What causes transsexualism?

On this page, I’m trying to give answers to the following question:

Is there a plausible biological mechanism that can cause a mismatch between mental gender identity and physical sex characteristics?

 

Spoiler alert: The answers is yes. I have tried to answer the questions by making a list of observations and supporting them with evidence from current scientific research.

To clarify: The root cause for transsexualism has not yet been found. Similar to other conditions, such as homosexuality, autism, and diabetes, there seems to be a multitude of factors working together, which makes research more difficult. In case of transsexualism it seems that the major biological origins are genetics, epigenetics and pre-natal hormones.  There might also be additional environmental triggers. The objective of this page is to show one or more possible, or even plausible, biological mechanisms that can cause gender dysphoria.

 

 

 

  1. Hormone exposure before and around birth can influence the sexual differentiation of the brain, including gender identity

    1. Human studies

    2. Animal studies

  2. Genetic factors can influence the sexual differentiation of the brain

    1. Human studies

    2. Animal studies

 

 

 

To provide evidence for the observations above, a number of scientific studies are listed. Please have a browse.

I very much appreciate corrections, amendments and additions.

All abstracts are taken verbatim from the respective studies, only the highlighting is mine. To avoid distorting the studies, the included abstracts are full-length, even if some parts are not relevant to the observation detailed in the chapter. Please read the original studies for more information; often the contents are even more interesting than the carefully worded abstract. Some studies are listed twice to illustrate separate points. I tried to provide mainly recently published and peer-reviewed studies and avoided case studies with few participants.

I would like to express my gratitude to all researchers and contributors to human biology and medicine – your work is continuously making this world a much better place for all of us. Thank you so much!

 

 

 

5.     Hormone exposure before and around birth can influence the sexual differentiation of the brain, including gender identity

5.a.    Human studies

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

Web link:         http://link.springer.com/chapter/10.1007/978-1-4614-7441-8_1

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

Web link:         http://ehp.niehs.nih.gov/wp-content/uploads/121/11/ehp.1306533.pdf

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

Web link:         http://hdl.handle.net/1871/40250

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

Web link:         http://link.springer.com/article/10.1007/s00424-013-1258-4

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

Web link:         http://link.springer.com/referenceworkentry/10.1007/978-1-4614-1997-6_115

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

Web link:         http://www.journalagent.com/z4/download_fulltext.asp?pdir=jtgga&plng=tur&un=JTGGA-86836

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

Web link:         http://www.jneurosci.org/content/32/2/674.abstract

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

Web link:         http://www.sciencedirect.com/science/article/pii/S0018506X1200044X

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/22738413

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/21438685

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/21397624

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

Web link:         http://www.sciencedirect.com/science/article/pii/S0191886909004620

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

Web link:         http://miami.uni-muenster.de/Record/fd13d060-2a21-4021-9ab6-581dd8ae498b

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

Web link:         http://www.degruyter.com/view/j/jpem.2010.23.issue-6/jpem.2010.095/jpem.2010.095.xml

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

Web link:         http://nro.sagepub.com/content/16/5/550.short

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

Web link:         http://dspace.library.uu.nl/handle/1874/182733

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:       I. Savic; Alicia Garcia-Falgueras; Dick F. Swaab

Publication:     Progress in brain research, 2010

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/21094885

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

Web link:         http://www.karger.com/Article/Abstract/262525

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

Web link:         http://www.hawaii.edu/PCSS/biblio/articles/2005to2009/2009-clinical-implications-hormones.html

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 O

Publication:     BMC Genomics, 2009

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/19570224

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; S. Baron-Cohen; E. Ashwin; R. Knickmeyer; K. Taylor; G. Hackett; M. Hines

Publication:     Psychological Science, 2009

Web link:         http://europepmc.org/abstract/MED/19175758

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

Web link:         http://europepmc.org/abstract/MED/17906922

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; A. Garcia-Falgueras

Publication:     Functional Neurology, 2009

Web link:         http://europepmc.org/abstract/MED/19403051

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/18585715

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/18803959

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/17875490

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

Web link:         http://europepmc.org/abstract/MED/17307903

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

Web link:         http://www.eje-online.org/content/155/suppl_1/S115.abstract

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

Web link:         http://www.psyneuen-journal.com/article/S0306-4530(05)00177-0/abstract

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

Web link:         http://www.shb-info.org/sitebuildercontent/sitebuilderfiles/desexposedhbs.pdf

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/15811504/

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/15349078

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/15177706

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

Web link:         http://informahealthcare.com/doi/abs/10.1080/09513590400018231

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': www.GIRES.com). 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

Web link:         http://dare.uva.nl/document/75961

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/14993060

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:       S. H. van Goozen; D. Slabbekoorn; L. J. Gooren; G. Sanders; Peggy T. Cohen-Kettenis

Publication:     Behavioral neuroscience, 2002

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/12492297/

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/12414881

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/11781536

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

Web link:         http://www.sciencedirect.com/science/article/pii/S0166432899000832

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

Web link:         https://gupea.ub.gu.se/handle/2077/12418

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

Web link:         http://europepmc.org/abstract/MED/9802133

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

Web link:         http://www.nature.com/nature/journal/v378/n6552/abs/378068a0.html

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

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/7644606

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

Web link:         http://pss.sagepub.com/content/3/3/203.abstract

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

Web link:         http://europepmc.org/abstract/MED/1778227

 

 

 

Testosterone exposure during the critical period decreases corticotropin-releasing hormone-immunoreactive neurons in the bed nucleus of the stria terminalis of female rats
  • We previously described sex differences in the number of corticotropin-releasing hormone-immunoreactive (CRH-ir) neurons in the dorsolateral division of the bed nucleus of the stria terminalis (BSTLD). Female rats were found to have more CRH neurons than male rats. We hypothesized that testosterone exposure during the critical period of sexual differentiation of the brain decreased the number of CRH-ir neurons in the hypothalamus, including the BSTLD and preoptic area. In the present study we confirm that testosterone exposure during the neonatal period results in changes to a variety of typical aspects of the female reproductive system, including estrous cyclicity as shown by virginal smear, the positive feedback effects of estrogen alone or combined with progesterone, luteinizing hormone secretions, and estrogen and progesterone-induced Fos expression in gonadotropin-releasing hormone neurons. The number of CRH-ir neurons in the preoptic area did not change, whereas CRH-ir neurons in the BSTLD significantly decreased in estrogen-primed ovariectomized rats exposed to testosterone during the neonatal period. These results suggest that the sexual differentiation of CRH neurons in the BSTLD is a result of testosterone exposure during the critical period and the BSTLD is more fragile than the preoptic area during sexual differentiation. Furthermore, sex differences in CRH in the preoptic area may not be caused by testosterone during this period.

Author/-s:       Atsushi Fukushima; Miyako Furuta; Fukuko Kimura; Tatsuo Akema; Toshiya Funabashi

Publication:     Neuroscience Letters, 2013

Web link:         http://www.sciencedirect.com/science/article/pii/S0304394012016035

Effects of prenatal androgens on rhesus monkeys: a model system to explore the organizational hypothesis in primates
  • After proposing the organizational hypothesis from research in prenatally androgenized guinea pigs (Phoenix, C.H., Goy, R.W., Gerall, A.A., Young, W.C., 1959. Organizational action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65, 369-382.), the same authors almost immediately extended the hypothesis to a nonhuman primate model, the rhesus monkey. Studies over the last 50 years have verified that prenatal androgens have permanent effects in rhesus monkeys on the neural circuits that underlie sexually dimorphic behaviors. These behaviors include both sexual and social behaviors, all of which are also influenced by social experience. Many juvenile behaviors such as play, mounting, and vocal behaviors are masculinized and/or defeminized, and aspects of adult sexual behavior are both masculinized (e.g. approaches, sex contacts, and mounts) and defeminized (e.g. sexual solicits). Different behavioral endpoints have different periods of maximal susceptibility to the organizing actions of prenatal androgens. Aromatization is not important, as both testosterone and dihydrotestosterone are equally effective in rhesus monkeys. Although the full story of the effects of prenatal androgens on sexual and social behaviors in the rhesus monkey has not yet completely unfolded, much progress has been made. Amazingly, a large number of the inferences drawn from the original 1959 study have proved applicable to this nonhuman primate model.

Author/-s:       J. Thornton; J. L. Zehr; M. D. Loose

Publication:     Hormones and Behavior, 2009

Web link:         http://europepmc.org/abstract/MED/19446080

Juvenile Rank Can Predict Male-Typical Adult Mating Behavior in Female Sheep Treated Prenatally with Testosterone
  • Previous research with female sheep indicates that exposure to excess testosterone for 60 days (from Gestational Days 30–90 of the 147-day gestation) leads to virilized genitalia, severe neuroendocrine deficits, as well as masculinization and defeminization of sexual behavior (T60 females). In contrast, 30 days of testosterone exposure (Gestational Days 60–90) produce animals with female-typical genitalia, less severe neuroendocrine alterations, and variable gender patterns of sexual behavior (T30 females). Variation in adult sexual behavior of male ungulates is influenced by early social experience, but this has never been tested in females. Here we investigate the influence of rank in the dominance hierarchy on the expression of adult sexual behavior in females. Specifically, we hypothesized that juvenile rank would predict the amount of male- and female-typical mating behavior exhibited by adult female sheep. This hypothesis was tested in two treatment groups and their controls (group 1: T60 females; group 2: T30 females). Dominance hierarchies were determined by observing competition over resources. Both groups of prenatal testosterone-treated females were higher ranking than controls (T60: P = 0.05; T30: P < 0.01). During the breeding season, both T60 and T30 females exhibited more male-typical mating behavior than did controls; however, the T30 animals also exhibited female-typical behavior. For the T60 group, prenatal treatment, not juvenile rank, best predicted male-typical sex behavior (P = 0.007), while juvenile rank better predicted male mating behavior for the T30 group (P = 0.006). Rank did not predict female mating behavior in the hormone-treated or control ewes. We conclude that the effect of prenatal testosterone exposure on adult male-specific but not female-specific mating behavior is modulated by juvenile social experiences.

Author/-s:       Eila K. Roberts; Jonathan N. Flak; Wen Ye; Vasantha Padmanabhan; Theresa M. Lee

Publication:     Biology of reproduction, 2009

Web link:         http://www.biolreprod.org/content/80/4/737.abstract

Sexual Differentiation of Behaviour in Monkeys: Role of Prenatal Hormones
  • The theoretical debate over the relative contributions of nature and nurture to the sexual differentiation of behaviour has increasingly moved towards an interactionist explanation that requires both influences. In practice, however, nature and nurture have often been seen as separable, influencing human clinical sex assignment decisions, sometimes with disastrous consequences. Decisions about the sex assignment of children born with intersex conditions have been based almost exclusively on the appearance of the genitals and how other’s reactions to the gender role of the assigned sex affect individual gender socialisation. Effects of the social environment and gender expectations in human cultures are ubiquitous, overshadowing the potential underlying biological contributions in favour of the more observable social influences. Recent work in nonhuman primates showing behavioural sex differences paralleling human sex differences, including toy preferences, suggests that less easily observed biological factors also influence behavioural sexual differentiation in both monkeys and humans. We review research, including Robert W. Goy’s pioneering work with rhesus monkeys, which manipulated prenatal hormones at different gestation times and demonstrated that genital anatomy and specific behaviours are independently sexually differentiated. Such studies demonstrate that, for a variety of behaviours, including juvenile mounting and rough play, individuals can have the genitals of one sex but show the behaviour more typical of the other sex. We describe another case, infant distress vocalisations, where maternal responsiveness is best accounted for by the mother’s response to the genital appearance of her offspring. Taken together, these studies demonstrate that sexual differentiation arises from complex interactions where anatomical and behavioural biases, produced by hormonal and other biological processes, are shaped by social experience into the behavioural sex differences that distinguish males and females.

Author/-s:       K. Wallen; J. M. Hassett

Publication:     Journal of Neuroendocrinology, 2009

Web link:         http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2826.2009.01832.x/abstract

Sex differences in rhesus monkey toy preferences parallel those of children
  • Sex differences in toy preferences in children are marked, with boys expressing stronger and more rigid toy preferences than girls, whose preferences are more flexible. Socialization processes, parents, or peers encouraging play with gender-specific toys are thought to be the primary force shaping sex differences in toy preference. A contrast in view is that toy preferences reflect biologically-determined preferences for specific activities facilitated by specific toys. Sex differences in juvenile activities, such as rough-and-tumble play, peer preferences, and infant interest, share similarities in humans and monkeys. Thus if activity preferences shape toy preferences, male and female monkeys may show toy preferences similar to those seen in boys and girls. We compared the interactions of 34 rhesus monkeys, living within a 135 monkey troop, with human wheeled toys and plush toys. Male monkeys, like boys, showed consistent and strong preferences for wheeled toys, while female monkeys, like girls, showed greater variability in preferences. Thus, the magnitude of preference for wheeled over plush toys differed significantly between males and females. The similarities to human findings demonstrate that such preferences can develop without explicit gendered socialization. We offer the hypothesis that toy preferences reflect hormonally influenced behavioral and cognitive biases which are sculpted by social processes into the sex differences seen in monkeys and humans.

Author/-s:       J. M. Hassett; E. R. Siebert; K. Wallen

Publication:     Hormones and Behavior, 2008

Web link:         http://europepmc.org/abstract/MED/18452921

The Role of Androgen Receptors in the Masculinization of Brain and Behavior: What we’ve learned from the Testicular Feminization Mutation
  • Many studies demonstrate that exposure to testicular steroids such as testosterone early in life masculinizes the developing brain, leading to permanent changes in behavior. Traditionally, masculinization of the rodent brain is believed to depend on estrogen receptors (ERs) and not androgen receptors (ARs). According to the aromatization hypothesis, circulating testosterone from the testes is converted locally in the brain by aromatase to estrogens, which then activate ERs to masculinize the brain. However, an emerging body of evidence indicates that the aromatization hypothesis cannot fully account for sex differences in brain morphology and behavior, and that androgens acting on ARs also play a role. The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete androgen insensitivity.

Author/-s:       Damian G. Zuloaga; David A. Puts; Cynthia L. Jordan; S. Marc Breedlove

Publication:     Hormones and Behavior, 2008

Web link:         http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706155/?tool=pubmed

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

Web link:         http://europepmc.org/abstract/MED/17307903

Hormonal influences on sexually differentiated behavior in nonhuman primates
  • Sexually dimorphic behavior in nonhuman primates results from behavioral predispositions organized by prenatal androgens. The rhesus monkey has been the primary primate model for understanding the hormonal organization of sexually dimorphic behavior. Historically, female fetuses have received high prenatal androgen doses to investigate the masculinizing and defeminizing effects of androgens. Such treatments masculinized juvenile and adult copulatory behavior and defeminized female-typical sexual initiation to adult estrogen treatment. Testosterone and the nonaromatizable androgen, 5alpha-dihydrotestosterone, produced similar effects suggesting that estrogenic metabolites of androgens are not critical for masculinization and defeminization in rhesus monkeys. Long duration androgen treatments masculinized both behavior and genitalia suggesting that socializing responses to the females' male-like appearance may have produced the behavioral changes. Treatments limited to 35 days early or late in gestation differentially affected behavioral and genital masculinization demonstrating direct organizing actions of prenatal androgens. Recent studies exposed fetal females to smaller doses of androgens and interfered with endogenous androgens using the anti-androgen flutamide. Low dose androgen treatment only significantly masculinized infant vocalizations and produced no behavioral defeminization. Females receiving late gestation flutamide showed masculinized infant vocalizations and defeminized interest in infants. Both late androgen and flutamide treatment hypermasculinized some male juvenile behaviors. Early flutamide treatment blocked full male genital masculinization, but did not alter their juvenile or adult behavior. The role of neuroendocrine feedback mechanisms in the flutamide effects is discussed. Sexually differentiated behavior ultimately reflects both hormonally organized behavioral predispositions and the social experience that converts these predispositions into behavior.

Author/-s:       K. Wallen

Publication:     Frontiers in Neuroendocrinology, 2005

Web link:         http://europepmc.org/abstract/MED/15862182

Perinatal Exposure to Low Levels of the Environmental Antiandrogen Vinclozolin Alters Sex-Differentiated Social Play and Sexual Behaviors in the Rat
  • In this study we examined the effects of exposure to the antiandrogenic fungicide vinclozolin (Vz) on the development of two sex-differentiated behaviors that are organized by the perinatal actions of androgens. Pregnant Long-Evans rats were administered a daily oral dose of 0, 1.5, 3, 6, or 12 mg/kg Vz from the 14th day of gestation through postnatal day (PND)3. The social play behavior of juvenile offspring was examined on PND22 and again on PND34 during play sessions with a same-sex littermate. After they reached adulthood, the male offspring were examined with the ex copula penile reflex procedure to assess erectile function. Vz did not produce any gross maternal or neonatal toxicity, nor did it reduce the anogenital distance in male pups. We observed no effects of Vz on play behavior on PND22. However, the 12-mg/kg Vz dose significantly increased play behavior in the male offspring on PND34 compared with controls. The most dramatic increases were seen with the nape contact and pounce behavior components of play. The Vz effect was more pronounced in male than in female offspring. As adults, male offspring showed a significant reduction of erections at all dose levels during the ex copula penile reflex tests. The 12-mg/kg dose was also associated with an increase in seminal emissions. These effects demonstrate that perinatal Vz disrupts the development of androgen-mediated behavioral functions at exposure levels that do not produce obvious structural changes or weight reductions in androgen-sensitive reproductive organs.

Author/-s:       Nathan K. W. Colbert; Nicole C. Pelletier; Joyce M. Cote; John B. Concannon; Nicole A. Jurdak; Sara B. Minott; Vincent P. Markowski

Publication:     Environmental Health Perspectives, 2005

Web link:         http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257594/

Sex steroid-related genes and male-to-female transsexualism
  • Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and—after aromatase-catalyzed conversion to estradiol—via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERβ gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERβ repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.

Author/-s:       Susanne Henningsson; Lars Westberg; Staffan Nilsson; Bengt Lundström; Lisa Ekselius; Owe Bodlund; Eva Lindström; Monika Hellstrand; Roland Rosmond; Elias Eriksson; Mikael Landén

Publication:     Psychoneuroendocrinology, 2005

Web link:         http://www.sciencedirect.com/science/article/pii/S0306453005000454

Induction of PGE2 by estradiol mediates developmental masculinization of sex behaviour
  • Adult male sexual behavior in mammals requires the neuronal organizing effects of gonadal steroids during a sensitive perinatal period. During development, estradiol differentiates the rat preoptic area (POA), an essential brain region in the male copulatory circuit. Here we report that increases in prostaglandin-E2 (PGE2), resulting from changes in cyclooxygenase-2 (COX-2) regulation induced by perinatal exposure to estradiol, are necessary and sufficient to organize the crucial neural substrate that mediates male sexual behavior. Briefly preventing prostaglandin synthesis in newborn males with the COX inhibitor indomethacin permanently downregulates markers of dendritic spines in the POA and severely impairs male sexual behavior. Developmental exposure to the COX inhibitor aspirin results in mild impairment of sexual behavior. Conversely, administration of PGE2 to newborn females masculinizes the POA and leads to male sex behavior in adults, thereby highlighting the pathway of steroid-independent brain masculinization. Our findings show that PGE2 functions as a downstream effector of estradiol to permanently masculinize the brain.

Author/-s:       Stuart K. Amateau; Margaret M. McCarthy

Publication:     Nature Neuroscience, 2004

Web link:         http://www.nature.com/neuro/journal/v7/n6/abs/nn1254.html

Changes in sexual behavior of adult male and female rats neonatally treated with vitamin D3
  • 1: Neonatal treatment of rats with vitamin D3 resulted in a change of sexual behavior in adulthood.

  • 2: 2.5 mg vitamin D 3 completely inhibited the ejaculation of males without any apparent influence on sexual desire. 250 mg vitamin D3 influenced both the desire and ejaculation.

  • 3: Sexual activity of females was depressed by both doses.

  • 4: The experiments demonstrate that vitamin D3, a steroid in structure, given in the critical period of hormonal imprinting may influence steroid hormone-receptor commanded events for life, in a way similar to the effects exhibited by synthetic steroid hormone analogues and benzpyrene in earlier studies.

Author/-s:       G. Csaba; O. Dobozy; Cs. Karabélyos; S. Mirzahosseini

Publication:     Human & Experimental Toxicology, 1996

Web link:         http://het.sagepub.com/cgi/content/abstract/15/7/573

Social play soliciting by male and female juvenile rats: effects of neonatal androgenization and sex of cagemates
  • Male and female juvenile rats were individually exposed to nonplayful juvenile social stimuli in a novel test of play-soliciting behavior to examine hormonal and experiential determinants of sex differences. In Experiment 1, neonatally androgenized females engaged in play soliciting at a level equal to that of male controls and greater than that of nonandrogenized female controls. In Experiment 2, males and females were reared in unisexual and bisexual groups in order to compare long-term sex-related social experience effects on juvenile play soliciting. Males exposed only to other young males engaged in greater play soliciting than males exposed to both sexes; females, in contrast, were unaffected by sex of cagemates. Within rearing conditions, however, males engaged in greater play soliciting than females. The combined results suggest that perinatal gonadal androgen exposure effects on social play are prepotent and contribute essentially to sex differences in the initiation of social play behavior.

Author/-s:       W. R. Holloway Junior; D. H. Thor

Publication:     Behavioral neuroscience, 1986

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/3964428

Testosterone implants into the amygdala during the neonatal period masculinize the social play of juvenile female rats
  • The masculinization of social play behavior in the rat is dependent upon the actions of androgens during the neonatal period. The amygdala, a major androgen-target region in the rat limbic brain, appears to be a critical site for this androgenic effect. We tested this hypothesis by implanting testosterone-bearing cannulae into the amygdala of female rat pups on Day 1 of life; the implants were removed on Day 8 of life. The animals were then observed daily between Days 26 and 40 of life and the frequency of play-fighting was recorded. Testosterone-implanted females, like normal males, engaged in significantly more play-fighting than did control females (implanted with cholesterol-bearing cannulae). We have also presented data indicating that the testosterone diffusion from the cannulae was, for the most part, restricted to the amygdala. Thus, testosterone implanted into the amygdala mimicked the effects previously reported for systemic testosterone injections, supporting the idea that the amygdala is a critical region for the actions of androgens on the sexual differentiation of social play behavior in the rat.

Author/-s:       B. S. McEwen; Michael J. Meaney

Publication:     Brain Research; 1986

 Web link:        http://www.ncbi.nlm.nih.gov/pubmed/3801906

 

 

 

6.     Genetic factors can influence the sexual differentiation of the brain

6.a.    Human studies

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

Web link:         http://dspace.library.uu.nl/handle/1874/182733

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

Web link:         http://europepmc.org/abstract/MED/17307903

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

Web link:         https://gupea.ub.gu.se/handle/2077/12418

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

Web link:         http://europepmc.org/abstract/MED/1778227

 

 

6.b.    Animal studies

The Role of Androgen Receptors in the Masculinization of Brain and Behavior: What we’ve learned from the Testicular Feminization Mutation
  • Many studies demonstrate that exposure to testicular steroids such as testosterone early in life masculinizes the developing brain, leading to permanent changes in behavior. Traditionally, masculinization of the rodent brain is believed to depend on estrogen receptors (ERs) and not androgen receptors (ARs). According to the aromatization hypothesis, circulating testosterone from the testes is converted locally in the brain by aromatase to estrogens, which then activate ERs to masculinize the brain. However, an emerging body of evidence indicates that the aromatization hypothesis cannot fully account for sex differences in brain morphology and behavior, and that androgens acting on ARs also play a role. The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete androgen insensitivity.

Author/-s:       Damian G. Zuloaga; David A. Puts; Cynthia L. Jordan; S. Marc Breedlove

Publication:     Hormones and Behavior, 2008

Web link:         http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706155/?tool=pubmed

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

Web link:         http://europepmc.org/abstract/MED/17307903

Tissue-specific expression and regulation of sexually dimorphic genes in mice
  • We report a comprehensive analysis of gene expression differences between sexes in multiple somatic tissues of 334 mice derived from an intercross between inbred mouse strains C57BL/6J and C3H/HeJ. The analysis of a large number of individuals provided the power to detect relatively small differences in expression between sexes, and the use of an intercross allowed analysis of the genetic control of sexually dimorphic gene expression. Microarray analysis of 23,574 transcripts revealed that the extent of sexual dimorphism in gene expression was much greater than previously recognized. Thus, thousands of genes showed sexual dimorphism in liver, adipose, and muscle, and hundreds of genes were sexually dimorphic in brain. These genes exhibited highly tissue-specific patterns of expression and were enriched for distinct pathways represented in the Gene Ontology database. They also showed evidence of chromosomal enrichment, not only on the sex chromosomes, but also on several autosomes. Genetic analyses provided evidence of the global regulation of subsets of the sexually dimorphic genes, as the transcript levels of a large number of these genes were controlled by several expression quantitative trait loci (eQTL) hotspots that exhibited tissue-specific control. Moreover, many tissue-specific transcription factor binding sites were found to be enriched in the sexually dimorphic genes.

Author/-s:       Xia Yang; Eric E. Schadt; Susanna Wang; Hui Wang; Arthur P. Arnold; Leslie Ingram-Drake; Thomas A. Drake; Aldons J. Lusis

Publication:     Genome Research, 2006

Web link:         http://genome.cshlp.org/content/16/8/995

Partial demasculinization of several brain regions in adult male (XY) rats with a dysfunctional androgen receptor gene
  • The adult rat posterodorsal medial amygdala (MePD) is sexually dimorphic in regional volume and neuronal soma size, both of which are larger in males than in females. This sexual dimorphism is entirely dependent on adult circulating levels of testicular androgens, and both androgen and estrogen treatment can masculinize MePD structure. We examined male rats that are rendered androgen-insensitive by the testicular feminization mutation (tfm) of the androgen receptor (AR) gene to determine how a dysfunctional AR affects this and other brain sexual dimorphisms. In adult wild-type rats, the MePD in males had a greater regional volume, rostrocaudal extent, and soma size than in females. In genetic males, defective ARs affected some but not all of these indices: MePD volume and soma size in tfm males were intermediate between those of wild-type males and females, but the rostrocaudal extent of the MePD was unaffected by the mutation, being as great in tfm males as in wild-type males. Regional volume and soma size in the suprachiasmatic nucleus was reduced in tfm males compared with wild-type males, suggesting that AR normally affects this region in male rats. Interestingly, whereas volume of the sexually dimorphic nucleus of the preoptic area was unaffected by the tfm allele, soma size in this region was reduced in tfm males compared with wild-type males. Although estrogen receptor activation has been shown to be vital for masculinization of the rodent brain, our results indicate that ARs also contribute to this process in several brain regions.

Author/-s:       John A. Morris; Cynthia L. Jordan; Brittany N. Dugger; S. Marc Breedlove

Publication:     The Journal of Comparative Neurology, 2005

Web link:         http://onlinelibrary.wiley.com/doi/10.1002/cne.20558/abstract

Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation
  • The classic view of brain sexual differentiation and behavior is that gonadal steroid hormones act directly to promote sex differences in neural and behavioral development. In particular, the actions of testosterone and its metabolites induce a masculine pattern of brain development, while inhibiting feminine neural and behavioral patterns of differentiation. However, recent evidence indicates that gonadal hormones may not solely be responsible for sex differences in brain development and behavior between males and females. Here we examine an alternative hypothesis that genes, by directly inducing sexually dimorphic patterns of neural development, can influence the sexual differences between male and female brains. Using microarrays and RT-PCR, we have detected over 50 candidate genes for differential sex expression, and confirmed at least seven murine genes which show differential expression between the developing brains of male and female mice at stage 10.5 days post coitum (dpc), before any gonadal hormone influence. The identification of genes differentially expressed between male and female brains prior to gonadal formation suggests that genetic factors may have roles in influencing brain sexual differentiation.

Author/-s:       Phoebe Dewing; Tao Shi; Steve Horvath; Eric Vilain

Publication:     Molecular Brain Research, 2003

Web link:         http://www.ncbi.nlm.nih.gov/pubmed/14559357

 

 

 

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The page is part of four reference pages:

What is transsexualism? | What causes transsexualism? | What helps?

More evidence: Disorders of sex development (DSD)

A summary of the findings of the reference pages is given here: Summary

 

More references can be found here (articles not directly relevant to the observations discussed on the main reference pages): Other references

 

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