Back to the Future: Is GnRHa treatment in transgender and gender diverse adolescents only an extended evaluation phase?

PURPOSE: The main aim of the present study was to explore several hormone, physical and psychological functioning changes during GnRH analogs (GnRHa) treatment in Transgender and gender diverse adolescents (TGDA). The potential relationship between the physical and hormone effects of GnRHa and psychological well-being, along with its magnitude, was assessed for the first time. METHODS: This prospective multidisciplinary study included 36 TGDA (22 assigned female at birth, and 14 assigned male at birth) who received psychological assessment followed by Triptorelin prescription referring to the Florence Gender Clinic. This study consisted of three time points: first referral (T0), psychological assessment (T1); treatment with intramuscular injections of Triptorelin for three up to twelve months (T2). Psychometric questionnaires were administered at each time, clinical and biochemical evaluations were performed at T1 and T2. RESULTS: The following results were found: (i) GnRHa showed efficacy in inhibiting puberty progression in TGDA; (ii) an increase in psychopathology was observed before starting GnRHa (T1) as compared to baseline levels; (iii) during GnRHa treatment (T2), a significant improvement in psychological functioning, as well as decrease in suicidality, body uneasiness, depression and anxiety levels were observed; (iv) hormone and physical changes (in terms of gonadotropin and sex steroids levels, height and body mass index percentiles, waist-hip ratio, and acne severity) observed during Triptorelin treatment significantly correlated with a reduction in suicidal ideation, anxiety and body image concerns. CONCLUSIONS: Psychological improvement in TGDA on GnRHa seems to be related to the objective body changes induced by GnRHa. Therefore, the rationale for treatment with GnRHa may not only be considered an extension of the evaluation phase, but also the start of a medical (even if reversible) gender-affirming path, especially in TGDA whose puberty has already progressed.

Exploring Gender Diversity in Transgender and Non-Binary Adults Accessing a Specialized Service in Italy.

In Italy, studies investigating gender identity and expression in gender non-conforming adults are lacking, as well as data regarding the non-binary population. The present study aimed at dimensionally exploring how transgender and non-binary Italian adults identify and express their gender. The Gender Diversity Questionnaire (GDQ) was administered to a sample of 112 adult subjects aged 18-60 years accessing a gender-specialized service in Rome. The majority of the participants were aged 18-24 years (53.6%), whereas fewer subjects were aged 25-35 years (32%) and 35 years and older (14.3%). Most participants (83.9%) identified themselves as trans binary, while the remaining (16.1%) identified as non-binary. Trans binary participants reported a stable gender identity, whereas non-binary participants reported a more fluid gender identity over time and across contexts. Younger subjects recognized the use of chosen names, pronouns, and clothes as important for their gender expression, whereas older subjects attributed more importance to physical appearance and emotions. Differences regarding gender-affirmative interventions emerged between non-binary and transbinary participants. Findings evidence that gender non-conforming adults accessing gender-specialized services have unique needs and features, thus it is essential to shed light on this population by providing greater visibility and recognition.

Internalized transphobia predicts worse longitudinal trend of body uneasiness in transgender persons treated with gender affirming hormone therapy: a 1-year follow-up study.

BACKGROUND: Given the relationship between interiorized stigma and body image, it could be hypothesized that high levels of internalized transphobia (IT) might predict higher levels of body uneasiness in subjects with gender dysphoria (GD) and worse improvement of body image after gender affirming hormone therapy (GAHT). AIM: We sought to evaluate the relationship between IT and body uneasiness in subjects with GD and the role of IT in moderating the improvement of body image after GAHT. METHODS: In total, 200 individuals with GD performed the baseline assessment; 99 were re-evaluated 12 months after starting GAHT. At baseline participants were evaluated through a face-to-face interview and filled self-administered questionnaires to evaluate GD (Utrecht Gender Dysphoria Scale [UGDS]), IT attitudes (Attitudes Toward Transgendered Individuals [ATTI] Scale), body uneasiness (Body Uneasiness Test, part A [BUT-A]), and general psychopathology (Symptom Checklist 90-Revised [SCL 90-R]). The same questionnaires, except ATTI, were readministered at follow-ups. OUTCOMES: Outcomes were based on measures of the associations between IT and baseline characteristics of the sample, the longitudinal trends of GD, body uneasiness, and general psychopathology; and IT as a moderator of the longitudinal trend of body uneasiness. RESULTS: At baseline, IT correlated with lower level of education, higher GD, and more severe body uneasiness. Longitudinal analyses showed significant improvements in GD, body uneasiness, and general psychopathology during GAHT. Moderation analysis confirmed that participants with more transphobic attitudes showed less improvement after GAHT with regard to body uneasiness (bTime*ATTI = -.002, P = .040). The Johnson-Neyman technique revealed that no significant improvement in body uneasiness was found for participants with ATTI scores lower than 71.14. CLINICAL IMPLICATIONS: The presence of IT should be investigated in subjects with GD who require gender affirming treatments to provide specific interventions aimed at targeting this dimension. STRENGTHS AND LIMITATIONS: Strengths of this study include the mixed cross-sectional and longitudinal design and the dimensional evaluation of the investigated constructs. Limitations include the small sample size and the limited follow-up. Furthermore, the effects of gender affirming surgery were not evaluated. CONCLUSION: The association of IT with both baseline body uneasinessand the longitudinal course of this dimension highlighted the clinical significance of body uneasiness and the importance of making continuous efforts to improve education and information to fight societal stigmas.

Prevalence and Correlates of Sexually Transmitted Infections in Transgender People: An Italian Multicentric Cross-Sectional Study.

The burden of sexually transmitted infections (STIs) in the transgender population remains an underestimated issue. The aims of the present study were to evaluate the prevalence of either self-reported and serological STIs and to describe socio-demographic and clinical characteristics of transgender individuals with STIs. A consecutive series of 705 transgender individuals (assigned-male at birth, AMAB n = 377; assigned-female at birth, AFAB n = 328) referring to six Italian gender clinics were included. Sociodemographic and clinical information was collected during the first visit. In a subsample of 126 individuals prevalence of STIs (human immunodeficiency virus, HIV; hepatitis C, HCV; hepatitis B, HBV; syphilis) were evaluated through serology tests. The self-reported prevalence of HIV, HBV, HCV and syphilis infection in the total sample were 3.4%, 1.6%, 2.6% and 2.0%, respectively. In the subsample who underwent serological tests, higher rates of serological prevalence were found (9.5%, 4.0%, 5.6% and 7.9% for HIV, HBV, HCV and syphilis, respectively). When comparing transgender people with or without self-reported STIs, unemployment, previous incarceration, justice problems and sex work resulted more frequent in the first group (p< 0.03 for all). Regarding health status, we observed higher rates of lifetime substance abuse and psychiatric morbidities in trans people with at least one reported STI (p < 0.05). The prevalence of STIs exceeded that reported in general population and STIs correlates underline the importance of stigma and discrimination as determinants of transgender health.

A Novel Compound Heterozygous Mutation of HSD17B3 Gene Identified in a Patient With 46,XY Difference of Sexual Development.

INTRODUCTION: Deficiency of the 17ß-hydroxysteroid dehydrogenase type 3 (17 ß-HSD3) is a rare autosomal recessive 46,XY Difference of sex development (DSD), resulting from pathogenetic variants in the HSD17B3 gene, which lead to absent or reduced ability to convert Δ4-androstenedione to testosterone in the fetal testes. AIM: This study aimed to present the clinical and genetic characteristics of an Italian patient receiving a diagnosis of 17 ß-HSD3 deficiency in adulthood. The patient was raised as female and underwent early surgical interventions to correct virilized genitalia, leading to a significant sexual distress. METHODS: At the time of the referral, a 20-gene Next Generation Sequencing custom-panel for DSD was performed on patient's genomic DNA. RESULTS: A novel compound heterozygous mutation in HSD17B3 gene was identified, detecting a new variant (c.257_265delAGGCCATTG, p.) CONCLUSION: Novel genotype causing 17 ß-HSD3 deficiency is presented. Furthermore, the patient's clinical history stresses the importance to actively involve these individuals in the decision-making process avoiding surgical intervention when the patient is not able to give fully informed consent. Cocchetti C, Baldinotti F, Romani A, et al. A Novel Compound Heterozygous Mutation of HSD17B3 Gene Identified in a Patient With 46,XY Difference of Sexual Development. Sex Med 2022;10:100522.

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.

Gender Identity and Non-Binary Presentations in Adolescents Attending Two Specialized Services in Italy.

BACKGROUND: Recently, the variability and heterogeneity of gender presentations in transgender youths have gained significant attention worldwide. Alongside this, specialized gender services have reported an increase in referrals of youths reporting non-binary identities. In Italy, studies investigating gender identity and expression in gender non-conforming youths are lacking, as are data regarding the non-binary population. AIM: The present study aimed at dimensionally exploring how transgender and non-binary Italian adolescents identify and express their gender. OUTCOMES: Gender expression in trans binary youths and non-binary youths. METHODS: The Gender Diversity Questionnaire (GDQ; Twist & de Graaf, 2019) was used to investigate gender identity, gender fluidity, and gender expression in a sample of 125 adolescent patients from the Gender Identity Development Service (SAIFIP) in Rome and the Gender Incongruence Unit of the Careggi Hospital in Florence, between April 2019-June 2021. RESULTS: The majority of participants (74.4%) identified as trans* binary and the remaining (25.6%) participants identified as non-binary. Trans binary participants reported a stable gender identity, whereas non-binary participants reported a more fluid gender identity across time and contexts. Almost all participants rated external appearance as important to their gender expression, yet trans binary participants attributed more importance to the body in this respect. Body discomfort and pubertal stage emerged as the most influential factors in participants' experiences of gender. Participants who were assigned male at birth expressed significantly more desire for puberty blockers, whereas those who were assigned female at birth had a stronger desire to engage in breast/chest surgery. Non-binary participants sought different medical interventions relative to trans binary participants. CLINICAL IMPLICATIONS: These results may be useful for clinicians working with transgender youths as they provide awareness regarding the features of young people who identify within and outside of binary constructions of gender. STRENGTHS & LIMITATIONS: This study provides useful data in gaining insight into understanding the variety of experiences and challenges of gender non-conforming youths. However as the sample was recruited from specialized services, it may not represent the entire gender non-conforming population in Italy. CONCLUSION: The results describe the range of gender identities and expressions among gender non-conforming youths attending gender specialized services in Italy, thereby improving our understanding of the variety of identities experienced and the specific medical needs of both trans binary and non-binary adolescents. Mirabella M, Piras I, Fortunato A, et al. Gender Identity and Non-Binary Presentations in Adolescents Attending Two Specialized Services in Italy. J Sex Med 2022;19:1035-1048.

Psychological Wellbeing and Perceived Social Acceptance in Gender Diverse Individuals.

BACKGROUND: Over the last few years, the gender binary has been questioned, highlighting the existence of gender diverse people, who identify as neither (exclusively) male nor female. AIM: The present study evaluated the possible differences in terms of psychological wellbeing between binary and gender diverse individuals, as well as the role of perceived social acceptance and religious fundamentalism as possible mediators of psychopathology in gender diverse people. Furthermore, the diversity of gender-affirming hormonal treatment requests according to gender identification was investigated. METHODS: A sample of 563 transgender people aged 18-70 was enrolled (n = 264 assigned female at birth, AFAB and n = 299 assigned male at birth, AMAB), all individuals referring to several Italian gender clinics. A subdivision of the study population based on the gender identity visual analog scale (GI-VAS) median was performed, in order to distinguish between gender diverse and binary transgender individuals. Moreover, a linear regression analysis was performed entering logarithmically transformed GI-VAS (Log GI-VAS) into the models with psychometric scales. OUTCOMES: Psychometric and sociodemographic data, as well as information regarding requests for gender-affirming treatments, were extrapolated from the clinical interviews conducted during the first referral. RESULTS: Gender diverse individuals showed significantly less intense gender dysphoria and higher levels of depression and anxiety compared to binary ones; accordingly, a less binary gender identity correlated with higher levels of depression and anxiety and lower levels of gender dysphoria. The depressive symptomatology in gender diverse people was partially mediated by perceived discrimination and humiliation. Moreover, gender diverse AMAB people sought a non-standard hormonal treatment more often than their binary counterpart. CLINICAL IMPLICATIONS: The present study highlights the importance for transgender health professionals, when planning gender-affirming hormonal treatments, to offer flexible interventions, tailored on the patient's needs and goals. STRENGTHS & LIMITATIONS: Strengths included exploring whether and how perceived discrimination may affect mental health in gender diverse people. Limitations included the enrolled sample of people referring to different gender clinics, which is not fully representative of the transgender population. CONCLUSION: This study highlights the importance of evaluating each individual's unique health care needs, exploring each single request and its underlying reasons. Romani A., Mazzoli F., Ristori J., et al. Psychological Wellbeing and Perceived Social Acceptance in Gender Diverse Individuals. J Sex Med 2021;18:1933-1944.

The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group.

BACKGROUND: In contrast to cisgender persons, transgender persons identify with a different gender than the one assigned at birth. Although research on the underlying neurobiology of transgender persons has been accumulating over the years, neuroimaging studies in this relatively rare population are often based on very small samples resulting in discrepant findings. AIM: To examine the neurobiology of transgender persons in a large sample. METHODS: Using a mega-analytic approach, structural MRI data of 803 non-hormonally treated transgender men (TM, n = 214, female assigned at birth with male gender identity), transgender women (TW, n = 172, male assigned at birth with female gender identity), cisgender men (CM, n = 221, male assigned at birth with male gender identity) and cisgender women (CW, n = 196, female assigned at birth with female gender identity) were analyzed. OUTCOMES: Structural brain measures, including grey matter volume, cortical surface area, and cortical thickness. RESULTS: Transgender persons differed significantly from cisgender persons with respect to (sub)cortical brain volumes and surface area, but not cortical thickness. Contrasting the 4 groups (TM, TW, CM, and CW), we observed a variety of patterns that not only depended on the direction of gender identity (towards male or towards female) but also on the brain measure as well as the brain region examined. CLINICAL TRANSLATION: The outcomes of this large-scale study may provide a normative framework that may become useful in clinical studies. STRENGTHS AND LIMITATIONS: While this is the largest study of MRI data in transgender persons to date, the analyses conducted were governed (and restricted) by the type of data collected across all participating sites. CONCLUSION: Rather than being merely shifted towards either end of the male-female spectrum, transgender persons seem to present with their own unique brain phenotype. Mueller SC, Guillamon A, Zubiaurre-Elorza L, et al. The Neuroanatomy of Transgender Identity: Mega-Analytic Findings From the ENIGMA Transgender Persons Working Group. J Sex Med 2021;18:1122-1129.

Neural Correlates of Gender Face Perception in Transgender People.

To date, MRI studies focused on brain sexual dimorphism have not explored the presence of specific neural patterns in gender dysphoria (GD) using gender discrimination tasks. Considering the central role of body image in GD, the present study aims to evaluate brain activation patterns with 3T-scanner functional MRI (fMRI) during gender face discrimination task in a sample of 20 hormone-naïve transgender and 20 cisgender individuals. Additionally, participants were asked to complete psychometric measures. The between-group analysis of average blood oxygenation level dependent (BOLD) activations of female vs. male face contrast showed a significant positive cluster in the bilateral precuneus in transmen when compared to the ciswomen. In addition. the transwomen group compared to the cismen showed higher activations also in the precuneus, as well as in the posterior cingulate gyrus, the angular gyrus and the lateral occipital cortices. Moreover, the activation of precuneus, angular gyrus, lateral occipital cortices and posterior cingulate gyrus was significantly associated with higher levels of body uneasiness. These results show for the first time the existence of a possible specific GD-neural pattern. However, it remains unclear if the differences in brain phenotype of transgender people may be the result of a sex-atypical neural development or of a lifelong experience of gender non-conformity.

Hormonal Treatment Strategies Tailored to Non-Binary Transgender Individuals.

INTRODUCTION: To date no standardized hormonal treatment protocols for non-binary transgender individuals have been described in the literature and there is a lack of data regarding their efficacy and safety. OBJECTIVES: To suggest possible treatment strategies for non-binary transgender individuals with non-standardized requests and to emphasize the importance of a personalized clinical approach. METHODS: A narrative review of pertinent literature on gender-affirming hormonal treatment in transgender persons was performed using PubMed. RESULTS: New hormonal treatment regimens outside those reported in current guidelines should be considered for non-binary transgender individuals, in order to improve psychological well-being and quality of life. In the present review we suggested the use of hormonal and non-hormonal compounds, which-based on their mechanism of action-could be used in these cases depending on clients' requests. CONCLUSION: Requests for an individualized hormonal treatment in non-binary transgender individuals represent a future challenge for professionals managing transgender health care. For each case, clinicians should balance the benefits and risks of a personalized non-standardized treatment, actively involving the person in decisions regarding hormonal treatment.

Brain Sex Differences Related to Gender Identity Development: Genes or Hormones?

The complex process of sexual differentiation is known to be influenced by biological and environmental determinants. The present review has the aim of summarizing the most relevant studies on the biological basis of sexual development, and in particular, it focuses on the impact of sex hormones and genetic background on the development of sexual differentiation and gender identity. The authors conducted a search of published studies on Medline (from January 1948 to December 2019). The evidence suggests that the sexual dimorphic brain could be the anatomical substrate of psychosexual development, on which gonadal hormones may have a shaping role during prenatal and pubertal periods. Additionally, according to several heritability studies, genetic components may have a role, but a promising candidate gene has not been identified. Even though growing evidence underlines the primary role of biological factors on psychosexual development, further studies are necessary to better explain their complex interactions.

Sexual habits among Italian transgender adolescents: a cross-sectional study.

Recent studies showed that transgender (TGN) adolescents are more at risk of negative sexual outcomes than their peers. However, little is known about the psychopathological and sociodemographic correlates of sexual-related experiences in TGN adolescents. This cross-sectional study aimed at overcoming this limitation describing this association in a sample of 18 transgirls and 32 transboys recruited at the Gender Clinic of the University of Florence between 2015 and 2020. Clinical, sociodemographic, and sexual-related features were collected through a face-to-face interview and anamnestic forms. Self-report questionnaires were administered to evaluate gender dysphoria (Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults), emotional and behavioral problems (Youth Self Report), and body uneasiness (Body Uneasiness Test). The percentage of subjects reporting to have had at least one romantic relationship in life was 62.5% among transboys and 16.7% in transgirls (ORsex = 8.65, p < 0.01), whereas 28.1% of transboys and 5.6% of transgirls were sexually active (ORsex = 6.63, p > 0.05). A worse psychological functioning and risk-taking behaviors were associated with being sexually active (p < 0.05). These results underline the deep interconnection between psychological vulnerability and sexual-related features in TGN adolescents, confirming the importance of developing gender inclusive sex education programs to prevent negative sexual outcomes in this population.

Management of hypoactive sexual desire disorder in transgender women: a guide for clinicians.

Hypoactive sexual desire disorder (HSDD) represents a common condition among transgender women. However, to date no specific guidelines for the management of HSDD in transgender persons are available. The aim of the present narrative Review is to evaluate evidence-based treatment for HSDD and to suggest treatment options for HSDD in transgender women. Clinically relevant publications on the management of HSDD (from 1985 to 2020) were searched in PubMed and Medline databases, using the following terms: "sexual desire", "sexual health", "HSDD", "transgender", "gender-affirming treatment", "sexual therapy", "testosterone treatment", "Central nervous system-active medications", and variants. Since sexual desire could be affected by several factors, a comprehensive assessment of HSDD- exploring biological, psychological, and social domains- is recommended, in order to identify possible predisposing, precipitating and maintaining factors. Among treatment options, transgender women may benefit of different sex therapy strategies and/or central nervous system-active medications-such as flibanserin, bremelanotide, bupropion and buspirone-and transdermal testosterone, bearing in mind that this option could be poorly accepted by patients due to the risk of virilizing effects. The lack of data regarding the efficacy of HSDD treatment options in transgender women emphasize the need for literature to focus more on this topic in the future.

Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data.

INTRODUCTION: As far as we know, no studies to date have investigated the psychobiological correlates of sexual distress (SD) nor the impact of hormonal treatment (HT) on SD in transgender persons. AIM: To evaluate the psychobiological correlates of SD and assess the effects of HT on SD in transgender persons without gender-affirming surgery. METHODS: A consecutive series of 301 transgender persons (160 transwomen and 141 transmen) was considered for the cross-sectional study, and a subset of 72 subjects was studied in a 2-year follow-up. A physical examination was performed. Blood samples were drawn for determination of cortisol levels. Subjects completed psychometric measures. During 2 years of HT, the evaluation of SD was prospectively repeated. MAIN OUTCOME MEASURE: Psychobiological correlates of SD in transgender population. Changes in SD during gender affirming hormonal treatment. CLINICAL IMPLICATIONS: Knowing how hormonal treatment influence SD will help care providers when counseling transgender people. STRENGTHS & LIMITATIONS: To the authors' knowledge, this is the first study prospectively evaluating the impact of gender affirming hormonal treatment on sexual distress in transgender individuals. The main limitations are represented by the small size of the sample and the use of questionnaires validated only in the cisgender population. RESULTS: SD showed a positive correlation with body uneasiness (P < .0001) and with dissatisfaction toward gender-related body parts or shapes (all P < .05). In addition, SD correlated positively with general psychopathology (P < .0001), alexithymia, social anxiety, and humiliation scales (all P < .05). In transmen, SD was positively associated with autism levels (P < .005), as well as with cortisol levels (P < .02). A significant correlation between SD and perceived discrimination was observed in transwomen (P < .05). In transwomen, SD was positively associated with hair density and negatively with breast growth (both P < .05). Finally, in transmen, a negative correlation was found between SD and hair density (P < .05). When the impact of HT on SD was evaluated, a significant reduction of SD was observed across time in both transwomen and transmen (P = .001 and P = .01, respectively). CONCLUSIONS: The present results support the efficacy of HT in reducing SD in transgender persons. Ristori J, Cocchetti C, Castellini G, et al. Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data. J Sex Med 2020;17:142-151.

Gender Dysphoria and Anorexia Nervosa Symptoms in Two Adolescents.

The co-occurrence of gender dysphoria and anorexia nervosa has been described in the scientific literature. This paper presents two adolescents with gender dysphoria and pathological eating behaviors and questions with longitudinal observations the clinical meaning of anorexia nervosa symptoms (e.g., restricting eating behaviors and fear of gaining weight) in adolescents with gender dysphoria. Both received psychological evaluations at different times: at first admission to the gender dysphoria clinic (T0) and 6 months after starting treatment with gonadotropin-releasing analogues (GnRHa; T1). In both cases, treatment with GnRHa not only improved psychological functioning, but also resolved pathological eating behaviors. In fact, both adolescents reported quick restoring of healthy food habits with restricting eating behaviors as well as intensive exercise no longer needed after treatment with GnRHa. Therefore, pathological eating behaviors (e.g., food avoidance and weight loss) could be assessed as a dysfunctional coping strategy adopted to gain control over a body developing in an unwanted direction and to block irreversible physical pubertal changes. This psychopathological conceptualization of pathological eating behaviors in adolescents with gender dysphoria stresses the importance of providing, in selected cases, early medical intervention such as pubertal suppression with GnRHa. Mental health professionals should therefore perform a specific and detailed assessment on gender identity within the evaluation of apparent eating disorders in adolescents. Restrictive eating behaviors as well as the intense fear of gaining weight or of becoming fat may, in fact, be considered secondary to a gender dysphoria diagnosis instead of anorexia nervosa symptoms.

The molecular mechanisms of sexual orientation and gender identity.

Differences between males and females are widely represented in nature. There are gender differences in phenotypes, personality traits, behaviors and interests, cognitive performance, and proneness to specific diseases. The most marked difference in humans is represented by sexual orientation and core gender identity, the origins of which are still controversial and far from being understood. Debates continue on whether sexual behavior and gender identity are a result of biological (nature) or cultural (nurture) factors, with biology possibly playing a major role. The main goal of this review is to summarize the studies available to date on the biological factors involved in the development of both sexual orientation and gender identity. A systematic search of published evidence was performed using Medline (from January 1948 to June 2017). Review of the relevant literature was based on authors' expertise. Indeed, different studies have documented the possible role and interaction of neuroanatomic, hormonal and genetic factors. The sexual dimorphic brain is considered the anatomical substrate of psychosexual development, on which genes and gonadal hormones may have a shaping effect. In particular, growing evidence shows that prenatal and pubertal sex hormones permanently affect human behavior. In addition, heritability studies have demonstrated a role of genetic components. However, a convincing candidate gene has not been identified. Future studies (e.i. genome wide studies) are needed to better clarify the complex interaction between genes, anatomy and hormonal influences on psychosexual development.

Cross-Sex Hormone Treatment and Psychobiological Changes in Transsexual Persons: Two-Year Follow-Up Data.

CONTEXT: To date, there are few studies investigating the impact of body changes induced by cross-sex hormonal treatment (CHT) on psychobiological well-being in gender-dysphoric persons (GDs). OBJECTIVE: The objective of the study was to assess whether CHT-related body changes affect psychobiological well-being in GDs. METHODS: A consecutive series of 359 GDs was considered for a cross-sectional section of the study. In addition, 54 GDs were studied in a 2-year follow-up. A physical examination was performed, including body mass index, waist circumference, and hair distribution. We also evaluated breast development and testis volume in male to female subjects and clitoris length in female to male. Subjects were asked to complete several psychometric measures for the assessment of body uneasiness, GD, and psychopathology levels. The evaluation was repeated 2 years prospectively. RESULTS: The following results were found: 1) GDs undergoing CHT reported significantly lower subjective levels of GD, body uneasiness, and depressive symptoms as compared with those without; 2) CHT-induced body modifications were significantly associated with a better psychological adjustment; 3) during CHT, GDs reported a significant reduction of general psychopathology, depressive symptoms, and subjective GD, whereas social and legal indicators of GD showed a significant increase across time; and 4) among body changes induced by CHT, only breast development and increased body mass index had a significant impact on psychopathology reduction across time in male to female subjects and female to male subjects, respectively. CONCLUSIONS: The aforementioned results support the efficacy of CHT intervention in improving subjective perception of one's own body, which was partially associated with objective changes.