Keywords: Gender Dysphoria; Gender Incongruence; Pediatric Transgender; Pediatric Endocrinology; GnRH analogue; Gender-Affirming Hormones.

Introduction

The number of youths with gender dysphoria (GD) and gender identity disorders seeking hormonal or other care seems to be rising in many countries worldwide [1-5].Therefore, efforts are directed towards setting standards of care and identifying areas of uncertainties in order to provide safe treatments in the short and long-term, and to promote corresponding research. Terminology in the field is a sensitive issue, varies and has been updated recently by the World Health Organization (WHO) [6]. In the 10th edition of the International Classification of Diseases (ICD10) of the WHO [7], which was in use until 2021, the diagnostic category was transsexualism. Therein transsexualism has been defined as the “desire to live and be accepted as a member of the opposite sex, usually accompanied by a sense of discomfort with, or inappropriateness of, one’s anatomic sex, and a wish to have surgery and hormonal treatment to make one’s body as congruent as possible with one’s preferred sex”. In the current version of ICD-11 [6], which is in effect since 2022, the diagnostic category “transsexualism” has been replaced with “gender incongruence” (GI), with the more comprehensive definition of “marked and persistent incongruence between an individual’s experienced gender and the assigned sex”.

The typically binary sex (female or male) is usually recorded at birth based on the appearance of the external genital organs. By contrast, gender identity refers to the personal sense of self in a holistic sense of the whole spectrum of male, female, in-between or beyond, and it can be binary or non-binary [8]. The development and self-recognition of gender identity is part of the individual psychological and sexual development, for which awareness mostly arises with puberty, although earlier or later occurrence is also possible [9-11]. To diagnose transsexualism, an assessment by a mental health professional has been recommended, especially in youths [12]. If desired, the individual may then be referred to an endocrinologist for hormonal therapies. Although the etiology of GD/GI and transsexualism has been investigated by several studies [13-21], it remains unsolved. Likewise, the exact prevalence of GD and transsexualism is unclear.

In the adult population, the prevalence of treated individuals with GD is 4.6 in 100,000 and shows a preponderance of trans females over trans males of 6.8 to 2.6 per 100,000, respectively [22]. In youth, the estimated prevalence is based on self-reported surveys and ranges from 0.5% to 2.7% [1, 23-25], with an overall increase in the last two decades [1, 2, 26]. More specifically, the self-reported prevalence for transsexualism has been reported with 1.2% to 1.3% [23, 24], and for GD with 2.7% [27]. Adolescents with GD and transsexualism have a statistically significant higher prevalence of psychiatric disorders and suicidal attempts compared to their cisgender peers [28-32]. A positive effect of gender-affirming hormones (GAH) has been suggested in the adult population [33]. Likewise, improved psychosocial functioning and decreased depression and anxiety were recently reported after 2 years of GAH treatment in GD youths [34].

The first report on hormonal and surgical treatment of transgender adults dates back to the early 1900s. However, only in 1979 the now-called World Professional Association for Transgender Health (WPATH) published the first standards of care. This guideline for professionals has since been updated to the 8th Version in 2022 [35]. In the pediatric and adolescent transgender population, the first report on hormonal interventions came from The Netherlands in 1987 [36]. It describes a two-step approach for hormonal treatments. This approach is still recommended in current guidelines from the Endocrine Society [12], with step 1 comprising of pubertal suppression with a gonadotropin-releasing hormone analogue (GnRHa), and step 2 that of GAH therapy (testosterone or estrogen). In addition, step 3 consists of surgical treatments, which should only be offered to adults.

Hormonal treatments of youth with transsexualism may not only have positive effects. Possible adverse effects on the developing brain and on psychological and psychosocial formation are critically discussed [37-40]. Other adverse effects may concern growth, body composition and physiognomy, fertility, bone health, cardiovascular as well as cancer risk [41-47]. Data on most of these topics are scarce and controversial; thus, further studies are needed.

This study aimed at characterizing individuals referred to a pediatric tertiary care center in Switzerland for GD during the last decade and comparing the findings of youth diagnosed and treated for transsexualism to other cohorts published in the literature.

Materials and methods

This observational study was conducted in a tertiary care center at the University Children's Hospital Bern, Switzerland, which started offering interdisciplinary transgender care in 2012. This center is one of the five University Hospitals in the country providing tertiary care to about 1.5 million of the Swiss population. Retrospective data analysis was allowed without informed consent under ethical approval BASEC ID 2016-01210. Inclusion criteria were age <18 years and referral to our center for GD. Exclusion criteria for being part of the group of hormonally treated individuals were chromosomal or anatomical anomalies (difference of sex development, DSD), not hormonally treated, or not treated at our center.

Referred children and adolescents were first evaluated by a mental health professional, who assessed GD and specifically diagnosed transsexualism according to the ICD-10 [7]. Only individuals with a diagnosis of transsexualism desiring a hormonal therapy were then seen in our endocrine clinic. Clinical assessment included medical history, physical exam, and laboratory analyses as recommended [12]. Only hormonal therapies of step 1 and 2 were offered, while surgical interventions (step 3) were not supported by our team. Clinical and anthropometrical data of children and adolescents were extracted from the electronic health record system from January 2012 to September 2021. In general, data are shown as absolute numbers, median, and range. Standard deviations (SD) of height and body mass index (BMI) were calculated for the sex recorded at birth according to the charts of the WHO [48]. The pubertal development was assessed by the Tanner stage [49, 50]. Bone mineral density (BMD) was evaluated with bone densitometry (DXA) of hip and spine according to the sex recorded at birth and expressed conforming to NHANES (National Health and Nutrition Examination Survey) and WHO charts [48, 51]. The results of DXA were categorized as “low” or “normal” BMD according to the International Society of Clinical Densitometry [52] with low BMD describing at least one of the two z-scores ≤ -2.0 SD.

In addition, a short questionnaire was sent to the leaders of the pediatric endocrine units of the nine largest children’s hospitals in Switzerland, asking for minimal information on their GD and transgender cohorts (e.g., size of cohort, numbers of new referrals per year in the past 5 to 10 years) to compare our data at a national level.

Data analysis was mostly descriptive taking the small numbers into account. Nevertheless, significance of increase in the number of GD and transsexual youths over the years was calculated with a linear regression. A paired t-test was used to analyze for statistically significant differences of height and BMI (on normalized data in SD) between step 1 and 2 of therapies in the GAH-treated subgroup. Statistical significance was set at p ≤ 0.05. Statistical analysis was performed with the Python package stats model [53].

Results

From 2012 to 2021, 57 children and adolescents were referred to the University Children Hospital for GD. Of these, 41 were biologic females, 14 biologic males, and two individuals had a diagnosis of a 46, XY DSD, recorded female at birth. The median age at referral was 14.9 years (range, 4.6-17.9 years). Of the 57 individuals evaluated by our mental health professionals, 45 had a diagnosis of transsexualism in conformity with ICD-10 [7] and 31 received hormonal treatments (Figure 1), 28 at our endocrine center (Table 1). Over the past 10 years, numbers of subjects with GD and transsexualism increased statistically significant at our center, while numbers of hormonally treated subjects with transsexualism increased less pronounced (Figure 2). Further characteristics of the GD group and the subgroup of hormonally treated individuals with transsexualism are depicted in Figure 3. Age and Tanner stage at referral and at the start of hormonal therapy as well as frequency of psychiatric comorbidities are shown. Referral for GD occurred mostly after 10 years of age and after puberty onset; only 7 children (out of them 4 with transsexualism) were seen at a younger age (Fig. 3A, B). Pubertal hormone suppression was started at the earliest at 10 years of age and a Tanner stage 2, but in most patients after 14 years of age and a Tanner stage 4 (Fig. 3D, E). Cross-sex GAH treatment was started at the earliest at 14 years of age (Fig. 3D). Psychiatric comorbidities were diagnosed in 42% of subjects in the GD group and in 61% in the subgroup of hormonally treated youths with transsexualism (Fig. 3C, F). Additional data for analysis were only available from the group of youths with transsexualism receiving hormonal treatment at our center (Table 1). Of these 28 teenagers, 22 (78%) were trans males and 6 (21%) trans females, 17 (61%) had psychiatric comorbidities, and drug abuse was recorded in three individuals. Psychiatric comorbidities were assessed by certified psychiatrists and specialized psychologists before being referred to the endocrine clinic and included mainly depression/ self-harm attitude (n = 13), autism spectrum- and attention-deficit/ hyperactivity disorders (n = 4). In the cohort, there were suicidal ideations (n = 3), but no suicidal attempts were recorded.

Table 1:  Characteristics of subjects with transsexualism hormonally treated at our center (n = 28); Psychiatric comorbidities: 3 main categories: D: Depression/Suicidal/Self-harm; ADHD (attention-deficit/hyperactivity disorders)/Asperger; M: mental disorders (ID 5 dissociative disorders, ID 23 unclear diagnosis). SDS: standard deviations, calculated based on sex recorded at birth. n/a: not applicable

Figure 1: Selection of individuals included in the study. 57 individuals were referred to our center for gender dysphoria (GD), 45 were diagnosed with transsexualism (ICD-10), and 31 received hormonal treatment, 28 at our center. Subjects with a diagnosis of DSD (Differences of sex development) were excluded; *ICD-10 [7]

Figure 2: Annual numbers of referrals. Numbers for gender dysphoria (GD), diagnosed subjects with transsexualism (ICD-10), and hormonally treated subjects are shown.

Figure 3: Characteristics of the study cohort given for all individuals referred for gender dysphoria (A-C, left panel, n = 57) and for hormonally treated transsexual youth (D-F, right panel, n = 28). A. Age at referral. B. Tanner stage at referral. C. Psychiatric comorbidities. D. Age at start hormonal therapies (step 1 and step 2); E. Tanner stage at start GnRHa, and F. Psychiatric comorbidities in transsexual subjects.