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See detailBrain functional connectivity patterns in children and adolescents with gender dysphoria: Sex-atypical or not?
Nota, Nienke M.; Kreukels, Baudewijntje P. C.; den Heijer, Martin et al

in Psychoneuroendocrinology (2017), 86

Various previous studies have reported that brains of people diagnosed with gender dysphoria (GD) show sex-atypical features. In addition, recent functional magnetic resonance imaging studies found that ... [more ▼]

Various previous studies have reported that brains of people diagnosed with gender dysphoria (GD) show sex-atypical features. In addition, recent functional magnetic resonance imaging studies found that several brain resting-state networks (RSNs) in adults with GD show functional connectivity (FC) patterns that are not sex-atypical, but specific for GD. In the current study we examined whether FC patterns are also altered in prepubertal children and adolescents with GD in comparison with non-gender dysphoric peers. We investigated FC patterns within RSNs that were previously examined in adults: visual networks (VNs), sensorimotor networks (SMNs), default mode network (DMN) and salience network. Thirty-one children (18 birth assigned males; 13 birth assigned females) and 40 adolescents with GD (19 birth assigned males or transgirls; 21 birth assigned females or transboys), and 39 cisgender children (21 boys; 18 girls) and 41 cisgender adolescents (20 boys; 21 girls) participated. We used independent component analysis to obtain the network maps of interest and compared these across groups. Within one of the three VNs (VN-I), adolescent transgirls showed stronger FC in the right cerebellum compared with all other adolescent groups. Sex differences in FC between the cisgender adolescent groups were observed in the right supplementary motor area within one of the two SMNs (SMN-II; girls>boys) and the right posterior cingulate gyrus within the posterior DMN (boys>girls). Within these networks adolescent transgirls showed FC patterns similar to their experienced gender (female). Also adolescent transboys showed a FC pattern similar to their experienced gender (male), but within the SMN-II only. The prepubertal children did not show any group differences in FC, suggesting that these emerge with aging and during puberty. Our findings provide evidence for the existence of both GD-specific and sex-atypical FC patterns in adolescents with GD. [less ▲]

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See detailDo sex differences in CEOAEs and 2D:4D ratios reflect androgen exposure? A study in women with complete androgen insensitivity syndrome.
van Hemmen, Judy; Cohen-Kettenis, Peggy T.; Steensma, Thomas D. et al

in Biology of Sex Differences (2017), 8

BACKGROUND: Studies investigating the influence of perinatal hormone exposure on sexually differentiated traits would greatly benefit from biomarkers of these early hormone actions. Click-evoked ... [more ▼]

BACKGROUND: Studies investigating the influence of perinatal hormone exposure on sexually differentiated traits would greatly benefit from biomarkers of these early hormone actions. Click-evoked otoacoustic emissions show sex differences that are thought to reflect differences in early androgen exposure. Women with complete androgen insensitivity syndrome (CAIS), who lack androgen action in the presence of XY-chromosomes, enabled us to study the effect of complete androgen inaction. The main goal was to investigate a possible link between click-evoked otoacoustic emissions and effective androgen exposure and, thus, whether this can be used as a biomarker. In addition, we aimed to replicate the only previous 2nd vs 4th digit-ratio study in women with CAIS, because despite the widely expressed criticisms of the validity of this measure as a biomarker for prenatal androgen exposure, it still is used for this purpose. METHODS: Click-evoked otoacoustic emissions and digit ratios from women with CAIS were compared to those from control men and women. RESULTS: The typical sex differences in click-evoked otoacoustic emissions and digit ratios were replicated in the control groups. Women with CAIS showed a tendency towards feminine, i.e., larger, click-evoked otoacoustic emission amplitudes in the right ear, and a significant female-typical, i.e., larger, digit ratio in the right hand. Although these results are consistent with androgen-dependent development of male-typical click-evoked otoacoustic emission amplitude and 2nd to 4th digit ratios, the within-group variability of these two measures was not reduced in women with CAIS compared with control women. CONCLUSIONS: In line with previous studies, our findings in CAIS women suggest that additional, non-androgenic, factors mediate male-typical sexual differentiation of digit ratios and click-evoked otoacoustic emissions. Consequently, use of these measures in adults as retrospective markers of early androgen exposure is not recommended. [less ▲]

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See detailMale-typical visuospatial functioning in gynephilic girls with gender dysphoria - organizational and activational effects of testosterone.
Burke, Sarah M.; Kreukels, Baudewijntje P. C.; Cohen-Kettenis, Peggy T. et al

in Journal of psychiatry & neuroscience : JPN (2016), 41(4), 150147

BACKGROUND: Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We ... [more ▼]

BACKGROUND: Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT). METHODS: Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well. RESULTS: We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (pFWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (pFWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation. LIMITATIONS: Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses. CONCLUSION: Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning. [less ▲]

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See detailNeural Activation During Mental Rotation in Complete Androgen Insensitivity Syndrome: the Influence of Sex Hormones and Sex Chromosomes.
van Hemmen, Judy; Veltman, Dick J.; Hoekzema, Elseline et al

in Cerebral Cortex (2016)

Sex hormones, androgens in particular, are hypothesized to play a key role in the sexual differentiation of the human brain. However, possible direct effects of the sex chromosomes, that is, XX or XY ... [more ▼]

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

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See detailPuberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria.
Staphorsius, Annemieke S.; Kreukels, Baudewijntje P. C.; Cohen-Kettenis, Peggy T. et al

in Psychoneuroendocrinology (2015), 56

Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since ... [more ▼]

Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether the performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD. [less ▲]

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See detailRegional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain.
Hoekzema, Elseline; Schagen, Sebastian E. E.; Kreukels, Baudewijntje P. C. et al

in Psychoneuroendocrinology (2015), 55C

The sexual differentiation of the brain is primarily driven by gonadal hormones during fetal development. Leading theories on the etiology of gender dysphoria (GD) involve deviations herein. To examine ... [more ▼]

The sexual differentiation of the brain is primarily driven by gonadal hormones during fetal development. Leading theories on the etiology of gender dysphoria (GD) involve deviations herein. To examine whether there are signs of a sex-atypical brain development in GD, we quantified regional neural gray matter (GM) volumes in 55 female-to-male and 38 male-to-female adolescents, 44 boys and 52 girls without GD and applied both univariate and multivariate analyses. In girls, more GM volume was observed in the left superior medial frontal cortex, while boys had more volume in the bilateral superior posterior hemispheres of the cerebellum and the hypothalamus. Regarding the GD groups, at whole-brain level they differed only from individuals sharing their gender identity but not from their natal sex. Accordingly, using multivariate pattern recognition analyses, the GD groups could more accurately be automatically discriminated from individuals sharing their gender identity than those sharing their natal sex based on spatially distributed GM patterns. However, region of interest analyses indicated less GM volume in the right cerebellum and more volume in the medial frontal cortex in female-to-males in comparison to girls without GD, while male-to-females had less volume in the bilateral cerebellum and hypothalamus than natal boys. Deviations from the natal sex within sexually dimorphic structures were also observed in the untreated subsamples. Our findings thus indicate that GM distribution and regional volumes in GD adolescents are largely in accordance with their respective natal sex. However, there are subtle deviations from the natal sex in sexually dimorphic structures, which can represent signs of a partial sex-atypical differentiation of the brain. [less ▲]

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See detailClick-Evoked Otoacoustic Emissions in Children and Adolescents with Gender Identity Disorder.
Burke, Sarah M.; Menks, Willeke M.; Cohen-Kettenis, Peggy T. et al

in Archives of Sexual Behavior (2014)

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds that are produced by the inner ear in response to click-stimuli. CEOAEs generally have a higher amplitude in women compared to men and ... [more ▼]

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds that are produced by the inner ear in response to click-stimuli. CEOAEs generally have a higher amplitude in women compared to men and neonates already show a similar sex difference in CEOAEs. Weaker responses in males are proposed to originate from elevated levels of testosterone during perinatal sexual differentiation. Therefore, CEOAEs may be used as a retrospective indicator of someone's perinatal androgen environment. Individuals diagnosed with Gender Identity Disorder (GID), according to DSM-IV-TR, are characterized by a strong identification with the other gender and discomfort about their natal sex. Although the etiology of GID is far from established, it is hypothesized that atypical levels of sex steroids during a critical period of sexual differentiation of the brain might play a role. In the present study, we compared CEOAEs in treatment-naive children and adolescents with early-onset GID (24 natal boys, 23 natal girls) and control subjects (65 boys, 62 girls). We replicated the sex difference in CEOAE response amplitude in the control group. This sex difference, however, was not present in the GID groups. Boys with GID showed stronger, more female-typical CEOAEs whereas girls with GID did not differ in emission strength compared to control girls. Based on the assumption that CEOAE amplitude can be seen as an index of relative androgen exposure, our results provide some evidence for the idea that boys with GID may have been exposed to lower amounts of androgen during early development in comparison to control boys. [less ▲]

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See detailHypothalamic response to the chemo-signal androstadienone in gender dysphoric children and adolescents.
Burke, Sarah M.; Cohen-Kettenis, Peggy T.; Veltman, Dick J. et al

in Frontiers in Endocrinology (2014), 5

The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate ... [more ▼]

The odorous steroid androstadienone, a putative male chemo-signal, was previously reported to evoke sex differences in hypothalamic activation in adult heterosexual men and women. In order to investigate whether puberty modulated this sex difference in response to androstadienone, we measured the hypothalamic responsiveness to this chemo-signal in 39 pre-pubertal and 41 adolescent boys and girls by means of functional magnetic resonance imaging. We then investigated whether 36 pre-pubertal children and 38 adolescents diagnosed with gender dysphoria (GD; DSM-5) exhibited sex-atypical (in accordance with their experienced gender), rather than sex-typical (in accordance with their natal sex) hypothalamic activations during olfactory stimulation with androstadienone. We found that the sex difference in responsiveness to androstadienone was already present in pre-pubertal control children and thus likely developed during early perinatal development instead of during sexual maturation. Adolescent girls and boys with GD both responded remarkably like their experienced gender, thus sex-atypical. In contrast, pre-pubertal girls with GD showed neither a typically male nor female hypothalamic activation pattern and pre-pubertal boys with GD had hypothalamic activations in response to androstadienone that were similar to control boys, thus sex-typical. We present here a unique data set of boys and girls diagnosed with GD at two different developmental stages, showing that these children possess certain sex-atypical functional brain characteristics and may have undergone atypical sexual differentiation of the brain. [less ▲]

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