Normal Sexual Dimorphism of the Adult Human Brain Assessed by In Vivo Magnetic Resonance Imaging

Goldstein, Jill M.; Seidman, Larry J.; Horton, Nicholas J.; Makris, Nikos; Kennedy, David N.; Caviness, Verne S.; Faraone, Stephen V.; Tsuang, Ming T.

doi:10.1093/cercor/11.6.490

Cited by 915 publications

(603 citation statements)

References 71 publications

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“…In line with theories of sexual differentiation, all the regions of sexual dimorphism identified in our study represent brain structures known to express high levels of sex steroid receptors during early brain development in other animal species (Goldstein et al, 2001), suggesting that brain regions homologous with those identified by animal studies as having a high sex steroid receptor density during critical periods of brain development are more likely to retain sexual dimorphisms throughout life. Accordingly, the volumetric differences observed between the GD groups and the control groups are also exclusively centered on brain structures rich in sex steroid receptors during fetal and early postnatal development.…”

Section: Discussionsupporting

confidence: 86%

“…Previous studies investigating sex differences in the human brain have also detected increased volume or cortical thickness in the GM comprising the superior frontal and more medial sections of the frontal cortex in women compared to men (Goldstein et al, 2001;Good et al, 2001;Lombardo et al, 2012;Luders et al, 2006Luders et al, , 2009a. It should be noted that in this study we did not obtain information regarding the menstrual cycle in the girls, and therefore we cannot exclude subtle cycle-related effects on GM volumes.…”

Section: Discussionmentioning

confidence: 62%

“…In humans, postmortem studies have also discovered several sexually dimorphic nuclei with higher cell numbers and larger volume in males within this region (Allen et al, 1989;Swaab and Fliers, 1985). Clusters of enlarged hypothalamic volume in men as well as in adolescent boys have also been detected in vivo (Goldstein et al, 2001;Lombardo et al, 2012).…”

Section: Discussionmentioning

confidence: 97%

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Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain

Hoekzema

Schagen

Kreukels

et al. 2015

Psychoneuroendocrinology

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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 * Corresponding author. 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.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 97%

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Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain

Hoekzema

Schagen

Kreukels

et al. 2015

Psychoneuroendocrinology

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“…In the adult human brain structural sex differences can be found from the macroscopic level (47) down to the ultramicroscopic level (48). Functionally, too, a large number of sex differences in different brain regions have recently been described (49)(50)(51)(52)(53).…”

Section: Sex Differences In the Human Brainmentioning

confidence: 99%

Sexual differentiation of the human brain in relation to gender identity and sexual orientation

Savić

Garcı́a-Falgueras

Swaab

2010

Sex Differences in the Human Brain, Their Underpinnings and Implications

116

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SummaryDuring the intrauterine period the fetal brain develops in the male direction through a direct action of testosterone on the developing nerve cells, or in the female direction through the absence of this hormone surge. In this way, our gender identity (the conviction of belonging to the male or female gender) and sexual orientation are programmed into our brain structures when we are still in the womb. However, since sexual differentiation of the genitals takes place in the first two months of pregnancy and sexual differentiation of the brain starts in the second half of pregnancy, these two processes can be influenced independently, which may result in transsexuality. This also means that in the event of ambiguous sex at birth, the degree of masculinization of the genitals may not reflect the degree of masculinization of the brain. There is no proof that social environment after birth has an effect on gender identity or sexual orientation.KEY WORDS: gender identity, homosexuality, human brain, sexual orientation, sexual differentiation, transsexuality. Sexual organization and activation of the human brainThe process of sexual differentiation of the brain brings about permanent changes in brain structures and functions via interactions of the developing neurons with the environment, understood in its widest sense. The environment of a developing neuron is formed by the surrounding nerve cells and the child's circulating hormones, as well as the hormones, nutrients, medication and other chemical substances from the mother and the environment that enter the fetal circulation via the placenta. All these factors may have a lasting effect on the sexual differentiation of the brain. The testicles and ovaries develop in the sixth week of pregnancy. This occurs under the influence of a cascade of genes, starting with the sex-determining gene on the Y chromosome (SRY). The production of testosterone by a boy's testes is necessary for sexual differentiation of the sexual organs between weeks 6 and 12 of pregnancy. The peripheral conversion of testosterone into dihydrotestosterone is essential for the formation of a boy's penis, prostate and scrotum. Instead, the development of the female sexual organs in the womb is based primarily on the absence of androgens (1). Once the differentiation of the sexual organs into male or female is settled, the next thing that is differentiated is the brain, under the influence, mainly, of sex hormones on the developing brain cells. The changes (permanent) brought about in this stage have organizing effects; later, during puberty, the brain circuits that developed in the womb are activated by sex hormones. This paradigm of sexual differentiation of the brain has been well established, ever since the first paper by Phoenix et al. (2). The fetal brain is protected against the effect of circulating estrogens from the mother by the protein α-fetoprotein, which is produced by the fetus and binds strongly to estrogens but not to testosterone (3,4). However, estrogens do not only reach th...

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“…It has been argued that an earlyonset psychosis in males is associated with the presence of structural cerebral pathology specifically involving the dominant hemisphere and that a later onset form of schizophrenia in some females is characterized by less pronounced structural cerebral involvement (37). Sexual dimorphisms in cortical regions (38) and ventricular brain ratio in schizophrenia have been reported (39). There are well-known examples of dimorphic gene expression in regions of the human brain such as the hypothalamus that are agerelated (for a review, see Ref.…”

Section: Neuroserpinmentioning

confidence: 99%

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

et al. 2004

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Microarray expression studies have reported decreased mRNA expression of histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the DLPFC have reported increased and decreased expression in individuals with schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the DLPFC in individuals with schizophrenia and controls were measured by real-time quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in situ hybridization. The Q-PCR results were compared by analysis of covariance between individuals with schizophrenia and controls. Gene expression levels for HINT1, MDH1, and SERPINI1 were significantly different between the groups. The male individuals with schizophrenia compared to male controls showed reductions by 2.8-to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in mRNA abundance for MDH1 (P ϭ 0.006), HINT1 (P ϭ 0.050), and neuroserpin (P ϭ 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there were no significant interactions with gender, gene expression between female patients and the female control group did not differ. These results confirm earlier reports and suggest abnormalities of specific genes related to metabolic and protease activities in the DLPFC might be considered as part of a molecular pathway in male patients with schizophrenia.

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Normal Sexual Dimorphism of the Adult Human Brain Assessed by In Vivo Magnetic Resonance Imaging

Cited by 915 publications

References 71 publications

Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain

Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain

Sexual differentiation of the human brain in relation to gender identity and sexual orientation

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

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