Publications of Julie Bakker
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See detailCellular and molecular features of EDC exposure: consequences for the GnRH network.
Lopez Rodriguez, David ULiege; Franssen, Delphine ULiege; Bakker, Julie ULiege et al

in Nature Reviews. Endocrinology (2020)

The onset of puberty and the female ovulatory cycle are important developmental milestones of the reproductive system. These processes are controlled by a tightly organized network of neurotransmitters ... [more ▼]

The onset of puberty and the female ovulatory cycle are important developmental milestones of the reproductive system. These processes are controlled by a tightly organized network of neurotransmitters and neuropeptides, as well as genetic, epigenetic and hormonal factors, which ultimately drive the pulsatile secretion of gonadotropin-releasing hormone. They also strongly depend on organizational processes that take place during fetal and early postnatal life. Therefore, exposure to environmental pollutants such as endocrine-disrupting chemicals (EDCs) during critical periods of development can result in altered brain development, delayed or advanced puberty and long-term reproductive consequences, such as impaired fertility. The gonads and peripheral organs are targets of EDCs, and research from the past few years suggests that the organization of the neuroendocrine control of reproduction is also sensitive to environmental cues and disruption. Among other mechanisms, EDCs interfere with the action of steroidal and non-steroidal receptors, and alter enzymatic, metabolic and epigenetic pathways during development. In this Review, we discuss the cellular and molecular consequences of perinatal exposure (mostly in rodents) to representative EDCs with a focus on the neuroendocrine control of reproduction, pubertal timing and the female ovulatory cycle. [less ▲]

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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 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 detailAlternative views on the role of sex steroid hormones on the emergence of phenotypic diversity in female sexual orientation
Cornil, Charlotte ULiege; Bakker, Julie ULiege

in Archives of Sexual Behavior (2019), 48(5), 1309-1313

In their Target Article, Luoto, Krams, and Rantala (2018) used the four questions of Tinbergen to gain a better understanding of the evolution and developmental origin of female sexual orientation and the ... [more ▼]

In their Target Article, Luoto, Krams, and Rantala (2018) used the four questions of Tinbergen to gain a better understanding of the evolution and developmental origin of female sexual orientation and the variety of homosexual phenotypes reported in women. In their endeavor, Luoto et al. propose a compelling model to explain the origin of female homosexuality, or what they carefully call female non-heterosexuality to take into account the greater flexibility that women exhibit regarding the sex of their sexual partner. Most studies on the origin of sexual orientation consider it as a binary variable with exclusive heterosexuals and homosexuals placed at the two extremes of a continuum. This might be true for male sexual orientation which is characterized by a bimodal distribution with the highest frequencies at the two extremes. By contrast, female sexual orientation shows a more spread out distribution of frequencies of intermediate phenotypes and a higher prevalence of bisexuality... [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 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 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 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 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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