Die Rolle von Testosteron und dem Y-Chromosom bei der Maskulinisierung des Gehirns

Eine interessante Studie dazu, welchen Anteil das Y-Chromoson bzw. Testosteron bei der Maskulinisierung des Gehirns hat:

Women with complete androgen insensitivity syndrome (CAIS) have a male (46,XY) karyotype but no functional androgen receptors. Their condition, therefore, offers a unique model for studying testosterone effects on cerebral sex dimorphism. We present MRI data from 16 women with CAIS and 32 male (46,XY) and 32 female (46,XX) controls. Methods: FreeSurfer software was employed to measure cortical thickness and subcortical structural volumes. Axonal connections, indexed by fractional anisotropy, (FA) were measured with diffusion tensor imaging, and functional connectivity with resting state fMRI. Results: Compared to men, CAIS women displayed a “female” pattern by having thicker parietal and occipital cortices, lower FA values in the right corticospinal, superior and inferior longitudinal tracts, and corpus callosum. Their functional connectivity from the amygdala to the medial prefrontal cortex, was stronger and amygdala-connections to the motor cortex weaker than in control men. CAIS and control women also showed stronger posterior cingulate and precuneus connections in the default mode network. Thickness of the motor cortex, the caudate volume, and the FA in the callosal body followed, however, a “male” pattern. Conclusion: Altogether, these data suggest that testosterone modulates the microstructure of somatosensory and visual cortices and their axonal connections to the frontal cortex. Testosterone also influenced functional connections from the amygdala, whereas the motor cortex could, in agreement with our previous reports, be moderated by processes linked to X-chromosome gene dosage. These data raise the question about other genetic factors masculinizing the human brain than the SRY gene and testosterone.

Quelle: Role of testosterone and Y chromosome genes for the masculinization of the human brain

Zu CAIS hatte ich schon etwas geschrieben:

Komplette Androgenresistenz ist ein Zustand, bei dem der Körper aufgrund der fehlenden oder defekten Rezeptoren kein Testosteron erkennen kann. Letztendlich zeigt sich damit der gleiche Effekt, der auch auftreten würden, wenn der Körper überhaupt kein Testosteron produzieren würde.

Da diese Personen einen weiblichen Phänotyp haben müssten sie im übrigen von der Sozialisation her typische Frauen sein.

Es zeigt sich aber, dass diese Frauen sich als ganz besonders weiblich ansehen und sich auch ganz besonders weiblich verhalten

Das passt zu der in der Biologie vertretenen Theorie, dass die Hormone eine Ausrichtung der Gehirne vornehmen, mit Testosteron in die männliche Richtung, ohne Testosteron in die weibliche Richtung. Es handelt sich aber tatsächlich nicht um eine binäre Ausrichtung, sondern mit einem höheren bzw niedrigeren Testosteronstand können sich andere Werte ergeben. Nach dieser Studie richtet sich die Formatierung aber nicht nur nach dem Testosteronstand, anscheinend wirken sich einige Gene über das Y-Chromosom auch direkt aus.

Dafür sind die CAIS Frauen eine gute Testgruppe, da bei ihnen Testosteron nicht wirkt. Das legt nahe, dass alle Effekte, die dennoch von dem sonst bei Frauen anzutreffenden in Richtung der Männer abweichen, auf das Y-Chromosom zurückzuführen sind.

Aus der Studie:

Women with CAIS have a 46,XY karyotype; they are born with testes that secrete male-typical or elevated amounts of testosterone prenatally and postnatally because they lack functional androgen receptors due to mutations of the androgen receptor (AR) gene [Cheikhelard et al., 2009; Hughes et al., 2012; Quigley et al., 1995]. Individuals with CAIS are thus born with female external genitalia, develop a female phenotype, are reared as girls, and undergo a feminizing puberty as a result of the aromatization of their testosterone to estradiol [Cheikhelard et al., 2009]. Due to secretion of antimüllerian hormone (AMH) from the sertoli cells of the testes, female internal genitalia do not develop and no uterus is formed, and therefore CAIS is often presented as primary amenorrhea. Studies using quantitative measures of psychosexual development indicate that individuals with CAIS have a female gender identity, show female-typical gender role behavior, and are most often androphilic (sexually attracted to men) [Koolschijn et al., 2014; Masica et al., 1971; Walhovd et al., 2010]; CAIS occurs in approximately 1–5 per 100,000 births [Mendoza and Motos, 2013].

Comparisons among women with CAIS, 46,XY males, and 46,XX female controls provide a unique opportunity to study the separate effects of testosterone and sex chromosome genes on the sexual differentiation of the brain.

We investigated this, using MR measurements of cortical thickness (Cth) and subcortical structural volumes. We also carried out DTI of fractional anisotropy (FA) indexing structural (axonal) connections in the brain, and resting state fMRI indexing cerebral functional connections. Sex differences have been reported in all these metrices, but the underpinnings of these differences may vary with the specific metric, and also between different neuronal networks. To better understand these complex interactions, multimethodological investigations of the same study groups would therefore be required, which are scarce in the literature, especially for populations with rare conditions. Based on previous studies suggesting pruning effects of testosterone [Fernandez et al., 2003; Rasgon et al., 2005], and its stimulating effect on white matter tracts [Rametti et al., 2012; van Hemmen et al., in press], we hypothesized that Cth of the parietal lobe (and probably also the occipital lobe) would be greater in both 46,XX women and women with CAIS, whereas the FA values in the long white matter tracts (the corticospinal tract, superior and inferior longitudinal fascicle, the fronto-occipital fascicle, and perhaps also the corpus callosum [CC]) would be lower compared to 46,XY men. Given our previous comparative studies between XXY men and controls suggesting that both testosterone and X-chromosome gene dosage could influence the amygdala [Savic and Arver, 2014], it was an open question as to whether the limbic and paralimbic networks would be affected by testosterone. This also applied to the caudate and putamen volumes for which we did not have a primary hypothesis.

Es geht also insbesondere darum, ob bestimmte Regionen des Gehirns eher wie sonst bei Frauen oder wie bei Männern ausgestaltet ist.

Zu den Ergebnissen:

Our results support the notion that testosterone has significant effects on cerebral structure. They accord with earlier observations of inverse correlations between partietal and occipital Cth and testosterone levels [Bramen et al., 2012; Nguyen et al., 2013a; Nopoulos et al., 2000; Savic and Arver, 2014], which were explained by the pruning effects of testosterone on cortical neurons. Because androgen receptors are expressed particularly in the parieto-occipital lobe [Abdelgadir et al., 1999; Goldstein et al., 2001; Simerly et al., 1990], testosterone effects on Cth are expected primarily in these regions. The present results suggest that testosterone also has effects on structural connections, indexed by FA values, which were higher in male controls, particularly in the long tracts—the cortico-spinal tract and the superior and inferior longitudinal tracts, and the CC. Notably, women with CAIS displayed lower FA values compared to 46,XYmen despite having similar intracranial volumes (ICV; Table 4). Testosterone’s stimulating effects on the white matter have been reported previously [Rametti et al., 2012; van Hemmen et al., in press], although some found also a negative association between testosterone levels and white matter integrity [Peper et al., 2015; Rametti et al., 2012; van Hemmen et al., in press]. A finding especially interesting from a behavioral perspective, was that functional connections between the amygdala and the ACC were stronger among women with CAIS (and female controls) compared to male controls. These connections are essential for emotional perception and modulation, they are reported to differ between men and women [Savic and Lindstrom, 2008; Wolk et al., 2010] and seem to be moderated by both testosterone and estrogen [Price et al., 2016]. Administration of testosterone to middle-aged women diminished orbitofrontal cortex activity and its effective connectivity with the amygdala during a matching task using angry and fearful faces [Ducharme et al., 2016]. Administration of estrogen to postmenopausal women, conversely, is reported to increase the amygdala–PFC connectivity [Weaver et al., 2014], and these connections are found to be stronger in women with higher estrogen levels [Nguyen et al., 2013b]. The women with CAIS in this study had low to moderate estrogen levels and also no effect of testosterone. The present findings, thus, accord with the view that the amygdala prefrontal connections are moderated by both estrogen and testosterone, and add to the discussion about the underpinnings of sex differences in regard to these neuronal connections that are important for emotional and stress-related processes. In line with some reports on sex hormonal effects during pubertal development [Herting et al., 2015; Peper et al., 2009] it is also possible that estrogen influenced the thickness of the left temporal, cortex, which was smaller in CAIS women and female controls than in male controls.

Sex Chromosome Gene Effects
A less predicted finding in the present study relates to the observed “masculine pattern” in several nodes of the motor network. That the motor cortex of women with CAIS was thinner than in control women and similar to that of control men is congruent with our hypothesis, based on studies of 47,XXY men, that the motor cortex is coded by X-chromosome genes, [Lentini et al., 2013; Marzelli et al., 2011; Savic and Arver, 2014]. More difficult to attribute to X-chromosome gene dosage are the results of caudate measures, because this structure is found to be smaller in women with 45,X0 as well as in men with 47,XXY compared to sex matched controls, thus, independently of the number of X-chromosomes [Marzelli et al., 2011; Savic and Arver, 2014]. The relative volume of the caudate is usually larger in females compared to male controls [Raz et al., 1995], a gender difference that seems to be present already before puberty [Giedd et al., 1997], but which, according to some [Herting et al., 2012; Mukherjee et al., 2012; Nguyen et al., 2013a; Nopoulos et al., 2000] but not all data [Koolschijn et al., 2014], also undergoes pubertal changes. The present data, with similar caudate volumes in male controls and women with CAIS, indicates that there was no major effect of testosterone. An alternative mechanism would be SRY-independent Y-chromosome gene mediated processes, indeed suggested by animal data, the four core genotype model in rats, which creates XX “males” and XY “females” [Arnold and Chen, 2009]. Overall, the present data, together with other recent studies [Savic and Arver, 2014] of rare conditions in humans such as sex chromosome aneuploidy provide important complement to the initial seminal studies of the 4 core genotype model emphasizing that brain sex differences stem from a complex mix of both hormonal and genetic mechanisms. Additional investigations in humans are, however, needed to further disentangle the specific biological underpinnings of sex differences, for example in the caudate volumes.

Hier ist also noch einiges an Forschung zu leisten.

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Ein Gedanke zu “Die Rolle von Testosteron und dem Y-Chromosom bei der Maskulinisierung des Gehirns

  1. So wie jeder Hundebesitzer weiß, dass der Hund intelligent ist, ihn versteht und eine „Seele“ hat, so weiß jeder Mensch der aufmerksam durchs Leben gehst, dass Jungs und Mädchen sich schon sehr früh unterscheiden.

    Auch offensichtlich sexuelle Präferenzen fangen schon vor der Pubertät an, wenn wohl auch nicht so deutlich ausgerichtet.

    Da wir uns äußerlich nur sehr wenig unterscheiden, vor allem in jungen Jahren muss es eine Prägung geben für das jeweils andere Geschlecht.

    Vor allem Frauen sagen oft witzelnd, dass ihre Mädchen sich in den jeweiligen Mann verliebt haben, bzw. sich zu ihm hingezogen fühlen. Viele Frauen sagten mir das ganz offen.

    Ab der Pubertät wird es dann unkontrolliert für die Eltern.

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