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A Structural MRI Study in Transgender Persons on Cross-Sex Hormone Therapy
Abstract
Background:
To date, research findings are inconsistent about whether neuroanatomy in transgender persons resembles that of their natal sex or their gender identity. Moreover, few studies have examined the effects of long-term, cross-sex hormonal treatment on neuroanatomy in this cohort. The purpose of the present study was to examine neuroanatomical differences in transgender persons after prolonged cross-sex hormone therapy.
Methods:
Eighteen transgender men (female-to-male), 17 transgender women (male-to-female), 30 non-transgender men (natal men), and 27 non-transgender women (natal women) completed a high-resolution structural MRI scan at 3Tesla. Eligibility criteria for transgender persons were gender affirming surgery and at least 2 years of cross-sex hormone therapy. Exclusion criteria for non-transgender persons were presence of psychiatric or neurological disorder.
Results:
Mean neuroanatomical volume for the amygdala, putamen and corpus callosum differed between transgender women and natal women but not between transgender women and natal men. Differences between transgender men and natal men were found in several brain structures, including the medial temporal lobe structures and cerebellum. Differences between transgender men and natal women were found in the medial temporal lobe, nucleus accumbens, and 3rd ventricle. Sexual dimorphism between non-transgender men and women included larger cerebellar volumes and smaller anterior corpus callosum in natal men relative to natal women. The results remained stable after correcting for additional factors including age, total intracranial volume, anxiety, and depressive symptoms.
Conclusions:
Neuroanatomical differences were region-specific between transgender persons and their natal sex as well as their gender identity suggesting localized influence of sex hormones on neuroanatomy.
... Due to previously smaller sample sizes (e.g., 7,12 ) and disparate findings 3,6−8,22 published in the literature, the goal was, by virtue of mega-analysis, to examine structural brain patterns in transgender persons prior to gender affirming hormonal treatment. Applying such a mega-analytic approach to the largest available dataset to date in over 800 participants, this study uncovered that transgender men and women may have their own unique neurobiological phenotypes depending on the brain region assessed. ...
... For example, particularly contentious is putamen volume. While Luders et al. 6 reported lager volume in TW relative to CM, Savic & Arver 8 documented smaller putamen volume in TM relative to CM, whereas in Mueller et al., 7 putamen volume was larger in TW relative to CW. Using a variety of regions of interest, we were able to identify 5 distinct patterns in the current data that emerged depending on the brain area queried. ...
... Reduced volumes and surface areas of parts of the frontal lobe and the insula in transgender men relative to their sex assigned at birth have previously not been documented in untreated transgender persons. Moreover, a prior, independent study of treated transgender persons highlighted this pattern, showcasing reduced fusiform volume in TM relative to CW. 7 Given that a reduction in volume also appears to be present in non-hormonally treated transgender men relative to CW indicates that the findings by Mueller et al. 7 were probably not due to treatment effects (although the brain region differed). Importantly, the current data are inconsistent with earlier thought on transgender people resembling, neurobiologically, either their sex assigned at birth 6,8,15,20 or their gender identity 3 and speak for a unique phenotype. ...
Background
In contrast to cisgender persons, transgender persons identify with a different gender than the one assigned at birth. Although research on the underlying neurobiology of transgender persons has been accumulating over the years, neuroimaging studies in this relatively rare population are often based on very small samples resulting in discrepant findings.
Aim
To examine the neurobiology of transgender persons in a large sample.
Methods
Using a mega-analytic approach, structural MRI data of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity) were analyzed.
Outcomes
Structural brain measures, including grey matter volume, cortical surface area, and cortical thickness.
Results
Transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), we observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined.
Clinical Translation
The outcomes of this large-scale study may provide a normative framework that may become useful in clinical studies.
Strengths and Limitations
While this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites.
Conclusion
Rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype.
Mueller SC, Guillamon A, Zubiaurre-Elorza L, et al. The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group. J Sex Med 2021;XXX:XXX–XXX.
... Studies examining children and studies only comparing total brain volumes or cortical thickness were excluded. This search process yielded 11 studies [9][10][11]15,17,[31][32][33][34][35][36]. ...
... The gender identity effect in the putamen in the present findings corroborates six of the seven previous studies reporting GMV differences in this region. Except for Savic and colleagues [10], six previous studies [9,[32][33][34][35][36] and the present study found larger GMV for trans-as compared to cisgender participants. It is beyond the scope of the present study to investigate the reasons for this discrepancy between Savic and colleagues [10] and the remaining studies. ...
... Similar to previous studies, we suggest that the observed putamen effect is most likely not influenced by GAHT status. In different studies, increased GMV in this region was found both for TW who had not started GAHT [9] and for TW who were already receiving GAHT (including the present study) [34]. Another aspect that further complicates the issue of GAHT influences in neuroanatomical studies of GI was reported by Kranz and colleagues [37]. ...
The brain structural changes related to gender incongruence (GI) are still poorly understood. Previous studies comparing gray matter volumes (GMV) between cisgender and transgender individuals with GI revealed conflicting results. Leveraging a comprehensive sample of transmen (n = 33), transwomen (n = 33), cismen (n = 24), and ciswomen (n = 25), we employ a region-of-interest (ROI) approach to examine the most frequently reported brain regions showing GMV differences between trans- and cisgender individuals. The primary aim is to replicate previous findings and identify anatomical regions which differ between transgender individuals with GI and cisgender individuals. On the basis of a comprehensive literature search, we selected a set of ROIs (thalamus, putamen, cerebellum, angular gyrus, precentral gyrus) for which differences between cis- and transgender groups have been previously observed. The putamen was the only region showing significant GMV differences between cis- and transgender, across previous studies and the present study. We observed increased GMV in the putamen for transwomen compared to both transmen and ciswomen and for all transgender participants compared to all cisgender participants. Such a pattern of neuroanatomical differences corroborates the large majority of previous studies. This potential replication of previous findings and the known involvement of the putamen in cognitive processes related to body representations and the creation of the own body image indicate the relevance of this region for GI and its potential as a structural biomarker for GI.
... Findings in other global measures, such as in the corpus callosum, are mixed and do not show any difference in size in trans persons before (34) or after CSHT (35), although they indicate a corpus callosum shape consistent with their gender identity (36). As for subcortical structures, putamen volume is either larger (32) or smaller (33) in trans women relative to cisgender men, with other studies suggesting a larger volume in trans women relative to cisgender women (35). Coming close to providing a neurostructural correlate of being a trans person, a valuable histological study in 42 postmortem brains (37) reported that the size of the hypothalamic uncinate nucleus (INAH-3) in 10 trans women resembled that in cisgender women, that is, it was consistent with their gender identity rather than their sex assigned at birth. ...
... A treatment study examining cortical thickness after 6 months of CSHT (43) indicated a variety of cortical thickness increases with androgen treatment in trans men and decreases with estrogens and antiandrogens in trans women. Again providing complementary evidence, while that study reported a volume increase in the global ventricular system in trans women, other groups have documented specific reductions in third ventricle size in trans men with hormonal treatment (35,41). Some, however, have suggested that this finding is related to volumetric changes in adjacent gray matter structures, including the hypothalamus (41), a conjecture requiring further confirmation. ...
... Some, however, have suggested that this finding is related to volumetric changes in adjacent gray matter structures, including the hypothalamus (41), a conjecture requiring further confirmation. However, serious caveats of currently available structural MRI studies include small numbers of transgender persons and cisgender comparison subjects (41), an absence of a cisgender comparison group (to establish baseline values for cisgender men and women) (43), an absence of pretreatment data (35), or separate publication of trans men and trans women, thus not allowing direct comparison (39,40). Moreover, given the clinical implications of early versus late age at onset of gender dysphoria and sexual orientation (30), such variables deserve future scrutiny. ...
Gender dysphoria describes the psychological distress caused by identifying with the sex opposite to the one assigned at birth. In recent years, much progress has been made in characterizing the needs of transgender persons wishing to transition to their preferred gender, thus helping to optimize care. This critical review of the literature examines their common mental health issues, several individual risk factors for psychiatric comorbidity, and current research on the underlying neurobiology. Prevalence rates of persons identifying as transgender and seeking help with transition have been rising steeply since 2000 across Western countries; the current U.S. estimate is 0.6%. Anxiety and depression are frequently observed both before and after transition, although there is some decrease afterward. Recent research has identified autistic traits in some transgender persons. Forty percent of transgender persons endorse suicidality, and the rate of self-injurious behavior and suicide are markedly higher than in the general population. Individual factors contributing to mental health in transgender persons include community attitudes, societal acceptance, and posttransition physical attractiveness. Neurobiologically, whereas structural MRI data are thus far inconsistent, functional MRI evidence in trans persons suggests changes in some brain areas concerned with olfaction and voice perception consistent with sexual identification, but here too, a definitive picture has yet to emerge. Mental health clinicians, together with other health specialists, have an increasing role in the assessment and treatment of gender dysphoria in transgender individuals.
... Os estudos sobre os efeitos a longo prazo do uso de hormônios em adultos ou em pessoas que iniciaram a terapia hormonal ainda na adolescência são escassos e inconclusivos. Recomenda-se que sejam feitos aconselhamentos sobre as técnicas de preservação da fertilidade, antes do início da hormonização, tanto em transgênero feminino adulta quanto adolescente, uma vez que o uso de supressores androgênicos diminui a maturação das células germinativas nas gônadas e a gonadectomia é irreversível (27,31,35). É importante que a paciente, ao buscar os serviços de saúde, seja informada sobre os riscos e efeitos reversíveis, potencialmente irreversíveis e irreversíveis da terapia hormonal, além de esclarecimentos sobre os procedimentos cirúrgicos de adequação de gênero (17,26,27,32,34,35 O Conselho Federal de Medicina (CFM) determina que a atenção médica especializada para o cuidado ao transgênero deve ser prestada por equipe mínima formada por pediatra, para pacientes menores de idade, psiquiatra, endocrinologista, ginecologista, urologista e cirurgião plástico, sem prejuízo de outras especialidades médicas (31). ...
... Recomenda-se que sejam feitos aconselhamentos sobre as técnicas de preservação da fertilidade, antes do início da hormonização, tanto em transgênero feminino adulta quanto adolescente, uma vez que o uso de supressores androgênicos diminui a maturação das células germinativas nas gônadas e a gonadectomia é irreversível (27,31,35). É importante que a paciente, ao buscar os serviços de saúde, seja informada sobre os riscos e efeitos reversíveis, potencialmente irreversíveis e irreversíveis da terapia hormonal, além de esclarecimentos sobre os procedimentos cirúrgicos de adequação de gênero (17,26,27,32,34,35 O Conselho Federal de Medicina (CFM) determina que a atenção médica especializada para o cuidado ao transgênero deve ser prestada por equipe mínima formada por pediatra, para pacientes menores de idade, psiquiatra, endocrinologista, ginecologista, urologista e cirurgião plástico, sem prejuízo de outras especialidades médicas (31). Contudo, as dificuldades encontradas no acesso à terapia hormonal são reflexos de vários fatores. ...
A comercialização dos hormônios como anticoncepcionais foi contemporânea do fenômeno transexual e, atualmente, o uso de hormônios estrogênicos e antiandrogênicos são fundamentais para a população transgênero feminina como ferramenta para o processo transexualizador garantido por lei. Esse estudo teve como objetivo investigar os eventos adversos relacionados ao uso de hormônios pela população transgênero feminina para fins de hormonização. Para tanto, foi realizada uma revisão integrativa da literatura, buscando artigos completos disponíveis nas bases de dados da Biblioteca Virtual de Saúde, publicados em inglês e português, entre 2011 e 2021, utilizando os descritores mulher transgênero, mulher transexual, pessoas trans, transgênero, transexual feminino e hormônios. Os hormônios acetato de estradiol, valerato de estradiol e ciproterona e os antiandrogênicos, espironolactona e finasterida foram os fármacos mais citados. Os eventos adversos mais frequentes foram desenvolvimento de trombos e alterações de humor, seguidos de alterações nos parâmetros da hematopoiese, diminuição da fertilidade, alterações dos níveis de prolactina e de densidade óssea. Equipes multiprofissionais de saúde, incluindo farmacêuticos, devem estar preparadas para atender a população trans feminina, fornecendo orientação sobre o uso correto doshormônios e monitorando o tratamento, a fim de contribuir na prestação de uma melhor assistênciae evitar ou reduzir a ocorrência de eventos adversos.
... It is usually impossible to disentangle biological sex differences from those which could be the result of environmental influences during development, differences in gender, and in sexual orientation ( Fig. 1). Strict causal tests for mechanistic models of sex-biased brain development are very hard to achieve in humans, although several informative approaches have been pursued including: (i) modeling sMRI data using normative variation in hypothalamic-pituitary-gonadal axis maturation or function (214); (ii) applying sMRI methods to cohorts undergoing gender-reassignment (215); and (iii) studying how sMRI features differ between typically developing groups and those affected by medical disorders involving the sex chromosomes (eg, sex chromosome aneuploidies) or sex steroids (eg, androgen insensitivity, congenital adrenal hyperplasia) (215,216). However, the opportunistic and correlational nature of these approaches places considerable limits on the inferential power of mechanistic studies of human sex-biased brain development. ...
... It is usually impossible to disentangle biological sex differences from those which could be the result of environmental influences during development, differences in gender, and in sexual orientation ( Fig. 1). Strict causal tests for mechanistic models of sex-biased brain development are very hard to achieve in humans, although several informative approaches have been pursued including: (i) modeling sMRI data using normative variation in hypothalamic-pituitary-gonadal axis maturation or function (214); (ii) applying sMRI methods to cohorts undergoing gender-reassignment (215); and (iii) studying how sMRI features differ between typically developing groups and those affected by medical disorders involving the sex chromosomes (eg, sex chromosome aneuploidies) or sex steroids (eg, androgen insensitivity, congenital adrenal hyperplasia) (215,216). However, the opportunistic and correlational nature of these approaches places considerable limits on the inferential power of mechanistic studies of human sex-biased brain development. ...
In May 2014, the National Institutes of Health (NIH) stated its intent to “require applicants to consider sex as a biological variable (SABV) in the design and analysis of NIH-funded research involving animals and cells.” Since then, proposed research plans that include animals routinely state that both sexes/genders will be used; however, in many instances, researchers and reviewers are at a loss about the issue of sex differences. Moreover, the terms sex and gender are used interchangeably by many researchers, further complicating the issue. In addition, the sex or gender of the researcher might influence study outcomes, especially those concerning behavioral studies, in both animals and humans. The act of observation may change the outcome (the “observer effect”) and any experimental manipulation, no matter how well-controlled, is subject to it. This is nowhere more applicable than in physiology and behavior. The sex of established cultured cell lines is another issue, in addition to aneuploidy; chromosomal numbers can change as cells are passaged. Additionally, culture medium contains steroids, growth hormone, and insulin that might influence expression of various genes. These issues often are not taken into account, determined, or even considered. Issues pertaining to the “sex” of cultured cells are beyond the scope of this Statement. However, we will discuss the factors that influence sex and gender in both basic research (that using animal models) and clinical research (that involving human subjects), as well as in some areas of science where sex differences are routinely studied. Sex differences in baseline physiology and associated mechanisms form the foundation for understanding sex differences in diseases pathology, treatments, and outcomes. The purpose of this Statement is to highlight lessons learned, caveats, and what to consider when evaluating data pertaining to sex differences, using 3 areas of research as examples; it is not intended to serve as a guideline for research design.
... Particularly, some authors reported a gray matter pattern superposable to the assigned sex [7,12], while other studies found structural characteristics similar to those observed in cisgender males [13,14]. Additionally, in transmen, morphologic patterns different from both cisgender groups have been described in literature [8,[15][16][17]. The discrepant results of the aforementioned studies could be partly attributed to several limitations including inhomogeneity of selected samples concerning sexual orientation, GD levels, age and previous hormonal treatments [18]. ...
... The gender identity/gender dysphoria questionnaire for adolescents and adults (GIDYQ-AA) is a 27-item questionnaire evaluating GD (17). Each item is rated on a 5-point response scale, considering the past 12 months as time frame. ...
To date, MRI studies focused on brain sexual dimorphism have not explored the presence of specific neural patterns in gender dysphoria (GD) using gender discrimination tasks. Considering the central role of body image in GD, the present study aims to evaluate brain activation patterns with 3T-scanner functional MRI (fMRI) during gender face discrimination task in a sample of 20 hormone-naïve transgender and 20 cisgender individuals. Additionally, participants were asked to complete psychometric measures. The between-group analysis of average blood oxygenation level dependent (BOLD) activations of female vs. male face contrast showed a significant positive cluster in the bilateral precuneus in transmen when compared to the ciswomen. In addition. the transwomen group compared to the cismen showed higher activations also in the precuneus, as well as in the posterior cingulate gyrus, the angular gyrus and the lateral occipital cortices. Moreover, the activation of precuneus, angular gyrus, lateral occipital cortices and posterior cingulate gyrus was significantly associated with higher levels of body uneasiness. These results show for the first time the existence of a possible specific GD-neural pattern. However, it remains unclear if the differences in brain phenotype of transgender people may be the result of a sex-atypical neural development or of a lifelong experience of gender non-conformity.
... The reported studies only investigated individuals before cross-sex hormone treatment (CHT). Comparisons between TW pre/post CHT with CG individuals exhibited heterogeneous results [17,18,19,20,21,22,10]. CHT in TW combines treatment with anti-androgens and estradiol that are associated with region-specific structural alterations of the brain [23]. ...
... Brain structural alterations of the putamen have been associated with TW across multiple studies and independent of treatment state (pre, post CHT) [13,12,17]. We examined the putamen volume across different treatment states. ...
Transgender individuals show brain structural alterations that differ from their biological sex as well as their perceived gender. To substantiate evidence that the brain structure of transgender individuals differs from male and female, we use a combined multivariate and univariate approach. Gray matter segments resulting from voxel-based morphometry preprocessing of N = 1753 cisgender (CG) healthy participants were used to train (N = 1402) and validate (20% hold-out N = 351) a support vector machine classifying the biological sex. As a second validation, we classified N = 1104 patients with depression. A third validation was performed using the matched CG sample of the transgender women (TW) application sample. Subsequently, the classifier was applied to N = 25 TW. Finally, we compared brain volumes of CG-men, women and TW pre/post treatment (CHT) in a univariate analysis controlling for sexual orientation, age and total brain volume. The application of our biological sex classifier to the transgender sample resulted in a significantly lower true positive rate (TPR-male = 56.0%). The TPR did not differ between CG-individuals with (TPR-male = 86.9%) and without depression (TPR-male = 88.5%). The univariate analysis of the transgender application sample revealed that TW pre/post treatment show brain structural differences from CG-women and CG-men in the putamen and insula, as well as the whole-brain analysis. Our results support the hypothesis that brain structure in TW differs from brain structure of their biological sex (male) as well as their perceived gender (female). This finding substantiates evidence that transgender individuals show specific brain structural alterations leading to a different pattern of brain structure than CG individuals.
... This question seems relevant from a scientific, societal, and clinical standpoint. The scarce neuroscience findings have pulled the discussion in different directions: data from functional magnetic resonance imaging (fMRI) studies provide a complex pattern of results and are often based on small samples, which have mostly not been replicated and in many cases involve studies with trans women only (Smith et al. 2015a(Smith et al. , 2015bMueller et al. 2017b). While earlier postmortem studies indicated a feminization of hypothalamic nuclei and the bed nucleus of the stria terminalis in Tw (Zhou et al. 1995), a more complex pattern emerges when also incorporating results from later post mortem studies investigating transgender subjects (Garcia-Falgueras and Swaab 2008;Garcia-Falgueras and Swaab 2009). ...
... On the other hand, there are studies which found hormonal effects on resting-state networks. These effects were only present for Tm and not Tw, and they were spatially confined to the frontal cortex and the cerebellum (Mueller et al. 2017b). In a different study comparing Tm and cis-controls, significant changes due to hormonal treatment in functional connectivity between parietal and frontal regions have been reported (Burke et al. 2018). ...
The exact neurobiological underpinnings of gender identity (i.e., the subjective perception of oneself belonging to a certain gender) still remain unknown. Combining both resting-state functional connectivity and behavioral data, we examined gender identity in cisgender and transgender persons using a data-driven machine learning strategy. Intrinsic functional
connectivity and questionnaire data were obtained from cisgender (men/women) and transgender (trans men/trans women) individuals. Machine learning algorithms reliably detected gender identity with high prediction accuracy in each of the four groups based on connectivity signatures alone. The four normative gender groups were classified with accuracies ranging from 48% to 62% (exceeding chance level at 25%). These connectivity-based classification accuracies exceeded those obtained from a widely established behavioral instrument for gender identity. Using canonical correlation analyses,
functional brain measurements and questionnaire data were then integrated to delineate nine canonical vectors (i.e., brain-gender axes), providing a multilevel window into the conventional sex dichotomy. Our dimensional gender perspective captures four distinguishable brain phenotypes for gender identity, advocating a biologically grounded
reconceptualization of gender dimorphism.We hope to pave the way towards objective, data-driven diagnostic markers for gender identity and transgender, taking into account neurobiological and behavioral differences in an integrative modeling
approach.
... As for the cerebellum, it appears to be consistently discriminating to biological sex regardless of gender identity. A study on 2year cross-sex hormone-treated transgender showed that this structure is bilaterally larger in cisgender male than in cisgender female and TM even after at least 2 years of therapy (Mueller et al. 2017). ...
... This is in line with previous findings by our group in the same sample showing significant volume decreases in the right hippocampus in TW subjects after 16 weeks of hormone administration compared to baseline, but no changes in TM subjects . Effects in TM participants might be only visible after a more prolonged treatment time (Nguyen et al. 2019), as evident in a recent study in which the mean neuroanatomical volume for the amygdala, putamen, and corpus callosum differed between TM and FC after gender affirming surgery and at least 2 years of cross-sex hormone therapy (Mueller et al. 2017). The same group reported a correlation of androgens and local functional connectivity in long-term (>80 months) treated TM in the cerebellum and frontal regions, an association that was not detected in TW with estrogens (Mueller et al. 2016). ...
Univariate analyses of structural neuroimaging data have produced heterogeneous results regarding anatomical sex- and gender-related differences. The current study aimed at delineating and cross-validating brain volumetric surrogates of sex and gender by comparing the structural magnetic resonance imaging data of cis- and transgender subjects using multivariate pattern analysis. Gray matter (GM) tissue maps of 29 transgender men, 23 transgender women, 35 cisgender women, and 34 cisgender men were created using voxel-based morphometry and analyzed using support vector classification. Generalizability of the models was estimated using repeated nested cross-validation. For external validation, significant models were applied to hormone-treated transgender subjects (n = 32) and individuals diagnosed with depression (n = 27). Sex was identified with a balanced accuracy (BAC) of 82.6% (false discovery rate [pFDR] < 0.001) in cisgender, but only with 67.5% (pFDR = 0.04) in transgender participants indicating differences in the neuroanatomical patterns associated with sex in transgender despite the major effect of sex on GM volume irrespective of the self-identification as a woman or man. Gender identity and gender incongruence could not be reliably identified (all pFDR > 0.05). The neuroanatomical signature of sex in cisgender did not interact with depressive features (BAC = 74.7%) but was affected by hormone therapy when applied in transgender women (P < 0.001).
... Thus, the control population was scanned twice only to avoid influence of scanner related factors (e.g., drift, less novelty during the second scan), and included both males and females. We found that oestrogen+antiandrogen treatment led to widespread decreases in Cth in TrW, similar to what has been reported with oestrogen treatment in regard to Cth and GMV in postmenopausal women (Zhang et al., 2016), and congruent with the few hitherto published studies of oestrogen effects on Cth in TrW (Mueller, Landre, Wierckx, & T'Sjoen, 2017;Seiger et al., 2016;Zubiaurre-Elorza et al., 2014). In contrast, testosterone treatment led to increases in Cth, and these increases were detected in testosterone-receptor abundant regions, the insular and superior temporal cortices (Table S2), and, to a lesser extent, also in the frontal cortex. ...
... This accords with previous reports in TrM participants (Burke et al., 2017;Zubiaurre-Elorza et al., 2014). The generated data are also in accord with previous reports about structural volumes in relation to testosterone treatment in TrM (Mueller et al., 2017;Seiger et al., 2016;Zubiaurre-Elorza et al., 2014). However, several of these previous, as well as the present study, also showed a general increase of the GMV and WMV due to testosterone treatment, and corresponding decreases, especially in the GMV, with anti-androgen and oestrogen treatment. ...
Transgender persons experience incongruence between their gender identity and birth‐assigned sex. The resulting gender dysphoria (GD), is frequently treated with cross‐sex hormones. However, very little is known about how this treatment affects the brain of individuals with GD,nor do we know the neurobiology of GD. We recently suggested that disconnection of fronto‐parietal networks involved in own‐body self‐referential processing could be a plausible mechanism, and that the anatomical correlate could be a thickening of the mesial prefrontal and precuneus cortex, which is unrelated to sex. Here, we investigate how cross‐sex hormone treatment affects cerebral tissue in persons with GD, and how potential changes are related to self‐body perception. Longitudinal MRI measurements of cortical thickness (Cth) were carried out in 40 transgender men (TrM), 24 transgender women (TrW), and 19 controls. Cth increased in the mesial temporal and insular cortices with testosterone treatment in TrM, whereas anti‐androgen and estrogen treatment in TrW caused widespread cortical thinning. However, after correction for treatment‐related changes in total grey and white matter volumes (increase with testosterone; decrease with anti‐androgen and estrogen), significant Cth decreases were observed in the mesial prefrontal and parietal cortices, in both TrM and TrW (vs controls) ‐ regions showing greater pretreatment Cth than in controls. The own body – self congruence ratings increased with treatment, and correlated with a left parietal cortical thinning. These data confirm our hypothesis that GD may be associated with specific anatomical features in own‐body/self‐processing circuits that reverse to the pattern of cisgender controls after cross‐sex hormone treatment.
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... Almost all research in this area has focused on trying to delineate neurobiological pathways that underpin transgenderism, rather on specific areas of the brain related to athletic performance. Overall, current evidence indicates that transgender hormone therapy either has no effect or generates structural and functional changes in the brain that are intermediate between biological males and females [57][58][59]. ...
There is increasing debate as to whether transwoman athletes should be included in the elite female competition. Most elite sports are divided into male and female divisions because of the greater athletic performance displayed by males. Without the sex division, females would have little chance of winning because males are faster, stronger, and have greater endurance capacity. Male physiology underpins their better athletic performance including increased muscle mass and strength, stronger bones, different skeletal structure, better adapted cardiorespiratory systems, and early developmental effects on brain networks that wires males to be inherently more competitive and aggressive. Testosterone secreted before birth, postnatally, and then after puberty is the major factor that drives these physiological sex differences, and as adults, testosterone levels are ten to fifteen times higher in males than females. The non-overlapping ranges of testosterone between the sexes has led sports regulators, such as the International Olympic Committee, to use 10 nmol/L testosterone as a sole physiological parameter to divide the male and female sporting divisions. Using testosterone levels as a basis for separating female and male elite athletes is arguably flawed. Male physiology cannot be reformatted by estrogen therapy in transwoman athletes because testosterone has driven permanent effects through early life exposure. This descriptive critical review discusses the inherent male physiological advantages that lead to superior athletic performance and then addresses how estrogen therapy fails to create a female-like physiology in the male. Ultimately, the former male physiology of transwoman athletes provides them with a physiological advantage over the cis-female athlete.
... For this purpose, we employed a recently developed multivariate classifier [34] that yields a continuous (rather than a binary) estimate for being male or female, in accordance with current biological models [39][40][41][42][43][44][45]. Our study sample consisted of 24 cisgender men, 24 cisgender women, and 24 transgender women before hormone therapy in order to rule out any modifying effects of circulating sex steroids [13,15,[35][36][37][46][47][48][49][50][51][52]. We hypothesized that the estimated brain sex in transgender women is shifted away from their biological sex (male) towards their gender identity (female), but still significantly different from both. ...
Transgender people report discomfort with their birth sex and a strong identification with the opposite sex. The current study was designed to shed further light on the question of whether the brains of transgender people resemble their birth sex or their gender identity. For this purpose, we analyzed a sample of 24 cisgender men, 24 cisgender women, and 24 transgender women before gender-affirming hormone therapy. We employed a recently developed multivariate classifier that yields a continuous probabilistic (rather than a binary) estimate for brains to be male or female. The brains of transgender women ranged between cisgender men and cisgender women (albeit still closer to cisgender men), and the differences to both cisgender men and to cisgender women were significant (p = 0.016 and p < 0.001, respectively). These findings add support to the notion that the underlying brain anatomy in transgender people is shifted away from their biological sex towards their gender identity.
... ± 7.12; age range = 20-50 years old; education 14.6 ± 2.46, range 8-19 years), 5 cis gender women (Mean age = 30.6 ± 8.849; age range = 20−44 years old; education 15.3 ± 2.11, range 13-18.5 years) and 10 cis gender men (Mean age = 30.30 ± 7.40, age range = 20-42; education 17.35 ± 4.11 years; range [13][14][15][16][17][18][19][20][21][22][23][24] participated in the longitudinal study of possible treatment effects. All participants were tested for handedness according to Oldfield 42 . ...
Referrals for gender dysphoria (GD), characterized by a distressful incongruence between gender identity and at-birth assigned sex, are steadily increasing. The underlying neurobiology, and the mechanisms of the often-beneficial cross-sex hormone treatment are unknown. Here, we test hypothesis that own body perception networks (incorporated in the default mode network—DMN, and partly in the salience network—SN), are different in trans-compared with cis-gender persons. We also investigate whether these networks change with cross-sex hormone treatment. Forty transmen (TrM) and 25 transwomen (TrW) were scanned before and after cross-sex hormone institution. We used our own developed Body Morph test (BM), to assess the perception of own body as self. Fifteen cisgender persons were controls. Within and between-group differences in functional connectivity were calculated using independent components analysis within the DMN, SN, and motor network (a control network). Pretreatment, TrM and TrW scored lower “self” on the BM test than controls. Their functional connections were weaker in the anterior cingulate-, mesial prefrontal-cortex (mPFC), precuneus, the left angular gyrus, and superior parietal cortex of the DMN, and ACC in the SN “Self” identification and connectivity in the mPFC in both TrM and TrW increased from scan 1 to 2, and at scan 2 no group differences remained. The neurobiological underpinnings of GD seem subserved by cerebral structures composing major parts of the DMN.
... Seiger and colleagues 227 analyzed brain MRIs of 14 TW (mean age 26.9 ± 6.1 years) at baseline and after at least 4 months (169 days ± SD 38 days) of continuous oral or transdermal oestradiol and anti-androgens (cyproterone acetate ± GnRHa ± finasteride) and found decreases in the hippocampal region, increases in the ventricles and a correlation between progesterone levels and changes in grey matter structure. Mueller and colleagues 228 found neuroanatomical volume differences in the amygdala, putamen and corpus callosum in TW compared with cis women but not cis men, suggesting the possibility of localized influence of sex hormones on neuroanatomy. These studies suggest there are hormonal influences on cortical and subcortical structures related to cognition, memory and emotional processing. ...
Transgender (trans) women (TW) were assigned male at birth but have a female gender identity or gender expression. The literature on management and health outcomes of TW has grown recently with more publication of research. This has coincided with increasing awareness of gender diversity as communities around the world identify and address health disparities among trans people. In this narrative review, we aim to comprehensively summarize health considerations for TW and identify TW-related research areas that will provide answers to remaining unknowns surrounding TW’s health. We cover up-to-date information on: (1) feminizing gender-affirming hormone therapy (GAHT); (2) benefits associated with GAHT, particularly quality of life, mental health, breast development and bone health; (3) potential risks associated with GAHT, including cardiovascular disease and infertility; and (4) other health considerations like HIV/AIDS, breast cancer, other tumours, voice therapy, dermatology, the brain and cognition, and aging. Although equally deserving of mention, feminizing gender-affirming surgery, paediatric and adolescent populations, and gender nonbinary individuals are beyond the scope of this review. While much of the data we discuss come from Europe, the creation of a United States transgender cohort has already contributed important retrospective data that are also summarized here. Much remains to be determined regarding health considerations for TW. Patients and providers will benefit from larger and longer prospective studies involving TW, particularly regarding the effects of aging, race and ethnicity, type of hormonal treatment (e.g. different oestrogens, anti-androgens) and routes of administration (e.g. oral, parenteral, transdermal) on all the topics we address.
... Mueller et al. also found there was mean neuroanatomical volume for the amygdala, putamen and corpus callosum differed between transgender men and cismen in several brain structures including medial temporal lobe structures and cerebellum. He suggested that there is localized influence of sex hormones neuroanatomy (Mueller et al. 2017). ...
... In CGM, negative association with androstenedione was found in cerebellar tonsils. These cerebellar changes were associated with circulating androgens and HRT duration; suggesting a masculinization pattern of the brain from a functional connectivity standpoint (Mueller et al. 2016). ...
Gender identity development is complex and involves several key processes. Transgender people experience incongruence between their biological and identified gender. This incongruence can cause significant impairment in overall functioning and lead to gender dysphoria (GD). The pathophysiology of GD is complex and is poorly understood. A PubMed search based on predetermined eligibility criteria was conducted to review neuropsychiatric articles focused on neurological, biological and neuroimaging aspects of gender development, transgender identity and GD. The information obtained from the literature was then used to formulize a GD model. Distinct gray matter volume and brain activation and connectivity differences were found in individuals with GD compared to controls, suggesting a neurobiological basis of GD; which leads to the concept of brain gender. Individuals with GD encounter a recurrent conflict between their brain gender and the societal feedback; which causes recurrent and ongoing cognitive dissonance, finally leading to GD and functional connectivity and activation changes in the transgender brain. GD has neurobiological basis, but it is closely associated with the individuals’ interaction with the external world, their self-perception and the feedback received in return. We propose a novel model where the development of GD includes cognitive dissonance, involving anterior cingulate cortex and ventral striatum as the key brain structures. This model can be used to generate testable hypotheses using behavioral and neuroimaging techniques to understand the neuropsychobiology of GD.
... One small cross-sectional study assessed the effects of at least 2 years of GAHT in 18 FTMs and 17 MTFs after gender-affirming surgery. Neuroanatomical differences in the brain were found to be region-specific between transgender individuals and their biological sex as well as their gender identity, suggesting localization of influence by sex hormones on brain structure [105]. More specifically, the mean neuroanatomical volume for the amygdala, putamen, and corpus callosum of MTFs was found to be significantly different from those of cisgender women, but not cisgender men (consistent with the natal sex of MTFs). ...
Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female "characteristics" in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.
... Although few people have likely given much thought to the idea, there are sexually dimorphic parts of the brain-meaning, across large groups of males and females, some parts of the brain exhibit structural differences. 158 Differences occur in absolute brain volume, 159 amount of white matter, 160 amount of grey matter, 161 cortical thickness, 162 and the hypothalamus, 163 among others. ...
In a divisive time, few issues are more polarizing than how Americans treat transgender (“trans”) individuals. Trans individuals make up 0.6% of Americans, or 1.4 million people. As states have passed conflicting legislation, some protecting trans individuals and others limiting access, the conversation has become increasingly polarized. Adding to this discourse is the recalibration of protections for trans individuals by the Trump Administration.
Recently, the larger debate over the status and protections of trans individuals has focused on whether being trans has any biological or genetic basis. A 2016 review article published by a pair of professors associated with Johns Hopkins University brought this question to center stage. The author’s essentially claim that there is no biological or genetic basis for being trans and thus they caution against any treatment for trans individuals. This controversial stance drew forceful criticism from the scientific community and advocates. At the same time, the paper has been used by legislators and the media to discredit the needs and experiences of trans individuals.
This Essay provides a brief overview of the debate, including a brief synopsis of the current status of science surrounding being trans. While the science is not settled, what is clear is that trans individuals face dramatically heightened rates of suicide, psychological distress, and other challenges. Most concerning, the suicide attempt rates for trans individuals have been reported as high as 41%--significantly outstripping the general population, which historically has hovered around 5%. Even at the lower end of estimates, the fact of the matter is that we are dealing with a public health crisis.
This Essay argues that the disagreement about biological explanations for being transgender misses the most critical point: trans individuals experience enormous psychological distress across their lives. An appropriate response to the difficulties facing trans persons should not become mired down in a scientific debate about causation. Compassion should guide the discussion.
... Age was entered as a covariate because of the trending difference in age between groups. TBV was included because we wanted to remove any variance possibly associated with subtle anatomical variations, as we had found small group differences (in different regions than the ones studied here) previously in this cohort (Mueller et al., 2017). When the data were reanalyzed without TBV as a covariate, the findings did not substantially change. ...
Background
Stigmatization in society carries a high risk for development of psychopathology. Transgender persons are at particularly high risk for such stigmatization and social rejection by others. However, the neural correlates of ostracism in this group have not been captured.
Method
Twenty transgender men (TM, female-to-male) and 19 transgender women (TW, male-to-female) already living in their gender identity and 20 cisgender men (CM) and 20 cisgender women (CW) completed a cyberball task assessing both exclusion and re-inclusion during functional magnetic resonance imaging (fMRI).
Results
During psychosocial stress between-group differences were found in the dorsal and ventral anterior cingulate cortex (ACC) and the inferior frontal gyrus (IFG). Patterns were consistent with sex assigned at birth, i.e. CW showed greater activation in dorsal ACC and IFG relative to CM and TW. During re-inclusion, transgender persons showed greater ventral ACC activity relative to CW, possibly indicating persistent feelings of exclusion. Functional connectivity analyses supported these findings but showed a particularly altered functional connectivity between ACC and lateral prefrontal cortex in TM, which may suggest reduced emotional regulation to the ostracism experience in this group. Depressive symptoms or hormonal levels were not associated with these findings.
Conclusion
The results bear implications for the role of social exclusion in development of mental health problems in socially marginalized groups.
... Therefore, the counterclockwise cerebellar torque of our ferret model may not have an influence on cerebro-cerebellar connections, and may be prenatal causes, for example, inhibitions of the growth of right cerebral hemisphere and interhemispherical callosal connections by perinatal testosterone [36,37]. On the other hand, circulating levels of androgens, but not estrogens, correlated with an activation of local functional connectivity between the frontal cortex and cerebellum [38]. This evidence showed the possibility that a continuously increasing level of circulating androgens altered morphological lateralization of the cerebellum via an activation of particular cerebro-cerebellar connections. ...
A three-dimensional (3D) T 1-weighted Magnetic Resonance Imaging (MRI) at 7-Tesla system was acquired with a high spatial resolution from fixed brains of male and female ferrets at postnatal days (PDs) 4 to 90, and their age-related sexual difference and laterality were evaluated by MRI-based ex vivo volumetry. The volume of both left and right sides of cerebellar cortex was larger in males than in females on PD 10 and thereafter. When the cerebellar cortex was divided into four transverse domains, i.e., anterior zone (AZ; lobules I–V), central zone (CZ; lobules VI and VII), posterior zone (PZ; lobules VIII–IXa), and nodular zone (NZ; lobules IXb and X), an age-related significantly greater volume in males than in females was detected on either side of all four domains on PD 42 and of the AZ on PD 90, but only on the left side of the PZ on PD 90. Regarding the volume laterality, significant leftward asymmetry was obtained in the CZ and PZ volumes in males, but not in females on PD 90. From asymmetry quotient (AQ) analysis, AQ scores were rightward in the AZ in both sexes already on PD 21, but gradually left-lateralized only in males in the CZ, PZ, and NZ during PDs 42 to 90. The present study suggests that a characteristic counterclockwise torque asymmetry (rostrally right-biased, and caudally left-biased or symmetrical) is acquired in both sexes of ferrets during PDs 42 to 90, although the leftward laterality of the posterior half of the cerebellum was more enhanced in males. View Full-Text
... Bildgebend konnten spezifische Unterschiede bei Trans*Menschen im Vergleich zur Neuroanatomie des biologischen Geschlechts dargestellt werdenteilweise in Post-mortem-Studien. Die Unterschiede betreffen die Neuronenzahl im limbischen System [21], die Kortexdicke [24] oder auch strukturelle Veränderungen der grauen Substanz in mehreren Regionen, beispielsweise beidseits im Gyrus frontalis superior, im rechten Gyrus orbitalis und ebenso im Parietal-und Okzipitallappen [23,35]. Neuroanatomische Unterschiede in der MRT bei Trans*Menschen waren abhängig von der jeweiligen Region [26]. Noch unbehandelte Frau-zu-Mann-Transgender zeigen in der MRT eine Kortexdicke, die mit der männlichen Kontrollgruppe vergleichbar ist, wohingegen Mann-zu-Frau-Transgender eher Ähnlichkeiten zur weiblichen Kontrollgruppe aufweisen [46]. ...
In der funktionellen Magnetresonanztomographie (fMRT) können Aktivitätsmuster in bestimmten Hirnregionen dargestellt werden. Bei der Ausführung bestimmter Aufgaben oder Handlungen und bei Präsentation verschiedener Reize lassen sich spezifische Muster darstellen, die sich in definierten Kollektiven unterscheiden. Mit neueren Methoden wie der Resting-state-fMRT werden zudem die spontanen Hirnaktivitäten analysiert, die ebenfalls spezifische Veränderungen in unterschiedlichen Gruppen zeigen können. So gibt es auch geschlechtstypische Aktivitätsmuster bei Männern und Frauen. Es wurde zunächst angenommen, dass Trans*Menschen hierbei Ergebnisse zeigen, die zwischen den Geschlechtern liegen. Die Studien müssen jedoch differenzierter interpretiert werden und zeigen widersprüchliche Resultate, gerade in Abhängigkeit von den präsentierten Reizen. Der Einfluss der Hormontherapie auf kognitive Fähigkeiten und Korrelate in den zerebralen Aktivitätsmustern wird ebenso kontrovers diskutiert. Insgesamt spiegeln die Ergebnisse bildgebender Verfahren bei Trans*Menschen ein spannendes Zusammenspiel von gesellschaftlichen, biologischen, kognitiven und beispielsweise sexuellen Komponenten wider, zeigen aber auch die Grenzen der Methodik auf.
Introduction: There is increasing public and research interest in transgender people and communities. Coupled with this interest is a renewed pursuit of research into the possible biological origins of transgender identity. In this review, we critically examine the biological literature which explores the etiology of transgender identity, including endocrinological, behavioral, genetic, and neuroimaging studies, with the goal of identifying key trends in this literature, limitations, critical gaps, and future directions. Methods: We searched the Pubmed database for peer reviewed original experimental research conducted since 1990, using a combination of six transgender identity-related search terms and 18 topic search terms. Results: A total of 102 articles across the disciplines of endocrinology, genetics, cognitive function, and neuroanatomy met our review criteria. Most studies were conducted at gender identity clinics. Several approaches yielded compelling results, but where replication has been attempted, results have varied. We identified several issues in experimental design and/or interpretation that might account for this inconsistency. Conclusion: A number of research studies have investigated biological factors that could potentially contribute to transgender identity, but results often contradict each other. Interpretation of etiological studies of transgender identity can be misunderstood and/or misused by media, politicians, and care providers, placing transgender people at risk. We question the utility of etiological studies in clinical care, given that transgender identity is not pathological. When etiological studies are undertaken, we recommend new, inclusive designs for a rigorous and compassionate approach to scientific practice in the service of transgender communities and the providers who serve them.
Alterations in gray matter (GM) and monoamine oxidase A (MAO-A) distribution across the brain have been found in various neuropsychiatric conditions. MAO-A catalyzes the oxidative degradation of various monoamines and is thus implicated in neuroplastic processes that influence GM density (GMD) and microstructure (GMM) of the brain. Sex-specific differences in these patterns are well documented, however studying the long-term effects of certain sex steroids on the brain are limited due to hormonal fluctuations under naturalistic conditions. Due to the exact monitoring of plasma hormone levels and sex steroid intake, transgender individuals undergoing gender-affirming hormone therapy represent a valuable cohort to investigate such changes of GM and concomitant MAO-A density. Here, we investigated the effects of long-term gender-affirming hormone therapy over a median time period of 4.5 months on GMD and GMM as well as MAO-A distribution volume. To this end, 20 cisgender women, 11 cisgender men, 20 transgender women and 10 transgender men were recruited. All participants underwent two MRI scans in a longitudinal design. PET scans using [ ¹¹ C]harmine were performed before each MRI session in a subset of 35 individuals. Between baseline and follow-up imaging, transgender subjects underwent gender-affirming hormone therapy. GM changes determined by diffusion weighted imaging (DWI) metrics for GMM and voxel based morphometry (VBM) for GMD were estimated using repeated measures ANOVA. Regions showing significant changes of both GMM and GMD were used for the subsequent analysis of MAO-A density. These involved the fusiform gyrus, rolandic operculum, inferior occipital cortex, middle and anterior cingulum, bilateral insula, cerebellum and the lingual gyrus (post-hoc tests: p FWE+Bonferroni < 0.025). In terms of MAO-A distribution volume, no significant effects were found. The present results are indicative of a reliable influence of gender-affirming hormone therapy on GMD and GMM following an interregional pattern. Nevertheless, future studies with larger sample sizes are needed to further investigate the relationship between sex steroids, gray matter alterations and MAO-A density.
Although the neuroanatomy of transgender persons is slowly being charted, findings are presently discrepant. Moreover, the major body of work has focused on Western populations. One important factor is the issue of power and low signal‐to‐noise (SNR) ratio in neuroimaging studies of rare study populations including endocrine or neurological patient groups. The present study focused on the structural neuroanatomy of a Non‐Western (Iranian) sample of 40 transgender men (TM), 40 transgender women (TW), 30 cisgender men (CM), and 30 cisgender women (CW), while assessing whether the reliability of findings across structural anatomical measures including gray matter volume (GMV), cortical surface area (CSA), and cortical thickness (CTh) could be increased by using two back‐to‐back within‐session structural MRI scans. Overall, findings in transgender persons were more consistent with sex assigned at birth in GMV and CSA, while no group differences emerged for CTh. Repeated measures analysis also indicated that having a second scan increased SNR in all regions of interest, most notably bilateral frontal poles, pre‐ and postcentral gyri and putamina. The results suggest that a simple time and cost‐effective measure to improve SNR in rare clinical populations with low prevalence rates is a second anatomical scan when structural MRI is of interest. This study assesses the reproducibility of previous neuroanatomical findings in Western transgender persons in a Non‐Western population. It then shows that repeating an anatomical MRI sequence can increase data reliability especially in brain regions that have previously been implicated to differ between transgender and cisgender persons. This scan–rescan method might enhance the power of studies with small samples due to low prevalence of target population.
Every cell has a genetic sex that is determined at the time of fertilization. However, the natal sex of cells may not match the hormonal environment in which they reside in transgender individuals. This discordance provides a unique opportunity to study the short- and long-term effects across a range of cellular functions, health conditions, physiologic processes and psychosocial outcomes to the benefit of transgender and cisgender communities. While there is a growing body of knowledge as the literature on sex differences in virtually every organ system accumulates, there remains a paucity of data on the effect of cross hormonal therapy on cellular function in transgender individuals. Beyond cellular function, the effect of cross hormonal therapy on neuroanatomy, the interpretation of neuropsychological assessments or even the effect of daily stressors of stigma and discrimination on long-term neurocognitive function remain unclear.In 2011 the Institute of Medicine indicated that transgender adults were an understudied population and in critical need of more biomedical and population health research, yet the experience of stigma, discrimination, microaggressions, limited access to culturally competent care continue to make this an unfulfilled mandate. In addition to using a life course perspective, it is essential to identify research gaps and formulate a responsive research agenda while maintaining scientific rigor and respectful involvement of the population under study. None of this, however, will enhance the participation of transgender communities in biomedical research until the transgender and biomedical research communities can engage in open, respectful and bidirectional dialogue.From respectful, sensitive and appropriate health care to culturally competent research engagement from study inception to data dissemination, transgender communities can make an important and valuable contribution to biomedical research. Inclusion of their voices at all levels, including investigators from transgender communities, are essential to advance this much overdue scientific agenda. Transgender, cisgender and the biomedical research communities will all benefit from a more inclusive and expansive research agenda.Ethn Dis. 2020;30(2):247- 250; doi:10.18865/ed.30.2.247
Investigating the effects of the gender-affirming hormone treatment of transgender people using neuroimaging provides a unique opportunity to study the impact of high dosages of sex hormones on human brain structure and function. This line of research is of relevance from a basic neuroscientific as well as from a psychiatric viewpoint. Prevalence rates, etiopathology, and disease course of many psychiatric disorders exhibit sex differences which are linked to differences in sex hormone levels. Here, we review recent neuroimaging studies from others and our group that investigate the effects of gender-affirming hormone treatment in a longitudinal design utilizing structural and functional magnetic resonance imaging and positron emission tomography. Studies point to a general anabolic and anticatabolic effect of testosterone on grey and white matter structure, whereas estradiol and antiandrogen treatment seems to have partly opposite effects. Moreover, preliminary research indicates that gender-affirming hormone treatment influences serotonergic neurotransmission, a finding that is especially interesting for psychiatry. A clear picture of a hormonal influence on brain activity has yet to emerge. In conclusion, the available evidence reviewed here clearly indicates that sex hormone applications influence brain structure and function in the adult human brain.
Transgender individuals (TIs) show brain-structural alterations that differ from their biological sex as well as their perceived gender. To substantiate evidence that the brain structure of TIs differs from male and female, we use a combined multivariate and univariate approach. Gray matter segments resulting from voxel-based morphometry preprocessing of N = 1753 cisgender (CG) healthy participants were used to train (N = 1402) and validate (20% holdout N = 351) a support vector machine classifying the biological sex. As a second validation, we classified N = 1104 patients with depression. A third validation was performed using the matched CG sample of the transgender women (TW) application sample. Subsequently, the classifier was applied to N = 26 TW. Finally, we compared brain volumes of CG-men, women, and TW-pre/post treatment (CHT) in a univariate analysis controlling for sexual orientation, age, and total brain volume. The application of our biological sex classifier to the transgender sample resulted in a significantly lower true positive rate (TPR-male = 56.0%). The TPR did not differ between CG-individuals with (TPR-male = 86.9%) and without depression (TPR-male = 88.5%). The univariate analysis of the transgender application-sample revealed that TW-pre/post treatment show brain-structural differences from CG-women and CG-men in the putamen and insula, as well as the whole-brain analysis. Our results support the hypothesis that brain structure in TW differs from brain structure of their biological sex (male) as well as their perceived gender (female). This finding substantiates evidence that TIs show specific brain-structural alterations leading to a different pattern of brain structure than CG-individuals.
Women’s mental health seems to be affected by different factors and present with particular epidemiology when compared to men’s mental health. In terms of mood disorders, these include the age of onset, seasonal features, incidence of suicidal attempts, and typicality of features. One hypothesis is that the difference in sex hormones is considered to impact the epidemiology and the course of psychiatric disorders in women. For example, changes in the hormonal milieu that occur in the end of pregnancy have been linked to peripartum depression, and the fluctuations of sex hormones during the menstrual cycle have been linked to premenstrual dysphoric disorder (PMDD). Neuroimage research has contributed to identifying potential biomarkers in respect to these disorders. For instance, peripartum depression has been associated with a decreased activation of the limbic structures, as well as a decreased functional connectivity between frontal cortex and limbic structures, which seems to point out different pathophysiologic mechanisms for postpartum depression. Regarding PMDD, being diagnosed with bipolar disorder while experiencing this comorbidity is related to a more challenging course of bipolar disorder. This seems to be related to female sex hormones’ neuroactivity, since they were shown to affect the glutamatergic and GABAergic systems. According to the phase of the menstrual cycle, women with PMDD seem to exhibit different brain activation in the motor and somatosensory cortices. Complementarily, a cortical thickness study showed that PMDD women with bipolar disorder present with an increased cortical thickness of the left superior temporal gyrus, a decreased cortical thickness of the left parietal, and superior frontal and left pericalcarine cortices, including, resting-state functional connectivity (rs-FC) between the left hippocampus and right frontal cortex, as well as decreased rs-FC between right hippocampus and right premotor cortex. Although there are not many neuroimaging studies investigating the influence of “female” sex hormones in the brain, and therefore, their relationship with psychiatric symptoms in transgender women/transgender person should also be considered a population vulnerable to female sex neuroactive steroids influence.
Although the neuroanatomy of transgender persons is slowly being charted, findings are presently discrepant. One important factor is the issue of power and low signal-to-noise (SNR) ratio in neuroimaging studies of rare study populations including endocrine or neurological patient groups. The present study assessed whether the reliability of findings across structural anatomical measures including thickness, volume, and surface area could be increased by using two back-to-back within session structural MRI scans in 40 transgender men (TM), 40 transgender women (TW), 30 cisgender men (CM), and 30 cisgender women (CW). Overall, findings in transgender persons were more consistent with at-birth assigned sex in brain volume and surface area while no group differences emerged for cortical thickness. Repeated measures analysis also indicated that having a second scan increased SNR in all ROIs, most notably bilateral frontal poles, accumbens nuclei and putamina. Furthermore, additional significant group differences emerged in cortical surface area when age and ICV were used as covariates. The results suggest that a simple time and cost effective measure to improve signal to noise ratio in rare clinical populations with low prevalence rates is a second anatomical scan when structural MRI is of interest.
For transgender individuals, gender-affirming surgery (GAS) and cross-sex hormone therapy (CSHT) are part of the gender transition process. Scientific evidence supporting the maintenance of CSHT after GAS-related gonadectomy is accumulating. However, few data are available with respect to the impact of CSHT on brain structure following hypogonadism. Thus, we aimed to investigate links between estradiol and brain cortical thickness and cognition in 18 post-gonadectomy transgender women using a longitudinal design. For this purpose, the participants underwent a voluntary period of CSHT washout of at least 30 days, followed by estradiol re-institution for 60 days. High-resolution T1-weighted brain images, hormonal measures, working and verbal memory were collected at two time points: on the last day of the washout (t1) and on the last day of the two-month CSHT period (t2). Between these two time points, cortical thickness increased within the left precentral gyrus and right precuneus but decreased within the right lateral occipital cortex. However, those findings did not survive corrections of multiple comparisons. Nevertheless, there was a significant negative correlation between changes in estradiol levels and changes in cortical thickness. This effect was evident in the left superior frontal gyrus, the left middle temporal gyrus, the right precuneus, the right superior temporal gyrus and the right pars opercularis. Although there was improvement in verbal memory following hypogonadism correction, we did not observe a significant relationship between changes in memory scores and cortical thickness. Altogether, these findings suggest that there is a link between estradiol and cortical thickness.
An extreme incongruence between sex and gender identity leads individuals with gender dysphoria (GD) to seek cross-sex hormone therapy (CSHT), and gender-affirming surgery (GAS). Although few studies have investigated the effects of CSHT on the brain prior to GAS, no studies in the extant literature have evaluated its impact during hypogonadism in post-GAS individuals. Here, we aimed to evaluate the effects of estradiol on resting-state functional connectivity (rs-FC) of the sensorimotor cortex (SMC) and basal ganglia following surgical hypogonadism. Eighteen post-GAS (male-to-female) participants underwent functional magnetic resonance imaging (fMRI) and neuropsychiatric and hormonal assessment at two time points (t1, hormonal washout; t2, CSHT reintroduction). Based on the literature, the thalamus was selected as a seed, while the SMC and the dorsolateral striatum were targets for seed-based functional connectivity (sbFC). A second sbFC investigation consisted of a whole-brain voxel exploratory analysis again using the thalamus as a seed. A final complementary data-driven approach using multivoxel pattern analysis (MVPA) was conducted to identify a potential seed for further sbFC analyses. An increase in the rs-FC between the left thalamus and the left SCM/putamen followed CSHT. MVPA identified a cluster within the subcallosal cortex (SubCalC) representing the highest variation in peak activation between time points. Setting the SubCalC as a seed, whole-brain analysis showed a decoupling between the SubCalC and the medial frontal cortex during CSHT. These results indicate that CSHT with estradiol post-GAS, modulates rs-FC in regions engaged in cognitive, emotional, and sensorimotor processes.
Untreated transsexuals have a brain cortical phenotype. Cross-sex hormone treatments are used to masculinize or feminize the bodies of female-to-male (FtMs) or male-to-female (MtFs) transsexuals, respectively.
A longitudinal design was conducted to investigate the effects of treatments on brain cortical thickness (CTh) of FtMs and MtFs.
This study investigated 15 female-to-male (FtMs) and 14 male-to-female (MtFs) transsexuals prior and during at least six months of cross-sex hormone therapy treatment. Brain MRI imaging was performed in a 3-Tesla TIM-TRIO Siemens scanner. T1-weighted images were analyzed with FreeSurfer software to obtain CTh as well as subcortical volumetric values.
Changes in brain CTh thickness and volumetry associated to changes in hormonal levels due to cross-sex hormone therapy.
After testosterone treatment, FtMs showed increases of CTh bilaterally in the postcentral gyrus and unilaterally in the inferior parietal, lingual, pericalcarine, and supramarginal areas of the left hemisphere and the rostral middle frontal and the cuneus region of the right hemisphere. There was a significant positive correlation between the serum testosterone and free testosterone index changes and CTh changes in parieto-temporo-occipital regions. In contrast, MtFs, after estrogens and antiandrogens treatment, showed a general decrease in CTh and subcortical volumetric measures and an increase in the volume of the ventricles.
Testosterone therapy increases CTh in FtMs. Thickening in cortical regions is associated to changes in testosterone levels. Estrogens and antiandrogens therapy in MtFs is associated to a decrease in the CTh that consequently induces an enlargement of the ventricular system. Zubiaurre-Elorza L, Junque C, Gómez-Gil E, and Guillamon A. Effects of cross-sex hormone treatment on cortical thickness in transsexual individuals. J Sex Med **;**:**-**.
Gender identity disorder (GID) refers to transsexual individuals who feel that their assigned biological gender is incongruent with their gender identity and this cannot be explained by any physical intersex condition. There is growing scientific interest in the last decades in studying the neuroanatomy and brain functions of transsexual individuals to better understand both the neuroanatomical features of transsexualism and the background of gender identity. So far, results are inconclusive but in general, transsexualism has been associated with a distinct neuroanatomical pattern. Studies mainly focused on male to female (MTF) transsexuals and there is scarcity of data acquired on female to male (FTM) transsexuals. Thus, our aim was to analyze structural MRI data with voxel based morphometry (VBM) obtained from both FTM and MTF transsexuals (n = 17) and compare them to the data of 18 age matched healthy control subjects (both males and females). We found differences in the regional grey matter (GM) structure of transsexual compared with control subjects, independent from their biological gender, in the cerebellum, the left angular gyrus and in the left inferior parietal lobule. Additionally, our findings showed that in several brain areas, regarding their GM volume, transsexual subjects did not differ significantly from controls sharing their gender identity but were different from those sharing their biological gender (areas in the left and right precentral gyri, the left postcentral gyrus, the left posterior cingulate, precuneus and calcarinus, the right cuneus, the right fusiform, lingual, middle and inferior occipital, and inferior temporal gyri). These results support the notion that structural brain differences exist between transsexual and healthy control subjects and that majority of these structural differences are dependent on the biological gender.
Research into the relationship between gender identity disorder and psychiatric problems has shown contradictory results.
To investigate psychiatric problems in adults fulfilling DSM-IV-TR criteria for a diagnosis of gender identity disorder.
Data were collected within the European Network for the Investigation of Gender Incongruence using the Mini International Neuropsychiatric Interview - Plus and the Structured Clinical Interview for DSM-IV Axis II Disorders (n = 305).
In 38% of the individuals with gender identity disorder a current DSM-IV-TR Axis I diagnosis was found, mainly affective disorders and anxiety disorders. Furthermore, almost 70% had a current and lifetime diagnosis. All four countries showed a similar prevalence, except for affective and anxiety disorders, and no difference was found between individuals with early-onset and late-onset disorder. An Axis II diagnosis was found in 15% of all individuals with gender identity disorder, which is comparable to the general population.
People with gender identity disorder show more psychiatric problems than the general population; mostly affective and anxiety problems are found.
The degree to which one identifies as male or female has a profound impact on one's life. Yet, there is a limited understanding of what contributes to this important characteristic termed gender identity. In order to reveal factors influencing gender identity, studies have focused on people who report strong feelings of being the opposite sex, such as male-to-female (MTF) transsexuals.
To investigate potential neuroanatomical variations associated with transsexualism, we compared the regional thickness of the cerebral cortex between 24 MTF transsexuals who had not yet been treated with cross-sex hormones and 24 age-matched control males.
Results revealed thicker cortices in MTF transsexuals, both within regions of the left hemisphere (i.e., frontal and orbito-frontal cortex, central sulcus, perisylvian regions, paracentral gyrus) and right hemisphere (i.e., pre-/post-central gyrus, parietal cortex, temporal cortex, precuneus, fusiform, lingual, and orbito-frontal gyrus).
These findings provide further evidence that brain anatomy is associated with gender identity, where measures in MTF transsexuals appear to be shifted away from gender-congruent men.
Introduction. Long-term effects and side effects of cross-sex hormone treatment in transsexual persons are not well known.
Aim. The aim of this study is to describe the effects and side effects of cross-sex hormone therapy in both transsexual men and women.
Main Outcome Measures. Hormone levels were measured by immunoassays. Physical health was assessed by physical examination and questionnaires on general health and specific side effects, areal bone parameters by dual energy X-ray absorptiometry.
Methods. Single center cross-sectional study in 100 transsexual persons post-sex reassignment surgery and on average 10 years on cross-sex hormone therapy.
Results. Transsexual men did not experience important side effects such as cardiovascular events, hormone-related cancers, or osteoporosis. In contrast, a quarter of the transsexual women had osteoporosis at the lumbar spine and radius. Moreover, 6% of transsexual women experienced a thromboembolic event and another 6% experienced other cardiovascular problems after on average 11.3 hormone treatment years. None of the transsexual women experienced a hormone-related cancer during treatment.
Conclusion. Cross-sex hormone treatment appears to be safe in transsexual men. On the other hand, a substantial number of transsexual women suffered from osteoporosis at the lumbar spine and distal arm. Twelve percent of transsexual women experienced thromboembolic and/or other cardiovascular events during hormone treatment, possibly related to older age, estrogen treatment, and lifestyle factors. In order to decrease cardiovascular morbidity, more attention should be paid to decrease cardiovascular risk factors during hormone therapy management. Wierckx K, Mueller, S, Weyers S, Van Caenegem E, Roef G, Heylens G, and T'Sjoen G. Long-term evaluation of cross-sex hormone treatment in transsexual persons. J Sex Med **;**:**–**.
A number of studies have reported that, "relative to brain size," the midsagittal corpus callosum cross-sectional area (CCA) in females is on average larger than in males. However, others suggest that these may be spurious differences created in the CCA-to-brain-size ratio because brain size tends to be larger in males. To help resolve this controversy, we measured the CCA on all 316 magnetic resonance imaging (MRI) scans of normal subjects (18-94 years) in the OASIS (Open Access Series of Imaging Studies) cross-sectional dataset, and used multiple regression analysis to statistically control for the confounding effects of brain size and age to test the null hypothesis that the average CCA is not different between genders. An additional analysis was performed on a subset of 74 young adults (37 males and 37 females; 18-29 years) matched closely to brain size. Our null hypothesis was rejected in both analyses. In the entire sample (n= 316), controlling for brain size and age, the average CCA was significantly (P< 0.03) larger in females. The difference favoring females was more pronounced in the young adults cohort (P< 0.0005). These results provide strong additional evidence that the CCA is larger in females after correcting for the confounding effect of brain size.
Objective : Sex hormones are not only involved in the formation of reproductive organs, but also induce sexually-dimorphic brain development and organization. Cross-sex hormone administration to transsexuals provides a unique possibility to study the effects of sex steroids on brain morphology in young adulthood.
Methods : Magnetic resonance brain images were made prior to, and during, cross-sex hormone treatment to study the influence of anti-androgen + estrogen treatment on brain morphology in eight young adult male-to-female transsexual human subjects and of androgen treatment in six female-to-male transsexuals.
Results : Compared with controls, anti-androgen + estrogen treatment decreased brain volumes of male-to-female subjects towards female proportions, while androgen treatment in female-to-male subjects increased total brain and hypothalamus volumes towards male proportions.
Conclusions : The findings suggest that, throughout life, gonadal hormones remain essential for maintaining aspects of sex-specific differences in the human brain.
An accurate description of changes in the brain in healthy aging is needed to understand the basis of age-related changes in cognitive function. Cross-sectional magnetic resonance imaging (MRI) studies suggest thinning of the cerebral cortex, volumetric reductions of most subcortical structures, and ventricular expansion. However, there is a paucity of detailed longitudinal studies to support the cross-sectional findings. In the present study, 142 healthy elderly participants (60-91 years of age) were followed with repeated MRI, and were compared with 122 patients with mild to moderate Alzheimer's disease (AD). Volume changes were measured across the entire cortex and in 48 regions of interest. Cortical reductions in the healthy elderly were extensive after only 1 year, especially evident in temporal and prefrontal cortices, where annual decline was approximately 0.5%. All subcortical and ventricular regions except caudate nucleus and the fourth ventricle changed significantly over 1 year. Some of the atrophy occurred in areas vulnerable to AD, while other changes were observed in areas less characteristic of the disease in early stages. This suggests that the changes are not primarily driven by degenerative processes associated with AD, although it is likely that preclinical changes associated with AD are superposed on changes due to normal aging in some subjects, especially in the temporal lobes. Finally, atrophy was found to accelerate with increasing age, and this was especially prominent in areas vulnerable to AD. Thus, it is possible that the accelerating atrophy with increasing age is due to preclinical AD.
Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), suitable to assess disease progression for multi-centre studies. This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T(1)-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimer's Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an epsilon 4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies.
By comparison with age-matched controls in employment, 17 institutionalised schizophrenic patients were shown by computerised axial tomography of the brain to have increased cerebral ventricular size. Within the group of schizophrenic patients increased ventricular size was highly significantly related to indices of cognitive impairment.
Transsexuals have the strong feeling, often from childhood onwards, of having been born the wrong sex. The possible psychogenic or biological aetiology of transsexuality has been the subject of debate for many years. Here we show that the volume of the central subdivision of the bed nucleus of the stria terminals (BSTc), a brain area that is essential for sexual behaviour, is larger in men than in women. A female-sized BSTc was found in male-to-female transsexuals. The size of the BSTc was not influenced by sex hormones in adulthood and was independent of sexual orientation. Our study is the first to show a female brain structure in genetically male transsexuals and supports the hypothesis that gender identity develops as a result of an interaction between the developing brain and sex hormones.
An extra X chromosome in males (XXY), known as Klinefelter syndrome, is associated with characteristic physical, cognitive, and behavioral features of variable severity. The objective of this study was to examine possible neuroanatomical substrates of these cognitive and behavioral features during childhood and adolescence.
MRI brain scans were acquired for 42 XXY and 87 healthy XY age-matched control males. We compared these 2 groups on regional brain volumes and cortical thickness.
Total cerebral volume and all lobar volumes except parietal white matter were significantly smaller in the XXY group, whereas lateral-ventricle volume was larger. Consistent with the cognitive profile, the cortex was significantly thinner in the XXY group in left inferior frontal, temporal, and superior motor regions.
The brain-imaging findings of preferentially affected frontal, temporal, and motor regions and relative sparing of parietal regions are consistent with observed cognitive and behavioral strengths and weaknesses in XXY subjects.
Several studies seem to support the hypothesis that brain anatomy is associated with transsexualism. However, these studies were still limited because few neuroanatomical findings have been obtained from female-to-male (FtM) transsexuals. This study compared the cerebral regional volumes of gray matter (GM) between FtM transsexuals and female controls using a voxel-based morphometry. Twelve FtM transsexuals who had undergone sex-reassignment surgery and 15 female controls participated in this study. Both groups were age matched and right-handed, with no history of neurological illness. Fifteen female controls were recruited to determine whether GM volumes in FtM transsexuals more closely resembled individuals who shared their biological sex. MRI data were processed using SPM 8 with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL). FtM transsexuals showed significantly larger volumes of the thalamus, hypothalamus, midbrain, gyrus rectus, head of caudate nucleus, precentral gyrus, and subcallosal area compared with the female controls. However, the female controls showed a significantly larger volume in the superior temporal gyrus including Heschl's gyrus and Rolandic operculum. These findings confirm that the volume difference in brain substructures in FtM transsexuals is likely to be associated with transsexualism and that transsexualism is probably associated with distinct cerebral structures, determining gender identity.
This is the first book to introduce the new statistics—effect sizes, confidence intervals, and meta-analysis-in an accessible way. It is chock full of practical examples and tips on how to analyze and report research results using these techniques. The book is invaluable to readers interested in meeting the new APA Publication Manual guidelines by adopting the new statistics—which are more informative than null hypothesis significance testing, and becoming widely used in many disciplines. This highly accessible book is intended as the core text for any course that emphasizes the new statistics, or as a supplementary text for graduate and/or advanced undergraduate courses in statistics and research methods in departments of psychology, education, human development, nursing, and natural, social, and life sciences. Researchers and practitioners interested in understanding the new statistics, and future published research, will also appreciate this book. A basic familiarity with introductory statistics
The prevalence, age of onset, and symptomatology of many neuropsychiatric conditions differ between males and females. To understand the causes and consequences of sex differences it is important to establish where they occur in the human brain. We report the first meta-analysis of typical sex differences on global brain volume, a descriptive account of the breakdown of studies of each compartmental volume by six age categories, and whole-brain voxel-wise meta-analyses on brain volume and density. Gaussian-process regression coordinate-based meta-analysis was used to examine sex differences in voxel-based regional volume and density. On average, males have larger total brain volumes than females. Examination of the breakdown of studies providing total volumes by age categories indicated a bias towards the 18-59 year-old category. Regional sex differences in volume and tissue density include the amygdala, hippocampus and insula, areas known to be implicated in sex-biased neuropsychiatric conditions. Together, these results suggest candidate regions for investigating the asymmetric effect that sex has on the developing brain, and for understanding sex-biased neurological and psychiatric conditions.
Mounting magnetic resonance imaging (MRI) research is characterising the neurobiological trajectories of healthy human brain development. In parallel, studies increasingly acknowledge the relevance of perturbations of these trajectories for adolescent and adult psychopathology. While an influence of steroid hormones on mood and anxiety disorders has been demonstrated in adults, very little is known how steroid hormones alter human brain development and contribute to adolescent psychopathology. This review will focus on recent evidence from structural and functional magnetic resonance imaging (MRI/fMRI) in children and adolescents with genetic endocrine disorders with characteristic fluctuations in androgen or estrogen levels (Familial Male Precocious Puberty, Congenital Adrenal Hyperplasia, Klinefelter Syndrome, and Turner Syndrome). It aims to highlight how neurobiological findings from these paediatric endocrine disorders can provide insight into the contribution of sex steroids to the development of neurocircuitry involved in affective processing (amygdala, hippocampus) and cognitive control (prefrontal cortex, inferior frontal gyrus, striatum). In addition, findings from these populations may also provide important information on aberrant psychological processes relevant for the clinical care and management of these populations. Finally, the findings are discussed within the context of current frameworks in animal models such as the organisational-activational hypothesis or the aromatisation hypothesis. The review ends with a discussion of open questions for future enquiry with the goal to integrate translational models with current knowledge of endocrine disorders and developmental studies in healthy populations. This article is protected by copyright. All rights reserved.
Research studies focusing on the psychometric properties of the Beck Depression Inventory (BDI) with psychiatric and nonpsychiatric samples were reviewed for the years 1961 through June, 1986. A meta-analysis of the BDI's internal consistency estimates yielded a mean coefficient alpha of 0.86 for psychiatric patients and 0.81 for nonpsychiatric subjects. The concurrent validitus of the BDI with respect to clinical ratings and the Hamilton Psychiatric Rating Scale for Depression (HRSD) were also high. The mean correlations of the BDI samples with clinical ratings and the HRSD were 0. 72 and 0.73, respectively, for psychiatric patients. With nonpsychiatric subjects, the mean correlations of the BDI with clinical ratings and the HRSD were 0.60 and 0.74, respectively. Recent evidence indicates that the BDI discriminates subtypes of depression and differentiates depression from anxiety.
Gender dysphoria is suggested to be a consequence of sex atypical cerebral differentiation. We tested this hypothesis in a magnetic resonance study of voxel-based morphometry and structural volumetry in 48 heterosexual men (HeM) and women (HeW) and 24 gynephillic male to female transsexuals (MtF-TR). Specific interest was paid to gray matter (GM) and white matter (WM) fraction, hemispheric asymmetry, and volumes of the hippocampus, thalamus, caudate, and putamen. Like HeM, MtF-TR displayed larger GM volumes than HeW in the cerebellum and lingual gyrus and smaller GM and WM volumes in the precentral gyrus. Both male groups had smaller hippocampal volumes than HeW. As in HeM, but not HeW, the right cerebral hemisphere and thalamus volume was in MtF-TR lager than the left. None of these measures differed between HeM and MtF-TR. MtF-TR displayed also singular features and differed from both control groups by having reduced thalamus and putamen volumes and elevated GM volumes in the right insular and inferior frontal cortex and an area covering the right angular gyrus.The present data do not support the notion that brains of MtF-TR are feminized. The observed changes in MtF-TR bring attention to the networks inferred in processing of body perception.
Major questions remain about how sex hormones influence human brain development and cognition. Studies in humans and animals suggest a strong impact of androgen on the structure and function of the medial temporal lobe (MTL) and striatum. Using voxel-based morphometry (DARTEL), we compared MTL and striatal structures in 13 [mean age (±S.D.) 12.7±3.2 yr, mean bone age 14.8±3.2 yr] boys with familial male precocious puberty (FMPP), characterized by early excess androgen secretion, and 39 healthy age-matched boys (mean age 14.3±2.5 yr). The FMPP group showed significantly larger grey-matter volume (GMV) in parahippocampal and fusiform gyri as well as putamen relative to controls. By comparison, larger GMV for controls relative to patients was only apparent in the precentral gyrus. Exploratory regression analyses that examined the impact of age on the current findings revealed a significant increase of GMV in the putamen with age in patients suffering from excess androgen but not in controls. Finally, current levels of free testosterone were obtained in the patient group. Analyses revealed a significant negative association indicating that FMPP boys with low levels of bioavailable testosterone exhibited high GMV in the bilateral striatum. The findings suggest a critical influence of androgen on human brain development and are discussed in relation to male-dominant psychiatric childhood disorders.
Gender identity-one's sense of being a man or a woman-is a fundamental perception experienced by all individuals that extends beyond biological sex. Yet, what contributes to our sense of gender remains uncertain. Since individuals who identify as transsexual report strong feelings of being the opposite sex and a belief that their sexual characteristics do not reflect their true gender, they constitute an invaluable model to understand the biological underpinnings of gender identity. We analyzed MRI data of 24 male-to-female (MTF) transsexuals not yet treated with cross-sex hormones in order to determine whether gray matter volumes in MTF transsexuals more closely resemble people who share their biological sex (30 control men), or people who share their gender identity (30 control women). Results revealed that regional gray matter variation in MTF transsexuals is more similar to the pattern found in men than in women. However, MTF transsexuals show a significantly larger volume of regional gray matter in the right putamen compared to men. These findings provide new evidence that transsexualism is associated with distinct cerebral pattern, which supports the assumption that brain anatomy plays a role in gender identity.
The way in which sex hormones influence cognitive and affective brain development is poorly understood. Despite increasing knowledge in the area of pediatric mood disorders, little is known about the influence of sex hormones on the regulation of emotion. Animal studies and preliminary human studies suggest a strong impact of testosterone on limbic structures such as the hippocampus and amygdala. We used functional magnetic resonance imaging (fMRI) to examine emotional processing in familial male-precocious puberty (FMPP), an extremely rare gonadotropin-independent form of precocious puberty characterized by early excess testosterone secretion. We compared this group (n = 7, mean age = 13 +/- 3.3 years) to healthy age and sex-matched controls (n = 14, mean age = 13 +/- 2.3 years). Participants were presented with emotional and neutral face stimuli and were required either to judge the hostility of the presented face, their subjective level of anxiety, or the width of the nose of the presented faces (nonemotional condition). In a fourth, passive viewing condition, no responses were required. Boys with FMPP responded faster to fearful faces during perception of threat compared to unaffected controls. Concurrently, fMRI data revealed significant differences in hippocampus activation in response to fearful faces relative to baseline whereas controls showed no differences. In contrast, no significant activation of the amygdala was found. These data are consistent with previous studies of the effects of sex hormones on brain function and support the role of testosterone on emotional development.
Previous postmortem anatomical studies have demonstrated differences between male and female in the size and shape of the splenium of the corpus callosum. The current study using the magnetic resonance imager compares the corpus callosum in 20 transsexuals and 40 controls to determine if the anatomic variance is related to anatomic sex or gender identity. No statistical differences were found in the cross-sectional areas of the entire corpus callosum, regardless of genetic sex or gender. However, the genetic males did have a larger whole-brain cross-sectional area. Also, even though there was a wide range of differences in shape and size in the splenium, the study found no significant differences between the sexes or between transsexual patients of either sex and the controls.
The distribution of cells that express mRNA encoding the androgen (AR) and estrogen (ER) receptors was examined in adult male and female rats by using in situ hybridization. Specific labeling appeared to be largely, if not entirely, localized to neurons. AR and ER mRNA-containing neurons were widely distributed in the rat brain, with the greatest densities of cells in the hypothalamus, and in regions of the telencephalon that provide strong inputs in the medial preoptic and ventromedial nuclei, each of which is thought to play a key role in mediating the hormonal control of copulatory behavior, as well as in the lateral septal nucleus, the medial and cortical nuclei of the amygdala, the amygdalohippocampal area, and the bed nucleus of the stria terminalis. Heavily labeled ER mRNA-containing cells were found in regions known to be involved in the neural control of gonadotropin release, such as the anteroventral periventricular and the arcuate nuclei, but only a moderate density of labeling for AR mRNA was found over these nuclei. In addition, clearly labeled cells were found in regions with widespread connections throughout the brain, including the lateral hypothalamus, intralaminar thalamic nuclei, and deep layers of the cerebral cortex, suggesting that AR and ER may modulate a wide variety of neural functions. Each part of Ammon's horn contained AR mRNA-containing cells, as did both parts of the subiculum, but ER mRNA appeared to be less abundant in the hippocampal formation. Moreover, AR and ER mRNA-containing cells were also found in olfactory regions of the cortex and in both the main and accessory olfactory bulbs. AR and ER may modulate nonolfactory sensory information as well since labeled cells were found in regions involved in the central relay of somatosensory information, including the mesencephalic nucleus of the trigeminal nerve, the ventral thalamic nuclear group, and the dorsal horn of the spinal cord. Furthermore, heavily labeled AR mRNA-containing cells were found in the vestibular nuclei, the cochlear nuclei, the medial geniculate nucleus, and the nucleus of the lateral lemniscus, which suggests that androgens may alter the central relay of vestibular and auditory information as well. However, of all the regions involved in sensory processing, the heaviest labeling for AR and ER mRNA was found in areas that relay visceral sensory information such as the nucleus of the solitary tract, the area postrema, and the subfornical organ. We did not detect ER mRNA in brainstem somatic motoneurons, but clearly labeled AR mRNA-containing cells were found in motor nuclei associated with the fifth, seventh, tenth, and twelfth cranial nerves. Similarly, spinal motoneurons contained AR but not ER mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
This paper studies brain morphometry variation associated with XXY males (Klinefelter's syndrome) by using an automated whole-brain volumetric analysis method. The application to 34 XXY males and 62 normal male controls reveals pronounced volume reduction in the brains of XXY males, relative to the brains of normal controls, localized at the insula, temporal gyri, amygdala, hippocampus, cingulate, and occipital gyri. Most of these statistically significant regions are in the gray matter structures, with the exception of one cluster of atrophy involved in white matter structure, i.e., right parietal lobe white matter. Compared to previous findings documented in the literature, our findings provide a better spatial localization of the affected regions. In addition to the reduction of local volume, overall enlargement of ventricles and overall volume reduction of both white matter and gray matter are also found in XXY males.
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