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.

Levels of physical activity and barriers to sport participation in young people with gender dysphoria.

OBJECTIVES: To determine the levels of physical activity (PA) in young people with gender dysphoria (GD) and help identify factors which deter participation. METHODS: Fifty-six young people who attended paediatric endocrinology because of GD, June to October 2019, and were on treatment with gonadotrophin-releasing hormone (GnRH) analogue were approached to participate in a survey. RESULTS: A total of 55 young people (98%) responded to the survey. Thirty-eight (69%) participated in PA for >1 h/week. Thirty-two (58%) reported high motivation level for exercise. Those had median age of 15.9 years (10.7, 18.7) at the time of survey, and 13.6 years (9.7, 17.6) at start of GnRH analogue compared to 16.7 years (13.9, 18.5) (p, 0.047) and 15.4 years (11.2, 18.0) (p, 0.009) of the 23 (42%) who reported low motivation. Forty-one (74.5%) reported barriers when accessing PA, such as not being as good as others (75%), revealing sports clothing (73%) and not satisfied with body image (47%). Those were older (16.4 years [10.9, 18.7] vs. 14.7 years [10.7, 18.4] [p, 0.011]) at the time of survey and at start of GnRH analogue (14.9 years [9.7, 18.0] vs. 12.5 years [10.6, 15.2] [p, 0.0001]) than those 14 (25.5%) who reported facing no barriers. Twelve (85.7%) of those reporting no barriers stated high motivation levels compared to 20 (48.8%) of those reporting barriers (p, 0.026). CONCLUSIONS: Strategies aimed at improving participation are twofold: first to improve motivation, especially in post-pubertal young people, and secondly to achieve societal change to help eliminate barriers.

Gender-affirming hormone treatment causes changes in gender phenotype in a 12-lead electrocardiogram.

BACKGROUND: Men and women have specific patterns in an electrocardiogram (ECG) differentiated by J-point elevation and ST-segment angle. Although gender-affirming hormone treatment is one of the treatments for gender dysphoria, its influence on an ECG has not been clarified yet. OBJECTIVE: The purpose of this study was to investigate ECG changes induced by gender-affirming hormone treatment. METHODS: The study population consisted of 29 transgender males and 8 transgender females and 37 age- and sex-matched cisgender females and males. Male pattern was defined as J-point elevation > 0.1 mV and ST-segment angle > 20° in precordial leads. RESULTS: In the comparison between 29 transgender males and cisgender females, the prevalence of the male pattern (89.7% vs 6.9%; P < .001), prevalence of the early repolarization pattern (51.7% vs 17.2%; P = .01), J-point elevation (leads V1-V6), T-wave amplitudes (leads V1-V6), QRS amplitudes (leads II, III, V1-V6), and P-wave amplitudes (leads V1-V3) were significantly higher in transgender males. The prevalence of the male pattern was lower in transgender females than in cisgender males (25.0% vs 87.5%; P = .04). In the analysis of transgender males for whom ECGs were available before and after gender-affirming hormone treatment (n = 13), J-point elevation and T-wave amplitudes significantly increased after gender-affirming hormone treatment, leading to a higher prevalence of the male pattern (23.1% vs 92.3%; P < .001). The prevalence of the early repolarization pattern and QRS amplitudes also significantly increased after the treatment, but the augmentation of P-wave amplitudes was modest. CONCLUSION: Gender-affirming hormone treatment for gender dysphoria is accompanied by a change in ECG phenotype toward affirming gender, in which change in androgen level may be involved.

[Endocrine care of gender-incongruent persons]. / Prise en charge des personnes avec incongruence de genre : le point de vue de l'endocrinologue.

Health care of gender-incongruent persons deserves optimization. The new World Health Organization ICD-11, introduced this year, classifies gender-incongruence to « conditions related to sexual health ¼, and not anymore to « mental and behavioral disorders ¼. From an endocrine perspective, gender-affirming hormonal treatment induces physical changes consistent with gender identity, but good-quality, long follow-up studies concerning efficacy and safety are needed. Improvements in training of medical professionals as well as a specialized multidisciplinary approach are important measures to be taken.

Les soins médicaux offerts aux personnes avec incongruence de genre méritent d'être optimisés. La nouvelle Classification internationale des maladies, 11e version, de l'OMS, présentée cette année, classe l'incongruence de genre parmi les « conditions liées à la santé sexuelle ¼, et non plus dans les « troubles mentaux et du comportement ¼. Sur le plan endocrinien, les traitements hormonaux d'affirmation de genre permettent d'induire des changements physiques correspondant à l'identité du genre, mais des études d'efficacité et sécurité de meilleure qualité et au long cours sont nécessaires. La prise en charge de cette population par une équipe spécialisée et multidisciplinaire et l'amélioration de la formation du corps médical sont des mesures indispensables pour le futur.

Systematic Review: Puberty suppression with GnRH analogues in adolescents with gender incongruity.

CONTEXT: Gender incongruence is defined as disharmony between assigned gender and gender identity. Several interventions are liable in this case including genital affirming surgery among other surgical interventions such as harmonization, and also the use of gonadotropin-releasing hormone agonists (GnRHa) for gonadal shielding. This aids in preventing the development of secondary sexual characteristics related to the genetic sex. OBJECTIVE: Systematically review the treatment of gender incongruity with GnRHa analogues. DATA SOURCES: The data source of this research is from Pubmed-Medline and Embase. STUDY SELECTION: Articles published between 2009 and 2019 which studied transgender adolescents treated with GnRHa were carefully selected. DATA EXTRACTION: Were extracted: design, sample size, study context, targeted subjects of intervention, outcome measures, and results. RESULTS: Eleven studies were included. The use of GnRHa seems to be well tolerated by the studied population. When started in pubertal transition, it was associated with a more distinct resemblance to body shape than to the affirmed sex. In addition to preventing the irreversible phenotypic changes that occur in cross-hormonal therapy, the use of GnRHa can equally contribute to the mental health of these adolescents. LIMITATION: There are few consistent studies on the use of GnRHa for gender incongruence. CONCLUSION: As the population of transgender children and adolescents grows, they acquire knowledge and greater access to the various forms and stages of treatment for sex reassignment. The medical community needs to be adequately prepared to better serve this population and offer the safest resources available.

Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming Hormones.

CONTEXT: Hormonal interventions in adolescents with gender dysphoria may have adverse effects, such as reduced bone mineral accrual. OBJECTIVE: To describe bone mass development in adolescents with gender dysphoria treated with gonadotropin-releasing hormone analogues (GnRHa), subsequently combined with gender-affirming hormones. DESIGN: Observational prospective study. SUBJECTS: 51 transgirls and 70 transboys receiving GnRHa and 36 transgirls and 42 transboys receiving GnRHa and gender-affirming hormones, subdivided into early- and late-pubertal groups. MAIN OUTCOME MEASURES: Bone mineral apparent density (BMAD), age- and sex-specific BMAD z-scores, and serum bone markers. RESULTS: At the start of GnRHa treatment, mean areal bone mineral density (aBMD) and BMAD values were within the normal range in all groups. In transgirls, the mean z-scores were well below the population mean. During 2 years of GnRHa treatment, BMAD stabilized or showed a small decrease, whereas z-scores decreased in all groups. During 3 years of combined administration of GnRHa and gender-affirming hormones, a significant increase of BMAD was found. Z-scores normalized in transboys but remained below zero in transgirls. In transgirls and early pubertal transboys, all bone markers decreased during GnRHa treatment. CONCLUSIONS: BMAD z-scores decreased during GnRHa treatment and increased during gender-affirming hormone treatment. Transboys had normal z-scores at baseline and at the end of the study. However, transgirls had relatively low z-scores, both at baseline and after 3 years of estrogen treatment. It is currently unclear whether this results in adverse outcomes, such as increased fracture risk, in transgirls as they grow older.

2D:4D Finger Length Ratios in Individuals with Gender Dysphoria. / Cinsiyet Hosnutsuzlugu Olan Bireylerde 2D:4D Parmak Uzunlugu Oranlari.

OBJECTIVE: The neurobiological basis of Gender Dysphoria (GD) is not yet fully known. In recent years, the role of prenatal exposure to testosterone has been emphasized in the development of the GD. The aim of this study was to compare the 2D:4D digit ratio, which is considered to be a morphological indicator of exposure to testosterone in the prenatal period, in individuals with GD. METHOD: The study included 99 participants diagnosed with GD comprising 54 assigned the female gender at birth [AFB-GD], 45 assigned the male gender at birth [AMB-GD], and 58 female and 58 male participants making up the control group. The right and the left hands of the participants were photocopied and finger lengths were measured using digital calipers. RESULTS: The 2D:4D digit ratio on the right hand of the AFB-GD group was significantly lower (p=0.028) than that of the female controls, but it did not differ significantly as compared to male controls. The ratio on the left hand of the AFB-GD group did not significantly differ from that of the female controls, but it was higher than that of the male controls (p=0.045). The 2D:4D digit ratio on the right hand of the AMB-GD group did not differ significantly from that of the male controls, but they had a lower finger ratio as compared to the female controls (p<0.001). The ratio on the left hand of the AMB-GD group did not differ significantly from those of the male and female controls. CONCLUSION: The results of this study present suggestive evidence that the AFB-GD individuals were exposed to testosterone in the prenatal period.

Postnatal Effects of Sex Hormones on Click-Evoked Otoacoustic Emissions: A Study of Adolescents with Gender Dysphoria.

Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds, generated by the inner ear in response to click-stimuli. A sex difference in emission strength is observed in neonates and adults, with weaker CEOAE amplitudes in males. These differences are assumed to originate from testosterone influences during prenatal male sexual differentiation and to remain stable throughout life. However, recent studies suggested activational, postnatal effects of sex hormones on CEOAEs. Adolescents diagnosed with gender dysphoria (GD) may receive gonadotropin-releasing hormone analogs (GnRHa) in order to suppress endogenous sex hormones and, therefore, pubertal maturation, followed by cross-sex hormone (CSH) treatment. Using a cross-sectional design, we examined whether hormonal interventions in adolescents diagnosed with GD (62 trans boys, assigned female at birth, self-identifying as male; 43 trans girls, assigned male at birth, self-identifying as female), affected their CEOAEs compared to age- and sex-matched controls (44 boys, 37 girls). Sex-typical differences in CEOAE amplitude were observed among cisgender controls and treatment-naïve trans boys but not in other groups with GD. Treatment-naïve trans girls tended to have more female-typical CEOAEs, suggesting hypomasculinized early sexual differentiation, in support of a prominent hypothesis on the etiology of GD. In line with the predicted suppressive effects of androgens, trans boys receiving CSH treatment, i.e., testosterone plus GnRHa, showed significantly weaker right-ear CEOAEs compared with control girls. A similar trend was seen in trans boys treated with GnRHa only. Unexpectedly, trans girls showed CEOAE masculinization with addition of estradiol. Our findings show that CEOAEs may not be used as an unequivocal measure of prenatal androgen exposure as they can be modulated postnatally by sex hormones, in the form of hormonal treatment.

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.

Gender dysphoria in children and adolescents: an overview.

Over the last decade, we have witnessed considerable progress in gender dysphoria (GD) terminology in an attempt to better describe the condition based on certain criteria. The ever-increasing social acceptance and destigmatization of children and adolescents with GD have resulted in an increased number of transgender individuals seeking endocrine care. In addition to terminology and diagnostic criteria, the tremendous progress of genetics and neuroimaging has enabled us to have a deeper understanding of the complex pathogenesis of GD. Although helpful guidelines for treatment with GnRH analogs and gender-affirming hormones have been proposed, several challenges and controversies still exist. In this article, the current knowledge about GD in adolescents is reviewed, with particular emphasis on terminology, clinical manifestations, and epidemiologic data. The neurobiological basis of the condition is presented, and both hormonal treatment and mental issues of transgender individuals are discussed. Undoubtedly, further research will optimize the diagnostic and therapeutic approach of children and adolescents with GD.

Sudden sex hormone withdrawal and the effects on body composition in late pubertal adolescents with gender dysphoria.

Background Sex hormones initiate profound physical and physiological changes during the pubertal process, but to what extent are they responsible for continuing the body composition changes of late adolescence and what happens to body composition on sudden sex hormone withdrawal? Methods Thirty-six healthy, phenotypically and chromosomally normal late and post-pubertal individuals aged 15-17 years with gender dysphoria (transgirls - birth-registered males identifying as female n = 11; and transboys - birth-registered females identifying as male n = 25) underwent Tanita body composition analysis at 0, 6 and 12 months during reproductive hormone suppression with Triptorelin as part of the standard therapeutic protocol. Results and conclusions In the transgirl cohort, paired t-test analysis demonstrated a significant decrease in height and lean mass standard deviation scores over the 12-month period, going against an expected trajectory over that time. In contrast, oestrogen suppression appeared not to affect the body composition of transboys; their measurements were not significantly different at baseline and after 12 months of treatment. The withdrawal of sex hormone secretion does not appear to have a significant impact on female post-pubertal body composition, in contrast to that seen at the menopause. This suggests that other factors may preserve normal body balance in adolescents in the absence of sex steroids.

Testosterone effects on functional amygdala lateralization: A study in adolescent transgender boys and cisgender boys and girls.

The influence of testosterone on the development of human brain lateralization has been subject of debate for a long time, partly because studies investigating this are necessarily mostly correlational. In the present study we used a quasi-experimental approach by assessing functional brain lateralization in trans boys (female sex assigned at birth, diagnosed with Gender Dysphoria, n = 21) before and after testosterone treatment, and compared these results to the functional lateralization of age-matched control groups of cisgender boys (n = 20) and girls (n = 21) around 16 years of age. The lateralization index of the amygdala was determined with functional magnetic resonance imaging (fMRI) during an emotional face matching task with angry and fearful faces, as the literature indicates that boys show more activation in the right amygdala than girls during the perception of emotional faces. As expected, the lateralization index in trans boys shifted towards the right amygdala after testosterone treatment, and the cumulative dose of testosterone treatment correlated significantly with amygdala lateralization after treatment. However, we did not find any significant group differences in lateralization and endogenous testosterone concentrations predicted rightward amygdala lateralization only in the cis boys, but not in cis girls or trans boys. These inconsistencies may be due to sex differences in sensitivity to testosterone or its metabolites, which would be a worthwhile course for future studies.

Mirror self recognition as a product of forward models; implications for delusions of body image and visual neglect.

Forward models allow individuals to learn to predict the sensory consequences of their own behavior. Social forward models have been proposed as an extension of forward models, allowing individuals to learn to predict the response of another to the individual's own behavior. This article proposes similarly that an individual who treats their reflection as another may learn to predict the behavior of their reflection, offering a new perspective on mirror self-recognition and a potential framework through which to investigate visual delusions. Specifically this article investigates this framework by considering four body image delusions; mirrored-self misidentification, body integrity disorder (BID), phantom limbs, and gender dysphoria, and two delusions associated with visual neglect; somatoparaphrenia and mirror agnosia.

Fertility desires and reproductive needs of transgender people: Challenges and considerations for clinical practice.

The majority of transgender and gender nonconforming persons seeking medical care are of reproductive age. Hormonal treatment and sex reassignment surgery, which are used in the management of gender dysphoria, compromise fertility potential. Children and adolescents with gender dysphoria have specific treatment regimens starting with puberty-blocking medications. According to international guidelines, fertility preservation should be discussed before any hormonal treatment, although our knowledge on the reproductive needs of transgender and gender nonconforming persons is limited. Recently, some data have emerged on fertility management in some centres for the adult population with gender dysphoria. The goal of this review was to summarize the available evidence on the fertility desires and parental roles of transgender and gender nonconforming people. In light of newly emerging societal challenges, we aim to provide some considerations for clinical practice and suggest further areas of research.

Gender dysphoria and XX congenital adrenal hyperplasia: how frequent is it? Is male-sex rearing a good idea?

INTRODUCTION: The frequency of gender dysphoria (GD) among 46,XX congenital adrenal hyperplasia (CAH) patients is unknown. These data are needed to put into perspective the debate about the timing of reconstructive surgery and possible male-raising of the most severely virilized children. OBJECTIVE: To analyze the frequency of female to male GD between 46,XX individuals raised as females; to identify subgroups with higher chances of showing GD; to describe the results of male-raising among 46,XX CAH patients. MATERIALS AND METHODS: Analytic/descriptive literature review (January 1988 to April 2018). RESULTS: Female-raised patients frequently report the desire to be male, adopt male-typical behavior and are frequently homosexual/bisexual as adults, but this does not correspond to GD. Declared GD among 46,XX CAH patients attained 9% of the reported cohorts, generally in late adolescence/adulthood. We could not prove a relationship between inadequate treatment, null-genotype, late diagnoses, a higher degree of virilization, type of CAH or higher levels of androgens and female to male GD, but this may be due to statistical limitations. Male gender raised patients (MGR) were 10.1% of CAH cohorts included in this review, mostly from underdeveloped countries, with a high proportion of late diagnoses (76.3%) and familial choices. GD was more common in this group than among female-raised patients. Opting for male gender relates to a short final height, the need for multiple surgeries, surgical castration before puberty and infertility. CONCLUSION: Both male to female and female to male GD may present in 46,XX CAH patients in a contemporaneous cohort. The proportion of GD is higher among patients raised as males. DSD patients sexual maladjustments are complex and not comparable to the transgender population. Many 46,XX CAH patients with GD define themselves as gender-fluid and do not seek for legal/formal transition. Male-raising Prader 4/5 46,XX CAH patients imply infertility and multiple surgeries. There is no proof that any subgroup of CAH is more prone to GD, despite null genotypes, salt wasting phenotypes and Prader 4/5 cases being related to male-typical behavior and female homosexuality. TYPE OF STUDY: Descriptive/analytic non-systematic REVIEW. LEVEL OF EVIDENCE: 3.

Progesterone Is Important for Transgender Women's Therapy-Applying Evidence for the Benefits of Progesterone in Ciswomen.

BACKGROUND: Although the 2017 Endocrine Society Guidelines for gender dysphoria stipulated that cross-sex hormone therapy (CHT) achieve gonadal steroid levels equivalent to those of a cisperson of the chosen sex, for transgender women (male-to-female gender dysphoria), current gonadal therapy is usually estradiol. Accumulated evidence indicates that normally ovulatory menstrual cycles are necessary for ciswomen's current fertility, as well as for later-life bone and cardiovascular health and the prevention of breast and endometrial cancers. EVIDENCE ACQUISITION: Extensive past clinical experience with transgender women's CHT using estradiol/estrogen combined with progesterone/medroxyprogesterone and pioneering the addition of spironolactone. Comprehensive progesterone physiology research plus a brief review of transgender women's literature to assess current therapy and clinical outcomes, including morbidity and mortality. PURPOSE: To emphasize that both ovarian hormones, progesterone as well as estradiol, are theoretically and clinically important for optimal transgender women's CHT. EVIDENCE SYNTHESIS: It is important to add progesterone to estradiol and an antiandrogen in transgender women's CHT. Progesterone may add the following: (i) more rapid feminization, (ii) decreased endogenous testosterone production, (iii) optimal breast maturation to Tanner stages 4/5, (iv) increased bone formation, (v) improved sleep and vasomotor symptom control, and (vi) cardiovascular health benefits. CONCLUSIONS: Evidence has accrued that normal progesterone (and ovulation), as well as physiological estradiol levels, is necessary during ciswomen's premenopausal menstrual cycles for current fertility and long-term health; transgender women deserve progesterone therapy and similar potential physiological benefits.

Possible Neurobiological Underpinnings of Homosexuality and Gender Dysphoria.

Although frequently discussed in terms of sex dimorphism, the neurobiology of sexual orientation and identity is unknown. We report multimodal magnetic resonance imaging data, including cortical thickness (Cth), subcortical volumes, and resting state functional magnetic resonance imaging, from 27 transgender women (TrW), 40 transgender men (TrM), and 80 heterosexual (40 men) and 60 homosexual cisgender controls (30 men). These data show that whereas homosexuality is linked to cerebral sex dimorphism, gender dysphoria primarily involves cerebral networks mediating self-body perception. Among the homosexual cisgender controls, weaker sex dimorphism was found in white matter connections and a partly reversed sex dimorphism in Cth. Similar patterns were detected in transgender persons compared with heterosexual cisgender controls, but the significant clusters disappeared when adding homosexual controls, and correcting for sexual orientation. Instead, both TrW and TrM displayed singular features, showing greater Cth as well as weaker structural and functional connections in the anterior cingulate-precuneus and right occipito-parietal cortex, regions known to process own body perception in the context of self.