual images. We cannot, however, rule out an effect of social experience on the brain responses of women with CAIS as all were raised as girls.

Author/-s:       Stephan Hamann; Jennifer Stevens; Janice Hassett Vick; Kristina Bryk; Charmian A.Quigley; Sheri A. Berenbaum; Kim Wallen

Publication:     Hormones and behaviour, 2014

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Exposure to prenatal life events stress is associated with masculinized play behavior in girls

Previous research has shown that prenatal exposure to endocrine-disrupting chemicals can alter children's neurodevelopment, including sex-typed behavior, and that it can do so in different ways in males and females. Non-chemical exposures, including psychosocial stress, may disrupt the prenatal hormonal milieu as well. To date, only one published study has prospectively examined the relationship between exposure to prenatal stress and gender-specific play behavior during childhood, finding masculinized play behavior in girls who experienced high prenatal life events stress, but no associations in boys. Here we examine this question in a second prospective cohort from the Study for Future Families. Pregnant women completed questionnaires on stressful life events during pregnancy, and those who reported one or more events were considered "stressed". Families were recontacted several years later (mean age of index child: 4.9 years), and mothers completed a questionnaire including the validated Preschool Activities Inventory (PSAI), which measures sexually dimorphic play behavior. In sex-stratified analyses, after adjusting for child's age, parental attitudes toward gender-atypical play, age and sex of siblings, and other relevant covariates, girls (n=72) exposed to prenatal life events stress had higher scores on the PSAI masculine sub-scale (β=3.48; p=0.006) and showed a trend toward higher (more masculine) composite scores (β=2.63; p=0.08). By contrast, in males (n=74), there was a trend toward an association between prenatal stress and higher PSAI feminine sub-scale scores (β=2.23; p=0.10), but no association with masculine or composite scores. These data confirm previous findings in humans and animal models suggesting that prenatal stress is a non-chemical endocrine disruptor that may have androgenic effects on female fetuses and anti-androgenic effects on male fetuses.

Author/-s:       E. S. Barrett; J. B. Redmon; C. Wang; A. Sparks; S. H. Swan

Publication:     Neurotoxicology, 2014

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Finger length ratios in Serbian transsexuals

Abstract: Atypical prenatal hormone exposure could be a factor in the development of transsexualism. There is evidence that the 2nd and 4th digit ratio (2D : 4D) associates negatively with prenatal testosterone and positively with estrogens. The aim was to assess the difference in 2D : 4D between female to male transsexuals (FMT) and male to female transsexuals (MFT) and controls. We examined 42 MFT, 38 FMT, and 45 control males and 48 control females. Precise measurements were made by X-rays at the ventral surface of both hands from the basal crease of the digit to the tip using vernier calliper. Control male and female patients had larger 2D : 4D of the right hand when compared to the left hand. Control male’s left hand ratio was lower than in control female’s left hand. There was no difference in 2D : 4D between MFT and control males. MFT showed similar 2D : 4D of the right hand with control women indicating possible influencing factor in embryogenesis and consequently finger length changes. FMT showed the lowest 2D : 4D of the left hand when compared to the control males and females. Results of our study go in favour of the biological aetiology of transsexualism.

Conclusion: Transsexualism in humans is biological in origin. Our findings support a biological etiology of MFT implicating decreased prenatal androgen exposure in MFT. 2D:4D could be potentially used as a marker for prenatal androgen exposure.

Author/-s:       Svetlana Vujović; Srdjan Popović; Ljiljana Mrvošević Marojević; Miomira Ivović; Milina Tančić-Gajić; Miloš Stojanović; Ljiljana V. Marina; Marija Barać; Branko Barać; Milena Kovačević; Dragana Duišin; Jasmina Barišić; Miroslav L. Djordjević; Dragan Micić

Publication:     The Scientific World Journal, 2014

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Identical Reared Apart Twins Concordant for Transsexuality

A growing twin-based literature supports genetic influence on gender identity development. An international survey of adult transsexual twin pairs reported transition concordance values of 33.3 % (13 ∕ 39) for identical [monozygotic (MZ)] male pairs and 22.9 % (8 ∕ 35) for MZ female pairs. By contrast, transition concordance values for fraternal [dizygotic (DZ)] male and female twins were zero or approached zero (1 ∕ 36), consistent with genetic influence. Here, we report the first case of transsexualism in both reared apart brothers of a male-to-female MZ twin pair.

One twin (AT) committed suicide at age 35 years; therefore, interviews were conducted in 2012–2013 with the surviving co-twin (LT) at age 50 years. Prior to AT’s death, DNA testing had confirmed the twins’ monozygosity, as did a twin-typing questionnaire administered to LT. […]

LT learned that he had a twin at the age of 15 when his mother revealed this secret information inadvertently. When the twins were 15.5 years of age, LT’s mother arranged a reunion. Prior to meeting, by age 8 years both twins experienced gender discomfort, engaged in cross-dressing, and felt that they should have been born as the other gender. Also prior to meeting, both twins experienced unease with the anticipated and actual secondary sexual development of puberty. Furthermore, unbeknownst to his twin, at age 14 years LT was fully committed to undergoing sex reassignment surgery and so convinced his mother that she took him to see an urologist. Thus, both twins met the diagnostic criteria of the fifth edition of the Diagnostic and Statistical Manual (DSM-5) for gender dysphoria, in particular persistent cross-gender identification and a strong desire to change the sexual characteristics to those of the other gender.

Genetic effects on transsexuality are strongly indicated by this unique case study. The nature and extent of family support also affect the behavioral adjustment of transsexual individuals, as evidenced by LT’s more favorable outcome and AT’s tragic outcome.

Author/-s:       Nancy Segal; Milton Diamond

Publication:     Letter to the Editor, Journal of Clinical and Experimental Medicine, 2014

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Increased Cross-Gender Identification Independent of Gender Role Behavior in Girls with Congenital Adrenal Hyperplasia: Results from a Standardized Assessment of 4- to 11-Year-Old Children

While reports showing a link between prenatal androgen exposure and human gender role behavior are consistent and the effects are robust, associations to gender identity or cross-gender identification are less clear. The aim of the current study was to investigate potential cross-gender identification in girls exposed prenatally to high concentrations of androgens due to classical congenital adrenal hyperplasia (CAH). Assessment included two standardized measures and a short parent interview assessing frequency of behavioral features of cross-gender identification as conceptualized in Part A of the diagnostic criteria for gender identity disorder (GID) in the DSM-IV-TR. Next, because existing measures may have conflated gender role behavior with gender identity and because the distinction is potentially informative, we factor analyzed items from the measures which included both gender identity and gender role items to establish the independence of the two constructs. Participants were 43 girls and 38 boys with CAH and 41 unaffected female and 31 unaffected male relatives, aged 4- to 11-years. Girls with CAH had more cross-gender responses than female controls on all three measures of cross-gender identification as well as on a composite measure of gender identity independent of gender role behavior. Furthermore, parent report indicated that 5/39 (12.8%) of the girls with CAH exhibited cross-gender behavior in all five behavioral domains which comprise the cross-gender identification component of GID compared to 0/105 (0.0%) of the children in the other three groups combined. These data suggest that girls exposed to high concentrations of androgens prenatally are more likely to show cross-gender identification than girls without CAH or boys with and without CAH. Our findings suggest that prenatal androgen exposure could play a role in gender identity development in healthy children, and may be relevant to gender assignment in cases of prenatal hormone disruption, including, in particular, cases of severely virilized 46,XX CAH.

Author/-s:       Vickie Pasterski; Kenneth J. Zucker; Peter C. Hindmarsh; Ieuan A. Hughes; Carlo Acerin; Debra Spencer; Sharon Neufeld; Melissa Hines

Publication:     Awaiting publication by Springer, 2014

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Neural Activation During Mental Rotation in Complete Androgen Insensitivity Syndrome: the Influence of Sex Hormones and Sex Chromosomes

Sex hormones, androgens in particular, are hypothesized to play a key role in the sexual differentiation of the human brain. However, possible direct effects of the sex chromosomes, that is, XX or XY, have not been well studied in humans. Individuals with complete androgen insensitivity syndrome (CAIS), who have a 46,XY karyotype but a female phenotype due to a complete androgen resistance, enable us to study the separate effects of gonadal hormones versus sex chromosomes on neural sex differences. Therefore, in the present study, we compared 46,XY men (n = 30) and 46,XX women (n = 29) to 46,XY individuals with CAIS (n = 21) on a mental rotation task using functional magnetic resonance imaging. Previously reported sex differences in neural activation during mental rotation were replicated in the control groups, with control men showing more activation in the inferior parietal lobe than control women. Individuals with CAIS showed a female-like neural activation pattern in the parietal lobe, indicating feminization of the brain in CAIS. Furthermore, this first neuroimaging study in individuals with CAIS provides evidence that sex differences in regional brain function during mental rotation are most likely not directly driven by genetic sex, but rather reflect gonadal hormone exposure.

Author/-s:       Judy van Hemmen; Dick J. Veltman; Elseline Hoekzema; Peggy T. Cohen-Kettenis; Arianne B. Dessens; Julie Bakker

Publication:     Cerebral Cortex, 2014

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Neurobiological bases of gender differences

The study of gender differences in neuroscience is quite recently but demostrate the sexual brain dimorphism. The aim of this review is study the anatomic and functional gender brain differences. We examined the differences in the brain structures, morphologie, volume, gray/white matter ratio and laterality. We analized the hormonal influence in body asymmetry development and in the abilities acquisition. For all brain structures, male volumes were greater then female, but the gray/white matter ratio was consistenly higher across structures in women than men. The cingulate gyrus and insula exhibit strong asymmetries. The prenatal androgens stimule the development of right brain hemisphere and the right hemibody. The early organizational effects of sex steroides on the mammalian brain imply differences between men and women in some specific cognitive abilities.

Author/-s:       Teresa Guilera Lladós

Publication:     [to be completed], 2014

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Otoacoustic Emissions, Auditory Evoked Potentials and Self-Reported Gender in People Affected by Disorders of Sex Development (DSD)

Both otoacoustic emissions (OAEs) and auditory evoked potentials (AEPs) are sexually dimorphic, and both are believed to be influenced by prenatal androgen exposure. OAEs and AEPs were collected from people affected by 1 of 3 categories of disorders of sex development (DSD) – (1) women with complete androgen insensitivity syndrome (CAIS); (2) women with congenital adrenal hyperplasia (CAH); and (3) individuals with 46,XY DSD including prenatal androgen exposure who developed a male gender despite initial rearing as females (men with DSD). Gender identity (GI) and role (GR) were measured both retrospectively and at the time of study participation, using standardized questionnaires. The main objective of this study was to determine if patterns of OAEs and AEPs correlate with gender in people affected by DSD and in controls. A second objective was to assess if OAE and AEP patterns differed according to degrees of prenatal androgen exposure across groups. Control males, men with DSD, and women with CAH produced fewer spontaneous OAEs (SOAEs) – the male-typical pattern – than control females and women with CAIS. Additionally, the number of SOAEs produced correlated with gender development across all groups tested. Although some sex differences in AEPs were observed between control males and females, AEP measures did not correlate with gender development, nor did they vary according to degrees of prenatal androgen exposure, among people with DSD. Thus, OAEs, but not AEPs, may prove useful as bioassays for assessing early brain exposure to androgens and predicting gender development in people with DSD.

Author/-s:       Amy B. Wisniewski; Blas Espinoza-Varas; Christopher E. Aston; Shelagh Edmundson; Craig A. Champlin; Edward G. Pasanen; Dennis McFadden

Publication:     Hormones and Behaviour, 2014

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Postnatal Testosterone Concentrations and Male Social Development

Converging evidence from over 40years of behavioral research indicates that higher testicular androgens in prenatal life and at puberty contribute to the masculinization of human behavior. However, the behavioral significance of the transient activation of the hypothalamic–pituitary–gonadal (HPG) axis in early postnatal life remains largely unknown. Although early research on non-human primates indicated that suppression of the postnatal surge in testicular androgens had no measurable effects on the later expression of the male behavioral phenotype, recent research from our laboratory suggests that postnatal testosterone concentrations influence male infant preferences for larger social groups and temperament characteristics associated with the later development of aggression. In later assessment of gender-linked behavior in the second year of life, concentrations of testosterone at 3–4 months of age were unrelated to toy choices and activity levels during toy play. However, higher concentrations of testosterone predicted less vocalization in toddlers and higher parental ratings on an established screening measure for autism spectrum disorder. These findings suggest a role of the transient activation of the HPG axis in the development of typical and atypical male social relations and suggest that it may be useful in future research on the exaggerated rise in testosterone secretion in preterm infants or exposure to hormone disruptors in early postnatal life to include assessment of gender-relevant behavioral outcomes, including childhood disorders with sex-biased prevalence rates.

Author/-s:       Gerianne M. Alexander

Publication:     Froniters in Endocrinology, 2014

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Sex Differentiation: Organizing Effects of Sex Hormones

Men and women differ, not only in their anatomy but also in their behavior. Research using animal models has convincingly shown that sex differences in the brain and behavior are induced by sex hormones during a specific, hormone-sensitive period during early development. Thus, a male-typical brain is organized under the influence of testosterone, mostly acting during fetal development, whereas a female-typical brain is organized under the influence of estradiol, mostly acting after birth, during a specific prepubertal period. Sex differences in behavior reflect sex differences in the brain, mostly in the hypothalamus and the olfactory system, the latter being important in mate selection. There is also evidence, albeit clinical, for a role of testosterone in the sexual differentiation of the human brain, in particular in inducing male gender role behavior and heterosexual orientation. However, whether estradiol is involved in the development of a female brain in humans still needs to be elucidated.

Author/-s:       Julie Bakker

Publication:     Focus on Sexuality Research, 2014

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The effect of 5a-reductase-2 deficiency on human fertility

A most interesting and intriguing male disorder of sexual differentiation is due to 5α-reductase-2 isoenzyme deficiency. These males are born with ambiguous external genitalia due to a deficiency in their ability to catalyze the conversion of testosterone to dihydrotestosterone (DHT). DHT is a potent androgen responsible for differentiation of the urogenital sinus and genital tubercle into the external genitalia, urethra and prostate. Affected males are born with a clitoral-like phallus, bifid scrotum, hypospadias, blind shallow vaginal pouch from incomplete closure of the urogenital sinus and a rudimentary prostate. At puberty, the surge in mainly testosterone production prompts virilization, causing most to choose gender reassignment to male.

Fertility is a challenge for affected men for several reasons. Uncorrected cryptorchidism is associated with low sperm production, and there is evidence of defective transformation of spermatogonia into spermatocytes. The underdeveloped prostate and consequent low semen volumes affect sperm transport. Additionally, semen may not liquefy due to a lack of prostate-specific antigen. In this review, we discuss the 5α-reductase-2 deficiency syndrome and its impact on human fertility.

Author/-s:       Hey-Joo Kang; Julianne Imperato-McGinley; Yuan-Shan Zhu; Zev Rosenwaks

Publication:     Fertility and sterility, 2014

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White Matter Microstructure in Transsexuals and Controls Investigated by Diffusion Tensor Imaging

Biological causes underpinning the well known gender dimorphisms in human behavior, cognition, and emotion have received increased attention in recent years. The advent of diffusion-weighted magnetic resonance imaging has permitted the investigation of the white matter microstructure in unprecedented detail. Here, we aimed to study the potential influences of biological sex, gender identity, sex hormones, and sexual orientation on white matter microstructure by investigating transsexuals and healthy controls using diffusion tensor imaging (DTI). Twenty-three female-to-male (FtM) and 21 male-to-female (MtF) transsexuals, as well as 23 female (FC) and 22 male (MC) controls underwent DTI at 3 tesla. Fractional anisotropy, axial, radial, and mean diffusivity were calculated using tract-based spatial statistics (TBSS) and fiber tractography. Results showed widespread significant differences in mean diffusivity between groups in almost all white matter tracts. FCs had highest mean diffusivities, followed by FtM transsexuals with lower values, MtF transsexuals with further reduced values, and MCs with lowest values. Investigating axial and radial diffusivities showed that a transition in axial diffusivity accounted for mean diffusivity results. No significant differences in fractional anisotropy maps were found between groups. Plasma testosterone levels were strongly correlated with mean, axial, and radial diffusivities. However, controlling for individual estradiol, testosterone, or progesterone plasma levels or for subjects' sexual orientation did not change group differences. Our data harmonize with the hypothesis that fiber tract development is influenced by the hormonal environment during late prenatal and early postnatal brain development.

Author/-s:       Georg S. Kranz;  Andreas Hahn; Ulrike Kaufmann; Martin Küblböck; Allan Hummer; Sebastian Ganger; Rene Seiger; Dietmar Winkler; Dick F. Swaab; Christian Windischberger, Siegfried Kasper; Rupert Lanzenberger

Publication:     The Journal of Neuroscience, 2014

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This study was reported in some media articles: and

Are there parental socialization effects on the sex-typed behavior of individuals with congenital adrenal hyperplasia?

Influences of prenatal androgen exposure on human sex-typical behavior have been established largely through studies of individuals with congenital adrenal hyperplasia (CAH). However, evidence that addresses the potential confounding influence of parental socialization is limited. Parental socialization and its relationship to sex-typical toy play and spatial ability were investigated in two samples involving 137 individuals with CAH and 107 healthy controls. Females with CAH showed more boy-typical toy play and better targeting performance than control females, but did not differ in mental rotations performance. Males with CAH showed worse mental rotations performance than control males, but did not differ in sex-typical toy play or targeting. Reported parental encouragement of girl-typical toy play correlated with girl-typical toy play in all four groups. Moreover, parents reported encouraging less girl-typical, and more boy-typical, toy play in females with CAH than in control females and this reported encouragement partially mediated the relationship between CAH status and sex-typical toy play. Other evidence suggests that the reported parental encouragement of sex-atypical toy play in girls with CAH may be a response to the girls' preferences for boys' toys. Nevertheless, this encouragement could further increase boy-typical behavior in girls with CAH. In contrast to the results for toy play, we found no differential parental socialization for spatial activities and little evidence linking parental socialization to spatial ability. Overall, evidence suggests that prenatal androgen exposure and parental socialization both contribute to sex-typical toy play.

Author/-s:       W. I. Wong; V. Pasterski; P. C. Hindmarsh; M. E. Geffner; M. Hines

Publication:     Archives of sexual behaviour, 2013

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Behavioral Sexual Dimorphism in School-Age Children and Early Developmental Exposure to Dioxins and PCBs: A Follow-Up Study of the Duisburg Cohort

Background: Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that have been characterized as endocrine disrupting chemicals (EDCs).

Objectives: Within the Duisburg birth cohort study we studied associations of prenatal exposure to PCDD/Fs and PCBs with parent-reported sexually dimorphic behavior in children.

Methods: We measured lipid-based and WHO2005-TEq-standardized PCDD/Fs and PCBs in maternal blood samples and in early breast milk using gas chromatography/high-resolution mass-spectrometry (GC/HRMS). At the age of 6–8 years parents (mostly mothers) reported sex-typical characteristics, preferred toys and play activities using the Preschool Activities Inventory (PSAI) which was used to derive feminine, masculine and difference (feminine – masculine) scores. We estimated exposure-outcome associations using multivariate linear regression. Between 91 and 109 children were included in this follow-up.

Results: Mean blood levels of WHO2005TEq-standardized dioxins (Σ PCDD/Fs) were 14.5 ± 6.4 pg/g blood lipids, and of Σ PCBs 6.9 ± 3.8 pg/g blood lipids, with similar values for milk lipids. Regression analyses revealed some highly significant interactions between sex and exposure, e.g. for Σ PCBs in milk, pronounced positive (boys: β = 3.24; CI = 1.35, 5.14) or negative (girls: β = −3.59; CI = −1.10, −6.08) associations with reported femininity. Less pronounced and mostly insignificant but consistent associations were found for the masculinity score, positive for boys and negative for girls.

Conclusions: Based on our results and the findings of previous studies, we conclude that there is sufficient evidence that EDCs modify behavioral sexual dimorphism in children, presumably by interacting with the hypothalamic-pituitary-gonadal (HPG) axis.

Author/-s:       Gerhard Winneke; Ulrich Ranft; Jürgen Wittsiepe; Monika Kasper-Sonnenberg; Peter Fürst; Ursula Krämer; Gabriele Seitner; Michael Wilhelm

Publication:     Environmental health perspectives, 2013

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Digit ratios (2D:4D), postnatal testosterone and eye contact in toddlers

Previous research has shown an association between eye contact and prenatal testosterone measured in amniocenteses samples. The purpose of this study was to test the association between eye contact and prenatal androgen action measured via second to fourth digit ratios (2D:4D ratios), and to explore the relationship between eye contact and postnatal testosterone levels. Participants included 72 children, between the ages of 18 and 24 months, and their parents. Salivary testosterone levels were obtained when children were 3-months old. At 18-months, 2D:4D ratios were measured and parent-child dyads participated in an 8-min play session that was recorded and later coded for duration and frequency of eye contact. Results indicated that larger 2D:4D ratios (indicative of lower androgen levels) significantly predicted longer duration and more frequency of eye contact, while postnatal testosterone levels were unrelated to eye contact. These novel findings suggest prenatal androgens may influence the emergence of social development.

Author/-s:       J. Saenz; Gerianne M. Alexander

Publication:     Biological psychology, 2013

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From Gender Variance to Gender Dysphoria: Psychosexual development of gender atypical children and adolescents

Summary: Children may show variability in their gender role behaviors, interests and preferences and/or their experienced gender identity (their experience to be male, female or a different gender). Within the male-female continuum of gender role expressions and gender identity three groups can be distinguished. First, the gender normative children: Their gender role and gender identity are congruent with their natal sex. Second, the gender variant children: These children show (mild) cross-gender behaviors, interests and preferences, and may experience a gender identity which is congruent with their natal sex to a lesser extent than is the case in gender normative children. And third, the gender dysphoric children: These children show extreme and enduring forms of cross-gender role expressions, experience a cross-gender identity and fulfill the criteria of a DSM-IV-TR diagnosis of Gender Identity Disorder (GID) (American Psychiatric Association 2000). In contrast to most of the gender variant children, gender dysphoric children may need clinical attention as a result of significant distress or a significant risk of distress, and/or impairment in important areas of functioning. Knowledge about the future development, the trajectories and possible associated factors of gender non-normative children (both gender variant and genderdysphoric) is however limited.
The studies described in this thesis aimed to enhance our understanding of the development of gender variant and gender dysphoric children and adolescents, and to identify factors associated with the persistence and desistence of gender dysphoria.

In chapter 2, we provided an overview of what is currently known about the trajectories and contributing factors to gender identity development, particularly during adolescence in the general population and in gender variant/gender dysphoric youth. Compared to what is known from gender identity development in gender variant or gender dysphoric children, studies of normative gender identity development during adolescence in the general population are lacking behind.

With regard to the factors contributing to non-normative gender identity development, earlier studies mainly focused on the role of psychosocial factors. Factors such as elevated levels of psychopathology in the parents, increased anxiety of the child, and a lack of parental limit setting have been put forward as possible determinants. However, the evidence from these studies showed to be equivocal and it is unclear whether the factors that were associated with a non-normative gender identity development were the cause of this development or a consequence of the gender variance or gender dysphoria. More recently, research has focused on the role of biological factors on a non-normative gender identity development. Studies of individuals with a Disorder of Sex Development (DSD), congenital condi- tions in which the development of chromosomal, gonadal and/or anatomical sex is atypical (Hughes et al. 2006), point to the role of prenatal exposure to gonadal hormones and their effects on gender role behavior and possibly on gender identity development. From post mortem, neuropsychological, and brain imaging studies of individuals with gender dysphoria, differences between gender dysphoric individuals and members of their natal sex have been found. However, these differences were not found for all measures and the direction of the differences is not always consistent or not yet sufficient to form a basis for a broad theory on gender identity development. The current evidence makes clear that there is no simple relationship between psychological and social factors and gender identity development, and brain development and the development of gender identity. In addition to this, although several researchers have acknowledged that nature and nurture interact, they have not tried to integrate both aspects in their studies thus far.

As for the future development of gender dysphoric children, our overview of the literature indicated that gender identity in childhood seems more malleable than later in adolescence or in adulthood. Furthermore, we described that adolescence is a crucial period for the consolidation of gender identity and persistence of gender dysphoria. We discussed that the onset of physical puberty in this period may steer this process, but that there are also indications that cognitive aspects of gender identity (e.g. confusion and ambivalence with ones gender identity) has its own influence. For those without a history of childhood gender dysphoria, adolescence may initiate gender dysphoria. Regardless of the various developmental trajectories of a non-normative gender identity development, adolescence can be denoted as a crucial developmental period for gender identity.

In chapter 3 we reported on a study where we validated a 12-item dimensional scale that aims to measure gender dysphoria, in a sample of 1119 adolescents and adults (M age 24.6, range 12–75). The male (UGDS-M) and female (UGDS-F) versions of the Utrecht Gender Dysphoria Scale (UGDS) were assessed in a group of participants diagnosed with a GID (N=545), a group who was subthreshold for GID (N=103), participants with a DSD (N=60), and non-transgender heterosexual (N=219), gay/lesbian (N=150), and bisexual (N=42) controls. Both versions of the UGDS appeared to be reliable scales with a strong ability to discriminate between clinically referred gender dysphoric individuals and non-clinically referred controls and DSD participants. Sensitivity was 88.3 % (UGDS-M) and 98.5 % (UGDS-F), specificity was 99.5 % (UGDS-M) and 97.9 % (UGDS-F). Comparison of the mean total scores showed that there was significantly more gender dysphoria in participants diagnosed with a GID, compared to participants who were subthreshold for GID, for both versions. The two transgender groups showed significantly more gender dysphoria than the DSD and control participants. We concluded from our findings that these qualities make the instrument useful for clinical and research purposes.

Chapter 4 reported on a 24 years longitudinal study where we examined whether childhood gender variance was associated with the report of a bi- or homosexual sexual orientation and gender discomfort in adulthood in the general population. In a sample of 406 boys and 473 girls we measured gender variance in childhood (M age 7.5, range 4–11) and sexual orientation and gender dysphoria in adulthood (M age 30.9, range  27–36). Our findings showed that the intensity and presence of childhood gender variance was higher in girls than in boys, and that gender variance was reported more frequently in younger children than in older children. Furthermore, we found that the presence of childhood gender variance was associated with the presence of a homosexual orientation in adulthood, but not with bisexuality. The chance of a homosexual orientation in sexual attraction, sexual fantasy, sexual behavior, and sexual identity were 8 to 15 times higher for both male and female participants with a history of gender variance as reported by the parents (10.2 % to12.2 %), compared to participants without a history of gender variance (1.2 % to 1.7 %). The presence of childhood gender variance was not significantly associated with gender discomfort/gender dysphoria in adulthood. We concluded in this study that childhood gender variance, at least as measured by the Child Behavior Checklist (CBCL), is not predictive for a gender dysphoric outcome in adulthood in the general population. Furthermore, the presence of childhood gender variance and a homosexual sexual orientation in adulthood are associated in the general population, but this association is much weaker than in clinically referred gender dysphoric children.

Chapter 5 described the findings from a qualitative study where we tried to obtain a better understanding of the developmental trajectories of persistence and desistence of childhood gender dysphoria and the psychosexual outcome of gender dysphoric children. We interviewed 25 adolescents (M age 15.9, range 14–18), who were diagnosed with a Gender Identity Disorder (DSM-IV or DSM-IV-TR) in childhood (M age 9.4, range 6–12). Our findings on possible predictors in childhood for the different trajectories showed that the 14 persisters and 11 desisters reported quite similar childhood experiences, but subtle differences in their experience of gender and the labelling of their feelings were observed.

As for underlying mechanisms and experiences that may have steered the persistence and desistence of gender dysphoria, we identified the period between the ages of 10 and 13 to be crucial. In the perceptions of the adolescents, three factors were related in this period to the intensification of gender dysphoria in persisters or remittance of gender dysphoric feelings in the desisters; (1) the changing social environment, where the social distance between boys and girls gradually increases, (2) the anticipation of, and actual body changes during puberty, and (3) the experience of falling in love, sexual attraction and sexual experiences. Interestingly, even in this relatively small sample of adolescents, we observed that the feelings of gender dysphoria did not completely remit in all desisters. Furthermore, our observation of high reports of sexual orientations and sexual attractions directed towards individuals of the same natal sex seemed to be in concordance with the earlier findings from the prospective quantitative literature on gender dysphoric children. Finally, the stories of the persisters and desisters on the effect of social role transitioning (in appearance and/or a name change or pronoun change) revealed that transitioning was experienced as a relief in persisters, but could result in a troublesome process of changing back to their original gender for desisters.

Chapter 6 reported on a quantitative follow-up study that examined the factors associated with the persistence and desistence of childhood gender dysphoria, and adolescent feelings of gender dysphoria and sexual orientation. In a sample of 127 adolescents (79 boys, 48 girls), who were referred for gender dysphoria in childhood (age range 6–12) and followed up in adolescence (age range 15–19), we observed a persistence rate of 37 % (47 persisters out of the 127 adolescents). We examined childhood differences among persisters (N=47) and desisters (N=80) in demographics, developmental background, childhood psychological functioning, the quality of peer relations and childhood gender dysphoria, and adolescent reports of gender dysphoria, body image and sexual orientation. Our findings showed that persisters reported higher intensities of gender dysphoria, more body dissatisfaction and higher reports of a same natal-sex sexual orientation, compared to the desisters, and were in line with earlier findings from prospective follow-up studies in clinical populations.
As for the factors associated with the persistence of gender dysphoria, we found that a higher intensity of childhood gender dysphoria (through self- and parental report, and through cognitive and/or affective gender identity responses), an older age at referral, and transitioning (at least partially) to the preferred gender role were predictive of childhood gender dysphoria persistence. In addition to this, we found that the chance of persisting was higher in natal gender dysphoric girls than in boys, but that factors such as psychological functioning, the quality of peer relations, demographic (e.g. family structure, parents’ social economic class), and developmental background (e.g. birth weight, pregnancy duration) were not associated with the persistence of childhood gender dysphoria. Finally, our findings showed that the factors associated with the persistence of gender dysphoria were different for the two natal sexes. For natal boys, the age at referral, the gender role presentation, the self report of a cross-gender identification (“I am a boy” or “I am a girl”), and the parental report of the intensity of gender role behavior showed to be the major predictive factors for the persistence of gender dysphoria, whereas for girls, the self reported cross-gender identification and the intensity of gender dysphoria turned out to have a higher predictive value than the other evaluated factors.

Chapter 7 presented a communication where we addressed the topic of social transitioning in gender dysphoric children in early childhood. We reported on our observation of increasing numbers in our clinical population of children who completely (change in clothing and hair style, first name, and use of pronouns) or partially (change in clothing and hair style, but did not have a name and pronoun change) transitioned between the period of the year 2000 and 2009.

Before the year 2000, 2 prepubertal boys, out of 112 referred children to our clinic, were living completely in the female gender role. Between 2000 and 2004, 3.3 % (4 out of 121 children) had completely transitioned, and 19 % (23 out of 121 children) were partially transitioned when they were referred. In the period between 2005 and 2009 we observed that 8.9 % (16 out of 180 children) completely transitioned and 33.3 % (60 out of 180 children) partially transitioned at the time of referral.

In discussing the increasing rates of socially transitioned gender dysphoric children we noted that follow-up studies show that the persistence rate of childhood gender dysphoria is about 15.8 %, and wondered what would happen to children who transitioned in childhood, but turned out to be desisters. We referred to two cases of natal girls, who transitioned early in childhood and for whom the gender dysphoria desisted. Their process of changing back to their original gender was reported to be a troublesome process (Chapter 5 and Steensma et al. 2011). We concluded that it is advisable to be very careful when taking steps regarding social transitioning during the early childhood years, as they might be difficult to reverse.

In chapter 8 we described a cross-national investigation that examined the psychological functioning and the quality of peer relations between gender dysphoric youth from Toronto, Canada and Amsterdam, the Netherlands. In a sample of 544 children and 174 adolescents, referred to the specialized gender identity clinics in both countries, we assessed the Teacher’s Report Form to measure emotional and behavioral problems, the quality of peer relations and gender dysphoria. Our findings in both countries showed that the children were, on average, better functioning than the adolescents, and that the gender dysphoric boys showed to have poorer peer relations and more internalizing than externalizing problems compared to the gender dysphoric girls. As for the degree of behavioral problems in both countries, the quality of peer relations showed to be the strongest predictor. In discussing our findings we concluded that gender dysphoric children and adolescents showed the same pattern of emotional and behavioral problems in both countries, although there were significant differences in the prevalence of problems.

Between the two countries, we found clear differences: Both the children and the adolescents from Canada had more emotional and behavioral problems and a poorer quality of peer relations than the children and adolescents from the Netherlands. In line with previous comparisons of gender dysphoric children from the two countries, we found that children and adolescents from the Netherlands presented with significantly more cross-gender behavior than those from Canada. The differences between the two countries seemed to be an effect of a poorer quality of peer relations in Canada, compared to the Netherlands. We hypothesized that this may be the result of a difference in social tolerance towards gender variant expressions, as cross-cultural studies indicate that the Netherlands is much more tolerant towards homosexuality, and most likely also towards gender variance, than most countries in the world (Veenhoven 2005).

Author/-s:       Thomas Dirk Steensma

Publication:     Dissertation, Vrije Universiteit Amsterdam, 2013

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Gender differences in neurodevelopment and epigenetics

The concept that the brain differs in make-up between males and females is not new. For example, it is well established that anatomists in the nineteenth century found sex differences in human brain weight. The importance of sex differences in the organization of the brain cannot be overstated as they may directly affect cognitive functions, such as verbal skills and visuospatial tasks in a sex-dependent fashion. Moreover, the incidence of neurological and psychiatric diseases is also highly dependent on sex. These clinical observations reiterate the importance that gender must be taken into account as a relevant possible contributing factor in order to understand the pathogenesis of neurological and psychiatric disorders. Gender-dependent differentiation of the brain has been detected at every level of organization—morphological, neurochemical, and functional—and has been shown to be primarily controlled by sex differences in gonadal steroid hormone levels during perinatal development. In this review, we discuss how the gonadal steroid hormone testosterone and its metabolites affect downstream signaling cascades, including gonadal steroid receptor activation, and epigenetic events in order to differentiate the brain in a gender-dependent fashion.

Author/-s:       Wilson C. J. Chung; Anthony P. Auger

Publication:     European Journal of Physiology, 2013

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Postnatal testosterone levels and disorder relevant behavior in the second year of life

The objective of the current study was to investigate the relationship between testosterone collected at 3-4 months of age and sex-linked disorder-relevant behaviors in the second year of life. Eighty-four children participated at 3-4 (when salivary testosterone levels were obtained and second to fourth digit ratios were measured) and 18-24 months of age (when behavioral ratings of aggression and verbal ability were coded from two 8-min play sessions). Parents also completed the Brief Infant-Toddler Social and Emotional Assessment, and the four subscales (Internalizing, Externalizing, Dysregulation, and Autism Spectrum Disorder) were used to indicate child specific problems. Greater postnatal testosterone levels in early infancy were predictive of more male-typical behaviors in the second year of life (i.e., more autism spectrum behaviors, less time vocalizing, and more Internalizing Problems). These results support the hypothesis that early infancy may be another critical period for the development of gender-linked behavior.

Author/-s:       J. Saenz; Gerianne M. Alexander

Publication:     Biological psychology, 2013

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Sexual Differentiation of the Human Brain in Relation to Gender-Identity, Sexual Orientation, and Neuropsychiatric Disorders

During the intrauterine period, a testosterone surge in boys masculinizes the fetal brain, whereas the absence of such a surge in girls results in a feminine brain. Since sexual differentiation of the genitals takes place much earlier in intrauterine life than sexual differentiation of the human brain, these two processes can be influenced independently of each other. Gender identity (the conviction of belonging to the male or female gender), sexual orientation (hetero-, homo-, or bisexuality), pedophilia, and the risks for neuropsychiatric disorders are programmed into our brain during early development. There is no proof that postnatal social environment has any crucial effect on gender identity or sexual orientation. We discuss the relationships between structural and functional sex differences of various brain areas and the way they change along with changes in the supply of sex hormones on the one hand and sex differences in behavior in health and disease on the other.

Author/-s:       Dick F. Swaab; Ai-Min Bao

Publication:     Neuroscience in the 21st century, 2013

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The effects of prenatal sex steroid hormones on sexual differentiation of the brain

Most of the anatomical, physiological and neurochemical gender-related differences in the brain occur prenatally. The sexual differences in the brain are affected by sex steroid hormones, which play important roles in the differentiation of neuroendocrine system and behavior. Testosterone, estrogen and dihydrotestosterone are the main steroid hormones responsible for the organization and sexual differentiation of brain structures during early development. The structural and behavioral differences in the female and male brains are observed in many animal species; however, these differences are variable between species. Animal and human (in vivo imaging and postmortem) studies on sex differences in the brain have shown many differences in the local distribution of the cortex, the gray-white matter ratio, corpus callosum, anterior commissure, hypothalamus, bed nucleus of the stria terminalis, limbic system and neurotransmitter systems. This review aims to evaluate the anatomical, physiological and neurochemical differences in the female and male brains and to assess the effect of prenatal exposure to sex steroid hormones on the developing brain.

Author/-s:       Serkan Karaismailoğlu; Ayşen Erdem

Publication:     Journal of the Turkish-German Gynecological Association, 2013

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Early androgen effects on spatial and mechanical abilities: evidence from congenital adrenal hyperplasia.

There is considerable controversy about the origins of sex differences in cognitive abilities, particularly the male superiority in spatial abilities. We studied effects of early androgens on spatial and mechanical abilities in adolescents and young adults with congenital adrenal hyperplasia (CAH). On tests of three-dimensional mental rotations, geography, and mechanical knowledge, females with CAH scored higher than their unaffected sisters, and males with CAH scored lower than their unaffected brothers. Exploratory regression analyses suggest that androgens affect spatial ability in females directly and through male-typed activity interests. Findings indicate that early androgens influence spatial and mechanical abilities, and that androgen effects on abilities may occur in part through effects on sex-typed activity interests.

Author/-s:       Sheri A. Berenbaum; K. L. Bryk; A. M. Beltz

Publication:     Behavioral neuroscience, 2012

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Early androgens, activity levels and toy choices of children in the second year of life

The hypothesis that stronger preferences for active play styles contribute to stronger preferences for male-typical toys was examined in 47 boys and 37 girls at 19-months of age using ambulatory monitoring technology (i.e., actigraphy) to measure activity levels during contact with male-typical, female-typical, and gender-neutral toys. Digit ratios and salivary testosterone levels were measured earlier in children at 3-4 months of age. There were no significant sex differences in digit ratios, salivary testosterone levels, or overall activity levels during toy play. In contrast, contact times showed large sex differences in infants' toy preferences. The within-sex comparisons showed that infant girls had significant preferences for female-typical toys over male-typical toys, whereas infant boys showed only a small preference for male-typical toys over female-typical toys. More male-typical digit ratios in early infancy predicted higher activity counts during toy play and less female-typical toy preferences in girls. However, in both sexes, activity levels were unrelated to toy preferences suggesting that factors other than activity level preferences contribute to the early emergence of gender-linked toy preferences.

Author/-s:       G. M. Alexander; J. Saenz

Publication:     Hormones and behaviour, 2012

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Fetal programming effects of testosterone on the reward system and behavioral approach tendencies in humans

Background: Sex differences are present in many neuropsychiatric conditions that affect emotion and approach-avoidance behavior. One potential mechanism underlying such observations is testosterone in early development. Although much is known about the effects of testosterone in adolescence and adulthood, little is known in humans about how testosterone in fetal development influences later neural sensitivity to valenced facial cues and approach-avoidance behavioral tendencies.

Methods: With functional magnetic resonance imaging we scanned 25 8 to 11-year-old children while viewing happy, fear, neutral, or scrambled faces. Fetal testosterone (FT) was measured via amniotic fluid sampled between 13 and 20 weeks gestation. Behavioral approach-avoidance tendencies were measured via parental report on the Sensitivity to Punishment and Sensitivity to Rewards questionnaire.

Results: Increasing FT predicted enhanced selectivity for positive compared with negatively valenced facial cues in reward-related regions such as caudate, putamen, and nucleus accumbens but not the amygdala. Statistical mediation analyses showed that increasing FT predicts increased behavioral approach tendencies by biasing caudate, putamen, and nucleus accumbens but not amygdala to be more responsive to positive compared with negatively valenced cues. In contrast, FT was not predictive of behavioral avoidance tendencies, either through direct or neurally mediated paths.

Conclusions: This work suggests that testosterone in humans acts as a fetal programming mechanism on the reward system and influences behavioral approach tendencies later in life. As a mechanism influencing atypical development, FT might be important across a range of neuropsychiatric conditions that asymmetrically affect the sexes, the reward system, emotion processing, and approach behavior.

Author/-s:       M. V. Lombardo; E. Ashwin; B. Auyeung; B. Chakrabarti; M. C. Lai; K. Taylor; G. Hackett; E. T. Bullmore; Sacha Baron-Cohen

Publication:     Biological psychiatry, 2012

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Fetal Testosterone Influences Sexually Dimorphic Gray Matter in the Human Brain

In nonhuman species, testosterone is known to have permanent organizing effects early in life that predict later expression of sex differences in brain and behavior. However, in humans, it is still unknown whether such mechanisms have organizing effects on neural sexual dimorphism. In human males, we show that variation in fetal testosterone (FT) predicts later local gray matter volume of specific brain regions in a direction that is congruent with sexual dimorphism observed in a large independent sample of age-matched males and females from the NIH Pediatric MRI Data Repository. Right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS), planum temporale/parietal operculum (PT/PO), and posterior lateral orbitofrontal cortex (plOFC) had local gray matter volume that was both sexually dimorphic and predicted in a congruent direction by FT. That is, gray matter volume in RTPJ/pSTS was greater for males compared to females and was positively predicted by FT. Conversely, gray matter volume in PT/PO and plOFC was greater in females compared to males and was negatively predicted by FT. Subregions of both amygdala and hypothalamus were also sexually dimorphic in the direction of Male > Female, but were not predicted by FT. However, FT positively predicted gray matter volume of a non-sexually dimorphic subregion of the amygdala. These results bridge a long-standing gap between human and nonhuman species by showing that FT acts as an organizing mechanism for the development of regional sexual dimorphism in the human brain.

Author/-s:       Michael V. Lombardo; Emma Ashwin; Bonnie Auyeung; Bhismadev Chakrabarti; Kevin Taylor; Gerald Hackett; Edward T. Bullmore; Simon Baron-Cohen

Publication:     The Journal of Neuroscience, 2012

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Intersex and Transsex: Atypical Gender Development and Social Construction

[…] In summary, the behaviors of intersexed and transgendered persons provide a wide range of evidence against many aspects of social science and social construction theory. Intersexed and transgendered persons, as well as typical persons, are each born with a certain background based upon evolutionary heritage, family genetics, uterine environment, and health factors that they will evidence in a socially permissive culture and limit in a restrictive one. The strongest gestational influences are from genetic and endocrinal organizing forces. Organizing factors are those genetic and hormonal influences established prenatally that influence postnatal behaviors set in motion by social or other environmental activation processes (such as puberty) or events (such as serious threats). Organizing factors influence or bias subsequent responses of the individual to environmental/social forces; they predispose the person to manifest behaviors and attitudes (biases) that have come to be recognized as appropriate. Sex-related activation effects occur postnatally; most noticeably at or after puberty. The lives of intersex and transgendered persons provide strong evidence for a realistic theory of sexual development: biased-interaction theory.

Author-/s:       Milton Diamond

Publication:     Women’s Studies Review, 2012

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Relating Prenatal Testosterone Exposure to Postnatal Behavior in Typically Developing Children: Methods and Findings

Testosterone levels during early development influence subsequent sex-typical behavior. These influences were initially identified in experimental research on nonhuman species. Additional research—primarily investigating individuals exposed to atypical hormone environments due to genetic disorders or maternal treatment with hormones during pregnancy—suggested that testosterone also influences the development of sex-typical behavior in humans. There is also interest in identifying relations between normal variability in the early hormone environment and normal variability in subsequent behavior. This article reviews studies that have assessed prenatal testosterone exposure in typically developing children using amniotic fluid sampling or maternal blood sampling. It concludes that both these approaches are promising, but both require larger samples than those used in most studies to date. Recommendations for future research also include using outcome measures that show sex differences, analyzing data within each sex, considering the time of day (as well as the time of gestation) when samples were taken, and reporting all the measures evaluated, not just those showing significant effects.

Author/-s:       Mihaela Constantinescu; Melissa Hines

Publication: Child Development Perspectives, 2012

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Sex Steroids and the Organization of the Human Brain

Studying the biological mechanisms underlying sexual differentiation in the human brain provides important insights into the etiology and trajectory of neurodevelopmental disorders in males and females (Baron-Cohen et al., 2011). Sex steroid hormones, the end products of the hypothalamus-pituitary-gonadal axis, exert powerful effects on the organization and sexual differentiation of brain structures. From animal studies, it has become clear that during early development, exposure of the brain to testosterone and estradiol leads to irreversible changes in the nervous system (McCarthy et al., 2012). Moreover, fetal exposure to sex steroids has a major impact on the sexual differentiation of the brain (McCarthy et al., 2012). For example, high levels of fetal testosterone (FT) result in brain masculinization in experimental animals, such as enlargements of the volume and soma size of the suprachiasmatic nucleus, bed nucleus of the stria terminalis, and ventromedial hypothalamus (Zuloaga et al., 2008).

In humans, studies of the effects of FT often rely on indirect measures such as the ratio between the index finger (2D) and ring finger (4D) or on opposite-sex twin studies. Specifically, a smaller 2D:4D ratio correlates with higher FT exposure, and through the intrauterine presence of a male fetus, opposite-sex twin girls are exposed to higher FT levels than same-sex twin girls. Using the latter indirect measure of FT, earlier reports showed that total brain volume and cerebellum volume, typically found to be larger in males, were positively correlated with higher FT exposure (Peper et al., 2009).

A recent paper by Lombardo et al. (2012) provided direct evidence for an association between FT levels and sexual differentiation of brain gray matter in humans. In this pioneering study of 28 developing boys, FT levels were determined from amniotic fluid. Amniocentesis was performed between 13 and 20 weeks of gestation, which is a critical period of brain masculinization. When these boys were 8–11 years old, a structural MRI was made. Using voxel-based morphometry, gray matter regions within the whole brain of these 28 boys were identified showing significant correlations with FT levels. The amygdala and hypothalamus were included as a priori regions of interest. Then, in a second normative sample of 217 (101 boys) children (NIH Pediatric MRI Data Repository), sexual dimorphisms in gray matter were determined. Finally, a conjunction analysis was performed to isolate brain regions whose direction of the FT correlation was congruent with the direction of sexual dimorphism.

Lombardo et al. (2012) hypothesized that the size of brain areas that were normally larger in males than in females would correlate positively with FT, whereas the size of brain areas that are normally larger in females would correlate negatively with FT. Results showed that higher levels of FT were associated with larger right temporal/parietal junction and posterior superior temporal sulcus. As predicted, these brain areas were larger in males than in females in the normative sample. Conversely, FT level was negatively correlated with gray matter volumes within the planum temporale/ parietal operculum and within the posterior lateral orbitofrontal cortex. Again, in line with the hypothesis, these brain areas were larger in females than males in the normative sample.

Having unique access to direct levels of FT, Lombardo and colleagues (2012) provide the first human evidence that FT contributes to the organization of gray matter structures in a sexually dimorphic way. The sexually dimorphic brain areas that Lombardo and colleagues (2012) found to be associated with FT could provide insight into sex differences found in cognitive and affective functioning, including language processing, mentalizing, social attention, and empathy. In summary, sex differences in these mental functions might result at least partially from FT effects on the underlying brain structures.

FT levels did not correlate with volume in all sexual dimorphic gray matter areas in Lombardo et al. (2012), however. For example, the hypothalamus and subregions of the amygdala were normally larger in males, but these volumes were not correlated with FT levels. This is not wholly surprising, because numerous factors likely contribute to sex differences in brain morphology, such as estrogens, proteins encoded on sex chromosomes, and environmental factors (McCarthy et al., 2012).

In contrast, FT levels did correlate with gray matter volume in a subregion of the amygdala (i.e., the ventromedial area of the amygdala) that is not sexually dimorphic. Interestingly, it has recently been proposed that some phenotypic endpoints that do not show sex differences nonetheless can be affected by different factors in males and females (McCarthy et al., 2012). Therefore, FT could affect the size of the ventromedial amygdala in males, but its size in females is affected by other factors. To test this hypothesis however, the inclusion of female (hormonal) data is required.

Influences of sex steroid hormones on fetal brain development such as those identified by Lombardo et al. (2012) are thought to set the stage for additional effects of such hormones that occur during puberty and adolescence. Animal literature increasingly suggests that puberty represents a second critical period during which sex-steroid-related brain reorganization takes place. For example, in male rodents, testosterone treatment before and during adolescence, but not after adolescence, caused reorganization in parts of the amygdala and hypothalamus— brain areas involved in social behavior (Schulz et al., 2009). These data indicate that the adolescent brain remains sensitive to the organizational effects of steroid hormones. In humans, sex differences in subcortical and cortical gray matter become more prominent during puberty, but the contribution of sex hormones to this process seems to be sex- and regionspecific (Peper et al., 2011). Animal studies have also demonstrated that sex steroids affect myelination by acting on glial cells (Garcia-Segura and Melcangi, 2006). In humans, white matter sexual dimorphisms also become more prominent during puberty and adolescence: in boys, white matter microstructure increases more steeply than in girls (Bava et al., 2011), possibly under the influence of pubertal hormones. Recent human evidence indicates that the pubertal reorganization of white matter pathways is associated with increased levels of pubertal sex steroid hormones (Herting et al., 2012). Lombardo and colleagues (2012) point out that some of their participants (8–11 years) might have already entered puberty. If so, pubertal testosterone might have interacted with gray matter sex differences established during the prenatal period. The authors argue that by correcting their analyses for age, possible current testosterone effects on gray matter should have been controlled (as age and testosterone are highly correlated during puberty). However, after controlling for age, pubertal testosterone has been associated with individual differences in structural brain development (Peper et al., 2011). For example, a larger amygdala and hippocampus volume are related to increased levels of testosterone in both sexes regardless of age (Neufang et al., 2009).

The importance of studying the effects of pubertal sex steroids on human brain structure is further underlined by the fact that there is a sexual differentiation in vulnerability to mental disorders before and around puberty (Zahn-Waxler et al., 2008). Sex differences in child and adolescent mental disorders can be roughly divided into two groups: (1) disorders with a marked male preponderance arising before puberty, such as conduct disorder, autism, and attention deficit-hyperactivity disorder;and (2) disorders with a marked female preponderance (2:1) arising during puberty, such as mood and anxiety-related disorders (Zahn- Waxler et al., 2008). Eating disorders show an even higher incidence in females and often arise in the course of puberty. Moreover, an earlier onset of pubertal development is associated with increases in eating and mood symptoms. It might be argued that during puberty, previously organized brain circuits are activated by changing gonadal hormoneenvironments, possibly setting the stage for sex differences in vulnerability to these mental disorders. Although sex steroids are not the single cause of these complex disorders, puberty might have a profound impact on the developmental trajectories of these neuropsychiatric illnesses (Zahn-Waxler et al., 2008).

In conclusion, studying the influence of sex steroids on human brain structure not only gives important insights into the etiology of healthy brain maturation, but can also serve as a model for the development of neuropsychiatric illnesses with a skewed sex ratio. As Lombardo and colleagues (2012) emphasize, FT is an important developmental mechanism contributing to sexual differentiation of brain anatomy. Later surges of sex steroid hormones during puberty might play a vital role in further refining gray and white matter observed during this period.

Author/-s:       Jiska S. Peper; P. Cédric; M. P. Koolschijn

Publication:     The Journal of Neuroscience, 2012

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Testosterone measured in infancy predicts subsequent sex-typed behavior in boys and in girls

The testes are active during gestation, as well as during early infancy. Testosterone elevation during fetal development has been shown to play a role in human neurobehavioral sexual differentiation. The role of early postnatal gonadal activation in human psychosexual development is largely unknown, however. We measured testosterone in 48 full term infants (22 boys, 26 girls) by monthly urinary sampling from day 7 postnatal to age 6 months, and related the area under the curve (AUC) for testosterone during the first 6 months postnatal to subsequent sex-typed behavior, at the age of 14 months, using the Pre-School Activities Inventory (PSAI), and playroom observation of toy choices. In boys, testosterone AUC correlated significantly with PSAI scores (Spearman's rho = 0.54, p = 0.04). In addition, play with a train and with a baby doll showed the anticipated sex differences, and play with the train correlated significantly and positively with testosterone AUC in girls (Spearman's rho = 0.43, p = 0.05), while play with the doll correlated significantly and negatively with testosterone AUC in boys (Spearman's rho = − 0.48, p < 0.03). These results may support a role for testosterone during early infancy in human neurobehavioral sexual differentiation.

Author/-s:       Annamarja Lamminmäki; Melissa Hines; Tanja Kuiri-Hänninen; Leena Kilpeläinen; Leo Dunkel; Ulla Sankilampi

Publication:     Hormones and Behavior, 2012

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The relationship between second-to-fourth digit ratio and female gender identity

Introduction: Gender identity and the second-to-fourth finger length ratio (2D : 4D) are discriminative between the sexes. However, the relationship between 2D : 4D and gender identity disorder (GID) is still controversial.

Aim: The aim of this study is to investigate the relationship between 2D : 4D and score on the Gender Identity Scale (GIS) in female-to-male (FtM) GID subjects.

Methods: Thirty-seven GID-FtM with testosterone replacement therapy from our clinic were included in this study. As controls, 20 male and 20 female volunteers participated from our institution (medical doctors and nurses). We photocopied left and right hands of the participants and measured the second and fourth finger lengths. Gender identity was measured with the GIS.

Main outcome measures: 2D : 4D digit ratio and GIS in male, female, and GID-FtM subjects.

Results: The 2D : 4D (mean ± standard deviation) in male, female, and GID-FtM were 0.945 ± 0.029, 0.999 ± 0.035, and 0.955 ± 0.029 in right hand and 0.941 ± 0.024, 0.979 ± 0.040, and 0.954 ± 0.036 in left hand, respectively. The 2D : 4D was significantly lower in male controls in both hands and GID-FtM in the right hand than in female controls (P < 0.05, analysis of variance). Multiple linear regression analysis revealed that "consistent gender identity" score in the higher domain in GIS and "persistent gender identity" score in the lower domain are statistically significant variables correlating with 2D : 4D in the right hands among biological females.

Conclusions: The finger length ratio 2D : 4D in GID-FtM was significantly lower than in female controls in the right hand in this study. 2D : 4D showed a positive correlation with GIS score. Because 2D : 4D influences are assumed to be established in early life and to reflect testosterone exposure, our results suggest a relationship between GID-FtM and perinatal testosterone.

Author/-s:       S. Hisasue; S. Sasaki; T. Tsukamoto; S. Horie

Publication:     The Journal of Sexual Medicine, 2012

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Biological and psychosocial correlates of gender-variant and gender-typical identities

The aim of this thesis is examine biological and psychosocial factors that contribute to the development of gender-variant or gender-typical identities. Blanchard’s autogynephilia theory (Blanchard, 1989b) suggests that these factors are different in birth-assigned males with different sexual orientations. Previous research has found that genetics, prenatal hormone exposure, neuroanatomy, handedness, dermatoglyphics, fraternal birth order, and abuse are related to gender identity. While a number of investigators have studied these variables individually, this is the first known study to have examined the inter-relationships of these variables in one sample and to include participants with a wide range of gender identities. Data were collected from a convenience sample of 2 277 online-recruited participants with gender-variant and gender-typical identities using an online questionnaire. Participants were mainly white/Caucasian (92 %) adults living in the USA (54 %) and New Zealand (19 %). From the results, reported family concordance for gender-variance and a systematic review of case reports of twins with gender-variant identities indicated genetic determinants of gender identities. Finger-length ratio, systemising, and a systematic review of case reports of gender identity outcomes for adults with intersex and related conditions indicated prenatal hormone determinants of gender identities. Further evidence for biological factors came from elevated levels of non-right handedness among birth assigned females with gender-variant identities. Structural equation modelling showed that the positive relationship between abuse experience and degree of adult gender variance was partially mediated by recalled childhood gender-variance. This suggests abuse may be a cause as well as a result of gender-variance. Contrary to Blanchard’s theory, there were no differences in biological and psychosocial factors between birth-assigned male participants of different sexual orientations. This was the first research to find evidence that biological and psychosocial factors are the same for transsexuals as for persons with other gender-variant identities. Overall, these findings add support for a biological predisposition for gender-variant and gender-typical identities. Psychosocial determinants are likely to be complex and work in interaction with biological factors.

Author/-s:       Jaimie F. Veale

Publication:     Doctoral thesis, Massey University, Albany, New Zealand, 2011

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Gender development and the human brain

Convincing evidence indicates that prenatal exposure to the gonadal hormone, testosterone, influences the development of children's sex-typical toy and activity interests. In addition, growing evidence shows that testosterone exposure contributes similarly to the development of other human behaviors that show sex differences, including sexual orientation, core gender identity, and some, though not all, sex-related cognitive and personality characteristics. In addition to these prenatal hormonal influences, early infancy and puberty may provide additional critical periods when hormones influence human neurobehavioral organization. Sex-linked genes could also contribute to human gender development, and most sex-related characteristics are influenced by socialization and other aspects of postnatal experience, as well. Neural mechanisms underlying the influences of gonadal hormones on human behavior are beginning to be identified. Although the neural mechanisms underlying experiential influences remain largely uninvestigated, they could involve the same neural circuitry as that affected by hormones.

Author/-s:       Melissa Hines

Publication:     Annual review of neuroscience, 2011

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Gendered Occupational Interests: Prenatal Androgen Effects on Psychological Orientation to Things Versus People

There is considerable interest in understanding women’s underrepresentation in science, technology, engineering, and mathematics careers. Career choices have been shown to be driven in part by interests, and gender differences in those interests have generally been considered to result from socialization. We explored the contribution of sex hormones to career-related interests, in particular studying whether prenatal androgens affect interests through psychological orientation to Things versus People. We examined this question in individuals with congenital adrenal hyperplasia (CAH), who have atypical exposure to androgens early in development, and their unaffected siblings (total N = 125 aged 9 to 26 years). Females with CAH had more interest in Things versus People than did unaffected females, and variations among females with CAH reflected variations in their degree of androgen exposure. Results provide strong support for hormonal influences on interest in occupations characterized by working with Things versus People.

Author/-s:       Adriene M. Beltz; Jane L. Swanson; Sheri A. Berenbaum

Publication:     Hormones and behavior, 2011

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Prenatal endocrine influences on sexual orientation and on sexually differentiated childhood behaviour

Both sexual orientation and sex-typical childhood behaviors, such as toy, playmate and activity preferences, show substantial sex differences, as well as substantial variability within each sex. In other species, behaviors that show sex differences are typically influenced by exposure to gonadal steroids, particularly testosterone and its metabolites, during early development (prenatally or neonatally). This article reviews the evidence regarding prenatal influences of gonadal steroids on human sexual orientation, as well as sex-typed childhood behaviors that predict subsequent sexual orientation. The evidence supports a role for prenatal testosterone exposure in the development of sex-typed interests in childhood, as well as in sexual orientation in later life, at least for some individuals. It appears, however, that other factors, in addition to hormones, play an important role in determining sexual orientation. These factors have not been well-characterized, but possibilities include direct genetic effects, and effects of maternal factors during pregnancy. Although a role for hormones during early development has been established, it also appears that there may be multiple pathways to a given sexual orientation outcome and some of these pathways may not involve hormones.

Author/-s:       Melissa Hines

Publication:     Frontiers in neuroendocrinology, 2011

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Prenatal hormones and childhood sex segregation: playmate and play style preferences in girls with congenital adrenal hyperplasia.

We investigated playmate and play style preference in children with congenital adrenal hyperplasia (CAH) (26 females, 31 males) and their unaffected siblings (26 females, 17 males) using the Playmate and Play Style Preferences Structured Interview (PPPSI). Both unaffected boys and girls preferred same-sex playmates and sex-typical play styles. In the conflict condition where children chose between a same-sex playmate engaged in an other-sex activity or an other-sex playmate engaged in a same-sex activity, boys (both CAH and unaffected brothers) almost exclusively chose playmates based on the preferred play style of the playmate as opposed to the preferred gender label of the playmate. By contrast, unaffected girls used play style and gender label about equally when choosing playmates. Girls with CAH showed a pattern similar to that of boys: their playmate selections were more masculine than unaffected girls, they preferred a boy-typical play style and, in the conflict condition, chose playmates engaged in a masculine activity. These findings suggest that prenatal androgen exposure contributes to sex differences in playmate selection observed in typically developing children and that, among boys and girls exposed to high levels of androgens prenatally, play style preferences drive sex segregation in play.

Author/-s:       V. Pasterski; M. E. Geffner, C. Brain; P. Hindmarsh; C. Brook; M. Hines

Publication:     Hormones and behaviour, 2011

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Sexual differentiation of human behavior: effects of prenatal and pubertal organizational hormones

A key question concerns the extent to which sexual differentiation of human behavior is influenced by sex hormones present during sensitive periods of development (organizational effects), as occurs in other mammalian species. The most important sensitive period has been considered to be prenatal, but there is increasing attention to puberty as another organizational period, with the possibility of decreasing sensitivity to sex hormones across the pubertal transition. In this paper, we review evidence that sex hormones present during the prenatal and pubertal periods produce permanent changes to behavior. There is good evidence that exposure to high levels of androgens during prenatal development results in masculinization of activity and occupational interests, sexual orientation, and some spatial abilities; prenatal androgens have a smaller effect on gender identity, and there is insufficient information about androgen effects on sex-linked behavior problems. There is little good evidence regarding long-lasting behavioral effects of pubertal hormones, but there is some suggestion that they influence gender identity and perhaps some sex-linked forms of psychopathology, and there are many opportunities to study this issue.

Author/-s:       Sheri A. Berenbaum; Adriene M. Beltz

Publication:     Frontiers in neuroendocrinology, 2011

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Biological and psychosocial correlates of adult gender-variant identities: A review

This article reviews research on biological and psychosocial factors relevant to the etiology of gender-variant identities. There is evidence for a genetic component of gender-variant identities through studies of twins and other within-family concordance and through studies of specific genes. Evidence that prenatal androgens play a role comes from studies that have examined finger length ratios (2D:4D), prevalence of polycystic ovary syndrome among female-to-male transsexuals, and individuals with intersex and related conditions who are more likely to have reassigned genders. There is also evidence that transsexuals have parts of their brain structure that is typical of the opposite birth-assigned gender. A greater likelihood of non-right-handedness suggests developmental instability may also contribute as a biological factor. There is a greater tendency for persons with gender-variant identities to report childhood abuse and a poor or absent relationship with parents. It is unclear if this is a cause or effect of a gender-variant identity. Parental encouragement of gender-variance is more common among individuals who later develop a gender-variant identity. We conclude that biological factors, especially prenatal androgen levels, play a role in the development of a gender-variant identity and it is likely that psychosocial variables play a role in interaction with these factors.

Author/-s:       Jaimie F. Veale; David E. Clarke; Terri C. Lomax

Publication:     Personality and Individual Differences, 2010

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Digit ratio (2D:4D) is associated with traffic violations for male frequent car drivers

Digit ratio (2D:4D) is a putative marker of prenatal hormone exposure. A lower digit ratio has been suggested as an index of higher testosterone relative to estrogen exposure during prenatal development. Digit ratio has been associated with a variety of psychological sex-dimorphic variables, including spatial orientation, aggression, or risk-taking behavior. The present study aimed to relate digit ratio to traffic violations for a male sample (N = 77) of frequent car drivers. Digit ratio was assessed via printout scans of the hand, and traffic offense behavior was assessed via self-reported penalty points as registered by the Central Register of Traffic Offenders in Germany. In addition, social desirability and sensation seeking were recorded. Results showed that digit ratio was inversely related to penalty point entries, suggesting more traffic violations for individuals with higher prenatal testosterone exposure. Sensation seeking was positively associated with traffic violations, but there was no relationship between sensation seeking and digit ratio, proposing additive effects of both variables. The results suggest that prenatal androgen exposure might be related to traffic violations for frequent car drivers.

Author/-s:       A. Schwerdtfeger; R. Heims; J. Heer

Publication:     Accident; analysis and prevention, 2010

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Empathizing, systemizing and finger length ratio in a Swedish sample

The Empathy- and Systemizing Quotients (EQ and SQ, respectively; Baron-Cohen, 2003) were determined in a Swedish sample consisting mainly of university undergraduates. Females had significantly higher EQ than males, who in turn scored higher on the SQ inventory. Gender explained 12-14% of the variation. Males were strikingly overrepresented in the group defined by a high SQ/low EQ profile or by a large SQ - EQ difference; females dominated among people with a low SQ/high EQ profile or by a large EQ - SQ difference. Students majoring in the natural sciences had higher SQs than psychology majors, but in both groups the gender difference in SQ and EQ was strong. For each participant a weighted composite score was generated by multivariate processing of the EQ and SQ data (Partial Least Square Discriminant Analysis). These scores were associated in a sex-linked fashion to a biometric measure reflecting prenatal testosterone exposure, i.e. the ratio between index (2D)- and ring (4D) finger lengths. In males a high (female-typical) 2D:4D ratio predicted an enhanced tendency to empathize and a reduced tendency to systemize; in women, by contrast, the 2D:4D ratio was unrelated to these traits. The present research confirms earlier work of a gender difference in EQ and SQ. The difference appears robust as it appears as large in Sweden (a country with high cultural gender-equality) as in countries with considerably lower gender-equality.

Author/-s:       A. von Horn; L. Bäckman; T. Davidsson; S. Hansen

Publication:     Scandinavian journal of psychology, 2010

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Mentale Rotation bei Mann-zu-Frau-Transsexuellen und Männern ohne Geschlechtsidentitätsstörung – eine fMRT-Studie

Excerpt: This study shows that untreated MtF-TS show differences to the male control group in cortical activation. MtF-TS activated frontal and occipitotemporal areas more than male controls; male controls activated the lobus parietalis inferior of the left brain hemisphere more. The differences in activation are similar to the known differences between males and females. This could point to prenatal hormone fluctuations being one of many factors imprinting sexually dimorphic cortical functions and causing transsexualism.

 Original: Es ist bekannt, dass Männer Frauen in räumlich-visuellen Fähigkeiten, vor allem in der mentalen Rotation dreidimensionaler Objekte, überlegen sind (Voyer et al., 1995). Diese Arbeit untersuchte elf Mann-zu-Frau-Transsexuelle (M-F-Transsexuelle) vor einer gegengeschlechtlichen Hormontherapie (HRT), elf M-F-Transsexuelle nach einer HRT und elf Männer ohne Geschlechtsidentitätsstörung (GIS). Mit den von Shepard und Metzler entworfenen dreidimensionalen Figuren wurden die kortikalen Aktivierungen mittels fMRT und die Leistungen in dem mentalen Rotationstest (Vandenberg und Kuse, 1978) erforscht.
Diese Arbeit konnte zeigen, dass schon im Vergleich von transsexuellen Männern vor HRT und Männern ohne GIS Unterschiede in der kortikalen Aktivierung bestehen. M-F-Transsexuelle vor HRT aktivierten vor allem frontale und occipitotemporale Areale stärker als Männer ohne GIS, während sich bei Männern ohne GIS im Vergleich zu M-F-Transsexuellen vor HRT Mehraktivierungen im Lobus parietalis inferior der linken Hemisphäre fanden. Es fielen bei den Aktivierungsunterschieden deutliche Parallelen zu den bekannten Aktivierungsunterschieden zwischen Männern und Frauen ohne GIS auf (Butler et al., 2006; Gizewski et al., 2006). Diese Beobachtungen liefern Indizien dafür, dass pränatale Hormonschwankungen möglicherweise ein Bestandteil der multifaktoriell bedingten Prägung sexuell dimorpher kortikaler Funktionen und der Entstehung der Transsexualität sein könnten.

Eine HRT bei M-F-Transsexuellen beeinflusste die kortikalen Aktivierungen in occipitotemporalen Arealen. Dennoch blieben die Aktivierungsunterschiede, die schon vor einer HRT zwischen M-F-Transsexuellen und Männern ohne GIS bestanden, vor allem in frontalen Arealen unverändert. Es wurden jedoch signifikante Leistungsunterschiede in der mentalen Rotation zwischen M-F-Transsexuellen nach HRT und Männern ohne GIS gefunden. Das repräsentiert einen aktivierenden Einfluss zirkulierender Geschlechtshormone auf kognitive Leistungen, der auch schon im Rahmen des Menstruationszykluses bei Frauen gesehen wurde (Hausmann et al., 2001).

Des Weiteren wurde in beiden transsexuellen Gruppen eine positive Korrelation zwischen der Höhe des Testosterons und der mentalen Rotationsleistung nachgewiesen. Dabei scheint das Testosteron vor allem parietale Areale zu beeinflussen.

Author/-s:       Christine Bauer

Publication:     Dissertation, Medizinische Fakultät, Westfälische Wilhelms-Universität Münster, 2010

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Psychosexual Development in Children with Disorder of Sex Development (DSD) – Results from the German Clinical Evaluation Study

Psychosexual development is influenced by biological and psychosocial factors. Human beings show a great variability in psychosexual development both between and within gender-groups. However, there are relatively stable gender-related behaviors and self-perceptions, in which males and females differ distinctly. There is strong evidence that high concentrations of androgens lead to more male-typical behavior and that this also influences gender identity. Disorders of sex development (DSD) provide the opportunity to analyze the role of different factors on psychosexual development. We examined 166 children age 4 to 12 with DSD using instruments concerning gender role behavior, gender identity, and friendship. Results underline the hypothesis that androgens play a decisive role in the masculinization of gender role behavior in children. There are also some relations between the experience of gender change and psychosexual outcomes which have to be discussed. Nevertheless, results indicated a high congruence between the children's gender identity and gender of rearing.

Author/-s:       M. Jürgensen; E. Kleinemeier; A. Lux; Thomas Dirk Steensma; Peggy T. Cohen-Kettenis; O. Hiort; U. Thyen

Publication:     Journal of Pediatric Endocrinology and Metabolism, 2010

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Sex Differences in the Brain, Behavior, and Neuropsychiatric Disorders

Sex differences in the brain are reflected in behavior and in the risk for neuropsychiatric disorders. The fetal brain develops in the male direction due to a direct effect of testosterone on the developing neurons, or in the female direction due to the absence of such a testosterone surge. Because sexual differentiation of the genitals takes place earlier in intrauterine life than sexual differentiation of the brain, these two processes can be influenced independently of each other. Gender identity (the conviction of belonging to the male or female gender), sexual orientation (heterosexuality, homosexuality, or bisexuality), pedophilia, sex differences in cognition, and the risks for neuropsychiatric disorders are programmed into our brains during early development. There is no proof that postnatal social environment has any crucial effect on gender identity or sexual orientation. Structural and functional sex differences in brain areas, together with changes in sex hormone levels and their receptors in development and adulthood, are closely related to sex differences in behavior and neuropsychiatric disorders. Knowing that such a relationship exists may help bring about sex-specific therapeutic strategies.

Author/-s:       Ai-Min Bao; Dick F. Swaab

Publication:     The Neuroscientist, 2010

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Sex-related variation in human behavior and the brain

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.

Author/-s:       Melissa Hines

Publication:     Trends in cognitive sciences, 2010

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Sexual differentiation of the brain related to gender identity: beyond hormones

The sexual differentiation of the brain starts in the second semester of pregnancy, which is, after the development of the genitals which differentiate in the second month of pregnancy. Because these two processes have different timetables, it could be that these are initiated through different pathways. Male gonads synthesize testosterone, which can be converted into estrogen by aromatase in the brain. In humans, the exact mechanism of male and female brain development has still to be elucidated. Based on clinical evidence from genetic men (XY) suffering from a mutation in the androgen receptor gene (complete androgen-insensitivity syndrome) and who show a female phenotype of the external genitals as well as the brain, it can be proposed that direct action of testosterone is probably causing the brain to differentiate in the male direction. However, when the process of genital development and of brain sexual development does not match the same sex, females with a male brain and vice versa can arise. These transsexual people have problems with their gender identity and have the conviction of being born in the wrong body. Twin and family studies show that there are genetic factors influencing the chances of a gender identity problem. Genetic factors could play a large role in the sexual differentiation of the brain, as can be shown from studies where differential genetic expression is found before development of the gonads. These genes could also function in other tissues than gonads and influence the sexual differentiation of the brain. The DMRT gene family which encodes transcription factors or the amount of sex hormone binding globulin (SHBG) is possibly influencing the development of sex differences, just as sex-biased differential splicing. Epigenetic mechanisms such as X-inactivation and genomic imprinting are also good candidates for causing differences in the sexual differentiation of the brain. These observations indicate that probably many processes operate together in the sexual differentiation of the brain and that diverse mutations can lead to gender identity problems.

Author/-s:       L. A. Worrell

Publication:     Master Thesis, Faculty of Medicine, Universiteit Utrecht, 2010

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Sexual differentiation of the human brain in relation to gender identity and sexual orientation

It is believed that during the intrauterine period the fetal brain develops in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. According to this concept, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation should be programmed into our brain structures when we are still in the womb. However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in transsexuality. This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain. There is no proof that social environment after birth has an effect on gender identity or sexual orientation. Data on genetic and hormone independent influence on gender identity are presently divergent and do not provide convincing information about the underlying etiology. To what extent fetal programming may determine sexual orientation is also a matter of discussion. A number of studies show patterns of sex atypical cerebral dimorphism in homosexual subjects. Although the crucial question, namely how such complex functions as sexual orientation and identity are processed in the brain remains unanswered, emerging data point at a key role of specific neuronal circuits involving the hypothalamus.

Author/-s:       Ivanka Savic; Alicia Garcia-Falgueras; Dick F. Swaab

Publication:     Progress in brain research, 2010

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Sexual Hormones and the Brain: An Essential Alliance for Sexual Identity and Sexual Orientation

The fetal brain develops during the intrauterine period in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. In this way, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation are programmed or organized into our brain structures when we are still in the womb. However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in extreme cases in trans-sexuality. This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain. There is no indication that social environment after birth has an effect on gender identity or sexual orientation.

Author/-s:       Alicia Garcia-Falgueras; Dick F. Swaab

Publication:     Pediatric Neuroendocrinology, 2010; Endocrine development, 2010

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Clinical Implications of the Organizational and Activational Effects of Hormones

Debate on the relative contributions of nature and nurture to an individual's gender patterns, sexual orientation and gender identity are reviewed as they appeared to this observer starting from the middle of the last century. Particular attention is given to the organization-activation theory in comparison to what might be called a theory of psychosexual neutrality at birth or rearing consistency theory. The organization-activation theory posits that the nervous system of a developing fetus responds to prenatal androgens so that, at a postnatal time, it will determine how sexual behavior is manifest. How organization-activation was or was not considered among different groups and under which circumstances it is considered is basically understood from the research and comments of different investigators and clinicians. The preponderance of evidence seems to indicate that the theory of organization-activation for the development of sexual behavior is certain for non-human mammals and almost certain for humans. This article also follows up on previous clinical critiques and recommendations and makes some new suggestions.

Author/-s:       Milton Diamond

Publication:     Hormones and Behavior, 2009

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Disorders of sex development expose transcriptional autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes

Background: Gender appears to be determined by independent programs controlled by the sex-chromosomes and by androgen-dependent programming during embryonic development. To enable experimental dissection of these components in the human, we performed genome-wide profiling of the transcriptomes of peripheral blood mononuclear cells (PBMC) in patients with rare defined "disorders of sex development" (DSD, e.g., 46, XY-females due to defective androgen biosynthesis) compared to normal 46, XY-males and 46, XX-females.

Results: A discrete set of transcripts was directly correlated with XY or XX genotypes in all individuals independent of male or female phenotype of the external genitalia. However, a significantly larger gene set in the PBMC only reflected the degree of external genital masculinization independent of the sex chromosomes and independent of concurrent post-natal sex steroid hormone levels. Consequently, the architecture of the transcriptional PBMC-"sexes" was either male, female or even "intersex" with a discordant alignment of the DSD individuals' genetic and hormonal sex signatures.

Conclusion: A significant fraction of gene expression differences between males and females in the human appears to have its roots in early embryogenesis and is not only caused by sex chromosomes but also by long-term sex-specific hormonal programming due to presence or absence of androgen during the time of external genital masculinization. Genetic sex and the androgen milieu during embryonic development might therefore independently modulate functional traits, phenotype and diseases associated with male or female gender as well as with DSD conditions.

Author/-s:       P. M. Holterhus; J. H. Bebermeier; R. Werner; J. Demeter; A. Richter-Unruh; G. Cario; M. Appari; R. Siebert; F. Riepe; J. D. Brooks; O. Hiort

Publication:     BMC Genomics, 2009

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Fetal testosterone predicts sexually differentiated childhood behavior in girls and in boys

Mammals, including humans, show sex differences in juvenile play behavior. In rodents and nonhuman primates, these behavioral sex differences result, in part, from sex differences in androgens during early development. Girls exposed to high levels of androgen prenatally, because of the genetic disorder congenital adrenal hyperplasia, show increased male-typical play, suggesting similar hormonal influences on human development, at least in females. Here, we report that fetal testosterone measured from amniotic fluid relates positively to male-typical scores on a standardized questionnaire measure of sex-typical play in both boys and girls. These results show, for the first time, a link between fetal testosterone and the development of sex-typical play in children from the general population, and are the first data linking high levels of prenatal testosterone to increased male-typical play behavior in boys.

Author/-s:       B. Auyeung; Simon Baron-Cohen; E. Ashwin; Rebecca Knickmeyer; K. Taylor; G. Hackett; Melissa Hines

Publication:     Psychological Science, 2009

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Finger length ratio (2D:4D) in adults with gender identity disorder

From early childhood, gender identity and the 2nd to 4th finger length ratio (2D:4D) are discriminative characteristics between sexes. Both the human brain and 2D:4D may be influenced by prenatal testosterone levels. This calls for an examination of 2D:4D in patients with gender identity disorder (GID) to study the possible influence of prenatal testosterone on gender identity. Until now, the only study carried out on this issue suggests lower prenatal testosterone levels in right-handed male-to-female GID patients (MtF). We compared 2D:4D of 56 GID patients (39 MtF; 17 female-to-male GID patients, FtM) with data from a control sample of 176 men and 190 women. Bivariate group comparisons showed that right hand 2D:4D in MtF was significantly higher (feminized) than in male controls, but similar to female controls. The comparison of 2D:4D ratios of biological women revealed significantly higher (feminized) values for right hands of right handed FtM. Analysis of variance confirmed significant effects for sex and for gender identity on 2D:4D ratios but not for sexual orientation or for the interaction among variables. Our results indirectly point to the possibility of a weak influence of reduced prenatal testosterone as an etiological factor in the multifactorially influenced development of MtF GID. The development of FtM GID seems even more unlikely to be notably influenced by prenatal testosterone.

Author/-s:       Bernd Kraemer; Thomas Noll; Aba Delsignore; Gabriella Milos; Ulrich Schnyder; Urs Hepp

Publication:     Archives of Sexual Behavior, 2009

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Hormone-behavior associations in early infancy

The physiological significance of hormonal changes in early postnatal life is emerging, but the behavioral significance in humans is unknown. As a first test of the relationship between hormones and behavior in early infancy we measured digit ratios and salivary hormone levels in forty-one male and female infants (3-4 months of age) who watched a video depicting stimuli differentially preferred by older males and females (toys, groups). An eye-tracker measured visual fixations and looking times. In female infants, hormones were unrelated to visual preferences. In male infants, higher androgen levels predicted stronger preferences for male-typical stimuli. These data provide the first evidence for a role for hormones in emerging sex-linked behavior in early development.

Author/-s:       Gerianne M. Alexander, T. Wilcox; M. E. Farmer

Publication:     Hormones and behavior, 2009

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Sex differences and the impact of steroid hormones on the developing human brain

Little is known about the hormonal effects of puberty on the anatomy of the developing human brain. In a voxel-based morphometry study, sex-related differences in gray matter (GM) volume were examined in 46 subjects aged 8–15 years. Males had larger GM volumes in the left amygdala, whereas females had larger right striatal and bilateral hippocampal GM volumes than males. Sexually dimorphic areas were related to Tanner stages (TS) of pubertal development and to circulating level of steroid hormones in a subsample of 30 subjects. Regardless of sex, amygdala and hippocampal volumes varied as a function of TS and were associated with circulating testosterone (TEST) levels. By contrast, striatal GM volumes were unrelated to pubertal development and circulating steroid hormones. Whole-brain regression analyses revealed positive associations between circulating estrogen levels and parahippocampal GM volumes as well as between TEST levels and diencephalic brain structures. In addition, a negative association was found between circulating TEST and left parietal GM volumes. These data suggest that GM development in certain brain regions is associated with sexual maturation and that pubertal hormones might have organizational effects on the developing human brain.

Author/-s:       S. Neufang; K. Specht; M. Hausmann; O. Güntürkün; B. Herpertz-Dahlmann; G. R. Fink; K. Konrad

Publication:     Cerebral Cortex, 2009

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Sexual differentiation of the human brain in relation to gender identity and sexual orientation

During the intrauterine period the fetal brain develops in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. In this way, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation are programmed into our brain structures when we are still in the womb. However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in transsexuality. This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain. There is no proof that social environment after birth has an effect on gender identity or sexual orientation.

Author/-s:       Dick F. Swaab; Alicia Garcia-Falgueras

Publication:     Functional Neurology, 2009

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2D:4D finger-length ratios in children and adults with gender identity disorder

Previous research suggests that prenatal testosterone affects the 2D:4D finger ratio in humans, and it has been speculated that prenatal testosterone also affects gender identity differentiation. If both things are true, then one would expect to find an association between the 2D:4D ratio and gender identity. We measured 2D:4D in two samples of patients with gender identity disorder (GID). In Study 1, we compared the 2D:4D ratios of 96 adult male and 51 female patients with GID to that of 90 heterosexual male and 112 heterosexual female controls. In Study 2, we compared the 2D:4D ratios of 67 boys and 34 girls with GID to that of 74 control boys and 72 control girls. In the sample of adults with GID, we classified their sexual orientation as either homosexual or non-homosexual (in relation to their birth sex) to examine whether or not there were any within-group differences as a function of sexual orientation. In the sample of adult men with GID (both homosexual and non-homosexual) and children with GID, we found no evidence of an altered 2D:4D ratio relative to same-sex controls. However, women with GID had a significantly more masculinized ratio compared to the control women. This last finding was consistent with the prediction that a variance in prenatal hormone exposure contributes to a departure from a sex-typical gender identity in women.

Author/-s:       Madeleine S. Wallien; Kennneth J. Zucker; Thomas Dirk Steensma; Peggy T. Cohen-Kettenis

Publication:     Hormones and Behavior, 2008

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On the relation between 2D:4D and sex-dimorphic personality traits

Several personality traits, including aggressiveness and sensation seeking, have been hypothesized to be influenced by prenatal androgen exposure, though evidence for this proposition is limited. We investigated whether individual differences in aggressiveness, sensation seeking, and several prosocial personality traits can be predicted from differences in the 2D:4D digit ratio, a putative marker of prenatal androgen activity. A total of 164 undergraduates (87 men, 77 women) completed self-report measures of physical and verbal aggression, as well as a standardized measure of sensation seeking, and five scales to assess empathy, nurturance, expressivity/femininity, instrumentality/masculinity, and assertiveness. Two sex-dimorphic tests of spatial ability also were included. Men had a lower 2D:4D ratio than women, confirming the typical sex difference in digit proportions. Significant sex differences were observed on 10 of the 11 personality scales purported to show sex differences and on both tests of spatial ability. The 2D:4D ratio was a significant predictor of scores on three of the four aggression subscales, total aggression, thrill and adventure seeking, and total sensation-seeking, in the sample as a whole and in women. In men, correlations with 2D:4D were significant only for total sensation-seeking and verbal aggression. In both sexes, lower 2D:4D ratios were associated with increased aggressiveness and sensation seeking. For the spatial tests, there was no evidence of any association with 2D:4D in either men or women. The 2D:4D digit ratio may be a valid, though weak, predictor of selective sex-dependent traits that are sensitive to testosterone.

Author/-s:       E. Hampson; C. L. Ellis; C. M. Tenk

Publication:     Archives of sexual behaviour, 2008

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Prenatal exposure to sex steroid hormones and behavioral/cognitive outcome

Experimental studies in animals indicate that androgen exposure in fetal or neonatal life largely accounts for known sex differences in brain structure and behavior. Clinical research in humans suggests similar influences of early androgen concentrations on some behaviors that show sex differences, including play behavior in childhood and sexual orientation in adulthood. Available research also suggests that sex steroid hormone exposure may contribute to sex differences in the risk of autism and affective disorders in schizophrenia. However, findings have been inconsistent for other characteristics that show sex differences, including aggression and spatial ability. Moreover, social and environmental factors may modulate some of the associations observed. This article reviews the evidence that early-life exposure to sex steroid hormones contributes to sexually dimorphic behavior and cognitive abilities in humans.

Author/-s:       J. E. Manson

Publication:     Metabolism: clinical and experimental, 2008

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Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess

46,XX individuals with classical congenital adrenal hyperplasia (CAH) due to deficiency of the enzyme, 21-hydroxylase, show variable degrees of masculinization of body and behavior due to excess adrenal androgen production. Increased bisexuality and homosexuality have also been reported. This article provides a review of existing reports of the latter and presents a new study aimed at replicating the previous findings with detailed assessments of sexual orientation on relatively large samples, and at extending the investigation to the mildest form, non-classical (NC) CAH. Also, this is the first study to relate sexual orientation to the specific molecular genotypes of CAH. In the present study, 40 salt-wasters (SW), 21 SV (simple-virilizing), 82 NC, and 24 non-CAH control women (sisters and female cousins of CAH women) were blindly administered the Sexual Behavior Assessment Schedule (SEBAS-A, 1983 ed.; H. F. L. Meyer-Bahlburg & A. A. Ehrhardt, Privately printed). Most women were heterosexual, but the rates of bisexual and homosexual orientation were increased above controls not only in women with classical CAH, but also in NC women, and correlated with the degree of prenatal androgenization. Classifying women by molecular genotypes did not further increase the correlation. Diverse aspects of sexual orientation were highly intercorrelated, and principal components analysis yielded one general factor. Bisexual/homosexual orientation was (modestly) correlated with global measures of masculinization of non-sexual behavior and predicted independently by the degree of both prenatal androgenization and masculinization of childhood behavior. We conclude that the findings support a sexual-differentiation perspective involving prenatal androgens on the development of sexual orientation.

Author/-s:       H. F. Meyer-Bahlburg; C. Dolezal; S. W. Baker; M. I. New

Publication:     Archives of sexual behavior, 2008

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Androgens and eye movements in women and men during a test of mental rotation ability

Eye movements were monitored in 16 women and 20 men during completion of a standard diagram-based test of mental rotation ability to provide measures of cognitive function not requiring conscious, decisional processes. Overall, women and men allocated visual attention during task performance in very similar, systematic ways. However, consistent with previous suggestions that sex differences in attentional processes during completion of the mental rotation task may exist, eye movements in men compared to women indicated greater discrimination and longer processing of correct alternatives during task performance. Other findings suggested that androgens may enhance cognitive processes that are recruited differentially by women and men as a function of the task. Specifically, smaller (i.e., more masculine) digit ratios were associated with men’s shorter fixations on distracters, suggesting that perinatal androgen action may influence brain systems that facilitate the identification of relevant task stimuli. In women, higher circulating testosterone levels appeared to contribute to more general processes engaged during task performance, for example higher levels of visual persistence. It is possible that variability in the relative contribution of such hormone sensitive cognitive processes to accuracy scores as a function of different sample characteristics or assessment methods may partially account for the inconsistent findings of previous research on hormonal factors in mental rotation ability.

Author/-s:       Gerianne M. Alexander; Troy Son

Publication:     Hormones and Behavior, 2007

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Sexual differentiation of the brain and behavior

During the intrauterine period the human brain develops in the male direction via direct action of a boy's testosterone, and in the female direction through the absence of this hormone in a girl. During this time, gender identity (the feeling of being a man or a woman), sexual orientation, and other behaviors are programmed. As sexual differentiation of the genitals takes places in the first 2 months of pregnancy, and sexual differentiation of the brain starts during the second half of pregnancy, these two processes may be influenced independently of each other, resulting in transsexuality. This also means that in the case of an ambiguous gender at birth, the degree of masculinization of the genitals may not reflect the same degree of masculinization of the brain. Differences in brain structures and brain functions have been found that are related to sexual orientation and gender.

Author/-s:       Dick F. Swaab

Publication:     Best Practice & Research Clinical Endocrinology & Metabolism, 2007

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The control of sexual differentiation of the reproductive system and brain

This review summarizes current knowledge of the genetic and hormonal control of sexual differentiation of the reproductive system, brain and brain function. While the chromosomal regulation of sexual differentiation has been understood for over 60 years, the genes involved and their actions on the reproductive system and brain are still under investigation. In 1990, the predicted testicular determining factor was shown to be the SRY gene. However, this discovery has not been followed up by elucidation of the actions of SRY, which may either stimulate a cascade of downstream genes, or inhibit a suppressor gene. The number of other genes known to be involved in sexual differentiation is increasing and the way in which they may interact is discussed. The hormonal control of sexual differentiation is well-established in rodents, in which prenatal androgens masculinize the reproductive tract and perinatal oestradiol (derived from testosterone) masculinizes the brain. In humans, genetic mutations have revealed that it is probably prenatal testosterone that masculinizes both the reproductive system and the brain. Sexual differentiation of brain structures and the way in which steroids induce this differentiation, is an active research area. The multiplicity of steroid actions, which may be specific to individual cell types, demonstrates how a single hormonal regulator, e.g. oestradiol, can exert different and even opposite actions at different sites. This complexity is enhanced by the involvement of neurotransmitters as mediators of steroid hormone actions. In view of current environmental concerns, a brief summary of the effects of endocrine disruptors on sexual differentiation is presented.

Author/-s:       C. A. Wilson; D. C. Davies

Publication:     Reproduction, 2007

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Associations among gender-linked toy preferences, spatial ability, and digit ratio: evidence from eye-tracking analysis.

Eye-tracking technology was used to monitor eye-movements in 64 adults (age range, 18-22 years) during simultaneous presentation of "masculine" and "feminine" toys. Women and men who showed more visual fixations on male-typical toys compared to female-typical toys had significantly better targeting ability and smaller (i.e., more masculine) digit ratios, a putative marker of prenatal androgen levels. In contrast, individuals with visual preferences for female-typical or male-typical toys did not differ in mental rotations ability and in their retrospective reports of childhood gender-linked activities. The finding that targeting ability and digit ratios varied according to visual preferences for gender-linked toys suggests that prenatal androgens promote enduring preferences for male-typical objects and indicate further that some gender-linked traits vary according to the direction of a visual preference for gender-linked toys. Visual preferences derived from eye-tracking, therefore, may be a useful supplement to current measures of psychosexual differentiation in hormone-behavior research, particularly because eye-movements are not dependent on verbal abilities or subjective evaluations of behavior.

Author/-s:       Gerianne M. Alexander

Publication:     Archives of sexual behavior, 2006

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Prenatal testosterone and gender-related behaviour

Testosterone plays an important role in mammalian brain development. In neural regions with appropriate receptors testosterone, or its metabolites, influences patterns of cell death and survival, neural connectivity and neurochemical characterization. Consequently, testosterone exposure during critical periods of early development produces permanent behavioural changes. In humans, affected behaviours include childhood play behaviour, sexual orientation, core gender identity and other characteristics that show sex differences (i.e. differ on average between males and females). These influences have been demonstrated primarily in individuals who experienced marked prenatal hormone abnormalities and associated ambiguities of genital development (e.g. congenital adrenal hyperplasia). However, there is also evidence that testosterone works within the normal range to make some individuals within each sex more sex-typical than others. The size of testosterone-related influences, and perhaps even their existence, varies from one sex-typed characteristic to another. For instance: prenatal exposure to high levels of testosterone has a substantial influence on sex-typical play behaviour, including sex-typed toy preferences, whereas influences on core gender identify and sexual orientation are less dramatic. In addition: there appears to be little or no influence of prenatal testosterone on mental rotations ability, although mental rotations ability shows a marked sex difference. These findings have implications for basic understanding of the role of testosterone in normative gender development, as well as for the clinical management of individuals with disorders of sex development (formerly called intersex syndromes).

Author/-s:       Melissa Hines

Publication:     European Journal of Endocrinology, 2006

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Topical Review: Fetal Testosterone and Sex Differences in Typical Social Development and in Autism

Experiments in animals leave no doubt that androgens, including testosterone, produced by the testes in fetal and/or neonatal life act on the brain to induce sex differences in neural structure and function. In human beings, there is evidence supporting a female superiority in the ability to read nonverbal signals, specific language-related skills, and theory of mind. Even more striking than the sex differences seen in the typical population is the elevated occurrence of social and communicative difficulties in human males. One such condition, autism, occurs four times more frequently in boys than in girls. Recently, a novel theory known as the ``extreme male brain'' has been proposed. It suggests that the behaviors seen in autism are an exaggeration of typical sex differences and that exposure to high levels of prenatal testosterone might be a risk factor. In this article, we argue that prenatal and neonatal testosterone exposures are strong candidates for having a causal role in sexual dimorphism in human behavior, including social development, and as risk factors for conditions characterized by social impairments, particularly autism spectrum conditions.

Author/-s:       Rebecca Christine Knickmeyer; Simon Baron-Cohen

Publication:     Journal of Child Neurology, 2006

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Typical female 2nd–4th finger length (2D:4D) ratios in male-to-female transsexuals – possible implications for prenatal androgen exposure

Prenatal exposure to androgens has been implicated in transsexualism but the etiology of the condition remains unclear. The ratio of the 2nd to the 4th (2D:4D) digit lengths has been suggested to be negatively correlated to prenatal androgen exposure. We wanted to assess differences in 2D:4D ratio between transsexuals and controls.

Sixty-three male-to-female transsexuals (MFT), 43 female-to-male transsexuals (FMT), and 65 female and 58 male controls were included in the study. Photocopies of the palms and digits of the hands were taken of all subjects and 2D:4D ratios were measured, according to standard published procedures.
Comparison between right-handed individuals revealed that the right-hand 2D:4D in MFT is higher than in control males but similar to that observed in control females. In FMT we found no differences in 2D:4D relative to control females. Our findings support a biological etiology of male-to-female transsexualism, implicating decreased prenatal androgen exposure in MFT. We have found no indication of a role of prenatal hormone exposure in female-to-male transsexualism.

Author/-s:       Harald J. Schneider; Johanna Pickel;  Günter K. Stalla

Publication:     Psychoneuroendocrinology, 2006

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Prenatal exposure to diethylstilbestrol (DES) in males and gender-related disorders: Results from a 5-year study

Abstract: For many years, researchers and public health specialists have been assessing the human health impact of prenatal exposure to the estrogenic anti-miscarriage drug, diethylstilbestrol (commonly known as DES or "stilbestrol"). The scope of adverse effects in females exposed to DES (often called "DES daughters") has been more substantially documented than the effects in males ("DES sons"). This paper contributes three areas of important research on DES exposure in males: (1) an overview of published literature discussing the confirmed and suspected adverse effects of prenatal exposure in DES sons; (2) preliminary results from a 5-year online study of DES sons involving 500 individuals with confirmed (60 % of sample) and suspected prenatal DES exposure; (3) documentation of the presence of gender identity disorders and male-to-female transsexualism reported by more than 100 participants in the study.

Discussion: Among the most significant findings from this study is the high prevalence of individuals with confirmed or strongly suspected prenatal DES exposure who self-identify as male-to-female transsexual or transgender, and individuals who have reported experiencing difficulties with gender dysphoria.
In this study, more than 150 individuals with confirmed or suspected prenatal DES exposure reported moderate to severe feelings of gender dysphoria across the lifespan. For most, these feelings had apparently been present since early childhood. The prevalence of a significant number of self-identified male- to-female transsexuals and transgendered individuals as well as some individuals who identify as intersex, androgynous, gay or bisexual males has inspired fresh investigation of historic theories about a possible biological/endocrine basis for psychosexual development in humans, including sexual orientation, core gender identity, and sexual identity (Benjamin, 1973; Cohen-Kettenis and Gooren, 1999; Diamond, 1965, 1996; Michel et al, 2001; Swaab, 2004).

Author/-s:       Scott P. Kerlin

Publication:     Paper prepared for the International Behavioral Development Symposium, 2005

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Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings

There is now good evidence that human sex-typed behavior is influenced by sex hormones that are present during prenatal development, confirming studies in other mammalian species. Most of the evidence comes from clinical populations, in which prenatal hormone exposure is atypical for a person's sex, but there is increasing evidence from the normal population for the importance of prenatal hormones. In this paper, we briefly review the evidence, focusing attention on the methods used to study behavioral effects of prenatal hormones. We discuss the promises and pitfalls of various types of studies, including those using clinical populations (concentrating on those most commonly studied, congenital adrenal hyperplasia, androgen insensitivity syndrome, ablatio penis, and cloacal exstrophy), direct measures of hormones in the general population (assayed through umbilical cord blood, amniotic fluid, and maternal serum during pregnancy), and indirect measures of hormones in the general population (inferred from intrauterine position and biomarkers such as otoacoustic emissions, finger length ratios, and dermatoglyphic asymmetries). We conclude with suggestions for interpreting and conducting studies of the behavioral effects of prenatal hormones.

Author/-s:       Celina C. C. Cohen-Bendahan; Cornelieke van de Beek; Sheri A. Berenbaum

Publication:     Neuroscience & Biobehavioral Reviews, 2005

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Pubertal hormones organize the adolescent brain and behaviour

Maturation of the reproductive system during puberty results in elevated levels of gonadal steroid hormones. These hormones sculpt neural circuits during adolescence, a time of dramatic rewiring of the nervous system. Here, we review the evidence that steroid-dependent organization of the adolescent brain programs a variety of adult behaviors in animals and humans. Converging lines of evidence indicate that adolescence may be a sensitive period for steroid-dependent brain organization and that variation in the timing of interactions between the hormones of puberty and the adolescent brain leads to individual differences in adult behavior and risk of sex-biased psychopathologies.

Author/-s:       C. L. Sisk; J. L. Zehr

Publication:     Frontiers in neuroendocrinology, 2005

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Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH).

We assessed core gender identity, sexual orientation, and recalled childhood gender role behavior in 16 women and 9 men with CAH and in 15 unaffected female and 10 unaffected male relatives, all between the ages of 18 and 44 years. Women with congenital adrenal hyperplasia (CAH) recalled significantly more male-typical play behavior as children than did unaffected women, whereas men with and without CAH did not differ. Women with CAH also reported significantly less satisfaction with the female sex of assignment and less heterosexual interest than did unaffected women. Again, men with CAH did not differ significantly from unaffected men in these respects. Our results for women with CAH are consistent with numerous prior reports indicating that girls with CAH show increased male-typical play behavior. They also support the hypotheses that these women show reduced heterosexual interest and reduced satisfaction with the female sex of assignment. Our results for males are consistent with most prior reports that boys with CAH do not show a general alteration in childhood play behavior. In addition, they provide initial evidence that core gender identity and sexual orientation are unaffected in men with CAH. Finally, among women with CAH, we found that recalled male-typical play in childhood correlated with reduced satisfaction with the female gender and reduced heterosexual interest in adulthood. Although prospective studies are needed, these results suggest that those girls with CAH who show the greatest alterations in childhood play behavior may be the most likely to develop a bisexual or homosexual orientation as adults and to be dissatisfied with the female sex of assignment.

Author/-s:       Melissa Hines; C. Brook; G. S. Conway

Publication:     Journal of sex research, 2004

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Environment- and gene-dependent human ontogenesis, sociogenesis and phylogenesis (eco-geno-onto-socio-phylogenesis)

Abstract: Prevention of environment- and gene-dependent, teratogenic malfunctions (“Functional Teratogenesis”) – caused by abnormal hormone, neurotransmitter and cytokine concentrations during organization of the neuro-endocrine-immune system (NEIS) should be considered as a global challenge of outstanding relevance. By optimizing the natural and social environment and correcting in time abnormal concentrations of hormones, neurotransmitters and cytokines during the critical perinatal (pre- and early postnatal) organization period of the NEIS (“Neuro-Endocrine-Immune Prophylaxis”) human ontogenesis and sociogenesis can be decisively improved (“Primary Prevention of Maldevelopments of Human Beings and their Societies”). Finally, phylogenesis is dependent on incessant sequencies of ontogenesis and sociogenesis (“Onto-Socio-Phylogenesis”).

From the text: We could demonstrate by experimental, clinical and epidemiological data that genuine bi- and homosexuality as natural variants of sexual orientation can be based – as well as transsexuality – on a gene- or environment-dependent variability of prenatal sex hormone concentrations. […]

Author/-s:       Günter Dörner

Publication:     Neuroendocrinology Letters, 2004

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Gender role across development in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

This study evaluated the degree of femininity and masculinity at different developmental stages in a group of adult women, some of whom were exposed to elevated prenatal adrenal androgens as a result of congenital adrenal hyperplasia (CAH) due to 21 hydroxylase (21-OH) deficiency. Women who had presented to the Johns Hopkins Hospital Pediatric Endocrine Clinic for treatment of CAH due to 21-OH deficiency were included. The control group consisted of sisters of CAH participants and women referred for evaluation of polycystic ovary syndrome. Study participants were given a questionnaire asking them to indicate their degree of masculinity and femininity during childhood, adolescence, and adulthood. In addition, participants were asked questions related to their play behavior during childhood, including playmate preferences, toy preferences, and admiration of male or female characters during fantasy play. Across participant groups, self-reported femininity decreased in a dose response manner, according to prenatal androgen exposure. For all groups, femininity increased through developmental stages. Women with salt-losing CAH remained less feminine than controls into adulthood. Conversely, self-reported masculinity increased in a dose-response manner, according to prenatal androgen exposure, across participant groups. Women with CAH showed a decrease in masculinity across developmental stages, such that by adulthood, there were no significant differences in masculinity between controls and the women with CAH. Women with salt-losing CAH were more likely to recall preferences for boy playmates, male-typical toys, and admiration for male characters during childhood than other study participants. Our data support the effect of both prenatal androgen exposure and socialization on gender role behavior in adult women with CAH due to 21-OH deficiency.

Author/-s:       D. N. Long; A. B. Wisniewski; C. J. Migeon

Publication:     Journal of pediatric endocrinology and metabolism, 2004

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Prenatal exposure to testosterone and functional cerebral lateralization: a study in same-sex and opposite-sex twin girls

In animals it has been shown that exposure to sex hormones is influenced by intrauterine position. Thus fetuses located between two male fetuses are exposed to higher levels of testosterone (T) than fetuses situated between two female fetuses or one female and one male fetus. In a group of opposite-sex (OS) twin girls and same-sex (SS) twin girls a potential effect of prenatal exposure to testosterone (T) on functional cerebral lateralization was investigated. We hypothesized that prenatal exposure to T would result in a more masculine, i.e. a more lateralized pattern of cerebral lateralization in OS twin girls than in SS twin girls. An auditory-verbal dichotic listening task (DLT) was used as an indirect method to study hemispheric specialization. Firstly, we established a sex difference on the DLT. Compared with SS girls, OS twin boys showed a more lateralized pattern of processing verbal stimuli. Secondly, as predicted OS girls had a more masculine pattern of cerebral lateralization, than SS girls. These findings support the notion of an influence of prenatal T on early brain organization in girls.

Author/-s:       C. C. Cohen-Bendahan; J. K. Buitelaar; Stephanie H. M. van Goozen; Peggy T. Cohen-Kettenis

Publication:     Psychoneuroendocrinology, 2004

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Sexual differentiation of the human brain: relevance for gender identity, transsexualism and sexual orientation

Male sexual differentiation of the brain and behavior are thought, on the basis of experiments in rodents, to be caused by androgens, following conversion to estrogens. However, observations in human subjects with genetic and other disorders show that direct effects of testosterone on the developing fetal brain are of major importance for the development of male gender identity and male heterosexual orientation. Solid evidence for the importance of postnatal social factors is lacking. In the human brain, structural differences have been described that seem to be related to gender identity and sexual orientation.

Author/-s:       Dick F. Swaab

Publication:     Gynecological Endocrinology, 2004

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Sex in the brain. Gender differences in the human hypothalamus and adjacent areas. Relationship to transsexualism, sexual orientation, sex hormone receptors and endocrine status.

Summary of Chapter 1: From the moment of conception until the moment we die we are living in a sex-differentiated world. Not only do men and women have different physiques, they also have sex differences in seeing, smelling, thinking, feeling, behaving, socializing and making love. Thee brain orchestrates these sex differences by irreversible structural ("organizational")) and reversible ("activational") sex differences. Examples of such differences are macroscopically sex differences in brain volume, weight and regional differences in size, shape or fiber connections. Microscopically sex differences may exist e.g. in neuronal cell numbers, perikaryal size, dendritic branching and synaptogenesis, while at the molecular level sex differences can exist e.g. at the level of neuropeptides, neurotransmitters, enzymes, proteins and mRNA.. Functional sex differences exist in various aspects of reproduction (e.g. in the presence of the menstrual cycle in the hypothalamo-pituitary-gonadal- [HPG]-- axis in women), gender identity (i.e. the feeling to be male or female), sexual orientation (i.e. hetero-, bi-, or homosexuality), autonomic functions (differences in e.g. biological rhythms in body temperature, stress hormones, bloodpressure and sleep) as well as in sex hormone dependent gender differences in the regulation of mood, cognition, behaviour and neuroprotection in health and disease. The present thesis was undertaken to investigate structural and functional differences in the human hypothalamus and adjacent areas in relation to sex, gender identity and sexual orientation by focussing on morphological sex differences, sex hormone receptors (i.e. estrogen receptor- alpha [ERa], beta [ER0], androgen receptors [ARs] and progesterone receptors [PRs]) and their relation to endocrine status. To this end potential structural sex differences were studied inn human post mortem brain material by volume measurements and neuron counts (Chapter 2), while, as a basis for the detection of their site of action and thee mechanisms involved in the functional sex differences, differences in the expression of gonadal hormone receptors were studied immunocytochemically (Chapters 3–8).

Summary of Chapter 2: First the central part of the human bed nucleus of the stria terminal is (BSTc) was studied in order to determine whether its previously reported sex difference in size and its striking sex reversed size in transsexual subjects were also reflected in neuronal numbers. Transsexuals experience themselves as being off the opposite sex, in spite of having all the biological characteristics of one sex. A crucial question resulting from a previous brain study in male-to-female transsexuals was whether the reported, gender identity related, female size of the central part of the bed nucleus of the stria terminalis (BSTc) was based upon a neuronal difference in the BSTc itself or just a reflection of a difference in vasoactive intestinal polypeptide (VIP) innervation from the amygdala and other areas, which was used as a marker. Therefore, we determined in 42 subjects the number of somatostatin (SOM) expressing neurons in the BSTc in relation to sex, sexual orientation, gender identity and hormonal status. Regardless of sexual orientation men had almost twice as many somatostatin neurons in the BSTcc as women (p<0.006). The number of neurons in the BSTc of male-to-female transsexual was similar to that of the females (p=0.83). In contrast, the neuron number of a female-to-male transsexual was found to be in the male range. Hormone treatment or sex hormone level variations in adulthood did not seem to have influenced BSTc neuron numbers. The present findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder.

Summary of Chapter 3: The next step was to find out whether the BSTc and other hypothalamic areas are sex hormone sensitive as judged by the presence of gonadal hormone receptors. For this purpose immunohistochemical protocols for paraffin embedded formalin fixed hypothalamic human brain material were developed. First androgen receptor (AR) distribution was described throughout the rostro-caudal hypothalamus and adjacent areas. In this chapter we report for the first time the distribution of androgen receptor immunoreactivity (AR-ir) in the human hypothalamus of 10 human subjects (5 men and 5 women) ranging between 20 and 399 years of age using the antibody PG21. Prolonged post mortem delay (72:00 hours)) or fixation time (100 days) did not influence the AR-ir. In men, intense nuclear AR-ir was found in neurons of the horizontal limb of the diagonal band off Broca, of the lateromamillary nucleus (LMN) and in the medial mammillary nucleus (MMN). An intermediate nuclear staining was found in the diagonal band of Broca, sexually dimorphic nucleus of the preoptic area, paraventricular nucleus, suprachiasmatic nucleus, ventromedial nucleus and infundibular nucleus, while weaker labelling was found in the bed nucleus of the stria terminalis, medial preoptic area, dorsal and ventral zone of the periventricular nucleus, supraoptic nucleus and nucleus basalis of Meynert. In most brain areas women revealed less staining than men. In the LMN and the MMN a strong sex difference was found. Cytoplasmic labelling was observed in neurons of both sexes, while women showed a higher variability in the intensity of such staining. No six differences in AR-ir were, however, observed in the bed nucleus of the stria terminalis, the nucleus basalis of Meynert (NBM) and islands of Calleja. Species differences and similarities of the AR-ir distribution were discussed. The present results suggest the participation of androgens in the regulation of various hypothalamic processes that are sexually dimorphic.

Summary of Chapter 4: In the previous study we found androgen receptor (AR) sex differences in several regions throughout the human hypothalamus. Generally men had a stronger nuclear androgen receptor immunoreactivity (AR-ir) than women. The strongest nuclear labelling was found in the caudal hypothalamus in the mamillary body complex (MBC), which is known to be involved in aspects of sexual behaviour. The study in this chapter was carried out to investigate whether the sex difference in AR-ir of the MBC is related to sexual orientation or gender identity (i.e. the feeling to be male or female) or rather to circulating levels of androgens, since nuclear AR-ir is known to be upregulated by androgens from animal experiments. Therefore, we studied the MBC in the following groups: young-heterosexual men, young-homosexual men, aged-heterosexual castrated and non-castrated men, castrated and non-castrated transsexuals, young-heterosexual women and a young virilized woman. Nuclear AR-ir did not differ significantly between heterosexual and homosexual men but was significantly stronger in men than in women. A female-like pattern of AR-ir (i.e. no to weak nuclear staining) was observed in 26 to 53 year old castrated male-to-female transsexuals and in old castrated and non-castrated males of 67 to 87 years of age. In analogy with animal studies showing strong activational effects of androgens on nuclear AR-ir, the present data suggest that nuclear AR-ir in the human MBC is dependent on the presence or absence of circulating levels of androgens. The group data were, moreover, supported by the fact that a male-like AR-ir (i.e. intense nuclear AR-ir), was found in a 36 year old bisexual non-castrated male-to-female transsexual and in a heterosexual virilized woman off 46 years of age with high levels of circulating testosterone. In conclusion, the sexually dimorphic AR-ir in the MBC seemed to be related to circulating levels of androgens and not to sexual orientation or gender identity. The functional implications of these alterations are discussed in relation to reproduction, cognition and neuroprotection.

Summary of Chapter 5: In 1996 a novel second genomic ER subtype of ERs was cloned in rodents and humans and designed ERp. Subsequently it has been demonstrated that the original 'classical' ERa and the second ERp subtype may play different often opposite (e.g. activating [ERa] versus inhibiting [ERp]) roles in gene regulation. In order to determine the putative sites of action of estrogens, mediated by Era and ERp in the human hypothalamus and adjacent areas immunocytochemical protocols were developed for systematic rostro-caudal mapping studies in relation to sex and endocrine status in the same young adults studied for AR-ir in chapter 3. Hypothalamic material taken from 10 subjects (5 men and 5 women), ranging between 20 and 39 years of age, was investigated. Since it is known from various animal and human studies that ERs can be down- or upregulated by circulating levels of estrogens in a region dependent way, hypothalami of a few rare cases with well documented abnormal estrogen levels were also studied: a castrated, estrogen treated 50 year old male-to-female transsexual (Tl), a 31 year old man with an estrogen producing tumor (S2) and an ovariectomized 46 year old woman (S8). A strong sex difference with more nuclear ERa-ir in women was observed rostrally in the diagonal band of Broca (DBB) and caudally in the medial mamillary nucleus (MMN). Less robust sex differences were observed in other brain areas with more intense nuclear ERa-ir in men, e.g., in the sexually dimorphic nucleus of the medial preoptic area (SDN-POA), paraventricular nucleus (P VN) and lateral hypothalamic area (LHA), while women had more nuclear ERa-ir in the suprachiasmatic nucleus (SCN) and ventromedial nucleus (VMN). No nuclear sex differences in ERa were found e.g. in the central part of the BST (BSTc). In addition to nuclear staining, ERa-ir appeared to also be sex-dependently present in the cytoplasm of neurons and was observed in astrocytes, plexus choroideus and vascular cells. The differences in ERa-ir in subjects T1, S2 and S8 indicated the presence off some activating effects of estrogens on hypothalamic ERa-ir. The female expression pattern of ERa-ir in the VMN and MMN of the genetic male subjects (Tl) and (S2) (see e.g. Fig. 14C) were related to higher circulating estrogen levels. On the other hand, no clear changes occurred in the BSTc, SDNN or DBB, and a strikingly low ERa-ir was found in the NBM (cf Fig. 7E; Fig. 8A; Fig. 11 A). These data seem to suggest that in addition to differential activational effects of estrogen on ERa-ir, also other regulatory mechanisms (that are independent on circulating estrogen levels occur, such as effects on an organizational level) might be involved in the regional control of some ERa-ir sex differences. However, ERa-ir in T1, S2 and S8 suggested that the majority off the observed sex differences in ERa-ir are "activational" (e.g., VMN/MMN) rather than "organizational" in nature. Species similarities and differences in ERa-ir distribution and possible functional implications for the human brain are discussed.

Summary of Chapter 6: Subsequently a systematic rostro-caudal distribution of ERp-ir was studied in the human hypothalamus and adjacent areas in 5 males and 5 females between 20–39 years of age and compared to the ERa distribution (Chapter 5)) in the same patients. ER0-ir was generally observed more frequently in the cytoplasm than in the nucleus and appeared to be stronger in women. In addition, basket-like fiber stainings, suggestive for ERp-ir in synaptic-terminals, were observed in various areas. Men showed more robust nuclear ERp-ir than women in the medial part of the bed nucleus of the stria terminalis (BSTm), paraventricular and paratenial nucleus of the thalamus (PV and PT), while less intense, but more nuclear, ERp-ir appeared to be present in e.g. the BSTc, SDN-POA, DBB and VMN. Women revealed more nuclear ERp-ir than men of a low to intermediate level e.g. in the SCN, supraoptic (SON), PVN, infundibular (INF) and MMN. ERp-irr expression patterns in subjects with abnormal hormone levels, i.e., a 50 year old castrated estrogen treated male-to-female transsexual, a 31 year old man with an estrogen producing tumor and a 46 year old ovariectomized woman, suggest that the majority of the observed sex differences in ERp-ir are "activational" rather than "organizational" in nature. Similarities, differences, potential functional and clinical implications of the observed sex and hormone dependent ERa and ERp distributions are discussed in relation to reproduction, autonomic-function, mood, cognition and neuroprotection in health and disease.

General discussion – Transsexuality: Transsexual individuals have the strong feeling, often from their earliest childhood memories onwards, of having been born the wrong sex. Gender identity disorder (GID) as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) consists of two components: (1) a strong and persistent cross-gender identification and (2) persistent discomfort with one’s biological sex or gender role behavior associated with one’s sex. The most extreme form, in which individuals need to adapt their phenotype with hormones and surgery to make it congruent with their gender identity, is called transsexualism (cf. 'Definition and Synopsis of the Etiology of Gender Identity Disorder and Transsexualism': Transsexualism is thus the condition in which the transsexual person is convinced that he or she is actually a member of the opposite sex (reviewed by Gooren and Kruijver, 2002). Transsexuality is a rare condition. The annual incidence of transsexuality has been estimated in Sweden to be about 1/500 0000 inhabitants. The sex ratio (genetic male:female) has been shown to vary from country to country between 1.4:1 and 3:1 (Landen et al., 1996; Garrels et al., 2000). In the Netherlands the prevalence of MTFs was found to be 1: 111 900 and 1: 30 400 for FTMs (Bakker et al., 1993). The frequency of regret cases of sex re-assigned transsexual individuals varies from 3.8 % in Sweden (Landen, 1999) to 0.4 % in Germany and The Netherlands (Weitze and Osburg, 1996; van Kesteren et al., 1996). Transsexualism cannot be explained, in general, by variations in gonadal, genital or hormonal systems in adulthood (Gooren, 1990; Cohen-Kettenis and Gooren, 1999). In most cases, it cannot be clearly explained by variations in chromosomal patterns either (Gooren, 1990; Cohen-Kettenis and Gooren, 1999), although recent studies identified some sex chromosome anomalies. Six cases of male-to-female transsexuals with 47, XYY chromosome and one female-to-male transsexual with 47, XXX have been reported (Tayfun Turan et al., 2000). Also in men with Klinefelter syndrome (47, XXY) transsexualism has been reported (Wyler et al., 1979; Seifert and Windgassen, 1995). A recent study on gender identity disorder (GID) in a child and adolescent mono- (n=96) and di-zygotic (N=61) pooled twin sample supports moreover the hypothesis that there is a heritable component to GID (Coolidge et al., 2002). This study also fits with other recent studies pointing to pairs of monozygotic female twins requesting for sex reassignment therapy and with familial cases of gender identity problems (Green, 2000; Sadeghi and Fakhrai, 2000). Together, these data do suggest a genetic basis in at least a subpopulation of transsexual people (reviewed by Swaab, 2002).

General discussion – The paradigm of transsexuality as a neuro-developmental condition: "The brain is the sexiest hidden organ that we have" – Frank P.M. Kruijver, 2002.

As pointed out in the introduction, sexual differentiation is a sequential process. At conception the configuration of the sex chromosomes determines the genetic sex, the genetic sex determines the gonadal sex and the gonadal sex influences the brain sex by gender specific secretion patterns of sex hormones: male by the presence of testicular androgens, female by the absence of testis and the lack of peaks in testicular androgen exposure, i.e. prenatally around 12–24 weeks of gestational age and postnatally around 4–24 weeks of neonatal age (reviewed by Hrabovszky and Hutson, 2002). The present thesis shows that the human limbic brain expresses regional sex differences in gonadal hormone receptors (Chapter 3–8). Also during early development sex hormone receptors are present in the human brain in a stage-dependent sexually dimorphic way (cf. Chung, 2003). It thus appears conceivable that due to local hormone dependent changes during development at least some areas of the brain may follow a different course than the genitals during the process of sexual differentiation. A partial or even complete brain-body sex reversal may eventually be the result. This could lead to the development of female-like brain structures in a brain of a subject so far male differentiated or vice versa. If these brain areas are particularly involved in the establishment of e.g. an individual’s sexual orientation or gender identity a sex reversed partner preference or gender identity may be the result. The present thesis has provided new neurobiological evidence to support the view that transsexualism can be explained by a sex reversed brain status.

Author/-s:       Frank P. M. Kruijver

Publication:     Dissertation, Faculty of Medicine, University of Amsterdam, 2004

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An evolutionary perspective of sex-typed toy preferences: pink, blue, and the brain.

Large sex differences in children's toy preferences are attributed to gender group identification and social learning. The proposal outlined in this paper is that contemporary conceptual categories of "masculine" or "feminine" toys are also influenced by evolved perceptual categories of male-preferred and female-preferred objects. Research on children exposed prenatally to atypical levels of androgens and research on typically developing infants suggest sex-dimorphic preferences exist for object features, such as movement or color/form. The evolution and neurobiology of mammalian visual processing--and recent findings on sex-dimorphic toy preferences in nonhuman primates--suggest further that an innate bias for processing object movement or color/form may contribute to behaviors with differential adaptive significance for males and females. In this way, preferences for objects such as toys may indicate a biological preparedness for a "masculine" or "feminine" gender role-one that develops more fully as early perceptual preferences are coupled with object experiences imposed by contemporary gender socialization.

Author/-s:       Gerianne M. Alexander

Publication:     Archives of sexual behaviour, 2003

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Prenatal androgens and gender-typed behavior: a study of girls with mild and severe forms of congenital adrenal hyperplasia.

Gender-typed behaviors and interests were investigated in 26 girls, aged 2–10 years, affected with congenital adrenal hyperplasia (CAH) and in 26 unaffected girls matched for age. Girls with CAH were more interested in masculine toys and less interested in feminine toys and were more likely to report having male playmates and to wish for masculine careers. Parents of girls with CAH rated their daughters' behaviors as more boylike than did parents of unaffected girls. A relation was found between disease severity and behavior indicating that more severely affected CAH girls were more interested in masculine toys and careers. No parental influence could be demonstrated on play behavior, nor did the comparison of parents' ratings of wished for behavior versus perceived behavior in their daughters indicate an effect of parental expectations. The results are interpreted as supporting a biological contribution to differences in play behavior between girls with and without CAH.

Author/-s:       A. Servin; A. Nordenström, A. Larsson; G. Bohlin

Publication:     Developmental psychology, 2003

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Sex steroids and human behavior: prenatal androgen exposure and sex-typical play behavior in children

Gonadal hormones, particularly androgens, direct certain aspects of brain development and exert permanent influences on sex-typical behavior in nonhuman mammals. Androgens also influence human behavioral development, with the most convincing evidence coming from studies of sex-typical play. Girls exposed to unusually high levels of androgens prenatally, because they have the genetic disorder, congenital adrenal hyperplasia (CAH), show increased preferences for toys and activities usually preferred by boys, and for male playmates, and decreased preferences for toys and activities usually preferred by girls. Normal variability in androgen prenatally also has been related to subsequent sex-typed play behavior in girls, and nonhuman primates have been observed to show sex-typed preferences for human toys. These findings suggest that androgen during early development influences childhood play behavior in humans at least in part by altering brain development.

Author/-s:       Melissa Hines

Publication:     Annals of the New York Academy of Sciences, 2003

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Androgen imprinting of the brain in animal models and humans with intersex disorders: review and recommendations.

Purpose: Psychosexual development, gender assignment and surgical treatment in patients with intersex are controversial issues in the medical literature. Some groups are of the opinion that gender identity and sexual orientation are determined prenatally secondary to the fetal hormonal environment causing irreversible development of the nervous system. We reviewed the evidence in animal and human studies to determine the possible role of early postnatal androgen production in gender development.

Materials and methods: An extensive literature review was performed of data from animal experiments and human studies.

Results: Many animal studies show that adding or removing hormonal stimulus in early postnatal life can profoundly alter gender behavior of the adult animal. Human case studies show that late intervention is unable to reverse gender orientation from male to female. Most studies have not permitted testing of whether early gender assignment and treatment as female with suppression/ablation of postnatal androgen production leads to improved concordance of the gender identity and sex of rearing.

Conclusions: Animal studies support a role for postnatal androgens in brain/behavior development with human studies neither completely supportive nor antagonistic. Therefore, gender assignment in infants with intersex should be made with the possibility in mind that postnatal testicular hormones at ages 1 to 6 months may affect gender identity. A case-control study is required to test the hypothesis that postnatal androgen exposure may convert ambisexual brain functions to committed male behavior patterns.

Author/-s:       Z. Hrabovszky; J. M. Hutson

Publication:     The Journal of urology, 2002

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Organizing and activating effects of sex hormones in homosexual transsexuals

The cause of transsexualism remains unclear. The hypothesis that atypical prenatal hormone exposure could be a factor in the development of transsexualism was examined by establishing whether an atypical pattern of cognitive functioning was present in homosexual transsexuals. Possible activating effects of sex hormones as a result of cross-sex hormone treatment were also studied. Female-to-male and male-to-female transsexuals were compared with female and male controls with respect to spatial ability before and after treatment. The data were consistent with an organizing effect, but there was no evidence of an activating effect. Homosexual transsexuals, who prior to hormone treatment scored in the direction of the opposite sex, may have reached a ceiling in performance and therefore do not benefit from activating hormonal effects.

Author/-s:       Stephanie H. M. van Goozen; Ditte Slabbekoorn; Louis J. G. Gooren; G. Sanders; Peggy T. Cohen-Kettenis

Publication:     Behavioral neuroscience, 2002

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Sex-typed toy play behavior correlates with the degree of prenatal androgen exposure assessed by CYP21 genotype in girls with congenital adrenal hyperplasia

Previous studies have shown that girls with congenital adrenal hyperplasia (CAH), a syndrome resulting in overproduction of adrenal androgens from early fetal life, are behaviorally masculinized. We studied play with toys in a structured play situation and correlated the results with disease severity, assessed by CYP21 genotyping, and age at diagnosis. Girls with CAH played more with masculine toys than controls when playing alone. In addition, we could demonstrate a dose-response relationship between disease severity (i.e. degree of fetal androgen exposure) and degree of masculinization of behavior. The presence of a parent did not influence the CAH girls to play in a more masculine fashion. Four CAH girls with late diagnosis are also described. Three of the four girls played exclusively with one of the masculine toys, a constructional toy. Our results support the view that prenatal androgen exposure has a direct organizational effect on the human brain to determine certain aspects of sex-typed behavior.

Author/-s:       A. Nordenström; A. Servin; G. Bohlin; A. Larsson; A. Wedell

Publication:     The Journal of clinical endocrinology and metabolism, 2002

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Genetic and epigenetic effects on sexual brain organization mediated by sex hormones

Alterations of sex hormone levels during pre- or perinatal sexual brain organization - responsible for long-term changes of gonadotropin secretion, sexual orientation, and gender role behavior - can be caused by: 1. Genetic effects, i.e. mutations or polymorphisms of a) 21-hydroxylase genes on chromosome 6, b) 3beta-hydroxysteroid dehydrogenase genes in chromosome 1 or c) X-chromosomal genes, and 2. Epigenetic effects, such as a) stressful situations - especially in combination with mutations - and b) endocrine disrupters, e.g. the pesticide DDT and its metabolites, which display estrogenic, antiandrogenic, and inhibitory effects on the enzyme 3beta-hydroxysteroid dehydrogenase leading to increased levels of dehydroepiandrosterone and its sulfate as precursors of endogenous androgens and estrogens.

In connection with the introduction and extensive use of the pesticide DDT, the following findings were obtained in subjects born before as compared to those born during this period: 1. The prevalence of patients with polycystic ovaries (PCO), idiopatic oligospermia (IO), and transsexualism (TS) increased significantly (about 3–4 fold). 2. Partial 21-hydroxylase deficiencies were observed in most patients with PCO and TS and some patients with IO born before this period. 3. In contrast, most patients with PCO and TS and several patients with IO born during the period of massive use of DDT displayed clearly increased plasma levels of dehydroepiandrosterone sulfate (DHEA-S) and DHEA-S/cortisol ratios suggesting partial 3beta-hydroxsteroid dehydrogenase (3beta-HSD) deficiencies. Interestingly enough, geneticists could not find any mutations of 3beta-HSD genes in such subjects. However, o,p'-DDT and/or its metabolite o,p'-DDD are strong inhibitors of 3beta-HSD, indicating their possible co-responsibility for such life-long ontogenetic alterations. Finally, some data suggest that endocrine disrupters may also be able to affect the development of sexual orientation.

Author/-s:       Günter Dörner; F. Götz; W. Rohde; A. Plagemann; R. Lindner; H. Peters; Z. Ghanaati

Publication:     Neuroendocrinology Letters, 2001

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Biological limits of gender construction

A biosocial theory of gender is constructed on both the macro and micro levels. A micro-model of within-sex differences among females integrates the biological model current in primatology with the prevailing social science model. It shows how sex differences in hormone experience from gestation to adulthood shape gendered behavior (that is, behavior that differs by sex). On the macro level, this model also illustrates how socialization and environment shape gendered behavior. It then demonstrates how hormone experiences can facilitate or dampen the effects of socialization and environment on gendered behavior. Data were analyzed from a sample of 163 White women who were studied from before they were born to the end of their 3rd decade. Results show that prenatal androgen exposures from the 2nd trimester affected gendered behavior, but not exposures from the 1st or 3rd trimesters. Further, the basic hormone model shows that in this sample, mothers' prenatal hormones had an effect on the gendered behavior of the Ss 3 decades later. The author speculates about the constraints placed by biology on the social reconstruction of gender.

Author/-s:       J. Richard Udry

Publication:     American Sociological Review, 2000

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Sex differences in the distribution of androgen receptors in the human hypothalamus

The present study reports for the first time the distribution of androgen receptor immunoreactivity (AR-ir) in the human hypothalamus of ten human subjects (five men and five women) ranging in age between 20 years and 39 years using the antibody PG21. Prolonged postmortem delay (72:00 hours) or fixation time (100 days) did not influence the AR-ir. In men, intense nuclear AR-ir was found in neurons of the horizontal limb of the diagonal band of Broca, in neurons of the lateromamillary nucleus (LMN), and in the medial mamillary nucleus (MMN). An intermediate nuclear staining was found in the diagonal band of Broca, sexually dimorphic nucleus of the preoptic area, paraventricular nucleus, suprachiasmatic nucleus, ventromedial nucleus, and infundibular nucleus, whereas weaker labeling was found in the bed nucleus of the stria terminalis, medial preoptic area, dorsal and ventral zones of the periventricular nucleus, supraoptic nucleus, and nucleus basalis of Meynert. In most brain areas, women revealed less staining than men. In the LMN and the MMN, a strong sex difference was found. Cytoplasmic labeling was observed in neurons of both sexes, although women showed a higher variability in the intensity of such staining. However, no sex differences in AR-ir were observed in the bed nucleus of the stria terminalis, the nucleus basalis of Meynert, or the islands of Calleja. Species differences and similarities of the AR-ir distribution are discussed. The present results suggest the participation of androgens in the regulation of various hypothalamic processes that are sexually dimorphic.

Author/-s:       A. Fernández-Guasti; F. P. Kruijver; M. Fodor; D. F. Swaab

Publication:     The Journal of comparative neurology, 2000

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The development of brain sex differences: a multisignaling process

In order to account for the development of sex differences in the brain, we took, as an integrative model, the vomeronasal pathway, which is involved in the control of reproductive physiology and behavior. The fact that brain sex differences take place in complex neural networks will help to develop a motivational theory of sex differences in reproductive behaviors. We also address the classic genomic actions in which three agents (the hormone, the intracellular receptor, and the transcription function) play an important role in brain differentiation, but we also point out refinements that such a theory requires if we want to account of the existence of two morphological patterns of sex differences in the brain, one in which males show greater morphological measures (neuron numbers and/or volume) than females and the opposite. Moreover, we also consider very important processes closely related to neuronal afferent input and membrane excitability for the developing of sex differences. Neurotransmission associated to metabotropic and ionotropic receptors, neurotrophic factors, neuroactive steroids that alter membrane excitability, cross-talk (and/or by-pass) phenomena, and second messenger pathways appear to be involved in the development of brain sex differences. The sexual differentiation of the brain and reproductive behavior is regarded as a cellular multisignaling process.

Author/-s:       Santiago Segovia; Antonio Guillamón; Marı́a Cruz R. del Cerro; Esperanza Ortega; Carmen Pérez-Laso; Mónica Rodriguez-Zafra; Carlos Beyer

Publication:     Behavioural brain research, 1999

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Transsexualism. Epidemiology, phenomenology, regret after surgery, aetiology, and public attitudes

Transsexualism denotes a condition in which the gender identity-the personal sense of being a man or a woman-contradicts the bodily sex characteristics. This thesis is based on three independent surveys about transsexualism.

FIRST, all 233 subjects applying for sex reassignment in Sweden during 1972-1992 were retrospectively examined through medical records. The incidence of applying for sex reassignment was 0.17/100 000 individuals over 15 years of age and per year. The male-to-female (M-F)/female-to-male (F-M) ratio was 1.4/1. With the exception of an incidence peak related to the legislation regulating sex reassignment in the early 1970s, the incidence has remained fairly stable since the first estimates in Sweden in the late 1960s. The M-F (n=134) and F-M (n=99) groups were phenomenologically compared. M-F transsexuals were older, and more often had a history of marriage and children than their F-M counterparts. M-F transsexuals also had more heterosexual experience. F-M transsexuals, on the other hand, more frequently reported cross-gender behaviour in childhood than did M-F transsexuals. It is concluded that transsexualism is manifested differently in males and females. The regret frequency (defined as applying for reversal to the original sex) was 3.8%. Prognostic factors for regret were, 'a poor support from the family', and 'belonging to the secondary group of transsexuals' (denotes people who develop transsexualism only after a significant period of transvestism or homosexuality).

SECOND, 28 M-F transsexuals and 30 male controls were investigated. To test the hypothesis that genes coding for proteins involved in the sexual differentiation of the brain influence the susceptibility of transsexualism, we analysed (1) a tetra nucleotide polymorphism of the aromatase gene, (2) a CAG repeat sequence in the first exon of the gene coding for the androgen receptor, and (3) a CA repeat polymorphism of the estrogen receptor beta gene. Results support the notion that the gender identity is related to the sex steroid-driven sexual differentiation of the brain, and that certain genetic variants of three of the genes critically involved in this process, may enhance the susceptibility for transsexualism.

THIRD, a questionnaire comprising questions about attitudes towards transsexualism and transsexuals was mailed to a random national sample (n=998) of Swedish residents, 18–75 years of age. The response rate was 67 %. The results showed that a majority supports the possibility for transsexuals to undergo sex reassignment. However, 63 % thought that the individual should bear the expenses for it. In addition, a majority supported the transsexuals' right to get married in their new sex, and their right to work with children. Transsexuals' right to adopt and raise children was supported by 43 % whereas 41 % opposed this. The results indicated that those who believed that transsexualism is caused by psychological factors had a more restrictive view on transsexualism than people who held a biological view.

Author/-s:       Mikael Landén

Publication:     Doctoral Thesis, University of Gothenburg, 1999

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Cognitive ability and cerebral lateralisation in transsexuals

It is still unclear to what extent cross-gender identity is due to pre- and perinatal organising effects of sex hormones on the brain. Empirical evidence for a relationship between prenatal hormonal influences and certain aspects of gender typical (cognitive) functioning comes from pre- and postpubertal clinical samples, such as women suffering from congenital adrenal hyperplasia and studies in normal children. In order to further investigate the hypothesis that cross-gender identity is influenced by prenatal exposure to (atypical) sex steroid levels we conducted a study with early onset, adult, male-to-female and female-to-male transsexuals, who were not yet hormonally treated, and nontranssexual adult female and male controls. The aim of the study was to find out whether early onset transsexuals performed in congruence with their biological sex or their gender identity. The results on different tests show that gender differences were pronounced, and that the two transsexual groups occupied a position in between these two groups, thus showing a pattern of performance away from their biological sex. The findings provide evidence that organisational hormonal influences may have an effect on the development of cross-gender identity.

Author-/s:       Peggy T. Cohen-Kettenis; Stephanie H. M. van Goozen; Cees D. Doorn; Louis J. G. Gooren

Publication:     Psychoneuroendocrinology, 1998

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A sex difference in the human brain and its relation to transsexuality

Transsexuals have the strong feeling, often from childhood onwards, of having been born the wrong sex. The possible psycho-genie or biological aetiology of transsexuality has been the subject of debate for many years. Here we show that the volume of the central subdivision of the bed nucleus of the stria terminalis (BSTc), a brain area that is essential for sexual behaviour, is larger in men than in women. A female-sized BSTc was found in male-to-female transsexuals. The size of the BSTc was not influenced by sex hormones in adulthood and was independent of sexual orientation. Our study is the first to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones.

Author/-s:       Jiang-Ning Zhou; Michel A. Hofman; Louis J. G. Gooren; Dick F. Swaab

Publication:     Nature, 1995

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Human behavioral sex differences: a role for gonadal hormones during early development?

Evidence that gonadal hormones during prenatal and neonatal development influence behavior is reviewed. Several theoretical models of hormonal influences, derived from research in other species, are described. These models are evaluated on the basis of data from humans with either normal or abnormal hormonal exposure. It is concluded that the evidence is insufficient to determine which model best explains the data. Sexual differentiation may involve several dimensions, and different models may apply to different behaviors. Gonadal hormones appear to influence development of some human behaviors that show sex differences. The evidence is strongest for childhood play behavior and is relatively strong for sexual orientation and tendencies toward aggression. Also, high levels of hormones do not enhance intelligence, although a minimum level may be needed for optimal development of some cognitive processes. Directions for future research are proposed.

Author/-s:       M. L. Collaer; Melissa Hines

Publication:     Psychological bulletin, 1995

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Roles of steroid hormones and their receptors in structural organization in the nervous system.

Due to their chemical properties, steroid hormones cross the blood-brain barrier where they have profound effects on neuronal development and reorganization both in invertebrates and vertebrates, including humans mediated through their receptors. Steroids play a crucial role in the organizational actions of cellular differentiation representing sexual dimorphism and apoptosis, and in the activational effects of phenotypic changes in association with structural plasticity. Their sites of action are primarily the genes themselves but some are coupled with membrane-bound receptor/ion channels. The effects of steroid hormones on gene transcription are not direct, and other cellular components interfere with their receptors through cross-talk and convergence of the signaling pathways in neurons. These genomic and non-genomic actions account for the divergent effects of steroid hormones on brain function as well as on their structure. This review looks again at and updates the tremendous advances made in recent decades on the study of the role of steroid (gonadal and adrenal) hormones and their receptors on developmental processes and plastic changes in the nervous system.

Author/-s:       M. Kawata

Publication:     Neuroscience Research, 1995

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Early Androgens Are Related to Childhood Sex-Typed Toy Preferences

Girls with congenital adrenal hyperplasia (CAH) who were exposed to high levels of androgen in the prenatal and early postnatal periods showed increased play with boys’ toys and reduced play with girls’ toys compared with their unexposed female relatives at ages 3 to 8. Boys with CAH did not differ from their male relatives in play with boys' or girls' toys. These results suggest that early hormone exposure in females has a masculinizing effect on sex-typed toy preferences.

Author/-s:       Sheri A. Berenbaum; Melissa Hines

Publication:     Psychological science, 1992

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Gene- and environment-dependent neuroendocrine etiogenesis of homosexuality and transsexualism

Sexual brain organization is dependent on sex hormone and neurotransmitter levels occurring during critical developmental periods. The higher the androgen levels during brain organization, caused by genetic and/or environmental factors, the higher is the biological predisposition to bi- and homosexuality or even transsexualism in females and the lower it is in males. Adrenal androgen excess, leading to heterotypical sexual orientation and/or gender role behavior in genetic females, can be caused by 21-hydroxylase deficiency, especially when associated with prenatal stress. The cortisol (F) precursor 21-deoxycortisol (21-DOF) was found to be significantly increased after ACTH stimulation in homosexual as compared to heterosexual females. 21-DOF was increased significantly before and even highly significantly after ACTH stimulation in female-to-male transsexuals. In view of these data, heterozygous and homozygous forms, respectively, of 21-hydroxylase deficiency represent a genetic predisposition to androgen-dependent development of homosexuality and transsexualism in females. Testicular androgen deficiency in prenatal life, giving rise to heterotypical sexual orientation and/or gender role behavior in genetic males, may be induced by prenatal stress and/or maternal or fetal genetic alterations. Most recently, in mothers of homosexual men--following ACTH stimulation--a significantly increased prevalence of high 21-DOF plasma values and 21-DOF/F ratios was found, which surpassed the mean + 1 SD level of heterosexual control women. In homosexual men as well--following ACTH stimulation--most of the 21-DOF plasma values and 21-DOF/F ratios also surpassed the mean + 1 SD level of heterosexual men. In only one out of 9 homosexual males, neither in his blood nor in that of his mother increased 21-DOF values and 21-DOF/F ratios were found after ACTH stimulation. In this homosexual man, however, the plasma dehydroepiandrosterone sulfate (DHEA-S) values and the DHEA-S/1000 x A (A = androstenedione) ratio were increased before and after ACTH stimulation. Furthermore, highly significantly increased basal plasma levels of dehydroepiandrosterone sulfate were found in male-to-female transsexuals as compared to normal males, suggesting partial 3 beta-ol hydroxysteroid dehydrogenase deficiency to be a predisposing factor for the development of male-to-female transsexualism.

Author/-s:       G. Dörner; I. Poppe; F. Stahl; J. Kölzsch; R. Uebelhack

Publication:     Experimental and Clinical Endocrinology, 1991

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