Publications of Julie Bakker
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See detailImplication of the ventrolateral part of the ventromedial hypothalamus in female sexual behavior
Bentefour, Yassine ULiege; Bakker, Julie ULiege

in Virtual International Meeting STEROIDS AND NERVOUS SYSTEM (2021)

As many women experience problems with low sexual desire, further uncovering the neural pathway of female sexual behavior is necessary. Kisspeptin, a protein synthesized and secreted by two different ... [more ▼]

As many women experience problems with low sexual desire, further uncovering the neural pathway of female sexual behavior is necessary. Kisspeptin, a protein synthesized and secreted by two different neuronal populations in the hypothalamus, regulates ovulation and sexual maturation. New evidence indicates that it also plays an important role in sexual behavior. Recently, it has been shown in female mice that peripheral injection of kisspeptin (Kp-10) increases the expression of lordosis behavior and sexual preference towards the opposite sex. Although the neuronal pathways of kisspeptin in the control of female sexual behavior still need to be elucidated, a potential target for kisspeptin could be the neurons expressing the neuronal form of NOS (nNOS) in the ventrolateral part of the ventromedial hypothalamus (VMHvl). It was demonstrated that peripheral injection of kisspeptin in nNOS-KO mice had no effect on lordosis, whereas injection of SNAP (NO donor) in Kiss- KO mice induced lordosis at a level similar to the one expressed by WT mice, indicating that nNOS is a downstream target of kisspeptin. Also, neural tracing studies showed that nNOS neurons in the VMHvl receive kisspeptin projections, indicating its potential involvement in controlling sexual behavior as a relay nucleus. To verify this hypothesis, C57bl/6 female mice were ovariectomized and implanted with an estradiol-containing implant. After a period of post-surgical recovery, the animals underwent stereotaxic surgery to implant a bilateral cannula aimed at the VMHvl. In different groups of animals, lordosis and sexual preference were evaluated after administration of the following drugs: Kp-10, L-NAME (nNOS inhibitor), SNAP/BAY (NO donor), and GnRH. The results revealed that Kp-10 and SNAP/BAY significantly increased lordosis, while L- NAME produced the opposite effect. However, all three substances had no effect on sexual preference. Interestingly, the administration of GnRH in the VMHvl had no effect on both lordosis and sexual preference. These results demonstrate that the VMHvl is specifically involved in controlling lordosis behavior through kisspeptin and nNOS and not mate preferences, suggesting the existence of two separate neural circuits underlying lordosis behavior and sexual preference. [less ▲]

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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 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 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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