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See detailKisspeptin Expression in the Human Infundibular Nucleus in Relation to Sex, Gender Identity, and Sexual Orientation.
Taziaux, Mélanie ULg; 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 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 ULg 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 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 detailPotential contribution of progesterone receptors to the development of sexual behavior in male and female mice.
Desroziers, Elodie; Brock, Olivier; Bakker, Julie ULg

in Hormones and Behavior (2016)

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 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 (New York, N.Y. : 1991) (2016)

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 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 detailRole of the progesterone receptor in the development of sexual behavior in female mice
Desroziers, Elodie ULg; Brock, Olivier; Baum, M.J. et al

Poster (2015, February)

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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 detailAbsence of female-typical pheromone-induced hypothalamic neural responses and kisspeptin neuronal activity in alpha-fetoprotein knockout female mice.
Taziaux, Mélanie ULg; Bakker, Julie ULg

in Endocrinology (2015)

Pheromones induce sexually dimorphic neuroendocrine responses, such as LH secretion. However, the neuronal network by which pheromones are converted into signals that will initiate and modulate endocrine ... [more ▼]

Pheromones induce sexually dimorphic neuroendocrine responses, such as LH secretion. However, the neuronal network by which pheromones are converted into signals that will initiate and modulate endocrine changes remains unclear. We asked whether two sexually dimorphic populations in the anteroventral periventricular and periventricular nuclei (AVPV/PeN) that express kisspeptin and tyrosine hydroxylase (TH) are potential candidates that will transduce the olfactory signal to the neuroendocrine system. Furthermore, we assessed whether this transduction is sensitive to perinatal actions of estradiol by using female mice deficient in alpha-fetoprotein (AfpKO), which lack the protective actions of Afp against maternal estradiol. Wild-type (WT) and AfpKO male and female mice were exposed to same- versus opposite-sex odors and the expression of c-Fos was analyzed along the olfactory projection pathways as well as whether kisspeptin, TH and gonadotropin-releasing hormone (GnRH) neurons are responsive to opposite-sex odors. Male odors induced a female-typical Fos expression in target forebrain sites of olfactory inputs involved in reproduction in WT, but not in AfpKO females, whereas female odors induced a male-typical Fos expression in males of both genotypes. In WT females, opposite-sex odors induced Fos in kisspeptin and TH neurons, whereas in AfpKO females and WT males, only a lower, but still significant, Fos expression was observed in TH, but not in kisspeptin neurons. Finally, opposite-sex odors did not induce any significant Fos expression in GnRH neurons of both sexes or genotypes. Our results strongly suggest a role for fetal estrogen in the sexual differentiation of neural responses to sex-related olfactory cues. [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 detailHypothalamic Expression Of Oestrogen Receptor Alpha And Androgen Receptor Is Sex, Age And Region Dependent In Mice.
Brock, Olivier; Mees, Christelle De; Bakker, Julie ULg

in Journal of neuroendocrinology (2015)

Sex steroid hormones act on developing neural circuits regulating the hypothalamic-pituitary-gonadal axis and are involved in hormone-sensitive behaviours. These hormones act mainly via nuclear receptors ... [more ▼]

Sex steroid hormones act on developing neural circuits regulating the hypothalamic-pituitary-gonadal axis and are involved in hormone-sensitive behaviours. These hormones act mainly via nuclear receptors, i.e. oestrogen receptor-alpha (ERalpha) and androgen receptor (AR). By using immunohistochemistry, we analysed the expression level of ERalpha and AR throughout perinatal life [at embryonic (E) day 19 and postnatal (P) days 5-15-25] and in adulthood in several hypothalamic nuclei controlling reproduction in both wild-type (WT) and aromatase knockout (ArKO) (which cannot convert testosterone into oestradiol) mice to determine whether there are sex differences in hypothalamic ERalpha and AR expression and if so, whether these are established by oestradiol action. As early as E19, ERalpha immunoreactivity (-ir) was observed at same expression levels in both sexes in the anteroventral periventricular nucleus (AVPv), the medial preoptic area (MPOA), the bed nucleus of the stria terminalis (BnST), the ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl) and the arcuate nucleus (ARC). Sex differences (female > male) in ERalpha-ir were only observed during the prepubertal period in the BnST (P5 to P25) and the MPOA (P15), but also in adulthood in these two brain regions. Sex differences in AR-ir (male > female) were observed at P5 in the AVPv and ARC, and at P25 in the MPOA and ARC as well as in adulthood in all hypothalamic regions analysed. In adulthood, gonadectomy and hormonal treatment (oestradiol or dihydrotestosterone) also strongly modulated ERalpha-ir and AR, respectively. Taken together, sex differences in ERalpha-ir and AR-ir were observed in all hypothalamic regions analysed, but most likely do not reflect oestradiol actions since ArKO mice of both sexes showed very similar expression levels as WT mice throughout perinatal development. This article is protected by copyright. All rights reserved. [less ▲]

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See detailRole of the progesterone receptor in the development of sexual behavior in female mice
Desroziers, Elodie ULg; Brock, Olivier; Baum, M.J. et al

Conference (2014, October)

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See detailRole of the progesterone receptor in the development of sexual behavior in female mice
Desroziers, Elodie ULg; Brock, Olivier; Baum, M.J. et al

Conference (2014, August)

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See detailRole of the progesterone receptor in the development of sexual behavior in female mice
Desroziers, Elodie ULg; Brock, Olivier; Baum, M.J. et al

Poster (2014, June)

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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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See detailRole of the progesterone receptor in the development of sexual behavior in female mice
Desroziers, Elodie ULg; Brock, Olivier; Baum, M.J. et al

Poster (2013, June)

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See detailAssessment of urinary pheromone discrimination, partner preference, and mating behaviors in female mice.
Brock, Olivier; Bakker, Julie ULg; Baum, Michael J.

in Methods in molecular biology (Clifton, N.J.) (2013), 1068

Behavioral testing methods are described for determining whether female mice can discriminate between volatile urinary pheromones of conspecifics of the same vs. opposite sex and/or in different endocrine ... [more ▼]

Behavioral testing methods are described for determining whether female mice can discriminate between volatile urinary pheromones of conspecifics of the same vs. opposite sex and/or in different endocrine conditions, for determining sexual partner preference, for quantifying receptive (lordosis) behavior, and for monitoring the expression of male-typical mounting behavior in female mice. [less ▲]

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See detailRoles of sex and gonadal steroids in mammalian pheromonal communication.
Baum, Michael J.; Bakker, Julie ULg

in Frontiers in neuroendocrinology (2013), 34(4), 268-84

A brain circuit (the accessory olfactory system) that originates in the vomeronasal organ (VNO) and includes the accessory olfactory bulb (AOB) plus additional forebrain regions mediates many of the ... [more ▼]

A brain circuit (the accessory olfactory system) that originates in the vomeronasal organ (VNO) and includes the accessory olfactory bulb (AOB) plus additional forebrain regions mediates many of the effects of pheromones, typically comprised of a variety of non-volatile and volatile compounds, on aspects of social behavior. A second, parallel circuit (the main olfactory system) that originates in the main olfactory epithelium (MOE) and includes the main olfactory bulb (MOB) has also been shown to detect volatile pheromones from conspecifics. Studies are reviewed that point to specific roles of several different steroids and their water-soluble metabolites as putative pheromones. Other studies are reviewed that establish an adult, 'activational' role of circulating sex hormones along with sex differences in the detection and/or processing of non-steroidal pheromones by these two olfactory circuits. Persisting questions about the role of sex steroids in pheromonal processing are posed for future investigation. [less ▲]

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See detailThe two kisspeptin neuronal populations are differentially organized and activated by estradiol in mice.
Brock, Olivier; Bakker, Julie ULg

in Endocrinology (2013)

In rodents, kisspeptin expressing neurons are localized in two hypothalamic brain nuclei [anteroventral periventricular nucleus/periventricular nucleus continuum (AVPv/PeN) and arcuate nucleus (ARC)] and ... [more ▼]

In rodents, kisspeptin expressing neurons are localized in two hypothalamic brain nuclei [anteroventral periventricular nucleus/periventricular nucleus continuum (AVPv/PeN) and arcuate nucleus (ARC)] and modulated by sex steroids. By using wild-type (WT) and aromatase knockout mice (ArKO, which cannot convert testosterone into estradiol) and immunohistochemistry, we observed that WT females showed a continuous increase in kisspeptin peptide expression in the ARC across postnatal ages (P5 to P25), whereas WT males did not show any expression before P25. Kisspeptin peptide expression was also present in ArKO females but did not increase over this early postnatal period, suggesting that kisspeptin peptide expression in the ARC is organized by estradiol-dependent and -independent mechanisms. We also compared kisspeptin peptide expression between groups of adult male and female mice which were left gonadally intact or gonadectomized and treated or not with estradiol (E2) or dihydrotestosterone (DHT). In the ARC, kisspeptin peptide expression decreased after gonadectomy but was completely rescued by either E2 or DHT treatment in each sex/genotype. However, kisspeptin peptide expression was lower in ArKO compared to WT subjects. In the AVPv/PeN, ArKO females showed a male-typical kisspeptin peptide expression, and adult E2 treatment partially restored kisspeptin peptide expression. Finally, we showed that, after E2 treatment of WT and ArKO mice between either P5 and P15 or P15 and P25, AVPv/PeN kisspeptin peptide expression could be still masculinized at P5, but was feminized from P15 onwards. In conclusion, the two kisspeptin neuronal populations (AVPv/PeN versus ARC) seem to be differentially organized and activated by E2. [less ▲]

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