Sex Differences in White Matter Microstructure in the Human Brain Predominantly Reflect Differences in Sex Hormone Exposure.

Sex differences have been described regarding several aspects of human brain morphology; however, the exact biological mechanisms underlying these differences remain unclear in humans. Women with the complete androgen insensitivity syndrome (CAIS), who lack androgen action in the presence of a 46,XY karyotype, offer the unique opportunity to study isolated effects of sex hormones and sex chromosomes on human neural sexual differentiation. In the present study, we used diffusion tensor imaging to investigate white matter (WM) microstructure in 46,XY women with CAIS (n = 20), 46,XY comparison men (n = 30), and 46,XX comparison women (n = 30). Widespread sex differences in fractional anisotropy (FA), with higher FA in comparison men than in comparison women, were observed. Women with CAIS showed female-typical FA throughout extended WM regions, predominantly due to female-typical radial diffusivity. These findings indicate a predominant role of sex hormones in the sexual differentiation of WM microstructure, although sex chromosome genes and/or masculinizing androgen effects not mediated by the androgen receptor might also play a role.

Oestrogens are Not Related to Emotional Processing: a Study of Regional Brain Activity in Female-to-Male Transsexuals Under Gonadal Suppression.

Although the prevailing opinion is that emotional processes are influenced by sex hormones, the literature is still inconclusive. The aim of the current study was to examine the effects of gonadal suppression on brain activity during affective picture processing. Twenty-one female-to-male (FtM) transsexuals and 19 control women were recruited and underwent functional magnetic resonance imaging scanning while rating emotional pictures adapted from the International Affective Picture System. The gonadal hormone production of the FtMs was suppressed for 8 weeks, the control group did not receive any treatment before scanning. Under gonadal suppression, FtMs showed less brain activation in the superior temporal lobe compared with female controls during perception of positive affective pictures. Regression analysis showed that during processing of positive affective images, brain activity within the right superior temporal lobe was not correlated with levels of estradiol, luteinizing hormone, and follicle-stimulating hormone. In the absence of associations with hormonal levels, the difference in activation in the superior temporal lobe during positive emotional stimuli between FtMs and control women may be attributed to a priori differences between the 2 groups. Future studies should clarify if these differences are a result of atypical sexual differentiation of the brain in FtMs.

Psychosexual Outcome Among Iranian Individuals With 5α-Reductase Deficiency Type 2 and Its Relationship With Parental Sexism.

INTRODUCTION: Few studies exist on the psychosexual outcome of homogeneous groups of individuals with 5α-reductase deficiency type 2 (5α-RD-2) and the relation between gender changes and parental hostile and benevolent sexism, which are two components of ambivalent sexism that assume a stereotypical approach toward women in an overtly negative way or a chivalrous, seemingly positive way. AIM: To report on the psychosexual outcome of individuals with 5α-RD-2 and to investigate its relation to the level of parental sexism in a relatively large sample of Iranians with 5α-RD-2. METHODS: Twenty participants (mean age = 19.5 years, SD = 6.345) with a molecularly confirmed diagnosis of 5α-RD-2 who were assigned the female gender at birth and raised as female were included in the study. Participants and their parents were interviewed and their medical records were assessed. Parents also completed the Ambivalent Sexism Inventory (ASI), which includes hostile and benevolent sexism subscales. MAIN OUTCOME MEASURES: Psychosexual outcome and parental hostile and benevolent sexism measurements. RESULTS: Twelve of 20 participants (60%) were diagnosed with gender identity disorder not otherwise specified (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision). Ten of these transitioned to the male gender. The other 10 participants (50%), including the two diagnosed with gender identity disorder not otherwise specified, continued living in a female gender role. When comparing the ASI subscale scores between families of participants who changed their gender and those who did not, no significant difference was found for ASI total and hostile sexism scores, but there was a difference for benevolent sexism (P = .049): those whose daughters had changed their gender had higher benevolent sexism scores. CONCLUSION: The high prevalence of gender change and gender dysphoria reported in the literature was confirmed in this relatively large and homogeneous sample of Iranians with 5-α-RD-2 raised as female. Prenatal exposure to testosterone is hypothesized to play a role in the development of gender identity and sexual orientation, but parental attitudes also might be important. Although gender change in individuals with 5-α-RD-2 is often attributed to high levels of hostile sexism in some cultures, our findings show this to be associated with benevolent sexism.

Increased sexual health after restored genital sensation in male patients with spina bifida or a spinal cord injury: the TOMAX procedure.

PURPOSE: In this study we prospectively investigated the contribution of restored penile sensation to sexual health in patients with low spinal lesions. MATERIALS AND METHODS: In 30 patients (18 with spina bifida, 12 with spinal cord injury, age range 13 to 55 years) with no penile sensation but good groin sensation the new TOMAX (TO MAX-imize sensation, sexuality and quality of life) procedure was performed. This involves microsurgical connection of the sensory ilioinguinal nerve to the dorsal nerve of the penis unilaterally. Extensive preoperative and postoperative neurological and psychological evaluations were made. RESULTS: A total of 24 patients (80%) gained unilateral glans penis sensation. This was initially felt as groin sensation but transformed into real glans sensation in 11 patients (33%). These patients had better overall sexual function (p = 0.022) and increased satisfaction (p = 0.004). Although 13 patients (43%) maintained groin sensation, their satisfaction with sexuality was only slightly less than that of those with glans sensation. Improved sensations helped them manage urinary incontinence, thereby improving personal hygiene and independence. Most patients felt more complete and less handicapped with their penis now part of their body image. They also reported having more open and meaningful sexual relationships with their partners. CONCLUSIONS: Tactile and erogenous sensitivity was restored in the glans penis in patients with a low spinal lesion. This new sensation enhanced the quality of sexual functioning and satisfaction. The TOMAX procedure should become standard treatment for such patients.

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.

Information processing, attention and visual-motor function of adolescents born after in vitro fertilization compared with spontaneous conception.

BACKGROUND: Adverse conditions during prenatal life are associated with changes in physical and mental functioning in later life, as shown in children born preterm or small for gestational age. While recently in IVF children cardiometabolic differences have been demonstrated, there might also be risks for disturbance in cognitive functions. Therefore, this study examined information processing, attention and visual-motor function in pubertal IVF children compared with spontaneously conceived controls from subfertile parents. Results of these cognitive functions were then related to cardiometabolic measures to explore whether both can be explained by changes in fetal programming due to IVF. METHODS: A total of 139 IVF and 143 control adolescents underwent various neuropsychological tests to measure information processing, attention and visual-motor function. The results were then related to data on blood pressure and glucose levels previously obtained from the same groups. RESULTS: No differences between IVF and control adolescents were found in the various test results for information processing and attention. A slight difference was found between the groups for motor speed, but these scores were within the normal range for the test. No direct relation was found between cognitive measures and cardiometabolic outcome. CONCLUSIONS: Comparison of IVF adolescents and controls revealed no disturbances in information processing, attention and visual-motor function. In addition, these cognitive functions were not directly related to cardiometabolic outcome. Therefore, these results do not support the hypothesis that cognition is influenced by IVF conception or an altered programming of metabolic systems due to IVF, and indicate that cognitive abilities in IVF children, as measured by the tasks assessed, appear to develop normally.

Coping strategies of retinoblastoma survivors in relation to behavioural problems.

OBJECTIVE: To assess coping strategies of long-term retinoblastoma (RB) survivors and explore determinants of behavioural functioning, including medical, socio-demographic and coping variables. METHODS: This population-based cross-sectional study included 117 RB survivors (12-35 years), registered in the Dutch national RB register. Survivors were asked to fill in coping, social support and behavioural questionnaires, and situational characteristics were obtained from medical archives and from an interview. Prevalence rates of coping strategies were computed based on self-reports. One-sample t-tests were applied to analyse differences in the use of coping strategies compared with healthy reference samples. Multiple regression analyses were performed to identify various determinants for behavioural problems within the RB sample. RESULTS: RB survivors differed from their healthy reference group in one coping style, i.e. they showed significantly less emotion-oriented coping behaviour. Adolescents who came from a single-parent family and/or experienced lower social support and used more emotion-oriented coping reported more total problem behaviour. More internalizing problems were reported for adolescents who experienced less social support and less acceptance of the disease. For adults, more life events, emotion-oriented coping and lower social support explained more total problem behaviour, especially internalizing problems. CONCLUSION: RB survivors showed less emotion-oriented coping behaviour compared with the reference group. Behavioural problems are best determined by emotion-oriented coping, social support, life events other than RB and acceptance of the disease, and not by medical variables. Therefore, these variables should be taken into consideration during interventions for this group.

[Girls detained under civil and criminal law in juvenile detention centres; psychiatric disorders, trauma and psychosocial problems]. / Civiel- en strafrechtelijk geplaatste meisjes in justitiële jeugdinrichtingen; psychiatrische stoornissen, traumatisering en psychosociale problemen.

BACKGROUND: As from 2008, juveniles sentenced under civil law and juveniles sentenced under criminal law can no longer be assigned to the same juvenile detention centres. The reasoning runs as follows: the centres are unlikely to provide adequate treatment for the 'civil' group, and the 'criminal' group may exert a negative influence on the 'civil' group. Hitherto, there has been no research into the question of whether the problems and treatment requirements of girls in the two categories call for detention in the same detention centres or in different ones. AIM: The aim of this study is to investigate differences between the two groups of girls with regard to offence history, sociodemographic characteristics, contact with the social services, psychiatric disorders and trauma. METHOD: Investigation of a representative sample of 211 female minors in three juvenile detention centres using standard instruments. results 82% of the girls were detained under civil law, 18% under criminal law. There were strong similarities between the groups. However, the 'criminal' group more often had a violent history of delinquency and a non-Dutch background, whereas the 'civil' group more often had a background of residential placements, oppositional-defiant disorder, suicidality and self-harm. CONCLUSIONS: Girls detained under civil and under criminal law differed in characteristics such as criminal record, but there were striking similarities in the girls' behavioural problems and psychiatric disorders. It is argued that assignment to a particular type of detention centre should depend on treatment requirements rather than on measures imposed by civil or criminal law.

Effects of cross-sex hormones on cerebral activation during language and mental rotation: An fMRI study in transsexuals.

Androgens and estrogens affect the performance on certain cognitive tests, particularly those measuring verbal fluency and mental rotation. Their effects on cognition have frequently been attributed to changes in cerebral lateralization. This study tested the impact of a reversal of the sex steroid milieu on cerebral activation and lateralization during verbal and spatial tasks in transsexuals. fMRI scans were obtained from 6 female-to-male and 8 male-to-female transsexuals at baseline and after cross-sex steroid treatment. Activation was measured during language and mental rotation tasks. Language activation increased after sex steroid treatment in both groups (F(1,12) =3.7, p=0.08), and total language activity was correlated to post-treatment estradiol levels (rho=0.54, p=0.05). Lateralization was not affected by the reversal of sex steroid milieus (F(1,12)=1.47, p=0.25). Activation during mental rotation did not increase during treatment (F(1,12)=0.54, p=0.34), but post-treatment testosterone levels correlated to total activation during mental rotation (rho=0.64, p=0.01). Findings suggest that sex steroids may influence cerebral activation, but lateralization remains stable.

Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development.

Ambiguous genitalia of the newborn is the paradigm of a disorder of sex development that demands a multidisciplinary team approach to management. The problem is immediately apparent at birth. Abnormalities of the external genitalia sufficient to warrant genetic and endocrine studies occur in one in 4500 births. In recent decades there have been improvements in diagnosis and early management, particularly with respect to congenital adrenal hyperplasia, the commonest cause of ambiguous genitalia of the newborn. However, dissatisfaction with overall management remains. A Clinical Guidelines and Handbook for Parents generated by a partnership of health professionals and support groups is available on the internet. The professional societies representing paediatric endocrinology responded by organizing a consensus meeting on the management of intersex. This resulted in the publication of a Consensus Statement encompassing many aspects of management, extending from birth to adulthood.

A network analysis of body satisfaction of people with gender dysphoria.

In gender dysphoria (GD), much of the experienced distress results from body dissatisfaction. The current study analyzed the configuration of body satisfaction in trans men and women using network analysis. In total, 485 individuals diagnosed with GD from four European countries, applying for medical treatment, filled out the Body Image Scale for Transsexuals. A six-factor model reflecting different body areas was confirmed via confirmatory factor analysis. A further configuration of body satisfaction was modelled using correlation network analysis techniques in R. Genital dissatisfaction showed limited connection with other body areas in comparison to other subscales. Body characteristics influencing social gender recognition were most centrally involved in body (dis)satisfaction in both natal sexes. In trans women these characteristics were related mostly to voice and hair, whereas in trans men these characteristics were related to muscularity and posture. Focusing on these socially influential body characteristics may provide important targets for transgender healthcare.

Adrenal androgens and aggression in conduct disorder prepubertal boys and normal controls.

BACKGROUND: The evidence for a role of androgens in human aggression is less convincing than in animals. We examined the relationship between androgens and aggression in prepubertal boys who were diagnosed as suffering from severe aggression and antisocial behavior. METHODS: Plasma levels of testosterone (T), androstenedione (A), and dehydroepiandrosterone sulphate (DHEAS) were measured in 15 boys with a conduct disorder (CD) and 25 normal control (NC) boys. Parents and teachers of the children rated the intensity of aggression and delinquency over the last 6 months. RESULTS: CD boys had significantly higher levels of DHEAS and marginally significantly higher levels of A; there were no differences in T. Moreover, DHEAS levels were significantly positively correlated with the intensity of aggression and delinquency as rated by both parents and teachers. CONCLUSIONS: The results suggest that adrenal androgen functioning plays an important role in the onset and maintenance, of aggression in young boys.

Salivary cortisol and cardiovascular activity during stress in oppositional-defiant disorder boys and normal controls.

BACKGROUND: Arousal-regulating mechanisms are important in explaining individual differences in antisocial behavior. METHODS: Alterations in salivary cortisol concentration and cardiovascular activity were studied in 21 boys with oppositional defiant disorder (ODD) and 31 normal controls (NC) during a 2-hour stressful procedure involving frustration and provocation. RESULTS: Baseline levels of heart rate (HR) were significantly lower in the ODD group, but their HR levels were higher during provocation and frustration. Cortisol levels in the ODD group were overall lower than those of the NC group, and the effect of stress seemed to be minimal and similar for both groups; however, individual differences were large. Since anxiety plays an important mediating role in cortisol response, subjects were divided into one of four groups based on the intensity of their externalizing behavior and anxiousness. Cortisol increase due to stress exposure was strongest in highly externalizing and highly anxious subjects; cortisol decrease was strongest in those subjects who were high in externalizing behavior and low in anxiousness. CONCLUSIONS: The results of the study support an important role for hypothalamic-pituitary-adrenal axis sympathetic autonomic functioning in persistent antisocial behavior in young boys.

Activating effects of androgens on cognitive performance: causal evidence in a group of female-to-male transsexuals.

It is still unclear whether sex differences in cognitive functioning are mainly due to perinatal organizing effects of sex hormones on the brain, or to activating effects in adulthood. In a group of 22 female-to-male transsexuals a battery of visuospatial and verbal ability tests was administered twice: shortly before and 3 months after the start of androgen treatment. The administering of androgens was clearly associated with an increase in spatial ability performance. In contrast, it had a deteriorating effect on verbal fluency tasks. This study offers preliminary evidence that androgens directly and quickly affect cognitive performance in females.

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.

Activating effects of cross-sex hormones on cognitive functioning: a study of short-term and long-term hormone effects in transsexuals.

In an earlier study we demonstrated that 3 months of cross-sex hormone treatment clearly influenced cognitive functioning in transsexuals. The aims of the present study were to examine: (a) whether we could replicate these findings in a new group of transsexuals; (b) whether a similar pattern of change could be found for novel tasks, i.e. tasks, not used in the previous study, that measured closely related cognitive abilities; (c) whether the cognitive changes following cross-sex hormone treatment had stabilized after 3 months or continued to develop over a period of 1 year; and finally, (d) whether the effects were quickly reversible when the hormone treatment was temporarily stopped. Again a pronounced effect of androgen treatment was found on spatial ability in female-to-male transsexuals (FMs) over a period of one and a half years. As expected, untreated male-to-female transsexuals (MFs) had higher scores on visuo-spatial tasks than untreated FMs; after 3 months of cross-sex hormone treatment, the group difference had disappeared, while after about 10 months of hormone treatment, the sex difference was reversed. These effects did not disappear after termination of cross-sex hormone therapy for a period of 5 weeks, but continued to change slightly in the same direction. Earlier findings of an opposite effect of cross-sex hormones on verbal fluency (i.e. MFs improved and FMs deteriorated after 3 months of cross-sex hormone treatment) were not replicated in this study, nor did we find an hormonal influence on other cognitive functions. This study shows that testosterone had an enhancing, and not quickly reversible effect, on spatial ability performance, but no deteriorating effect on verbal fluency in adult women (FMs). In contrast, anti-androgen treatment in combination with estrogen therapy had no declining effect on spatial ability, nor an enhancing effect on verbal fluency in adult men (MFs).

The dermatoglyphic characteristics of transsexuals: is there evidence for an organizing effect of sex hormones.

It has been proposed that gender identity and sexual orientation are influenced by the prenatal sex steroid milieu. Human dermatoglyphics and brain asymmetry have also been ascribed to prenatal hormone levels. This study investigated dermatoglyphics (total ridge count and finger ridge asymmetry) in 184 male-to-female transsexuals and 110 female-to-male transsexuals. In a subgroup, the relationship between dermatoglyphic asymmetry and spatial ability was tested. All investigations included controls. For all subjects hand preference and sexual orientation were noted. We hypothesized that the dermatoglyphics of male-to-female transsexuals would show similarities with control women and those of female-to-male transsexuals with control men. Our results showed a trend for a sex difference in total ridge count (P<.1) between genetic males and females, but no difference in directional asymmetry was found. Contrary to our expectations, the total ridge count and finger ridge asymmetry of transsexuals were similar to their genetic sex controls. Additionally, directional asymmetry was neither related to sexual orientation, nor to different aspects of spatial ability. In conclusion, we were unable to demonstrate that our chosen dermatoglyphic variables, total ridge count and finger ridge asymmetry are related to gender identity and sexual orientation in adult transsexuals. Hence, we found no support for a prenatal hormonal influence on these characteristics, at least insofar as dermatoglyphics may be regarded as a biological marker of organizing hormonal effects.

Gender differences in behaviour: activating effects of cross-sex hormones.

The relative contribution of organizing and activating effects of sex hormones to the establishment of gender differences in behaviour is still unclear. In a group of 35 female-to-male transsexuals and a group of 15 male-to-female transsexuals a large battery of tests on aggression, sexual motivation and cognitive functioning was administered twice: shortly before and three months after the start of cross-sex hormone treatment. The administration of androgens to females was clearly associated with an increase in aggression proneness, sexual arousability and spatial ability performance. In contrast, it had a deteriorating effect on verbal fluency tasks. The effects of cross-sex hormones were just as pronounced in the male-to-female group upon androgen deprivation: anger and aggression proneness, sexual arousability and spatial ability decreased, whereas verbal fluency improved. This study offers evidence that cross-sex hormones directly and quickly affect gender specific behaviours. If sex-specific organising effects of sex hormones do exist in the human, they do not prevent these effects of androgen administration to females and androgen deprivation of males to become manifest.

A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities.

BACKGROUND: Risperidone is an atypical antipsychotic drug that blocks dopamine as well as serotonin receptor systems. The present study was designed to examine the efficacy and safety of risperidone in a 6-week double-blind, randomized, parallel-group design in the treatment of aggression in adolescents with a primary diagnosis of DSM-IV disruptive behavior disorders and with subaverage intelligence. METHOD: We randomly assigned 38 adolescents (33 boys; 10 subjects with slightly subaverage IQ, 14 with borderline IQ, and 14 with mild mental retardation), who were hospitalized for treatment of psychiatric disorders associated with severe aggression, to receive risperidone or placebo. The main efficacy measures were the Clinical Global Impressions-Severity of Illness scale (CGI-S), the modified Overt Aggression Scale (OAS-M), and the Aberrant Behavior Checklist (ABC). Side effects were measured using the Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: The mean daily dose of risperidone at the end of treatment was 2.9 mg (range, 1.5-4 mg). Risperidone, compared with placebo, was associated with significant improvements on the CGI-S (p < .001) and the at-school ABC overall and hyperactivity scales (p < .05). During a 2-week washout following the 6-week trial, a statistically significant worsening was found in the risperidone group on the CGI-S scale, the OAS-M. and the ABC. Extrapyramidal symptoms were absent or very mild during risperidone treatment. Transient tiredness was present in 11 (58%) of 19 drug-treated subjects. Other untoward effects included sialorrhea, nausea, and slight weight gain (mean = 3.5% of body weight in the risperidone group). No clinically relevant changes were found in laboratory parameters, electrocardiogram, heart rate, or blood pressure. CONCLUSION: These results suggest that risperidone may be effective for severe aggression in adolescents with disruptive behavior disorders and subaverage intelligence, and these results are consistent with reports suggesting its effectiveness for treating severe aggression in adolescents in general.

Sex hormones affect spatial abilities during the menstrual cycle.

The aim of this study was (a) to show that different measures of spatial cognition are modulated by the menstrual cycle and (b) to analyze which steroid is responsible for these cognitive alterations. The authors collected blood samples in 3-day intervals over 6 weeks from 12 young women with a regular menstrual cycle to analyze concentrations of estradiol, progesterone, testosterone, luteinizing hormone, and follicle-stimulating hormone. The performance on 3 spatial tests was measured during the menstrual and the midluteal phases. A significant cycle difference in spatial ability as tested by the Mental Rotation Test was found, with high scores during the menstrual phase and low scores during the midluteal phase. Testosterone had a strong and positive influence on mental rotation performance, whereas estradiol had a negative one. These results clearly indicate that testosterone and estradiol are able to modulate spatial cognition during the menstrual cycle.