Children and adolescents in the Amsterdam Cohort of Gender Dysphoria: trends in diagnostic- and treatment trajectories during the first 20 years of the Dutch Protocol.

BACKGROUND: Twenty years ago, the Dutch Protocol-consisting of a gonadotropin-releasing hormone agonist (GnRHa) to halt puberty and subsequent gender-affirming hormones (GAHs)-was implemented to treat adolescents with gender dysphoria. AIM: To study trends in trajectories in children and adolescents who were referred for evaluation of gender dysphoria and/or treated following the Dutch Protocol. METHODS: The current study is based on a retrospective cohort of 1766 children and adolescents in the Amsterdam Cohort of Gender Dysphoria. OUTCOMES: Outcomes included trends in number of intakes, ratio of assigned sex at birth, age at intake, age at start of GnRHa and GAH, puberty stage at start of GnRHa, proportions of adolescents starting and stopping GnRHa, reasons for refraining from GnRHa, and proportions of people undergoing gender-affirming surgery. RESULTS: A steep increase in referrals was observed over the years. A change in the AMAB:AFAB ratio (assigned male at birth to assigned female at birth) was seen over time, tipping the balance toward AFAB. Age at intake and at start of GnRHa has increased over time. Of possibly eligible adolescents who had their first visit before age 10 years, nearly half started GnRHa vs around two-thirds who had their first visit at or after age 10 years. The proportion starting GnRHa rose only for those first visiting before age 10. Puberty stage at start of GnRHa fluctuated over time. Absence of gender dysphoria diagnosis was the main reason for not starting GnRHa. Very few stopped GnRHa (1.4%), mostly because of remission of gender dysphoria. Age at start of GAH has increased mainly in the most recent years. When a change in law was made in July 2014 no longer requiring gonadectomy to change legal sex, percentages of people undergoing gonadectomy decreased in AMAB and AFAB. CLINICAL IMPLICATIONS: A substantial number of adolescents did not start medical treatment. In the ones who did, risk for retransitioning was very low, providing ongoing support for medical interventions in comprehensively assessed gender diverse adolescents. STRENGTHS AND LIMITATIONS: Important topics on transgender health care for children and adolescents were studied in a large cohort over an unprecedented time span, limited by the retrospective design. CONCLUSION: Trajectories in diagnostic evaluation and medical treatment in children and adolescents referred for gender dysphoria are diverse. Initiating medical treatment and need for surgical procedures depends on not only personal characteristics but societal and legal factors as well.

Sexual Self-Concept in Women with Disorders/Differences of Sex Development.

Many women born with disorders or differences of sex development (DSD) report sexual problems, in particular women who have undergone extensive genital reconstruction. Examining cognitions and emotions that hinder or promote sexuality may facilitate understanding these sexual problems and may contribute to the development of specific interventions. In this study, sexual self-concept, body image, and sexual functioning were investigated in relation to genital surgery. To conduct the study, the women's Sexual Self-Concept Scale was translated to Dutch. Evaluation of psychometric properties was conducted in a sample of healthy Belgian and Dutch women participating in an anonymous web-based survey (N = 589, Mdn age, 23 years). The resulting three-factor structure corresponded largely to that of the original version. Compared to control women, women born with a DSD who were included in the Dutch DSD study (N = 99, Mdn age, 26 years) described themselves as being less interested in sex and less sexually active. These women also harbored more negative emotions and cognitions regarding their sexuality and were less satisfied with their external genitalia. In women with a DSD, sexual self-concept was associated with compromised outcomes on sexual functioning and distress. Women who were in a steady relationship, and/or had been sexually active in the past 4 weeks had a more positive sexual self-concept, took a more active role in their sexual relationship, experienced more sexual desire and arousal and less sexual distress than women who were not involved in a partner relationship. Findings in this study indicate that cognitions and emotions related to sexual self-concept play a role in sexual functioning of women with a DSD. A cognitive behavioral counseling approach with focus on coping and exploration of their own sexual needs could prove useful in this group.

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.

Psychological symptoms and body image in individuals with gender dysphoria: A comparison between Iranian and Dutch clinics.

Background: Few studies have compared the psychological functioning of individuals with gender dysphoria in Western and non-Western cultures. To our knowledge, this is the first study comparing the mental health of transgender individuals from an Islamic and non-Islamic country (Iran and the Netherlands). Methods: In this study, the psychological functioning and body image of 163 individuals with gender dysphoria (100 transgender women (75 in the Netherlands, 25 in Iran) and 63 transgender men (45 in the Netherlands, 18 in Iran) in two clinics located in Iran (N = 43) and the Netherlands (N = 120) was evaluated using the SCL-90 and the Body Image Scale (BIS). Also, none of these individuals had yet received hormonal therapy and/or surgery in their clinics. Results: Dutch participants (M = 31.56, SD = 12.26) were older than Iranian participants (M = 25.21, SD = 3.04). Dutch transwomen were less often androphilic (sexually attracted to men) than Iranian transwomen, and Iranian trans people were more often bisexual than the Dutch trans people. Significantly more Dutch transgender people were married (we had no information about the gender of the spouse), and indicated to have more contact with their families than the participants in Iran. The participants from Iran had significantly more psychological complaints than the Dutch participants. Compared to participants in Iran, participants in the Netherlands were more dissatisfied with their secondary sexual characteristics and neutral body characteristics, but there was no significant difference between the countries in terms of satisfaction with primary sex characteristics. Conclusions: Although transgender people in many countries face social and mental health problems, this study suggests that socio-cultural factors may increase the likelihood of psychopathology.

Changes in Adrenal Androgens During Puberty Suppression and Gender-Affirming Hormone Treatment in Adolescents With Gender Dysphoria.

INTRODUCTION: Gender-affirming hormone treatment is known to affect adrenal androgen levels in adult individuals with gender dysphoria (GD). This may be clinically relevant because the adrenal gland plays a critical role in many different metabolic processes. AIM: This study aims to assess the effects of gonadotropin-releasing hormone analogs (GnRHa) treatment and gender-affirming hormone treatment on adrenal androgen levels in adolescents with GD. METHODS: In this prospective study, dehydroepiandrosterone-sulfate (DHEAS) and androstenedione values were measured every 6 months during 2 years of GnRHa treatment only, and 2 years of GnRHa combined with gender-affirming hormone treatment (estradiol or testosterone) in 73 transgirls and 54 transboys. To determine trends in adrenal androgen levels a linear mixed model was used to approximate androgen levels. MAIN OUTCOME MEASURES: DHEAS and androstenedione levels were the main outcome measures. RESULTS: DHEAS levels rose in transboys during GnRHa treatment, which may represent the normal increase during adolescence. In transgirls no change in DHEAS levels during GnRHa treatment was found. Gender-affirming hormone treatment did not affect DHEAS levels in either sex. In transboys androstenedione levels decreased during the first year of GnRHa treatment, which may reflect reduced ovarian androstenedione synthesis, and rose during the first year of gender-affirming hormone treatment, possibly due to conversion of administered testosterone. In transgirls androstenedione levels did not change during either GnRHa or gender-affirming hormone treatment. CLINICAL IMPLICATIONS: No deleterious effects of treatment on adrenal androgen levels were found during approximately 4 years of follow-up. STRENGTHS & LIMITATIONS: This is one of the largest cohort of adolescents with GD, treated using a uniform protocol, with standardized follow-up. The lack of a control group is a limitation. CONCLUSION: The changes in androstenedione levels during GnRHa and gender-affirming hormone treatment in transboys may not be of adrenal origin. The absence of changes in androstenedione levels in transgirls or DHEAS levels in either sex during gender-affirming hormone treatment suggests that gender-affirming hormone treatment does not significantly affect adrenal androgen production. Schagen SEE, Lustenhouwer P, Cohen-Kettenis PT, et al. Changes in Adrenal Androgens During Puberty Suppression and Gender-Affirming Hormone Treatment in Adolescents With Gender Dysphoria. J Sex Med 2018;15:1357-1363.

Surgical Satisfaction, Quality of Life, and Their Association After Gender-Affirming Surgery: A Follow-up Study.

We assessed the outcomes of gender-affirming surgery (GAS, or sex-reassignment surgery) 4 to 6 years after first clinical contact, and the associations between postoperative (dis)satisfaction and quality of life (QoL). Our multicenter, cross-sectional follow-up study involved persons diagnosed with gender dysphoria (DSM-IV-TR) who applied for medical interventions from 2007 until 2009. Of 546 eligible persons, 201 (37%) responded, of whom 136 had undergone GAS (genital, chest, facial, vocal cord and/or thyroid cartilage surgery). Main outcome measures were procedure performed, self-reported complications, and satisfaction with surgical outcomes (standardized questionnaires), QoL (Satisfaction With Life Scale, Subjective Happiness Scale, Cantril Ladder), gender dysphoria (Utrecht Gender Dysphoria Scale), and psychological symptoms (Symptom Checklist-90). Postoperative satisfaction was 94% to 100%, depending on the type of surgery performed. Eight (6%) of the participants reported dissatisfaction and/or regret, which was associated with preoperative psychological symptoms or self-reported surgical complications (OR = 6.07). Satisfied respondents' QoL scores were similar to reference values; dissatisfied or regretful respondents' scores were lower. Therefore, dissatisfaction after GAS may be viewed as indicator of unfavorable psychological and QoL outcomes.

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.

Efficacy and Safety of Pubertal Induction Using 17ß-Estradiol in Transgirls.

Context: Puberty suppression using gonadotropin-releasing hormone agonists, followed by induction of the desired sex characteristics using sex steroids, has been recommended by the current guidelines as the treatment of choice for gender dysphoric adolescents, although little evidence is available. Aim: To evaluate the efficacy and safety of estrogen treatment for pubertal induction in transgirls (female-identifying adolescents assigned male at birth). Methods: Twenty-eight adolescents treated with oral estrogen for ≥1 year were included. The Tanner stage, anthropometry, laboratory parameters, bone age, and body composition were evaluated. Results: Breast development started within 3 months in 83% of adolescents, and after 3 years, 86% had Tanner breast stage 4 to 5. The hip circumference increased and the waist/hip ratio decreased. The median serum estradiol was 100 pmol/L (range, 24 to 380) at the standard adult dose of 2 mg of 17ß-estradiol. The adult height standard deviation score was +1.9 (for females). The body mass index standard deviation score, lean body mass percentage, fat percentage, and blood pressure did not change. No abnormalities of creatinine or liver enzymes were detected, and the hematocrit and hemoglobin A1c did not change. One individual developed hyperprolactinemia during high-dose ethinylestradiol treatment to limit growth. Conclusions: Pubertal induction using estradiol is effective; however, an adult dose of 2 mg does not always result in appropriate serum estradiol levels. Monitoring renal function, liver enzymes, hematocrit, and hemoglobin A1c during pubertal induction with estradiol is not necessary. Further studies are needed to establish effective and safe methods to limit growth.

Effects of Medical Interventions on Gender Dysphoria and Body Image: A Follow-Up Study.

OBJECTIVE: The aim of this study from the European Network for the Investigation of Gender Incongruence is to investigate the status of all individuals who had applied for gender confirming interventions from 2007 to 2009, irrespective of whether they received treatment. The current article describes the study protocol, the effect of medical treatment on gender dysphoria and body image, and the predictive value of (pre)treatment factors on posttreatment outcomes. METHODS: Data were collected on medical interventions, transition status, gender dysphoria (Utrecht Gender Dysphoria Scale), and body image (Body Image Scale for transsexuals). In total, 201 people participated in the study (37% of the original cohort). RESULTS: At follow-up, 29 participants (14%) did not receive medical interventions, 36 hormones only (18%), and 136 hormones and surgery (68%). Most transwomen had undergone genital surgery, and most transmen chest surgery. Overall, the levels of gender dysphoria and body dissatisfaction were significantly lower at follow-up compared with clinical entry. Satisfaction with therapy responsive and unresponsive body characteristics both improved. High dissatisfaction at admission and lower psychological functioning at follow-up were associated with persistent body dissatisfaction. CONCLUSIONS: Hormone-based interventions and surgery were followed by improvements in body satisfaction. The level of psychological symptoms and the degree of body satisfaction at baseline were significantly associated with body satisfaction at follow-up.

Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents.

INTRODUCTION: Puberty suppression using gonadotropin-releasing hormone agonists (GnRHas) is recommended by current guidelines as the treatment of choice for gender dysphoric adolescents. Although GnRHas have long been used to treat precocious puberty, there are few data on the efficacy and safety in gender dysphoric adolescents. Therefore, the Endocrine Society guideline recommends frequent monitoring of gonadotropins, sex steroids, and renal and liver function. AIM: To evaluate the efficacy and safety of GnRHa treatment to suppress puberty in gender dysphoric adolescents. METHODS: Forty-nine male-to-female and 67 female-to-male gender dysphoric adolescents treated with triptorelin were included in the analysis. MAIN OUTCOME MEASURES: Physical examination, including assessment of Tanner stage, took place every 3 months and blood samples were drawn at 0, 3, and 6 months and then every 6 months. Body composition was evaluated using dual energy x-ray absorptiometry. RESULTS: GnRHa treatment caused a decrease in testicular volume in 43 of 49 male-to-female subjects. In one of four female-to-male subjects who presented at Tanner breast stage 2, breast development completely regressed. Gonadotropins and sex steroid levels were suppressed within 3 months. Treatment did not have to be adjusted because of insufficient suppression in any subject. No sustained abnormalities of liver enzymes or creatinine were encountered. Alkaline phosphatase decreased, probably related to a slower growth velocity, because height SD score decreased in boys and girls. Lean body mass percentage significantly decreased during the first year of treatment in girls and boys, whereas fat percentage significantly increased. CONCLUSION: Triptorelin effectively suppresses puberty in gender dysphoric adolescents. These data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function is not necessary during treatment with triptorelin. Further studies should evaluate the extent to which changes in height SD score and body composition that occur during GnRHa treatment can be reversed during subsequent cross-sex hormone treatment.

Perceptions of Sex, Gender, and Puberty Suppression: A Qualitative Analysis of Transgender Youth.

International guidelines recommend the use of Gonadotropin-Releasing Hormone (GnRH) agonists in adolescents with gender dysphoria (GD) to suppress puberty. Little is known about the way gender dysphoric adolescents themselves think about this early medical intervention. The purpose of the present study was (1) to explicate the considerations of gender dysphoric adolescents in the Netherlands concerning the use of puberty suppression; (2) to explore whether the considerations of gender dysphoric adolescents differ from those of professionals working in treatment teams, and if so in what sense. This was a qualitative study designed to identify considerations of gender dysphoric adolescents regarding early treatment. All 13 adolescents, except for one, were treated with puberty suppression; five adolescents were trans girls and eight were trans boys. Their ages ranged between 13 and 18 years, with an average age of 16 years and 11 months, and a median age of 17 years and 4 months. Subsequently, the considerations of the adolescents were compared with views of clinicians treating youth with GD. From the interviews with the gender dysphoric adolescents, three themes emerged: (1) the difficulty of determining what is an appropriate lower age limit for starting puberty suppression. Most adolescents found it difficult to define an appropriate age limit and saw it as a dilemma; (2) the lack of data on the long-term effects of puberty suppression. Most adolescents stated that the lack of long-term data did not and would not stop them from wanting puberty suppression; (3) the role of the social context, for which there were two subthemes: (a) increased media-attention, on television, and on the Internet; (b) an imposed stereotype. Some adolescents were positive about the role of the social context, but others raised doubts about it. Compared to clinicians, adolescents were often more cautious in their treatment views. It is important to give voice to gender dysphoric adolescents when discussing the use of puberty suppression in GD. Otherwise, professionals might act based on assumptions about adolescents' opinions instead of their actual considerations. We encourage gathering more qualitative research data from gender dysphoric adolescents in other countries.

Does polycystic ovary syndrome affect cognition? A functional magnetic resonance imaging study exploring working memory.

OBJECTIVE: To study effects of overexposure to androgens and subsequent antiandrogenic treatment on brain activity during working memory processes in women with polycystic ovary syndrome (PCOS). DESIGN: In this longitudinal study, working memory function was evaluated with the use of functional magnetic resonance imaging (MRI) in women with PCOS before and after antiandrogenic treatment. SETTING: Department of reproductive medicine, university medical center. PATIENT(S): Fourteen women with PCOS and with hyperandrogenism and 20 healthy control women without any features of PCOS or other hormonal disorders. INTERVENTION(S): Antiandrogenic hormone treatment. MAIN OUTCOME MEASURE(S): Functional MRI response during a working memory task. RESULT(S): At baseline women with PCOS showed more activation than the control group within the right superior parietal lobe and the inferior parietal lobe during task (all memory conditions). Task performance (speed and accuracy) did not differ between the groups. After antiandrogenic treatment the difference in overall brain activity between the groups disappeared and accuracy in the high memory load condition of the working memory task increased in women with PCOS. CONCLUSION(S): Women with PCOS may need additional neural resources during a working memory task compared with women without PCOS, suggesting less efficient executive functioning. This inefficiency may have effects on daily life functioning of women with PCOS. Antiandrogenic treatment appears to have a beneficial effect on this area of cognitive functioning. CLINICAL TRIAL REGISTRATION NUMBER: NTR2493.

Partial Treatment Requests and Underlying Motives of Applicants for Gender Affirming Interventions.

INTRODUCTION: Historically, only individuals with a cross-gender identity who wanted to receive a full treatment, were eligible for "complete sex reassignment" consisting of feminizing/masculinizing hormone treatment and several surgical interventions including genital surgery (full treatment). Currently, it is unclear what motives underlie a request for hormones only or surgery only or a combination of hormones and surgery (e.g., a mastectomy), but no genital surgery (partial treatment). AIMS: The aims of this study were (i) to describe treatment requests of applicants at a specialized gender identity clinic in the Netherlands; and (ii) to explore the motives underlying a partial treatment request, including the role of (non-binary) gender identity. METHODS: Information was collected on all 386 adults who applied for treatment at the Center of Expertise on Gender Dysphoria of the VU University Medical Center in Amsterdam, the Netherlands, in the year 2013. Treatment requests were available for 360 individuals: 233 natal men (64.7%) and 127 natal women (35.3%). Treatment requests were systematically collected during assessment. Individuals were classified as either desiring a full or partial treatment. The motives behind a partial treatment request were collected and categorized as well. RESULTS: The majority of applicants at our gender identity clinic requested full treatment. Among those who requested partial treatment, the most reported underlying motive was surgical risks/outcomes. Only a small number of applicants requested partial treatment to bring their body into alignment with their non-binary gender identity. CONCLUSION: It becomes clear that partial treatment is requested by a substantial number of applicants. This emphasizes the need for gender identity clinics to provide information about the medical possibilities and limitations, and careful introduction and evaluation of non-standard treatment options.

Early Medical Treatment of Children and Adolescents With Gender Dysphoria: An Empirical Ethical Study.

PURPOSE: The Endocrine Society and the World Professional Association for Transgender Health published guidelines for the treatment of adolescents with gender dysphoria (GD). The guidelines recommend the use of gonadotropin-releasing hormone agonists in adolescence to suppress puberty. However, in actual practice, no consensus exists whether to use these early medical interventions. The aim of this study was to explicate the considerations of proponents and opponents of puberty suppression in GD to move forward the ethical debate. METHODS: Qualitative study (semi-structured interviews and open-ended questionnaires) to identify considerations of proponents and opponents of early treatment (pediatric endocrinologists, psychologists, psychiatrists, ethicists) of 17 treatment teams worldwide. RESULTS: Seven themes give rise to different, and even opposing, views on treatment: (1) the (non-)availability of an explanatory model for GD; (2) the nature of GD (normal variation, social construct or [mental] illness); (3) the role of physiological puberty in developing gender identity; (4) the role of comorbidity; (5) possible physical or psychological effects of (refraining from) early medical interventions; (6) child competence and decision making authority; and (7) the role of social context how GD is perceived. Strikingly, the guidelines are debated both for being too liberal and for being too limiting. Nevertheless, many treatment teams using the guidelines are exploring the possibility of lowering the current age limits. CONCLUSIONS: As long as debate remains on these seven themes and only limited long-term data are available, there will be no consensus on treatment. Therefore, more systematic interdisciplinary and (worldwide) multicenter research is required.

Adolescents with gender dysphoria.

Young people with gender dysphoria are increasingly seen by pediatric endocrinologists. Mental health child specialists assess the adolescent and give advice about psychological or medical treatment. Provided they fulfill eligibility and readiness criteria, adolescents may receive pubertal suspension, consisting of using gonadotrophin-releasing hormone analogs, later followed by cross-sex hormones (sex steroids of the experienced gender). If they fulfill additional criteria, they may have various types of gender affirming surgery. Current issues involve safety aspects. Although generally considered safe in the short-term, the long-term effects regarding bone health and cardiovascular risks are still unknown. Therefore, vigilance is warranted during and long after completion of the last gender affirming surgeries. The timing of the various treatment steps is also under debate: instead of fixed age limits, the cognitive and emotional maturation, along with the physical development, are now often considered as more relevant.

Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria.

Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether the performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD.

Young adult psychological outcome after puberty suppression and gender reassignment.

BACKGROUND: In recent years, puberty suppression by means of gonadotropin-releasing hormone analogs has become accepted in clinical management of adolescents who have gender dysphoria (GD). The current study is the first longer-term longitudinal evaluation of the effectiveness of this approach. METHODS: A total of 55 young transgender adults (22 transwomen and 33 transmen) who had received puberty suppression during adolescence were assessed 3 times: before the start of puberty suppression (mean age, 13.6 years), when cross-sex hormones were introduced (mean age, 16.7 years), and at least 1 year after gender reassignment surgery (mean age, 20.7 years). Psychological functioning (GD, body image, global functioning, depression, anxiety, emotional and behavioral problems) and objective (social and educational/professional functioning) and subjective (quality of life, satisfaction with life and happiness) well-being were investigated. RESULTS: After gender reassignment, in young adulthood, the GD was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population. Improvements in psychological functioning were positively correlated with postsurgical subjective well-being. CONCLUSIONS: A clinical protocol of a multidisciplinary team with mental health professionals, physicians, and surgeons, including puberty suppression, followed by cross-sex hormones and gender reassignment surgery, provides gender dysphoric youth who seek gender reassignment from early puberty on, the opportunity to develop into well-functioning young adults.

Severity of virilization is associated with cosmetic appearance and sexual function in women with congenital adrenal hyperplasia: a cross-sectional study.

INTRODUCTION: Women with the classical form of congenital adrenal hyperplasia (CAH) are born with different degrees of virilization of the external genitalia. Feminizing surgery is often performed in childhood to change the appearance of the genitalia and to enable penile-vaginal intercourse later in life. There are suggestions that this affects sexual functioning. AIMS: The aim is to study the anatomical, surgical, cosmetic, and psychosexual outcomes in women with CAH. METHODS: Forty women with CAH, aged over 15 years, from two referral centers for management of Disorders of Sex Development in the Netherlands were included. Physical and functional status were assessed by a gynecological interview and examination. Sexual functioning was assessed with the Female Sexual Function Index and Female Sexual Distress Scale-Revised scales and compared with a reference group. MEAN OUTCOME MEASURES: Surgery performed, anatomy, cosmetic score, sexual function and distress. RESULTS: Thirty-six of the 40 women had undergone feminizing surgery; 25 women (69%) underwent more than one operation. Resurgery was performed in seven of the 13 (54%) women who had had a single-stage procedure. Anatomical assessment showed reasonable outcomes. Multiple linear regression showed that only level of confluence had a significant effect on cosmetic outcome, the impact depending on the number of surgeries performed. Cosmetic evaluations did not differ between the women and the gynecologists. Only 20 women had experience of intercourse. Eight women reported dyspareunia; seven women reported urinary incontinence. The women's perceived sexual functioning was less satisfactory than in the reference group, and they reported more sexual distress. CONCLUSION: The level of confluence was the major determinant for cosmetic outcome; the impact depended on the number of surgeries performed. Fifty-four percent of the women required resurgery after a single-stage procedure in childhood. Anatomical assessment showed reasonable outcomes. The women evaluated their sexual functioning and functional outcome less favorable than the reference group, and they experienced less often sexual intercourse.

Psychological aspects of the treatment of patients with disorders of sex development.

Research on the psychological development of persons with Disorders of Sex Development (DSD) has focused on understanding the influence of atypical sex hormone exposure during steroid-sensitive periods of prenatal brain development on the process of psychosexual differentiation (i.e., gender identity, gender role, and sexual orientation). In contrast, analysis of clinical management strategies has focused on gender assignment and the desirability and timing of genital surgery. This review focuses on the psychological issues that confront clinicians managing the care of persons born with DSD and their families. Particular attention is paid to processes and factors that potentially mediate or moderate psychosocial and psychosexual outcomes within and across developmental stages.

Treatment of adolescents with gender dysphoria in the Netherlands.

In the Netherlands, gender dysphoric adolescents may be eligible for puberty suppression at age 12, subsequent cross-sex hormone treatment at age 16, and gender reassignment surgery at age 18. Initially, a thorough assessment is made of the gender dysphoria and vulnerabilities in functioning or circumstances. Psychological interventions and/or gender reassignment may be offered. Psychological interventions are offered if the adolescent needs to explore gender identity and treatment wishes, suffers from coexisting problems, or needs support and counseling during gender reassignment. Although more studies are necessary, this approach seems to contribute significantly to the well-being of gender dysphoric adolescents.