Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline

OBJECTIVE: To update the "Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline," published by the Endocrine Society in 2009. PARTICIPANTS: The participants include an Endocrine Society-appointed task force of nine experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: Group meetings, conference calls, and e-mail communications enabled consensus. Endocrine Society committees, members and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. CONCLUSION: Gender affirmation is multidisciplinary treatment in which endocrinologists play an important role. Gender-dysphoric/gender-incongruent persons seek and/or are referred to endocrinologists to develop the physical characteristics of the affirmed gender. They require a safe and effective hormone regimen that will (1) suppress endogenous sex hormone secretion determined by the person's genetic/gonadal sex and (2) maintain sex hormone levels within the normal range for the person's affirmed gender. Hormone treatment is not recommended for prepubertal gender-dysphoric/gender-incongruent persons. Those clinicians who recommend gender-affirming endocrine treatments-appropriately trained diagnosing clinicians (required), a mental health provider for adolescents (required) and mental health professional for adults (recommended)-should be knowledgeable about the diagnostic criteria and criteria for gender-affirming treatment, have sufficient training and experience in assessing psychopathology, and be willing to participate in the ongoing care throughout the endocrine transition. We recommend treating gender-dysphoric/gender-incongruent adolescents who have entered puberty at Tanner Stage G2/B2 by suppression with gonadotropin-releasing hormone agonists. Clinicians may add gender-affirming hormones after a multidisciplinary team has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent to this partially irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years, although there is minimal published experience treating prior to 13.5 to 14 years of age. For the care of peripubertal youths and older adolescents, we recommend that an expert multidisciplinary team comprised of medical professionals and mental health professionals manage this treatment. The treating physician must confirm the criteria for treatment used by the referring mental health practitioner and collaborate with them in decisions about gender-affirming surgery in older adolescents. For adult gender-dysphoric/gender-incongruent persons, the treating clinicians (collectively) should have expertise in transgender-specific diagnostic criteria, mental health, primary care, hormone treatment, and surgery, as needed by the patient. We suggest maintaining physiologic levels of gender-appropriate hormones and monitoring for known risks and complications. When high doses of sex steroids are required to suppress endogenous sex steroids and/or in advanced age, clinicians may consider surgically removing natal gonads along with reducing sex steroid treatment. Clinicians should monitor both transgender males (female to male) and transgender females (male to female) for reproductive organ cancer risk when surgical removal is incomplete. Additionally, clinicians should persistently monitor adverse effects of sex steroids. For gender-affirming surgeries in adults, the treating physician must collaborate with and confirm the criteria for treatment used by the referring physician. Clinicians should avoid harming individuals (via hormone treatment) who have conditions other than gender dysphoria/gender incongruence and who may not benefit from the physical changes associated with this treatment.

Sex Differences in White Matter Microstructure in the Human Brain Predominantly Reflect Differences in Sex Hormone Exposure.

Sex differences have been described regarding several aspects of human brain morphology; however, the exact biological mechanisms underlying these differences remain unclear in humans. Women with the complete androgen insensitivity syndrome (CAIS), who lack androgen action in the presence of a 46,XY karyotype, offer the unique opportunity to study isolated effects of sex hormones and sex chromosomes on human neural sexual differentiation. In the present study, we used diffusion tensor imaging to investigate white matter (WM) microstructure in 46,XY women with CAIS (n = 20), 46,XY comparison men (n = 30), and 46,XX comparison women (n = 30). Widespread sex differences in fractional anisotropy (FA), with higher FA in comparison men than in comparison women, were observed. Women with CAIS showed female-typical FA throughout extended WM regions, predominantly due to female-typical radial diffusivity. These findings indicate a predominant role of sex hormones in the sexual differentiation of WM microstructure, although sex chromosome genes and/or masculinizing androgen effects not mediated by the androgen receptor might also play a role.

Psychosexual Outcome Among Iranian Individuals With 5α-Reductase Deficiency Type 2 and Its Relationship With Parental Sexism.

INTRODUCTION: Few studies exist on the psychosexual outcome of homogeneous groups of individuals with 5α-reductase deficiency type 2 (5α-RD-2) and the relation between gender changes and parental hostile and benevolent sexism, which are two components of ambivalent sexism that assume a stereotypical approach toward women in an overtly negative way or a chivalrous, seemingly positive way. AIM: To report on the psychosexual outcome of individuals with 5α-RD-2 and to investigate its relation to the level of parental sexism in a relatively large sample of Iranians with 5α-RD-2. METHODS: Twenty participants (mean age = 19.5 years, SD = 6.345) with a molecularly confirmed diagnosis of 5α-RD-2 who were assigned the female gender at birth and raised as female were included in the study. Participants and their parents were interviewed and their medical records were assessed. Parents also completed the Ambivalent Sexism Inventory (ASI), which includes hostile and benevolent sexism subscales. MAIN OUTCOME MEASURES: Psychosexual outcome and parental hostile and benevolent sexism measurements. RESULTS: Twelve of 20 participants (60%) were diagnosed with gender identity disorder not otherwise specified (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision). Ten of these transitioned to the male gender. The other 10 participants (50%), including the two diagnosed with gender identity disorder not otherwise specified, continued living in a female gender role. When comparing the ASI subscale scores between families of participants who changed their gender and those who did not, no significant difference was found for ASI total and hostile sexism scores, but there was a difference for benevolent sexism (P = .049): those whose daughters had changed their gender had higher benevolent sexism scores. CONCLUSION: The high prevalence of gender change and gender dysphoria reported in the literature was confirmed in this relatively large and homogeneous sample of Iranians with 5-α-RD-2 raised as female. Prenatal exposure to testosterone is hypothesized to play a role in the development of gender identity and sexual orientation, but parental attitudes also might be important. Although gender change in individuals with 5-α-RD-2 is often attributed to high levels of hostile sexism in some cultures, our findings show this to be associated with benevolent sexism.

A network analysis of body satisfaction of people with gender dysphoria.

In gender dysphoria (GD), much of the experienced distress results from body dissatisfaction. The current study analyzed the configuration of body satisfaction in trans men and women using network analysis. In total, 485 individuals diagnosed with GD from four European countries, applying for medical treatment, filled out the Body Image Scale for Transsexuals. A six-factor model reflecting different body areas was confirmed via confirmatory factor analysis. A further configuration of body satisfaction was modelled using correlation network analysis techniques in R. Genital dissatisfaction showed limited connection with other body areas in comparison to other subscales. Body characteristics influencing social gender recognition were most centrally involved in body (dis)satisfaction in both natal sexes. In trans women these characteristics were related mostly to voice and hair, whereas in trans men these characteristics were related to muscularity and posture. Focusing on these socially influential body characteristics may provide important targets for transgender healthcare.

Oestrogens are Not Related to Emotional Processing: a Study of Regional Brain Activity in Female-to-Male Transsexuals Under Gonadal Suppression.

Although the prevailing opinion is that emotional processes are influenced by sex hormones, the literature is still inconclusive. The aim of the current study was to examine the effects of gonadal suppression on brain activity during affective picture processing. Twenty-one female-to-male (FtM) transsexuals and 19 control women were recruited and underwent functional magnetic resonance imaging scanning while rating emotional pictures adapted from the International Affective Picture System. The gonadal hormone production of the FtMs was suppressed for 8 weeks, the control group did not receive any treatment before scanning. Under gonadal suppression, FtMs showed less brain activation in the superior temporal lobe compared with female controls during perception of positive affective pictures. Regression analysis showed that during processing of positive affective images, brain activity within the right superior temporal lobe was not correlated with levels of estradiol, luteinizing hormone, and follicle-stimulating hormone. In the absence of associations with hormonal levels, the difference in activation in the superior temporal lobe during positive emotional stimuli between FtMs and control women may be attributed to a priori differences between the 2 groups. Future studies should clarify if these differences are a result of atypical sexual differentiation of the brain in FtMs.

Increased sexual health after restored genital sensation in male patients with spina bifida or a spinal cord injury: the TOMAX procedure.

PURPOSE: In this study we prospectively investigated the contribution of restored penile sensation to sexual health in patients with low spinal lesions. MATERIALS AND METHODS: In 30 patients (18 with spina bifida, 12 with spinal cord injury, age range 13 to 55 years) with no penile sensation but good groin sensation the new TOMAX (TO MAX-imize sensation, sexuality and quality of life) procedure was performed. This involves microsurgical connection of the sensory ilioinguinal nerve to the dorsal nerve of the penis unilaterally. Extensive preoperative and postoperative neurological and psychological evaluations were made. RESULTS: A total of 24 patients (80%) gained unilateral glans penis sensation. This was initially felt as groin sensation but transformed into real glans sensation in 11 patients (33%). These patients had better overall sexual function (p = 0.022) and increased satisfaction (p = 0.004). Although 13 patients (43%) maintained groin sensation, their satisfaction with sexuality was only slightly less than that of those with glans sensation. Improved sensations helped them manage urinary incontinence, thereby improving personal hygiene and independence. Most patients felt more complete and less handicapped with their penis now part of their body image. They also reported having more open and meaningful sexual relationships with their partners. CONCLUSIONS: Tactile and erogenous sensitivity was restored in the glans penis in patients with a low spinal lesion. This new sensation enhanced the quality of sexual functioning and satisfaction. The TOMAX procedure should become standard treatment for such patients.

A European network for the investigation of gender incongruence: the ENIGI initiative.

Studies on diagnostic subtypes of gender identity disorder (GID) or gender incongruence (GI), comorbidity and treatment outcome show considerable variability in results. Clinic/country specific factors may account for the contradictory results, but these factors have never been studied. This article is the first of a series reporting on a unique collaborative study of four European gender identity clinics (the European network for the investigation of gender incongruence [ENIGI]). Here, we present the diagnostic procedures of the four clinics (Amsterdam, Ghent, Hamburg, and Oslo), the standard battery of instruments, and the first results regarding applicants with GI who seek treatment. Applicants in the four clinics did not differ in living situation, employment status, sexual orientation, and age of onset of GI feelings. However, the Amsterdam and Ghent clinic were visited by a majority of natal males, whereas Hamburg and Oslo see more natal females. Male applicants were older than female applicants within each country, but female applicants in one country were sometimes older than male applicants in another country. Also, educational level differed between applicants of the four clinics. These data indicate that certain sociodemographic and/or cultural characteristics of applicants have to be taken into account in future studies.

Psychosexual development in children with disorder of sex development (DSD)--results from the German Clinical Evaluation Study.

Psychosexual development is influenced by biological and psychosocial factors. Human beings show a great variability in psychosexual development both between and within gender-groups. However, there are relatively stable gender-related behaviors and self-perceptions, in which males and females differ distinctly. There is strong evidence that high concentrations of androgens lead to more male-typical behavior and that this also influences gender identity. Disorders of sex development (DSD) provide the opportunity to analyze the role of different factors on psychosexual development. We examined 166 children age 4 to 12 with DSD using instruments concerning gender role behavior, gender identity, and friendship. Results underline the hypothesis, that androgens play a decisive role in the masculinization of gender role behavior in children. There are also some relations between the experience of gender change and psychosexual outcomes which have to be discussed. Nevertheless, results indicated a high congruence between the children's gender identity and gender of rearing.

Psychosocial and psychosexual aspects of disorders of sex development.

Psychosocial aspects of the treatment of disorders of sex development (DSDs) concern gender assignment, information management and communication, timing of medical interventions, consequences of surgery, and sexuality. Although outcome is often satisfactory, a variety of medical and psychosocial factors may jeopardise the psychological development of children with DSDs. This sometimes results in the desire to change gender later in life. The clinical management of gender dysphoria in individuals with DSD may profit from methods and insights that have been developed for gender dysphoric individuals without DSD. In DSD care, clinical decisions are often made with long-lasting effects on quality of life and should be based on empirical evidence. Yet, such evidence (e.g., regarding gender assignment, information management and timing of surgery) is largely non-existent. DSD-specific protocols and educational materials need to be developed to standardise and evaluate interventions in order to facilitate decision making of professionals and individuals with DSD and enhance psychosocial care in this area.

Sex specific effect of prenatal testosterone on language lateralization in children.

Brain lateralization refers to the division of labour between the two hemispheres in controlling a wide array of functions and is remarkably well developed in humans. Based on sex differences in lateralization of handedness and language, several hypotheses have postulated an effect of prenatal exposure to testosterone on human lateralization development, the topic of a long-standing and unresolved debate. Here we demonstrate a clear relationship between prenatal levels of testosterone as assessed from amniotic fluid of healthy pregnant mothers and language lateralization of their offspring at the age of 6 years. Using focused attention conditions in the dichotic listening task, in which the child is instructed to report information from the left ear or the right ear, we were able to differentiate between potential effects of early testosterone on the left hemisphere and effects on inter-hemispheric connectivity. This provides a new method to distinguish between the claims of the different hypotheses. The results suggest that in girls higher prenatal testosterone exposure facilitates left hemisphere language processing, whereas in boys it reduces the information transfer via the corpus callosum.

Coping strategies of retinoblastoma survivors in relation to behavioural problems.

OBJECTIVE: To assess coping strategies of long-term retinoblastoma (RB) survivors and explore determinants of behavioural functioning, including medical, socio-demographic and coping variables. METHODS: This population-based cross-sectional study included 117 RB survivors (12-35 years), registered in the Dutch national RB register. Survivors were asked to fill in coping, social support and behavioural questionnaires, and situational characteristics were obtained from medical archives and from an interview. Prevalence rates of coping strategies were computed based on self-reports. One-sample t-tests were applied to analyse differences in the use of coping strategies compared with healthy reference samples. Multiple regression analyses were performed to identify various determinants for behavioural problems within the RB sample. RESULTS: RB survivors differed from their healthy reference group in one coping style, i.e. they showed significantly less emotion-oriented coping behaviour. Adolescents who came from a single-parent family and/or experienced lower social support and used more emotion-oriented coping reported more total problem behaviour. More internalizing problems were reported for adolescents who experienced less social support and less acceptance of the disease. For adults, more life events, emotion-oriented coping and lower social support explained more total problem behaviour, especially internalizing problems. CONCLUSION: RB survivors showed less emotion-oriented coping behaviour compared with the reference group. Behavioural problems are best determined by emotion-oriented coping, social support, life events other than RB and acceptance of the disease, and not by medical variables. Therefore, these variables should be taken into consideration during interventions for this group.

[Girls detained under civil and criminal law in juvenile detention centres; psychiatric disorders, trauma and psychosocial problems]. / Civiel- en strafrechtelijk geplaatste meisjes in justitiële jeugdinrichtingen; psychiatrische stoornissen, traumatisering en psychosociale problemen.

BACKGROUND: As from 2008, juveniles sentenced under civil law and juveniles sentenced under criminal law can no longer be assigned to the same juvenile detention centres. The reasoning runs as follows: the centres are unlikely to provide adequate treatment for the 'civil' group, and the 'criminal' group may exert a negative influence on the 'civil' group. Hitherto, there has been no research into the question of whether the problems and treatment requirements of girls in the two categories call for detention in the same detention centres or in different ones. AIM: The aim of this study is to investigate differences between the two groups of girls with regard to offence history, sociodemographic characteristics, contact with the social services, psychiatric disorders and trauma. METHOD: Investigation of a representative sample of 211 female minors in three juvenile detention centres using standard instruments. results 82% of the girls were detained under civil law, 18% under criminal law. There were strong similarities between the groups. However, the 'criminal' group more often had a violent history of delinquency and a non-Dutch background, whereas the 'civil' group more often had a background of residential placements, oppositional-defiant disorder, suicidality and self-harm. CONCLUSIONS: Girls detained under civil and under criminal law differed in characteristics such as criminal record, but there were striking similarities in the girls' behavioural problems and psychiatric disorders. It is argued that assignment to a particular type of detention centre should depend on treatment requirements rather than on measures imposed by civil or criminal law.

Information processing, attention and visual-motor function of adolescents born after in vitro fertilization compared with spontaneous conception.

BACKGROUND: Adverse conditions during prenatal life are associated with changes in physical and mental functioning in later life, as shown in children born preterm or small for gestational age. While recently in IVF children cardiometabolic differences have been demonstrated, there might also be risks for disturbance in cognitive functions. Therefore, this study examined information processing, attention and visual-motor function in pubertal IVF children compared with spontaneously conceived controls from subfertile parents. Results of these cognitive functions were then related to cardiometabolic measures to explore whether both can be explained by changes in fetal programming due to IVF. METHODS: A total of 139 IVF and 143 control adolescents underwent various neuropsychological tests to measure information processing, attention and visual-motor function. The results were then related to data on blood pressure and glucose levels previously obtained from the same groups. RESULTS: No differences between IVF and control adolescents were found in the various test results for information processing and attention. A slight difference was found between the groups for motor speed, but these scores were within the normal range for the test. No direct relation was found between cognitive measures and cardiometabolic outcome. CONCLUSIONS: Comparison of IVF adolescents and controls revealed no disturbances in information processing, attention and visual-motor function. In addition, these cognitive functions were not directly related to cardiometabolic outcome. Therefore, these results do not support the hypothesis that cognition is influenced by IVF conception or an altered programming of metabolic systems due to IVF, and indicate that cognitive abilities in IVF children, as measured by the tasks assessed, appear to develop normally.

Effects of cross-sex hormones on cerebral activation during language and mental rotation: An fMRI study in transsexuals.

Androgens and estrogens affect the performance on certain cognitive tests, particularly those measuring verbal fluency and mental rotation. Their effects on cognition have frequently been attributed to changes in cerebral lateralization. This study tested the impact of a reversal of the sex steroid milieu on cerebral activation and lateralization during verbal and spatial tasks in transsexuals. fMRI scans were obtained from 6 female-to-male and 8 male-to-female transsexuals at baseline and after cross-sex steroid treatment. Activation was measured during language and mental rotation tasks. Language activation increased after sex steroid treatment in both groups (F(1,12) =3.7, p=0.08), and total language activity was correlated to post-treatment estradiol levels (rho=0.54, p=0.05). Lateralization was not affected by the reversal of sex steroid milieus (F(1,12)=1.47, p=0.25). Activation during mental rotation did not increase during treatment (F(1,12)=0.54, p=0.34), but post-treatment testosterone levels correlated to total activation during mental rotation (rho=0.64, p=0.01). Findings suggest that sex steroids may influence cerebral activation, but lateralization remains stable.

Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development.

Ambiguous genitalia of the newborn is the paradigm of a disorder of sex development that demands a multidisciplinary team approach to management. The problem is immediately apparent at birth. Abnormalities of the external genitalia sufficient to warrant genetic and endocrine studies occur in one in 4500 births. In recent decades there have been improvements in diagnosis and early management, particularly with respect to congenital adrenal hyperplasia, the commonest cause of ambiguous genitalia of the newborn. However, dissatisfaction with overall management remains. A Clinical Guidelines and Handbook for Parents generated by a partnership of health professionals and support groups is available on the internet. The professional societies representing paediatric endocrinology responded by organizing a consensus meeting on the management of intersex. This resulted in the publication of a Consensus Statement encompassing many aspects of management, extending from birth to adulthood.

[Concerns relating to care for transsexuals]. / Zorgen rond de zorg aan transseksuelen.

In the last decade, transsexual patients have increasingly sought sex reassignment (cross-sex hormones and sex reassignment surgery), whilst avoiding adequate diagnostic procedures. They ask non-specialized physicians to prescribe hormones or to perform sex reassignment surgery. Sometimes hormones are ordered through the Internet or obtained from other illegitimate sources. If these patients later turn to a specialized team (for instance for sex reassignment surgery), the obligatory standard diagnostic procedure is problematic: the patient does not accept having to go through a long period of assessment and objective decisionmaking, while the attending health professional feels pressured by the patient's impatience. Non-expert health professionals should draw patients' attention to the necessity of a thorough diagnostic procedure, thus avoiding wrong decisions and future regrets.

Do adolescent anorexia nervosa patients have deficits in emotional functioning?

Adult eating disorder patients have been characterised by alexithymia. We investigated whether adolescent eating disorder patients also show deficits in emotional functioning. To measure emotional functioning a questionnaire (the TAS) and an emotion recognition test were administered to 30 eating disorder (ED) adolescent girls and 31 healthy controls (HC), matched for age, education, and social status. Non-emotional, cognitive parallel tasks were administered on the same occasion to find out whether a possible deficit was emotion-specific or of a more general cognitive nature. The ED patients scored higher on the TAS and performed worse on the emotion recognition test, but no differences between the groups were found on the non-emotional cognitive instruments. It was concluded that adolescent eating disorder patients, just like adult eating disorder patients, are characterised by alexithymia and show specific deficits in emotional functioning. The implications of these findings are discussed.

Association of prenatal phenobarbital and phenytoin exposure with genital anomalies and menstrual disorders.

BACKGROUND: Animal studies demonstrated that early exposure to phenobarbital decreases reproductive function. This study investigates whether prenatal exposure to these anticonvulsants affects human genital tract development. METHODS: Genital anomalies at birth were studied retrospectively in 90 phenobarbital-exposed, 108 phenobarbital plus phenytoin-exposed, and 198 matched control infants. Of this group, 72 drug-exposed males, 75 drug-exposed females, and 147 matched control subjects participated in a follow-up and were interviewed at age 19-35. Differences between groups were tested by chi-square and t-tests. RESULTS: A total of 15% of the phenobarbital-exposed boys versus 2.8% control boys had undescended testes at birth. More anticonvulsant-exposed (24%) than control males (11%) had received medical treatment for genital anomalies. Anticonvulsant-exposed females more often had irregularities in menstrual cycles (31% vs. 17%) and bleeding (15% vs. 3%) and reported more problems during pregnancy. CONCLUSIONS: Prenatal exposure to anticonvulsants seems to induce minor genital anomalies and may affect reproductive function.