Changes to hypothalamic volume and associated subunits during gender-affirming hormone therapy.

BACKGROUND: Among its pleiotropic properties, gender-affirming hormone therapy (GHT) affects regional brain volumes. The hypothalamus, which regulates neuroendocrine function and associated emotional and cognitive processes, is an intuitive target for probing GHT effects. We sought to assess changes to hypothalamus and hypothalamic subunit volumes after GHT, thereby honouring the region's anatomical and functional heterogeneity. METHODS: Individuals with gender dysphoria and cisgender controls underwent 2 MRI measurements, with a median interval of 145 days (interquartile range [IQR] 128.25-169.75 d, mean 164.94 d) between the first and second MRI. Transgender women (TW) and transgender men (TM) underwent the first MRI before GHT and the second MRI after approximately 4.5 months of GHT, which comprised estrogen and anti-androgen therapy in TW or testosterone therapy in TM. Hypothalamic volumes were segmented using FreeSurfer, and effects of GHT were tested using repeated-measures analysis of covariance. RESULTS: The final sample included 106 participants: 38 TM, 15 TW, 32 cisgender women (CW) and 21 cisgender men (CM). Our analyses revealed group × time interaction effects for total, left and right hypothalamus volume, and for several subunits (left and right inferior tubular, left superior tubular, right anterior inferior, right anterior superior, all p corr < 0.01). In TW, volumes decreased between the first and second MRI in these regions (all p corr ≤ 0.01), and the change from the first to second MRI in TW differed significantly from that in CM and CW in several subunits (p corr < 0.05). LIMITATIONS: We did not address the influence of transition-related psychological and behavioural changes. CONCLUSION: Our results suggest a subunit-specific effect of GHT on hypothalamus volumes in TW. This finding is in accordance with previous reports of positive and negative effects of androgens and estrogens, respectively, on cerebral volumes.

The fMRI correlates of visuo-spatial abilities: sex differences and gender dysphoria.

The contribution of brain regions to visuospatial abilities according to sex differences and gender identity is inconsistently described. One potential explaining factor may be the different tasks employed requiring a variable load of working memory and other cognitive resources. Here we asked to 20 cis and 20 transgender participants to undergo functional Magnetic Resonance Imaging during performance of a judgement line of orientation test that was adapted to explore the basic visuospatial processing while minimizing the working memory load. We show that V1 activation may be viewed as a brain area with enhanced activation in males, regardless of participants' gender identity. On its turn, gender identity exclusively influences the visuospatial processing of extrastriate visual areas (V5) in women with gender dysphoria. They showed enhanced V5 activation and an increased functional connectivity between V5 and V1. Overall our neuroimaging results suggest that the basic visuospatial abilities are associated with different activations pattern of cortical visual areas depending on the sex assigned at birth and gender identity.

Gray matter volume differences between transgender men and cisgender women: A voxel-based morphometry study.

OBJECTIVE: Gender dysphoria (GD) is characterized by distress due to inconsistency between gender identity and biological sex. Individuals with GD often desire to be the other gender, which is called transgender. Although altered brain volumes in transgender people, particularly transgender women, have been reported, the particular brain regions have been inconsistent among studies. This study aimed to investigate neuroanatomical differences in transgender men without physical interventions. METHOD: T1-weighted magnetic resonance images (MRIs) were acquired in 21 transgender men and 21 cisgender women matched for biological sex and age. Whole-brain comparisons using voxel-based morphometry (VBM) were performed to identify gray matter volume (GMV) differences between transgender men and cisgender women. RESULTS: Transgender men showed greater GMV in the right posterior cingulate gyrus (PFWE-corr = 3.06×10-6) and the left occipital pole (PFWE-corr = 0.017) and lower GMV in the left middle temporal gyrus (PFWE-corr = 0.017) than cisgender women. Even after including serum sex hormone levels as covariates, the posterior cingulate gyrus was still significant (PFWE-corr < 0.05). In contrast, the occipital pole and the middle temporal gyrus were not significant after controlling for the sex hormone levels (PFWE-corr > 0.05), especially affected by testosterone but not estradiol. CONCLUSION: These findings suggest that transgender men have altered brain structure. We suggest that larger posterior midline structures may contribute to sensitivity to self-referential processing through altered visual perception in transgender people.

Brain connectivity dynamics in cisgender and transmen people with gender incongruence before gender affirmative hormone treatment.

Large-scale brain network interactions have been described between trans- and cis-gender binary identities. However, a temporal perspective of the brain's spontaneous fluctuations is missing. We investigated the functional connectivity dynamics in transmen with gender incongruence and its relationship with interoceptive awareness. We describe four states in native and meta-state spaces: (i) one state highly prevalent with sparse overall connections; (ii) a second with strong couplings mainly involving components of the salience, default, and executive control networks. Two states with global sparse connectivity but positive couplings (iii) within the sensorimotor network, and (iv) between salience network regions. Transmen had more dynamical fluidity than cismen, while cismen presented less meta-state fluidity and range dynamism than transmen and ciswomen. A positive association between attention regulation and fluidity and meta-state range dynamism was found in transmen. There exist gender differences in the temporal brain dynamism, characterized by distinct interrelations of the salience network as catalyst interacting with other networks. We offer a functional explanation from the neurodevelopmental cortical hypothesis of a gendered-self.

Cortical Gyrification in Transgender Individuals.

Gender incongruence (GI) is characterized by a feeling of estrangement from the own body in the context of self. GI is often described in people who identify as transgender. The underlying mechanisms are unknown. Data from MRI measurements and tests of own body perception triggered us to pose a model that GI in transgender persons (TGI) could be associated with a disconnection within the brain circuits mediating the perception of own body as self. This is a departure from a previous model of sex atypical cerebral dimorphism, introducing a concept that better accords with a core feature of TGI. The present MRI study of 54 hormone naive transmen (TrM), 38 transwomen (TrW), 44 cismen and 41 ciswomen show that cortical gyrification, a metric that reflects early maturation of cerebral cortex, is significantly lower in transgender compared with cisgender participants. This reduction is limited to the occipito-parietal cortex and the sensory motor cortex, regions encoding own body image and body ownership. Moreover, the cortical gyrification correlated inversely with own body-self incongruence in these regions. These novel data suggest that GI in TGI may originate in the neurodevelopment of body image encoding regions. The results add potentially to understanding neurobiological contributors to gender identity.

Brain network interactions in transgender individuals with gender incongruence.

Functional brain organization in transgender persons remains unclear. Our aims were to investigate global and regional connectivity differences within functional networks in transwomen and transmen with early-in-life onset gender incongruence; and to test the consistency of two available hypotheses that attempted to explain gender variants: (i) a neurodevelopmental cortical hypothesis that suggests the existence of different brain phenotypes based on structural MRI data and genes polymorphisms of sex hormone receptors; (ii) a functional-based hypothesis in relation to regions involved in the own body perception. T2*-weighted images in a 3-T MRI were obtained from 29 transmen and 17 transwomen as well as 22 cisgender women and 19 cisgender men. Resting-state independent component analysis, seed-to-seed functional network and graph theory analyses were performed. Transmen, transwomen, and cisgender women had decreased connectivity compared with cisgender men in superior parietal regions, as part of the salience (SN) and the executive control (ECN) networks. Transmen also had weaker connectivity compared with cisgender men between intra-SN regions and weaker inter-network connectivity between regions of the SN, the default mode network (DMN), the ECN and the sensorimotor network. Transwomen had lower small-worldness, modularity and clustering coefficient than cisgender men. There were no differences among transmen, transwomen, and ciswomen. Together these results underline the importance of the SN interacting with DMN, ECN, and sensorimotor networks in transmen, involving regions of the entire brain with a frontal predominance. Reduced global connectivity graph-theoretical measures were a characteristic of transwomen. It is proposed that the interaction between networks is a keystone in building a gendered self. Finally, our findings suggest that both proposed hypotheses are complementary in explaining brain differences between gender variants.

Neuroimaging gender dysphoria: a novel psychobiological model.

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.

Gender Affirmation Surgery: A Primer on Imaging Correlates for the Radiologist.

OBJECTIVE. The purpose of this article is to provide an overview of common gender affirmation surgical therapies, define key anatomy, and describe select complications using multidisciplinary, multimodality approaches. CONCLUSION. Gender affirmation therapy may be tailored to the needs of each individual patient. There are three major categories of gender affirmation surgery: genital reconstruction (comprising vaginoplasty and either metoidioplasty or phalloplasty), body contouring, and maxillofacial contouring (facial feminization or masculinization). If encountered in diagnostic imaging, routine evaluation should take into consideration normal postsurgical anatomy and key associated unique complications.

Imaging of transgender patients: expected findings and complications of gender reassignment therapy.

OBJECTIVES: Gender dysphoria is defined as a conflict between the biological gender and the gender with which the person identifies. Gender reassignment therapy can alter external sexual features to resemble those of the desired gender and are broadly classified into two types, female to male (FTM) and male to female (MTF). In this paper we describe expected findings and complications of gender reassignment therapy. METHODS: Collaborative multi-institutional project supported by Ovarian and Uterine Cancer Disease Focused panel of Society of Abdominal Radiology. RESULTS: Gender dysphoria is defined as a conflict between the biological gender and the gender with which the person identifies. Gender reassignment therapy can alter external sexual features to resemble those of the desired gender and are broadly classified into two types, female to male (FTM) and male to female (MTF). These therapies include hormonal treatment as well as surgical procedures. FTM genital reconstructive therapy includes creation of a neophallus, which can be achieved by metoidioplasty or phalloplasty with mastectomy, along with testosterone administration. MTF gender reassignment surgery includes complete removal of external genitalia with penectomy and orchiectomy, with vaginoplasty, clitoroplasty, labiaplasty, and breast augmentation along with estrogen supplements. CONCLUSION: Surgical techniques alter the standard anatomy and make imaging interpretation challenging if radiologists are unfamiliar with expected post-operative appearances. It is important to recognize the complications related to surgical and non-surgical treatment of gender dysphoria to avoid interpretation errors. Furthermore, increasing the prevalence of transgender patients requires increased sensitivity when interpreting imaging studies to reduce the potential for misdiagnoses in reporting due to frequently incomplete available clinical history.

Cross sex hormone treatment is linked with a reversal of cerebral patterns associated with gender dysphoria to the baseline of cisgender controls.

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 oestrogen 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 oestrogen), significant Cth decreases were observed in the mesial prefrontal and parietal cortices, in both TrM and TrW (vs. controls) - regions showing greater pre-treatment 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.

Intrinsic network connectivity and own body perception in gender dysphoria.

Gender dysphoria (GD) is characterized by incongruence between one's identity and gender assigned at birth. The biological mechanisms of GD are unclear. We investigated brain network connectivity patterns involved in own body perception in the context of self in GD. Twenty-seven female-to-male (FtM) individuals with GD, 27 male controls, and 27 female controls underwent resting state fMRI. We compared functional connections within intrinsic connectivity networks involved in self-referential processes and own body perception -default mode network (DMN) and salience network - and visual networks, using independent components analyses. Behavioral correlates of network connectivity were also tested using self-perception ratings while viewing own body images morphed to their sex assigned at birth, and to the sex of their gender identity. FtM exhibited decreased connectivity of anterior and posterior cingulate and precuneus within the DMN compared with controls. In FtM, higher "self" ratings for bodies morphed towards the sex of their gender identity were associated with greater connectivity of the anterior cingulate within the DMN, during long viewing times. In controls, higher ratings for bodies morphed towards their gender assigned at birth were associated with right insula connectivity within the salience network, during short viewing times. Within visual networks FtM showed weaker connectivity in occipital and temporal regions. Results suggest disconnectivity within networks involved in own body perception in the context of self in GD. Moreover, perception of bodies in relation to self may be reflective rather than reflexive, as a function of mesial prefrontal processes. These may represent neurobiological correlates to the subjective disconnection between perception of body and self-identification.

Male-typical visuospatial functioning in gynephilic girls with gender dysphoria - organizational and activational effects of testosterone.

BACKGROUND: Sex differences in performance and regional brain activity during mental rotation have been reported repeatedly and reflect organizational and activational effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD), before and after 10 months of testosterone treatment, showed male-typical brain activity during a mental rotation task (MRT). METHODS: Girls with GD underwent fMRI while performing the MRT twice: when receiving medication to suppress their endogenous sex hormones before onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-matched control groups participated twice as well. RESULTS: We included 21 girls with GD, 20 male controls and 21 female controls in our study. In the absence of any group differences in performance, control girls showed significantly increased activation in frontal brain areas compared with control boys (pFWE = 0.012). Girls with GD before testosterone treatment differed significantly in frontal brain activation from the control girls (pFWE = 0.034), suggesting a masculinization of brain structures associated with visuospatial cognitive functions. After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed increases in brain activation in areas implicated in mental rotation. LIMITATIONS: Since all girls with GD identified as gynephilic, their resemblance in spatial cognition with the control boys, who were also gynephilic, may have been related to their shared sexual orientation rather than their shared gender identity. We did not account for menstrual cycle phase or contraceptive use in our analyses. CONCLUSION: Our findings suggest atypical sexual differentiation of the brain in natal girls with GD and provide new evidence for organizational and activational effects of testosterone on visuospatial cognitive functioning.