GAHT effects on brain structure

Cross-sectional studies

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). FTMs, on the other hand, differed from cisgender women in the third ventricle and nucleus accumbens, which is consistent with their preferred gender, and differed from cisgender men in the medial temporal lobe structures and cerebellum. FTMs differed from both cismen and ciswomen in fusiform volume. These findings suggest that brain structures are not uniformly influenced by GAHT, and that while some structures become more like those of the preferred gender, others may not, or fall somewhere in the middle. This lends credence to the concept of the gender mosaic, which falls between the two rigidly defined binary gender identities.

A similar finding of region-specific volumetric differences between gender and natal sex was noted in a study with 20 GAHT-naïve MTFs, 20 MTFs treated with GAHT for at least 1 year, 20 cisgender men controls, and 20 cisgender women controls [106]. The cisgender women had lower global brain volumes and regional gray matter volumes in a large portion of the posterior–superior frontal cortex compared with treated MTFs and cisgender men. However, both transgender groups presented lower bilateral insular gray matter volumes than the cisgender women group. Given that the insula is linked to body awareness, one possible interpretation of these results is that this difference in insular volume could be characteristic of MTFs and related to the neural network of body perception, reflecting the distress associated with GD.

Longitudinal studies

Six studies examining the long-term effects of GAHT on the brain structure of transgender individuals (Table 2) have been published [106,107,108,109,110,112]. Overall, these morphological studies have shown that GAHT either feminizes brain structures in MTFs or defeminizes brain structures in FTMs.

Table 2 GAHT effects on brain structure (Structural MRI) Full size table

In MTFs, 4 months of anti-androgen and estrogen GAHT resulted in decreased brain volumes and increased ventricle volumes “toward female proportions” compared with male controls [108, 111]. This decrease in brain volume was ten times more than the average annual decrease in non-transgender adults [111], occurred specifically in the right hippocampal region, and was correlated with changes in progesterone levels [108]. Conversely, FTMs in the Hulshoff Pol et al. [111], study displayed an increase in total brain and hypothalamic volume and decreased ventricle volumes toward male proportions compared with female controls after 4 months of androgen GAHT. These results suggest plastic changes of the transgender adult human brain structure, specifically subcortical structures related to memory and emotional processing, toward the typical size of the identified gender under the influence of GAHT.

Similarly, diffusion tensor imaging (DTI) studies showed that GAHT alters white matter microstructure in FTMs such that they become more like cisgender males and less like their cisgender female counterparts [107, 110, 112]. After at least 7 months of GAHT, fractional anisotropy (FA) values – a measure of connectivity – increased in the right superior longitudinal fasciculus (SLF) and the right corticospinal tract (CST) compared with pre-treatment values among 15 FTMs [107]. This suggests that prescribed exogenous hormones mimic endogenous hormone effects on brain structure as previous work has shown that the right SLF, the forceps minor, and the CST of cisgender males are characterized by significantly higher FA values than those of cisgender females. Interestingly, greater increases in FA values in the SLF and CST were associated with higher free testosterone index values in FTMs even before beginning a course of GAHT, leading to the conclusion that the right SLF in FTMs is inherently masculinized prior to hormone treatment. Testosterone administration further increases (masculinizes) the FA values in the SLF. Likewise, testosterone GAHT in FTMs has been found to change adult hypothalamic microstructure and potentially related neural activity toward “male” patterns [112]. Testosterone-related reductions in mean diffusivity were observed in the lateral hypothalamus, with significant reductions occurring unilaterally after 1 month and bilaterally after 4 months of GAHT. These reductions in mean diffusivity were significantly correlated with GAHT-induced increases in free androgen index and bioavailable testosterone. Additionally, 14.4 ± 6 months of masculinizing GAHT in 22 FTMs was found to increase FA in the posterior portion of the fronto-occipital tract connecting the medial prefrontal cortex (mPFC) and occipital cortex, as well as increase functional connectivity between the mPFC and temporo–parietal junction [110]. Therefore, testosterone GAHT seems to result in functional changes in brain areas potentially linked to self-referential and own-body perception.

In FTMs, at least 6 months of testosterone therapy also increases cortical thickness in posterior regions of the cortex [109], increases bilateral cortical thickness in the insular and superior cortices, and changes the cortico-cortical thickness covariation between the mPFC and occipital cortex [110]. This may indicate some coordinated, testosterone-induced “structural connectivity” changes between frontal, occipital, and temporal regions in FTMs [110]. There is also a significant positive correlation between the serum testosterone and free testosterone index changes and cortical thickness changes in the parieto-occipito-temporal regions among these FTM individuals, as reported by Zubiaurre-Elorza et al. [109]. However, Burke et al. [110] described that the mPFC in FTMs remained unchanged after GAHT, even though the mPFC was thicker in FTMs than in both FCs and MCs to begin with. In MTFs, at least 6 months of estrogen and anti-androgen therapy is associated with decreased cortical thickness, decreased subcortical volumetric measures, and an enlargement of the ventricular system [109].

Taken together, the above six studies suggest that even relatively short-term administration of GAHT influences the gross morphology and white matter microstructure of the brain in such a manner that trans individuals become more like their identified gender with respect to these brain outcomes. Additional research would need to elucidate the specific mechanisms behind these changes as well as the clinical consequences of using GAHT for years instead of months.

GAHT effects on neuronal activation

Cross-sectional studies

Three cross-sectional studies in adults assessed brain activation patterns using fMRI in response to GAHT [112,113,115]. No pre-GAHT baseline measures were obtained and these studies focused primarily on tasks for which there is a known sex-bias in either performance or brain response. Both performance differences as well as brain activation differences between groups are highlighted in Table 3. In a four-group study which included cisgender and transgender male and female adults, cisgender males performed more accurately on a 3D mental rotation task than cisgender females, as expected [115]. Surprisingly, performance as assessed by reaction time among FTMs using high dose testosterone was slower than that of cisgender females suggesting that for this measure, testosterone treatment did not make FTMs more consistently “masculine” in their performance. Again, baseline behavioral differences in performance cannot be ruled out, but worse performance in the testosterone treated group is of concern and should be evaluated using a longitudinal study design.

Table 3 GAHT effects on neuronal activation (fMRI) Full size table

In this same study, brain activation outcomes as measured by the blood oxygen level dependent (BOLD) signal during performance of the mental rotation tasks suggests that trans and cisgender individuals differ in several brain regions when trans individuals have undergone GAHT. Typically, parietal activation during task performance differs by sex, with greater activation among cisgender males than cisgender females [116, 117]. Although the expected occipito-parietal-frontal pattern of brain activation during mental rotation was observed in all groups, parietal activation was less in MTF individuals compared with cisgender males. In addition, number of months of GAHT was negatively correlated with parietal activation among MTF participants. While it is tempting to conclude from these data that GAHT “de-masculinizes” parietal activation, one must remember that these differences between cis and trans XY chromosome individuals could have been present at baseline, prior to GAHT. Interestingly, FTM individuals in this study did not differ from either control group. In a smaller study of MTFs using estrogen, MTFs not using estrogen, and cisgender male controls, there were no group differences in BOLD signal during task performance. However, MTFs relied on verbal strategies for task performance to a greater degree than cisgender males, providing additional support for baseline differences in cognition between MTFs and cisgender male controls. This finding is further indication that transgender individuals have cognitive processes that align with their gender identity rather than natal sex. In contrast, those in both transgender groups showed greater temporo-occipital activation than male controls [114]. These findings are based upon 11 individuals in each group and must therefore be considered preliminary and interpreted with caution.

In a small cross-sectional study of transmen and women using long-term GAHT (FTM for a mean duration of 84.52 months, MTF for 81.56 months) compared with cisgender men and cisgender women, differences between FTMs and cisgender female controls were reported on both intensity of spontaneous resting-state activity and local synchronization of specific brain areas in the frontal cortex, medial temporal lobe, and cerebellum [113]. For FTMs, resting-state activity in the cerebellum and frontal cortex was correlated with circulating androgen levels.

Longitudinal studies

Again, longitudinal studies of GAHT on brain activation during task performance (Table 3) are uncommon and focus solely on tasks with known sex differences in performance (i.e., verbal fluency and mental rotation). Sommer et al. [118] reported that 3 months of GAHT may influence cerebral activation patterns during language and mental rotation tasks in transgender individuals (MTF = 8, FTM = 6), but lateralization of language and spatial functioning is stable. The total language-related activation increased after GAHT compared with baseline in both FTMs and MTFs (p = 0.08), and correlated to post-treatment serum estradiol levels (p = 0.05). However, activation during mental rotation did not increase during treatment (p = 0.34), but post-GAHT testosterone levels correlated with total activation during mental rotation (p = 0.01). The investigators did not conduct whole brain analyses of effects of sex steroid treatment on activation patterns for either task, but instead focused on task-activated ROIs.

Another study also focused on whether activation patterns in trans people were either more sex-typical or sex-atypical, but this time with respect to resting state functional connectivity patterns [119]. Similar functional connectivity patterns were found in 21 FTMs, 13 MTFs, 20 cisgender female controls, and 17 cisgender male controls within the default mode (DMN), salience (SN), and working memory (WMN) networks. However, cisgender males displayed significantly greater functional connectivity in the right caudate nucleus within the right WMN compared with cisgender females. MTFs and FTMs did not differ significantly in functional connectivity, and they did not differ significantly from either of the cisgender groups as well. Functional connectivity also did not appear to be affected by 4 months of GAHT in MTFs and FTMs or by circulating sex steroids in the cisgender individuals. Therefore, it is possible that the right WMN undergoes sexually dimorphic differentiation between cisgender males and females, but this differentiation is reduced in transgender individuals.

Performance on measures of empathy and emotional processing are also known to vary by sex [119,120,122]. Empathy scores and resting state functional connectivity (rsFC) measurements were examined in male and female controls as well as both MTFs and FTMs prior to, and after 4 weeks and 4 months of GAHT [123]. MTFs differed at baseline from all other groups in a rsFC network around the supramarginal gyrus, a region important for interpersonal emotion processing, but became more similar to the other groups over the course of GAHT administration. While taking GAHT was not correlated with rsFC in this network, a GAHT-independent association between empathy scores and rsFC was found.

GAHT effects on cognitive performance

Cross-sectional studies

Estrogen therapy in MTFs has been shown to impact performance on some (paired associate learning: immediate and delayed recall), but not all (mental rotation, controlled associates) tasks for which there are typical sex differences and in the direction that one would expect. No effect was observed on at least one task (digit symbol) for which there is no gender bias among cisgender individuals (Table 4) [124]. In another sample, no differences in mental rotation performance were observed between cisgender men, MTF individuals naïve to GAHT, and MTF individuals after at least 6 months of GAHT (Table 3) [113]. However, definitive conclusions from this study are limited given its small sample size, cross-sectional methodology, and lack of cisgender female control group.

Table 4 GAHT effects on cognitive performance Full size table

FTM transgender individuals on androgen treatment for at least 6 months performed better than FTM subjects off treatment on the same two visual memory tasks, but no differences were noted for a verbal memory test [125]. Like the studies above, this finding signifies some correlation between GAHT and alignment of performance to gender identity as opposed to natal sex. While their performance on the male-biased task improved, no negative effect was observed for performance on the female-biased task.

With regard to cerebral lateralization, which has been shown to vary between the sexes in cis-gender populations, MTF transgender subjects who received at least 3 months of GAHT demonstrated less exclusive right-handedness as opposed to cisgender control males, but did not differ significantly in cognitive tests that have been shown to favor one sex over the other (identical pictures, 3D mental rotation, building memory). No group differences were found on the visual-split-field or cognitive tasks [126]. The cognitive test battery included three sex-specific tasks: a female-biased perceptual speed test, a map memory test, and a male-biased mental rotations test. Furthermore, there are no direct associations between endocrine measures (elevated estradiol and suppressed testosterone concentrations), lateralization, and cognition. However, this study suffers from methodological missteps, as it did not control for demographic characteristics such as age at transition, sexual orientation, or marital status. Furthermore, the data would have been stronger had untreated MTF transgender individuals been used as controls instead of cisgender males.

Longitudinal studies

Cognitive performance also seems to be affected by GAHT. Most studies (Table 4) suggest that GAHT in FTMs enhances performance on visual memory [125] and 3D spatial memory tasks [127, 128], and worsens verbal fluency [128, 129] and arithmetic answering strategies [130].

A small sample of FTM transgender participants (n = 14) tested before and after 6 months of androgen treatment showed significant improvement in their performance on a visual memory task, a skill that generally tends to favor males [125]. However, androgen GAHT did not have any influence on verbal memory, which is a domain that typically favors females. This indicates that androgens may have an activational effect on visual memory in FTM transgender individuals, causing greater alignment with the performance of their identified gender. However, this study lacked an untreated transgender control group for comparison.

An investigation on whether GAHT influenced test answering strategy found no baseline differences between untreated gender dysphoric (GD) males and cisgender male controls in number of questions left blank on an arithmetic test. In subsequent retests 3 and 12 months post-GAHT initiation for the GD group, cismale controls appeared to gain confidence and leave fewer items unanswered than the transgender group, indicating that GAHT is associated with a lack of adjustment in answering strategy in MTF individuals. No difference was found between FTM individuals and cisgender control females at any time point [131].

A pronounced effect of androgen treatment was found on spatial ability in FTM subjects over a period of 18 months [127]. Untreated MTF individuals originally performed better on visuo-spatial tasks than untreated FTMs, reflecting the typical male bias on spatial ability. However, after about 10 months of GAHT, the sex difference reversed, with both groups performing more in line with their identified gender. This study demonstrates that testosterone has an enhancing effect on spatial ability performance, but no deteriorating effect on verbal fluency in FTMs.

There is further evidence that androgens quickly affect cognitive performance in FTM individuals [128]. For example, enhanced spatial ability and deteriorating verbal fluency are clearly associated with as little as 3 months of androgen treatment, though there was no control group for comparison in this sample of 22 FTM participants. Later, this study followed up with an even bigger sample of FTM and MTF transgender individuals and worked with a large battery of tests on aggression, sexual motivation, and cognitive functioning [129]. Administration of androgens to FTMs over 3 months was strongly associated with an increase in aggression, sexual arousal, and spatial ability, as well as a decrease in verbal fluency. Conversely, androgen deprivation in MTFs was linked to a decrease in anger and aggression, sexual arousal, and spatial ability, as well as an increase in verbal fluency. These findings offer support for the hypothesis that GAHT can affect gender-specific behaviors, likely as a result of specific brain changes.

Studies on the cognitive performance effects of GAHT overwhelmingly support the gender-affirming effect on cognitive tasks that have shown well-established sex differences. Androgens enhance “male-like” characteristics among FTMs and are associated with decreases in performance on typically male-dominated cognitive tasks among MTFs. In contrast, longitudinal studies suggest that the opposite is true for hormone manipulations used by males transitioning to female. MTFs show a reduction in performance on 3D visuospatial tasks [127, 129] and increased verbal fluency. Relatively few studies have concluded that GAHT results in no change in verbal or visual spatial performance among those transitioning from one gender to the other [25, 131, 132].

No differential effect on six cognitive abilities (perception, arithmetic, rotation, visualization, logic, and verbalization) was found between untreated cisgender control subjects and gender dysphoric patients tested before initiating GAHT and 3 and 12 months after [131]. Both the gender dysphoric individuals and controls show an identical time-dependent improvement in cognitive performance, perhaps implying that GAHT does not change sex-sensitive cognitive performance in gender dysphoric patients. However, this conclusion is weakened by the fact that the study used cisgender individuals as the control rather than untreated gender dysphoric patients.

In MTF individuals, there is reportedly no evidence that duration or dosage of treatment over the course of 3–12 months was related to any verbal fluency, visual-spatial, verbal memory, and visual memory outcomes [132]. These results suggest that MTF transgender patients do not need to anticipate any appreciable changes in sex-typed aspects of memory or cognitive function due to estrogen treatment.

Van Goozen et al. [25] reported evidence of an organizing effect of sex hormones on cognitive functioning and visuospatial ability in transgender individuals. Performance on four different visuospatial tests revealed a linear increase in accuracy from cisgender female controls, to FTMs (before GAHT), to MTFs (before GAHT), and finally to cisgender male controls. Furthermore, after 14 weeks of GAHT, there was no effect of sex hormones on the visuospatial ability of transgender individuals, highlighting the lack of activational effects of short-term GAHT with respect to this particular cognitive task. Using a medium-sized sample of ~20 for each transgender group, this study used standardized levels of GAHT, which makes for more reliable conclusions across individuals.

GAHT effects on psychology and behavior

Studies of mental health among transgender people consistently report alarmingly elevated rates of anxiety, depression, and suicide risk [11, 137,133,134,135,136,138]. Though behavioral health risks generally decline with GAHT [102], risk remains elevated above that of cisgender individuals matched for age, natal sex, and new assigned sex [138]. No consensus has been reached regarding the sex specificity of psychopathology; while some studies report higher incidence of psychopathology in transgender women relative to transgender men [125, 140, 141], one study suggested the opposite [142]. These symptoms of psychopathology are thought to be the result of distress stemming from incongruence between appearance and gender identity, as well as social rejection – prejudice, discrimination, and stigma [134, 143]. Consequently, many transgender people face greater socioeconomic barriers and disproportionately higher rates of sexual abuse and assault.

Although being trans is associated with increasing mental health problems due to social circumstances, there is now growing evidence suggesting that gender-affirming social support and GAHT are linked to better mental health outcomes. A 2-year follow-up study observed a significant reduction (p < 0.01) in body dissatisfaction and GD after 3 months of GAHT in MTFs and FTMs, as measured by the Body Uneasiness Test and Gender Identity/GD Questionnaire. In addition, 12 months of GAHT is significantly associated with psychopathology reduction (p < 0.001) as assessed by the Symptoms Checklist (SCL-90R) [144]; significantly lower self-reported anxiety, depression, and global psychological symptoms, as well as psychiatric distress and functional impairment [11]; and greater self-esteem, less severe depression symptoms, and higher “psychological-like” dimensions of quality of life (psychological wellbeing and taking care of oneself) [145]. The degree to which these effects of GAHT are secondary to receiving social and medical support for one’s decision to transition, enhancing congruence between gender identity and physical appearance, or modulating brain neurochemistry, structure and function with exogenous sex steroids is not known.

Though GAHT is thought to enhance overall well-being, there are different effects of estrogen versus testosterone therapies. Androgen GAHT in FTMs has been shown to significantly enhance anger proneness, aggressive tendencies, sexual arousability, and motivation, while feminizing treatment is associated with the reverse in MTFs [129]. Anti-androgenic therapy, using the pure antiandrogen nilutamide (Anandron®, Sanofi Aventis) and no estradiol, reduced sexual arousal and sexual desire after 8 weeks in MTFs [146]. Nilutamide functions by blocking the biological effects of androgens produced by the organism through competition at the level of hormone receptors in androgen-sensitive tissues (skin, prostate, pituitary, central nervous system, etc.). MTFs receiving 12 or more months of estradiol and progesterone were less likely to exhibit scores reflective of psychopathology on the Minnesota Multiphasic Personality Inventory (MMPI) compared with untreated gender dysphoric males [147]. Longer periods of feminizing treatment are associated with greater emotional adjustment scores on the MMPI.

In summary, the safety of GAHT and efficacy with respect to improving psychological well-being is encouraging, particularly for MTFs. However, this literature is limited greatly by studies with small sample sizes and extensive variations in methodology (i.e., age at which GAHT was initiative, duration of treatment, pharmacologic regimen, documentation of hormone levels post GAHT).

Summary and future research directions

The extant literature describing neuroimaging outcomes among transgender populations focuses primarily on questions of how similar the brain of the transgender individual is to their natal sex and whether use of GAHT enhances similarity between the brain of their natal sex and that of their desired gender. Most, but not all studies, indicate that the transgender individual is more similar to their preferred gender with respect to cerebral and gray matter volume and performance on gender-biased cognitive tasks (e.g., verbal and spatial tasks). There is a signal for GAHT to enhance the transgender individuals’ similarity to their preferred gender.

While these outcomes may have been of interest in previous decades, this information is not particularly useful or relevant to most transgender individuals and their health care providers with respect to their day-to-day quality of life. As discussed earlier, the prefrontal cortex – the site of estrogen modulation of executive function – is necessary for cognitive processes such as sustained attention, working memory, organization, and planning. It is well known that premature loss of estradiol among cisgender women leads to significant risk for medical comorbidities of aging including increased risk for executive dysfunction [18] and dementia [63]. Whether the same is true for FTM individuals is not known, but high dose testosterone variably diminishes endogenous estradiol production in FTMs, leaving the individual in a relative hypoestrogenic state. Therefore, the long-term effects of hypoestrogenism in the context of hypertestoteronism should be investigated. If the logic behind PCOS and lower levels of estrogen post-menopause were applied to current GAHT, then one would expect that suppression of estrogen levels and increased testosterone levels in FTM individuals would impact cognition and possibly adversely impact psychological well-being, increasing irritability and impulsivity [73]. While cisgender males aromatize testosterone to estradiol in the CNS [148], it is not known whether FTM transgender individuals also aromatize testosterone to estradiol sufficiently to estrogenize the brain. Finally, it is possible that the organizational effects of gonadal steroids in utero for the transgender individual would create a scenario that alters their need for various gonadal steroids for optimal brain health across the lifespan.

Currently, investigations on the neuroanatomical changes in transgender individuals after prolonged GAHT are too few in number to examine the putative effects of GAHT on neuroanatomy. To date, there are no studies assessing the effects of GAHT on functional network connectivity. Recent findings from our laboratory indicate enduring impact of childhood adversity on within network connectivity among early postmenopausal cis-gender women [17]. That estradiol treatment enhanced within network connectivity among those women with high levels of childhood adversity, but had no appreciable impact on those with low levels of childhood adversity, suggests a differential impact of gonadal steroids on brain structure and function based upon adverse exposures during critical windows of development. This would seem particularly relevant to the transgender community as their exposures to childhood adversity can be substantial.

Application of fMRI to the investigation of the transgender brain and effects of GAHT is in its infancy, but holds promise as a tool to determine regional and network effects of GAHT. Gonadal steroids have a profound impact on brain structure, function, regional connectivity, and neurochemistry [16] which underpin executive functions, affect, and reward processing. It is critical that future research considers these cognitive domains and focus substantially less on “sexually dimorphic” cognitive processes which typically show sex differences among cisgender individuals. We would argue that learning and memory, the capacity to organize, focus and manage one’s affect as well as appreciate the rewarding nature of appetitive stimuli is critical to long-term health and quality of life. Special attention should be paid to effects of GAHT on the neural correlates of behavior during the transition process since research to date has not examined emotional or affective responding despite high rates of affective disorders in this population.

The currently available structural MRI studies also contain small numbers of transgender adults and even fewer transgender adolescents. Given the profound impact of post-pubertal levels of and fluctuations in gonadal steroids on brain structure and function, data obtained from transgender adults who are many years post-puberty should not be extrapolated to adolescents who choose to block their transition to puberty. Similarly, individual factors such as socioeconomic status, race/ethnicity, education, exposures to childhood adversity, and lifetime stress or trauma could dramatically impact central nervous system function during critical windows of development leading to risk or resilience to cognitive and mood changes during hormonal manipulations [2, 3, 149].

Furthermore, most studies to date have been cross-sectional in nature, included small samples, and examined the effects of short-term GAHT (≤18 months), though most individuals will use GAHT for decades. There are no randomized controlled trials of GAHT. Therefore experimental, longitudinal studies (>18 months) must be prioritized, using neuroimaging methods to focus on the effects of GAHT on brain regions/networks directly related to accomplishing daily tasks, to allow direct comparison between baseline and post-GAHT values. And given that the current literature has almost exclusively treated gender as a binary thus far (e.g., a person can be either male, female, FTM, or MTF), future studies should consider gender as a spectrum to be more inclusive to those who are transgender, gender non-binary, gender non-conforming, gender fluid, etc. In particular, research should seek to include transfeminine and especially transmasculine individuals. Considering the majority of transgender research studies thus far have looked at MTFs, there are many unanswered questions regarding the potential impact of high dose testosterone on long term brain health of FTM and transmasculine patients, with significant causes for concern, as mentioned above.

With more people identifying as transgender and requesting GAHT, the field of transgender health needs to be able to provide better information about the potential brain effects of long-term GAHT. Importantly, the bulk of the data suggests that self-reported level of function and quality of life is improved with GAHT, though still below that of cisgender individuals. The precise clinical relevance of neuroanatomical changes after GAHT remains unknown. Characterizing the different modulations associated with GAHT is critical, considering reports of physiological risk with hormonal treatment and rates of psychopathology in transgender individuals. Future studies are required to replicate previous findings and examine whether these neuroanatomical differences are associated with functional or cognitive changes. In summary, we recommend that upcoming brain imaging studies examine long-term (years) use of GAHT, study sufficiently large samples to address potential modifiers of hormone response (e.g., early life stress, hormone levels), focus on cognitive domains crucial for executive function, broaden gender definitions beyond binarized male and female identities, and enroll more FTM and transmasculine individuals.