Publications of Julie Bakker
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See detailTestosterone effects on functional amygdala lateralization: A study in adolescent transgender boys and cisgender boys and girls
Beking, T.; Burke, S. M.; Geuze, R. H. et al

in Psychoneuroendocrinology (2020), 111

The influence of testosterone on the development of human brain lateralization has been subject of debate for a long time, partly because studies investigating this are necessarily mostly correlational ... [more ▼]

The influence of testosterone on the development of human brain lateralization has been subject of debate for a long time, partly because studies investigating this are necessarily mostly correlational. In the present study we used a quasi-experimental approach by assessing functional brain lateralization in trans boys (female sex assigned at birth, diagnosed with Gender Dysphoria, n = 21) before and after testosterone treatment, and compared these results to the functional lateralization of age-matched control groups of cisgender boys (n = 20) and girls (n = 21) around 16 years of age. The lateralization index of the amygdala was determined with functional magnetic resonance imaging (fMRI) during an emotional face matching task with angry and fearful faces, as the literature indicates that boys show more activation in the right amygdala than girls during the perception of emotional faces. As expected, the lateralization index in trans boys shifted towards the right amygdala after testosterone treatment, and the cumulative dose of testosterone treatment correlated significantly with amygdala lateralization after treatment. However, we did not find any significant group differences in lateralization and endogenous testosterone concentrations predicted rightward amygdala lateralization only in the cis boys, but not in cis girls or trans boys. These inconsistencies may be due to sex differences in sensitivity to testosterone or its metabolites, which would be a worthwhile course for future studies. © 2019 The Authors [less ▲]

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See detailPostnatal Effects of Sex Hormones on Click-Evoked Otoacoustic Emissions: A Study of Adolescents with Gender Dysphoria.
Burke, Sarah M.; van Heesewijk, Jason O.; Menks, Willeke M. et al

in Archives of sexual behavior (2020), 49(2), 455-465

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds, generated by the inner ear in response to click-stimuli. A sex difference in emission strength is observed in neonates and adults, with ... [more ▼]

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds, generated by the inner ear in response to click-stimuli. A sex difference in emission strength is observed in neonates and adults, with weaker CEOAE amplitudes in males. These differences are assumed to originate from testosterone influences during prenatal male sexual differentiation and to remain stable throughout life. However, recent studies suggested activational, postnatal effects of sex hormones on CEOAEs. Adolescents diagnosed with gender dysphoria (GD) may receive gonadotropin-releasing hormone analogs (GnRHa) in order to suppress endogenous sex hormones and, therefore, pubertal maturation, followed by cross-sex hormone (CSH) treatment. Using a cross-sectional design, we examined whether hormonal interventions in adolescents diagnosed with GD (62 trans boys, assigned female at birth, self-identifying as male; 43 trans girls, assigned male at birth, self-identifying as female), affected their CEOAEs compared to age- and sex-matched controls (44 boys, 37 girls). Sex-typical differences in CEOAE amplitude were observed among cisgender controls and treatment-naïve trans boys but not in other groups with GD. Treatment-naïve trans girls tended to have more female-typical CEOAEs, suggesting hypomasculinized early sexual differentiation, in support of a prominent hypothesis on the etiology of GD. In line with the predicted suppressive effects of androgens, trans boys receiving CSH treatment, i.e., testosterone plus GnRHa, showed significantly weaker right-ear CEOAEs compared with control girls. A similar trend was seen in trans boys treated with GnRHa only. Unexpectedly, trans girls showed CEOAE masculinization with addition of estradiol. Our findings show that CEOAEs may not be used as an unequivocal measure of prenatal androgen exposure as they can be modulated postnatally by sex hormones, in the form of hormonal treatment. [less ▲]

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See detailConsensus Parameter: Research Methodologies to Evaluate Neurodevelopmental Effects of Pubertal Suppression in Transgender Youth.
Chen, Diane; Strang, John F.; Kolbuck, Victoria D. et al

in Transgender Health (2020), 5(4), 246-257

Purpose: Pubertal suppression is standard of care for early pubertal transgender youth to prevent the development of undesired and distressing secondary sex characteristics incongruent with gender ... [more ▼]

Purpose: Pubertal suppression is standard of care for early pubertal transgender youth to prevent the development of undesired and distressing secondary sex characteristics incongruent with gender identity. Preliminary evidence suggests pubertal suppression improves mental health functioning. Given the widespread changes in brain and cognition that occur during puberty, a critical question is whether this treatment impacts neurodevelopment. Methods: A Delphi consensus procedure engaged 24 international experts in neurodevelopment, gender development, puberty/adolescence, neuroendocrinology, and statistics/psychometrics to identify priority research methodologies to address the empirical question: is pubertal suppression treatment associated with real-world neurocognitive sequelae? Recommended study approaches reaching 80% consensus were included in the consensus parameter. Results: The Delphi procedure identified 160 initial expert recommendations, 44 of which ultimately achieved consensus. Consensus study design elements include the following: a minimum of three measurement time points, pubertal staging at baseline, statistical modeling of sex in analyses, use of analytic approaches that account for heterogeneity, and use of multiple comparison groups to minimize the limitations of any one group. Consensus study comparison groups include untreated transgender youth matched on pubertal stage, cisgender (i.e., gender congruent) youth matched on pubertal stage, and an independent sample from a large-scale youth development database. The consensus domains for assessment includes: mental health, executive function/cognitive control, and social awareness/functioning. Conclusion: An international interdisciplinary team of experts achieved consensus around primary methods and domains for assessing neurodevelopmental effects (i.e., benefits and/or difficulties) of pubertal suppression treatment in transgender youth. [less ▲]

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See detailThe Sexual Differentiation of the Human Brain: Role of Sex Hormones Versus Sex Chromosomes.
Bakker, Julie ULiege

in Current Topics in Behavioral Neurosciences (2019)

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 ... [more ▼]

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, male-typical psychosexual characteristics seem to develop under the influence of testosterone, mostly acting during early development. By contrast, female-typical psychosexual characteristics may actually be organized under the influence of estradiol during a specific prepubertal period. The sexual differentiation of the human brain also seems to proceed predominantly under the influence of sex hormones. Recent studies using magnetic resonance imaging have shown that several sexually differentiated aspects of brain structure and function are female-typical in women with complete androgen insensitivity syndrome (CAIS), who have a 46 XY karyotype but a female phenotype due to complete androgen resistance, suggesting that these sex differences most likely reflect androgen action, although feminizing effects of estrogens or female-typical socialization cannot be ruled out. By contrast, some male-typical neural characteristics were also observed in women with CAIS suggesting direct effects of sex chromosome genes in the sexual differentiation of the human brain. In conclusion, the sexual differentiation of the human brain is most likely a multifactorial process including both sex hormone and sex chromosome effects, acting in parallel or in combination. [less ▲]

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See detailThe Role of Kisspeptin in Sexual Behavior.
Hellier, Vincent ULiege; Brock, Olivier ULiege; Bakker, Julie ULiege

in Seminars in reproductive medicine (2019), 37(2), 84-92

Sexual behavior is essential for the perpetuation of a species. In female rodents, mate preference and lordosis behavior depend heavily on the integration of olfactory cues into the neuroendocrine brain ... [more ▼]

Sexual behavior is essential for the perpetuation of a species. In female rodents, mate preference and lordosis behavior depend heavily on the integration of olfactory cues into the neuroendocrine brain, yet its underlying neural circuits are not well understood. We previously revealed that kisspeptin neurons in the anteroventral periventricular nucleus/periventricular nucleus continuum (AVPv/PeN) are activated by male olfactory cues in female mice. Here, we further reveal that male-directed mate preferences and lordosis are impaired in kisspeptin knockout mice but are rescued by a single injection with kisspeptin. Acute ablation of AVPV/PeN kisspeptin neurons in adult females impaired mate preference and lordosis behavior. Conversely, optogenetic activation of these neurons triggered lordosis behavior. Kisspeptin neurons act through classical GPR54/GnRH signaling in stimulating mate preferences, but unexpectedly, GPR54/GnRH neuronal ablation did not affect lordosis behavior. Therefore, to identify the downstream components of the neural circuit involved in lordosis behavior, we employed genetic transsynaptic tracing in combination with viral tract tracing from AVPV/PeN kisspeptin neurons. We observed that kisspeptin neurons are communicating with neurons expressing the neuronal form of nitric oxide synthase. These results suggest that hypothalamic nitric oxide signaling is an important mechanism downstream of kisspeptin neurons in the neural circuit governing lordosis behavior in female mice. [less ▲]

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See detailExpérimentation animale: la recette d'une polémique scientifique
Muraille, Eric; de kerchove, Alban; Muylkens, Benoit et al

Article for general public (2018)

La majorité du grand public accepte l’expérimentation animale à condition que celle-ci contribue à l’amélioration de la santé humaine et qu’aucune autre alternative n’existe. En face, les opposants ... [more ▼]

La majorité du grand public accepte l’expérimentation animale à condition que celle-ci contribue à l’amélioration de la santé humaine et qu’aucune autre alternative n’existe. En face, les opposants décrédibilisent la recherche et stigmatise une profession à des fins idéologiques. Relevé de leurs arguments. [less ▲]

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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See detailAnalyse détaillée de la seconde version de l’avant-projet de Code du bien-être animal wallon. Lecture commentée au 21/03/2018 du Chapitre 8 (Expérimentation animale)
Drion, Pierre ULiege; Corhay, Albert ULiege; Haubruge, Eric ULiege et al

Report (2018)

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par ... [more ▼]

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par les décrets du Gouvernement wallon). Certains éléments sont repris tels quels de la Directive 2010/63. Cela est nécessaire car la Directive européenne en tant que telle n’a pas de force obligatoire en Belgique. Elle doit être transcrite par un instrument législatif (avant, la Loi de 1984 et ses modifications, aujourd’hui, le projet de code pour la Région wallonne). Certains aspects semblent flous, mais renvoient à des dispositions que le Gouvernement doit encore prendre (au travers d’arrêtés du Gouvernement wallon, comme le faisaient avant les nombreux arrêtés royaux et du gouvernement qui réglementent la matière). Les arrêtés d’exécution devront obligatoirement tenir compte de la Directive européenne et s’inspirer de dispositions actuellement en vigueur. [less ▲]

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See detailFemale sexual behavior in mice is controlled by kisspeptin neurons.
Hellier, Vincent ULiege; Brock, Olivier ULiege; Candlish, Michael et al

in Nature Communications (2018), 9(1), 400

Sexual behavior is essential for the survival of many species. In female rodents, mate preference and copulatory behavior depend on pheromones and are synchronized with ovulation to ensure reproductive ... [more ▼]

Sexual behavior is essential for the survival of many species. In female rodents, mate preference and copulatory behavior depend on pheromones and are synchronized with ovulation to ensure reproductive success. The neural circuits driving this orchestration in the brain have, however, remained elusive. Here, we demonstrate that neurons controlling ovulation in the mammalian brain are at the core of a branching neural circuit governing both mate preference and copulatory behavior. We show that male odors detected in the vomeronasal organ activate kisspeptin neurons in female mice. Classical kisspeptin/Kiss1R signaling subsequently triggers olfactory-driven mate preference. In contrast, copulatory behavior is elicited by kisspeptin neurons in a parallel circuit independent of Kiss1R involving nitric oxide signaling. Consistent with this, we find that kisspeptin neurons impinge onto nitric oxide-synthesizing neurons in the ventromedial hypothalamus. Our data establish kisspeptin neurons as a central regulatory hub orchestrating sexual behavior in the female mouse brain. [less ▲]

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See detailL’expérimentation animale reste indispensable (OPINION)
Amorim, Christiani; Andris, Fabienne; Arckens, Lut et al

Article for general public (2017)

Trop fréquemment, l’expérimentation animale est présentée comme une pratique archaïque. Elle a bien changé. Et 100 % des patients traités le sont grâce aux concepts et techniques développés grâce à elle.

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See detailReconsidering Prenatal Hormonal Influences on Human Sexual Orientation: Lessons from Animal Research.
Baum, Michael J.; Bakker, Julie ULiege

in Archives of Sexual Behavior (2017)

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See detailPotential contribution of progesterone receptors to the development of sexual behavior in male and female mice.
Desroziers, Elodie; Brock, Olivier; Bakker, Julie ULiege

in Hormones and Behavior (2017)

We previously showed that estradiol can have both defeminizing and feminizing effects on the developing mouse brain. Pre- and early postnatal estradiol defeminized the ability to show lordosis in ... [more ▼]

We previously showed that estradiol can have both defeminizing and feminizing effects on the developing mouse brain. Pre- and early postnatal estradiol defeminized the ability to show lordosis in adulthood, whereas prepubertal estradiol feminized this ability. Furthermore, we found that estradiol upregulates progesterone receptors (PR) during development, inducing both a male-and female-typical pattern of PR expression in the mouse hypothalamus. In the present study, we took advantage of a newly developed PR antagonist (ZK 137316) to determine whether PR contributes to either male- or female-typical sexual differentiation. Thus groups of male and female C57Bl/6j mice were treated with ZK 137316 or oil as control: males were treated neonatally (P0-P10), during the critical period for male sexual differentiation, and females were treated prepubertally (P15-P25), during the critical period for female sexual differentiation. In adulthood, mice were tested for sexual behavior. In males, some minor effects of neonatal ZK treatment on sexual behavior were observed: latencies to the first mount, intromission and ejaculation were decreased in neonatally ZK treated males; however, this effect disappeared by the second mating test. By contrast, female mice treated with ZK during the prepubertal period showed significantly less lordosis than OIL-treated females. Mate preferences were not affected in either males or females treated with ZK during development. Taken together, these results suggest a role for PR and thus perhaps progesterone in the development of lordosis behavior in female mice. By contrast, no obvious role for PR can be discerned in the development of male sexual behavior. [less ▲]

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See detailAge-related changes in the morphology of tanycytes in the human female infundibular nucleus/median eminence.
Koopman, A. C. M.; Taziaux, M.; Bakker, Julie ULiege

in Journal of Neuroendocrinology (2017), 29(5),

Tanycytes are emerging as key players in the neuroendocrine control of gonadotrophin-releasing hormone (GnRH) release. Rodent studies have demonstrated that the structural relationship between tanycytes ... [more ▼]

Tanycytes are emerging as key players in the neuroendocrine control of gonadotrophin-releasing hormone (GnRH) release. Rodent studies have demonstrated that the structural relationship between tanycytes and GnRH terminals in the median eminence is highly dynamic, regulated by gonadal steroids and undergoes age-related changes. The present study aimed to determine whether the number and organisation of tanycytes changes throughout life in the female infundibular nucleus/median eminence (INF/ME) region. Post-mortem hypothalamic tissues were collected at the Netherlands Brain Bank and were stained for vimentin by immunohistochemistry. Hypothalami of 22 control female subjects were categorised into three periods: infant/prepubertal, adult and elderly. We measured the fractional area covered by vimentin immunoreactivity in the INF. Qualitative analysis demonstrated a remarkable parallel organisation of vimentin-immunoreactive processes during the infant/prepubertal and adult periods. During the elderly period, this organisation was largely lost. Semi-quantitatively, the fractional area covered in vimentin immunoreactivity was significantly higher at the infant/prepubertal compared to the adult period and almost reached statistical significance compared to the elderly period. By contrast, the number of tanycyte cell bodies did not appear to change throughout life. The results of the present study thus demonstrate that the number and structure of tanycytic processes are altered during ageing, suggesting that tanycytes might be involved in the age-related changes observed in GnRH release. [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 detailSex Differences in White Matter Microstructure in the Human Brain Predominantly Reflect Differences in Sex Hormone Exposure.
van Hemmen, J.; Saris, I. M. J.; Cohen-Kettenis, P. T. et al

in Cerebral Cortex (2017)

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 ... [more ▼]

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. [less ▲]

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See detailEstradiol-induced neurogenesis in the female accessory olfactory bulb is required for the learning of the male odor.
Brus, Maina; Trouillet, Anne-Charlotte; Hellier, Vincent ULiege et al

in Journal of Neurochemistry (2016)

Odors processed by the main and accessory olfactory bulbs (MOB, AOB) are important for sexual behavior. Interestingly, both structures continue to receive new neurons during adulthood. A role for ... [more ▼]

Odors processed by the main and accessory olfactory bulbs (MOB, AOB) are important for sexual behavior. Interestingly, both structures continue to receive new neurons during adulthood. A role for olfactory neurogenesis in sexual behavior in female mice has recently been shown and gonadal hormones such as estradiol can modulate adult neurogenesis. Therefore, we wanted to determine the role of estradiol in learning the odors of sexual partners and in the adult neurogenesis of female aromatase-knockout mice (ArKO), unable to produce estradiol. Female WT and ArKO mice were exposed to male odors during 7 days and olfactory preferences, cell proliferation, cell survival and functional involvement of newborn neurons were analyzed, using BrdU injections, in combination with a marker of cell activation (Zif268) and neuronal fate (DCX, NeuN). Behavioral tasks indicated that both WT and ArKO females were able to discriminate between the odors of two different males, but ArKO mice failed to learn the familiar male odor. Proliferation of newborn cells was reduced in ArKO mice only in the dentate gyrus of the hippocampus. Olfactory exposure decreased cell survival in the AOB in WT females, suggesting a role for estradiol in a structure involved in sexual behavior. Finally, newborn neurons do not seem to be functionally involved in the AOB of ArKO mice compared with WT, when females were exposed to the odor of a familiar male, suggesting that estradiol-induced neurogenesis in the AOB is required for the learning of the male odor in female mice. This article is protected by copyright. All rights reserved. [less ▲]

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See detailKisspeptin Expression in the Human Infundibular Nucleus in Relation to Sex, Gender Identity, and Sexual Orientation.
Taziaux, Mélanie ULiege; Staphorsius, Annemieke S.; Ghatei, Mohammad A. et al

in Journal of Clinical Endocrinology and Metabolism (2016), 101(6), 2380-9

CONTEXT: Since the discovery of its central role in reproduction, our functional neuroanatomical knowledge of the hypothalamic kisspeptin system is predominantly based on animal studies. Although sex ... [more ▼]

CONTEXT: Since the discovery of its central role in reproduction, our functional neuroanatomical knowledge of the hypothalamic kisspeptin system is predominantly based on animal studies. Although sex differences in kisspeptin expression have been shown in humans in adulthood, the developmental origin of this sex difference is unknown. OBJECTIVES: Our objectives were to determine the following: 1) when during development the sex difference in kisspeptin expression in the infundibular nucleus would emerge and 2) whether this sex difference is related to sexual orientation or transsexuality. DESIGN AND SETTING: Postmortem hypothalamic tissues were collected by The Netherlands Brain Bank, and sections were stained for kisspeptin by immunohistochemistry. PATIENTS: Hypothalami of 43 control subjects were categorized into three periods: infant/prepubertal (six girls, seven boys), adult (11 women, seven men), and elderly (six aged women, six aged men). Eight male-to-female (MTF) transsexuals, three HIV(+) heterosexual men, and five HIV(+) homosexual men were also analyzed. MAIN OUTCOME MEASURE: We estimated the total number of kisspeptin-immunoreactive neurons within the infundibular nucleus. RESULTS: Quantitative analysis confirmed that the human infundibular kisspeptin system exhibits a female-dominant sex difference. The number of kisspeptin neurons is significantly greater in the infant/prepubertal and elderly periods compared with the adult period. Finally, in MTF transsexuals, but not homosexual men, a female-typical kisspeptin expression was observed. CONCLUSIONS: These findings suggest that infundibular kisspeptin neurons are sensitive to circulating sex steroid hormones throughout life and that the sex reversal observed in MTF transsexuals might reflect, at least partially, an atypical brain sexual differentiation. [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 and Neuroscience (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 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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