White matter microstructure in transmasculine and cisgender adolescents: A multiparametric and multivariate study.

Adolescence is a sensitive developmental period for neural sex/gender differentiation. The present study used multiparametric mapping to better characterize adolescent white matter (WM) microstructure. WM microstructure was investigated using diffusion tensor indices (fractional anisotropy; mean, radial, and axial diffusivity [AD]) and quantitative T1 relaxometry (T1) in hormone therapy naïve adolescent cisgender girls, cisgender boys, and transgender boys (i.e., assigned female at birth and diagnosed with gender dysphoria). Diffusion indices were first analyzed for group differences using tract-based spatial statistics, which revealed a group difference in AD. Thus, two multiparametric and multivariate analyses assessed AD in conjunction with T1 relaxation time, and with respect to developmental proxy variables (i.e., age, serum estradiol, pubertal development, sexual attraction) thought to be relevant to adolescent brain development. The multivariate analyses showed a shared pattern between AD and T1 such that higher AD was associated with longer T1, and AD and T1 strongly related to all five developmental variables in cisgender boys (10 significant correlations, r range: 0.21-0.73). There were fewer significant correlations between the brain and developmental variables in cisgender girls (three correlations, r range: -0.54-0.54) and transgender boys (two correlations, r range: -0.59-0.77). Specifically, AD related to direction of sexual attraction (i.e., gynephilia, androphilia) in all groups, and T1 related to estradiol inversely in cisgender boys compared with transgender boys. These brain patterns may be indicative of less myelination and tissue density in cisgender boys, which corroborates other reports of protracted WM development in cisgender boys. Further, these findings highlight the importance of considering developmental trajectory when assessing the subtleties of neural structure associated with variations in sex, gender, and sexual attraction.

Cortical Structure Differences in Relation to Age, Sexual Attractions, and Gender Dysphoria in Adolescents: An Examination of Mean Diffusivity and T1 Relaxation Time.

Recent research found that the combination of masculine gender identity and gynephilia was associated with cortical T1 relaxation time, which is considered to reflect gray matter density. We hypothesized that mean diffusivity (MD), a diffusion tensor imaging metric that reflects the degree to which water movement is free versus constrained, in combination with T1 relaxation time would provide further insight regarding cortical tissue characteristics. MD and T1 relaxation time were measured in 76 cortical regions in 15 adolescents assigned female at birth who experience gender dysphoria (GD AFAB) and were not receiving hormone therapy, 17 cisgender girls, and 14 cisgender boys (ages 12-17 years). Sexual orientation was represented by the degree of androphilia-gynephilia and the strength of sexual attraction. In multivariate analyses, cortical T1 relaxation time showed a weak but statistically significant positive association with MD across the cortex, suggesting that macromolecule-rich cortical tissue also tends to show water movement that is somewhat more constrained. In further multivariate analyses, in several left frontal, parietal, and temporal regions, the combination of shorter T1 relaxation time and faster MD was associated with older age and greater gynephilia in GD AFAB individuals and cisgender boys and with stronger attractions in cisgender boys only. Thus, for these cortical regions in these groups, older age, gynephilia, and stronger attractions (cisgender boys only) were associated with macromolecule-rich tissue in which water movement was freer-a pattern that some prior research suggests is associated with greater cell density and size. Overall, this study indicates that investigating T1 relaxation time and MD together can further inform how cortical gray matter tissue characteristics relate to age and psychosexuality.

Inter-Network Brain Functional Connectivity in Adolescents Assigned Female at Birth Who Experience Gender Dysphoria.

Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Brain functional connectivity in adolescents who experience GD may be associated with experienced gender (vs. assigned sex) and/or brain networks implicated in own-body perception. Furthermore, sexual orientation may be related to brain functional organization given commonalities in developmental mechanisms proposed to underpin GD and same-sex attractions. Here, we applied group independent component analysis to resting-state functional magnetic resonance imaging (rs-fMRI) BOLD timeseries data to estimate inter-network (i.e., between independent components) timeseries correlations, representing functional connectivity, in 17 GD adolescents assigned female at birth (AFAB) not receiving gender-affirming hormone therapy, 17 cisgender girls, and 15 cisgender boys (ages 12-17 years). Sexual orientation was represented by degree of androphilia-gynephilia and sexual attractions strength. Multivariate partial least squares analyses found that functional connectivity differed among cisgender boys, cisgender girls, and GD AFAB, with the largest difference between cisgender boys and GD AFAB. Regarding sexual orientation and age, the brain's intrinsic functional organization of GD AFAB was both similar to and different from cisgender girls, and both differed from cisgender boys. The pattern of group differences and the networks involved aligned with the hypothesis that brain functional organization is different among GD AFAB (vs. cisgender) adolescents, and certain aspects of this organization relate to brain areas implicated in own-body perception and self-referential thinking. Overall, brain functional organization of GD AFAB was generally more similar to that of cisgender girls than cisgender boys.

Suicidality in clinic-referred transgender adolescents.

Gender and sexually diverse adolescents have been reported to be at an elevated risk for suicidal thoughts and behaviors. For transgender adolescents, there has been variation in source of ascertainment and how suicidality was measured, including the time-frame (e.g., past 6 months, lifetime). In studies of clinic-referred samples of transgender adolescents, none utilized any type of comparison or control group. The present study examined suicidality in transgender adolescents (M age, 15.99 years) seen at specialty clinics in Toronto, Canada, Amsterdam, the Netherlands, and London, UK (total N = 2771). Suicidality was measured using two items from the Child Behavior Checklist (CBCL) and the Youth Self-Report (YSR). The CBCL/YSR referred and non-referred standardization samples from both the U.S. and the Netherlands were used for comparative purposes. Multiple linear regression analyses showed that there was significant between-clinic variation in suicidality on both the CBCL and the YSR; in addition, suicidality was consistently higher among birth-assigned females and strongly associated with degree of general behavioral and emotional problems. Compared to the U.S. and Dutch CBCL/YSR standardization samples, the relative risk of suicidality was somewhat higher than referred adolescents but substantially higher than non-referred adolescents. The results were discussed in relation to both gender identity specific and more general risk factors for suicidality.

Validation of the Chinese Version of the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults.

BACKGROUND: The number of individuals with potential gender dysphoria (GD) being referred to specialized gender identity clinics or programs is increasing internationally; these cases are initially screened using the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults (GIDYQ-AA). AIM: The current study aimed to assess the psychometric properties of the GIDYQ-AA in a sample of adolescents and young adults from China. METHODS: A cross-sectional study was conducted in October 2020. Sociodemographic information of the participants was first collected. Participants then completed the GIDYQ-AA, the Generalized Anxiety Disorder-7 scale, the Patient Health Questionnaire-9, and a suicidal ideation assessment. A total of 2,533 participants with a mean age of 19.30 (SD = 1.19) years were recruited. Of the participants, 841 (33.2%) were cis men, 1,589 (62.7%) were cis women, 66 (2.6%) self-identified as transgender, 17 (0.7%) self-identified as non-binary, and 20 (0.8%) self-identified as gender queer. RESULTS: The GIDYQ-AA had high internal consistency with a Cronbach's alpha = 0.89. Exploratory factor analysis showed that the GIDYQ-AA had a four-factor structure in China. The GIDYQ-AA was significantly correlated with anxiety symptoms (r = -0.32, P < .01), depressive symptoms (r = -0.33, P < .01), and suicidal ideation (r = -0.20, P < .01). CLINICAL TRANSLATION: The Chinese version of GIDYQ-AA is a useful measurement with high practical value, which could promote the assessment and research of GD across China or among Chinese migrants in other countries. STRENGTHS AND LIMITATIONS: This is the first study assessing the psychometric properties of the GIDYQ-AA in Chinese adolescents and young adults. The convergent and divergent validity of the GIDYQ-AA were not examined due to the unavailability of data. Also, the sample did not have an equal distribution of male to males and female to females. CONCLUSION: The Chinese version of GIDYQ-AA is a useful measure, which could promote both the assessment and research of GD in the Chinese population. Wang Y, Feng Y, Su D, et al. Validation of the Chinese Version of the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults. J Sex Med 2021;18:1632-1640.

A Follow-Up Study of Boys With Gender Identity Disorder.

This study reports follow-up data on the largest sample to date of boys clinic-referred for gender dysphoria (n = 139) with regard to gender identity and sexual orientation. In childhood, the boys were assessed at a mean age of 7.49 years (range, 3.33-12.99) at a mean year of 1989 and followed-up at a mean age of 20.58 years (range, 13.07-39.15) at a mean year of 2002. In childhood, 88 (63.3%) of the boys met the DSM-III, III-R, or IV criteria for gender identity disorder; the remaining 51 (36.7%) boys were subthreshold for the criteria. At follow-up, gender identity/dysphoria was assessed via multiple methods and the participants were classified as either persisters or desisters. Sexual orientation was ascertained for both fantasy and behavior and then dichotomized as either biphilic/androphilic or gynephilic. Of the 139 participants, 17 (12.2%) were classified as persisters and the remaining 122 (87.8%) were classified as desisters. Data on sexual orientation in fantasy were available for 129 participants: 82 (63.6%) were classified as biphilic/androphilic, 43 (33.3%) were classified as gynephilic, and 4 (3.1%) reported no sexual fantasies. For sexual orientation in behavior, data were available for 108 participants: 51 (47.2%) were classified as biphilic/androphilic, 29 (26.9%) were classified as gynephilic, and 28 (25.9%) reported no sexual behaviors. Multinomial logistic regression examined predictors of outcome for the biphilic/androphilic persisters and the gynephilic desisters, with the biphilic/androphilic desisters as the reference group. Compared to the reference group, the biphilic/androphilic persisters tended to be older at the time of the assessment in childhood, were from a lower social class background, and, on a dimensional composite of sex-typed behavior in childhood were more gender-variant. The biphilic/androphilic desisters were more gender-variant compared to the gynephilic desisters. Boys clinic-referred for gender identity concerns in childhood had a high rate of desistance and a high rate of a biphilic/androphilic sexual orientation. The implications of the data for current models of care for the treatment of gender dysphoria in children are discussed.

A Multi-Modal MRI Analysis of Cortical Structure in Relation to Gender Dysphoria, Sexual Orientation, and Age in Adolescents.

Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Sex-differentiated brain regions are hypothesized to reflect the experienced gender in GD and may play a role in sexual orientation development. Magnetic resonance brain images were acquired from 16 GD adolescents assigned female at birth (AFAB) not receiving hormone therapy, 17 cisgender girls, and 14 cisgender boys (ages 12-17 years) to examine three morphological and microstructural gray matter features in 76 brain regions: surface area (SA), cortical thickness (CT), and T1 relaxation time. Sexual orientation was represented by degree of androphilia-gynephilia and sexual attraction strength. Multivariate analyses found that cisgender boys had larger SA than cisgender girls and GD AFAB. Shorter T1, reflecting denser, macromolecule-rich tissue, correlated with older age and stronger gynephilia in cisgender boys and GD AFAB, and with stronger attractions in cisgender boys. Thus, cortical morphometry (mainly SA) was related to sex assigned at birth, but not experienced gender. Effects of experienced gender were found as similarities in correlation patterns in GD AFAB and cisgender boys in age and sexual orientation (mainly T1), indicating the need to consider developmental trajectories and sexual orientation in brain studies of GD.

Mental Health Status of Cisgender and Gender-Diverse Secondary School Students in China.

Importance: Transgender or gender nonconforming (TGNC) adolescents face a wide range of physical and mental health concerns. However, there has been no school-based study to explore the prevalence and mental health status of these adolescents in mainland China. Objectives: To assess the mental well-being of TGNC adolescents in China by comparing them with their cisgender peers. Design, Setting, and Participants: This was a cross-sectional survey study. Of the 12 354 adolescents who completed the questionnaire, 246 did not specify to which sex they identified and were therefore excluded from further analysis. Therefore, a total of 12 108 adolescents were included from 18 secondary schools in Suzhou city, China, from June 2019 to July 2019. Participants provided consent and answered questions on sex assigned at birth and gender identity. Main Outcomes and Measures: All participants completed questionnaires, including the Patient Health Questionnaire for the measurement of depressive symptoms, a generalized anxiety disorder screening, the Pittsburgh Sleep Quality Index, and a self-harm and suicide risk checklist. The frequency of being bullied at school was also measured. Participants who reported their perceived gender as the opposite of their assigned sex at birth were classified as transgender, those who identified as neither male nor female were classified as nonbinary, and those who were not sure about their perceived gender were classified as questioning. All of these participants were categorized as TGNC adolescents. Results: A total of 12 108 adolescents (mean [SD] age, 15.8 [1.0] years; 6518 [53.8%] assigned male at birth [AMAB]) participated in the study. Of the 6518 participants AMAB in the sample, 5855 (89.8%) were classified as cisgender boys, 208 (3.2%) as transgender girls (transgender youth who perceive their current gender identity to be female), 138 (2.1%) as nonbinary youth AMAB, and 317 (4.9%) as questioning youth AMAB. Of the 5590 participants assigned female at birth (AFAB), 4142 (74.1%) were classified as cisgender girls, 861 (15.4%) as transgender boys (transgender youth who perceive their current gender identity to be male), 112 (2.0%) as nonbinary youth AFAB, and 475 (8.5%) as questioning youth AFAB. Compared with cisgender adolescents, TGNC adolescents reported significantly higher health concerns including lower overall health (t11 872 = -7.36; P < .001), poorer sleep (t11 683 = 10.49; P < .001), higher depression and anxiety symptoms (t11 830 = 12.43 and t11 847 = 11.47, respectively; P < .001), and higher rate of self-harm and suicide ideation (t11 860 = 12.22; P < .001). The TGNC youth who were AMAB were also more likely to be bullied at school than cisgender boys (transgender girls: odds ratio [OR], 2.34 [95% CI, 1.64-3.33]; nonbinary youth AMAB: OR, 1.97 [95% CI, 1.23-3.16]; and questioning youth AMAB: OR, 1.95 [95% CI, 1.43-2.67]). The TGNC groups also reported significantly greater amounts of thoughts of self-harm (transgender girls: OR, 3.06 [95% CI, 2.24-4.19]; transgender boys: OR, 4.06 [95% CI, 3.47-4.74]; nonbinary youth AMAB: OR, 2.86 [95% CI, 1.93-4.23]; nonbinary youth AFAB: OR, 3.71 [95% CI, 2.46-5.59]; questioning youth AMAB: OR, 2.61 [95% CI, 1.98-3.44]; and questioning youth AFAB: OR, 3.35 [95% CI, 2.70-4.16]), thoughts of suicide (transgender girls: OR, 3.93 [95% CI, 2.88-5.38]; transgender boys: OR, 3.71 [95% CI, 3.10-4.21]; nonbinary youth AMAB: OR, 3.13 [95% CI, 2.11-4.63]; nonbinary youth AFAB: OR, 3.78 [95% CI, 2.50-5.71]; questioning youth AMAB: OR, 2.53 [95% CI, 1.93-3.33]; and questioning youth AFAB: OR, 3.94 [95% CI, 3.17-4.88]), suicide plan formation (transgender girls: OR, 4.44 [95% CI, 2.88-6.83]; transgender boys: OR, 2.66 [95% CI, 2.03-3.50]; nonbinary youth AMAB: OR, 5.36 [95% CI, 3.22-8.93]; nonbinary youth AFAB: OR, 4.06 [95% CI, 2.25-7.30]; and questioning youth AFAB: OR, 2.36 [95% CI, 1.63-3.43]), deliberate self-harm during the last month (cisgender girls: OR, 1.49 [95% CI, 1.33-1.68]; transgender girls: OR, 2.74 [95% CI, 1.93-3.91]; transgender boys: OR, 3.06 [95% CI, 2.57-3.66]; nonbinary youth AMAB: OR, 2.56 [95% CI, 1.66-3.94]; nonbinary youth AFAB: OR, 3.06 [95% CI, 1.95-4.81]; questioning youth AMAB: OR, 2.14 [95% CI, 1.56-2.92]; and questioning youth AFAB: OR, 2.53 [95% CI, 2.00-3.01]), and attempts of suicide (transgender girls: OR, 4.35 [95% CI, 2.88-6.56]; transgender boys: OR, 2.92 [95% CI, 2.26-3.76]; nonbinary youth AMAB: OR, 3.94 [95% CI, 2.36-6.55]; nonbinary youth AFAB: OR, 3.06 [95% CI, 1.67-5.63]; questioning youth AMAB: OR, 2.61 [95% CI, 1.73-3.94]; and questioning youth AFAB: OR, 1.93 [95% CI, 1.33-2.81]) compared with cisgender boys. Conclusions and Relevance: Results of this cross-sectional survey study suggest poor mental health status among TGNC adolescents in China; in addition, findings suggest a compelling need for researchers, practitioners, and policy makers to address these mental health problems. Particular school-based interventions are recommended to support the mental health well-being of TGNC adolescents.

Debate: Different strokes for different folks.

A gender social transition in prepubertal children is a form of psychosocial treatment that aims to reduce gender dysphoria, but with the likely consequence of subsequent (lifelong) biomedical treatments as well (gender-affirming hormonal treatment and surgery). Gender social transition of prepubertal children will increase dramatically the rate of gender dysphoria persistence when compared to follow-up studies of children with gender dysphoria who did not receive this type of psychosocial intervention and, oddly enough, might be characterized as iatrogenic. Parents who bring their children for clinical care hold different philosophical views on what is the best way to help reduce the gender dysphoria, which require both respect and understanding.

A method yielding comparable estimates of the fraternal birth order and female fecundity effects in male homosexuality.

The fraternal birth order effect (FBOE) is the finding that older brothers increase the probability of homosexuality in later-born males, and the female fecundity effect (FFE) is the finding that the mothers of homosexual males produce more offspring than the mothers of heterosexual males. In a recent paper, Khovanova proposed a novel method for computing independent estimates of these effects on the same samples and expressing the magnitude and direction of the effects in the same metric. In her procedure, only families with one or two sons are examined, and daughters are ignored. The present study investigated the performance of Khovanova's method using archived data from 10 studies, comprising 14 samples totalling 5390 homosexual and heterosexual subjects. The effect estimate for the FBOE showed that an increase from zero older brothers to one older brother is associated with a 38% increase in the odds of homosexuality. By contrast, the effect estimate for the FFE showed that the increase from zero younger brothers to one younger brother is not associated with any increase in the odds of homosexuality. The former result supports the maternal immune hypothesis of male homosexuality; the latter result does not support the balancing selection hypothesis.

Birth Order and Sibling Sex Ratio in Androphilic Males and Gynephilic Females Diagnosed With Gender Dysphoria From Iran.

BACKGROUND: This study investigated the effect of older brothers on sexual orientation in male adults diagnosed with gender dysphoria and the effect of older sisters on sexual orientation in female adults diagnosed with gender dysphoria from Iran. AIM: To assess for the presence of a fraternal birth order effect in transgender androphilic males and a sororal birth order effect in transgender gynephilic females. METHODS: The subjects were 92 transgender males and 107 transgender females (all of whom met the DSM-5 criteria for gender dysphoria), together with 72 male and 78 female clinical controls. All the transgender males were androphilic, all the transgender females were gynephilic (preferentially attracted to members of their own biological sex), and all of the clinical controls were heterosexual (none were transgender or had a diagnosis of gender dysphoria). OUTCOMES: In relation to the probands, we analyzed the sibship composition of our groups with regard to birth order and sibling sex ratio (brothers to sisters). RESULTS: The results for the transgender males confirmed the findings of 2 recent meta-analyses that older brothers increase the odds of androphilia in later-born males. The results for the transgender females did not clearly confirm one previous finding that older sisters increase the odds of gynephilia in later-born females-a finding obtained in a relatively large study that included gynephilic cisgender girls as well as girls diagnosed with gender dysphoria who will probably be predominantly gynephilic. CLINICAL IMPLICATIONS: The fraternal (later-born) birth order effect that we found for the transgender androphilic males, similar to that found in gay men, suggests a common underlying causal mechanism. STRENGTHS AND LIMITATIONS: Our study on Iranian patients diagnosed with gender dysphoria provides further generalizability for the study of birth order and sibling sex ratio that has, more often than not, been restricted to Western samples of adults diagnosed with gender dysphoria. It would be important to study these variables in Iranian gay men and lesbian women (without gender dysphoria) to further examine evidence for cross-cultural similarities when compared to Western samples. CONCLUSIONS: In contrast to the well-established fraternal birth order effect for males, the possible sororal birth order effect for females needs to be examined with additional samples. Khorashad BS, Zucker KJ, Talaei A. Birth Order and Sibling Sex Ratio in Androphilic Males and Gynephilic Females Diagnosed With Gender Dysphoria from Iran. J Sex Med 2020;17:1195-1202.

Adolescents with Gender Dysphoria: Reflections on Some Contemporary Clinical and Research Issues.

This article provides an overview of five contemporary clinical and research issues pertaining to adolescents with a diagnosis of gender dysphoria: (1) increased referrals to specialized gender identity clinics; (2) alteration in the sex ratio; (3) suicidality; (4) "rapid-onset gender dysphoria" (ROGD) as a new developmental pathway; (5) and best practice clinical care for adolescents who may have ROGD.