Gender Incongruence and Dysphoria in Children and Adolescents: Advances in Diagnosis and Management

Gender identity and gender variation are frequently discussed in today’s modern society. Less than 50 years ago, the traditional roles of men and women were clearly defined. There was a taboo around topics such as homosexuality and gender incongruence.

Today, most Western societies are more open to variations in sexuality and gender identity. Gender identity refers to a person’s identification as male, female, or neither/both [1].

Gender incongruence (GI) is defined as the condition in which a person’s gender identity does not align with the gender assigned at birth.

People with IG who experience significant burdens are described in the DSM classification as having gender dysphoria (GD). Compared to the binary approach of being a man or a woman, the concept of gender is accepted today as a continuum. Non-binary people currently comprise up to 10% of people with IG [2, 3].

The prevalence of GD in children and adolescents is approximately 0.6% to 1.7% and depends on the selection of the study cohort, age, and research method [4]. In recent years, the number of children and adolescents with IG and GD seeking help has increased dramatically [4-6]. A notable change concomitant with the increase in referrals is the variation in the proportion of clinically referred adolescents by sex, with referral of girls assigned at birth prevailing [7].

In this review, we describe the current approach to IG/DG in children and adolescents. Etiologic factors, evaluation procedures, counseling issues, and decisions/options available for medical and surgical treatment are addressed. Additionally, recent evidence on long-term outcomes in young adulthood is described.

To date, the etiology of GI remains largely unidentified. Current research suggests that psychosocial and biological factors play a role in the development of GI.

In fact, there are findings that suggest that there is a biological/anatomical basis for IG: post-mortem brain studies have shown that specific brain structures that are different between men and women without IG show a great similarity in volume and number of neurons in people with IG. GI with respect to the gender with which they identify [13].

Recent studies have focused on brain connectivity between people with and without IG, showing differences in brain networks related to body image [15]. However, much is still unknown about the extent and period in which these psychosocial and biological factors make their (specific) contribution to development, as well as

On the possible interactions between the various factors involved [5, 8]. Previous studies on the development of IG mainly focused on the influence of individual psychological factors, such as mother-child interaction and/or the absence or passive presence of the father [9]. However, evidence for the role of individual psychological factors is limited [10]. Later theories proposed that the development of GI was a multi-factor process in which parental, childhood and environmental issues make their contribution.

IG develops when general child factors (such as anxiety) and parent factors (such as psychological difficulties), as well as specific factors (such as a lack of parental limit setting) occur simultaneously. during a certain period of critical time in the development of the child [11]. Although for some general factors, such as childhood anxiety, research has found some support, evidence on child- and parent-specific factors is limited or non-existent[10].

Research on the role of biological factors involved in the development of GI has focused mainly on genetic factors, the role of (prenatal) sex hormones, and differences in the brain.

The genetic contribution in the development of IG has been demonstrated in twin studies, showing high IG concordance in monozygotic twin pairs and IG discordance in dizygotic twin pairs [12], although the true candidate genes have not yet been identified. [13].

Brain imaging studies have found support for the role of prenatal exposure to hormones (androgens) in the development of IG. Several studies, using various measures, have shown that the brains of people with IG show similarity to the brains of the gender with which they identify and differences to the brains of the gender they were assigned at birth; however, variations in results are large between studies [12].

Although a significant contribution has been observed for all these factors, the causal relationship between genes, hormones, brain structure, behavior and GI is still questioned [16], and how these different factors relate to each other is less clear and less studied.

There is great diversity in the questions children, adolescents and parents ask about their gender when they seek professional help. Some have made the social transition at an age

Young and feel secure in their gender identity, while others are still exploring their gender identity even in (late) adolescence. Exploring one’s gender identity is a normal developmental process [1, 2] during which the child learns to label his or her own gender (gender labeling) and experiences a stable gender identity (gender constancy) [14].

Gender incongruence in childhood tends to be more fluid and developing than in adolescence, where gender identity appears to be more fixed [6, 12, 15].

In young children, most parents seek help for their concerns about how to handle their child’s gender issues. In adolescents (young adults), on the other hand, there is a shift towards children themselves, when physical changes as a result of pubertal development urge their need for support.

It is necessary to pay special attention to the language with which the child or adolescent is addressed. Gender-declaring words like “boy,” “girl,” “son,” “daughter,” “he,” and “she” can make both children with GI and their parents feel uncomfortable. It is important to be attentive to these emotions and take a step towards gender perspective work by asking how someone wants to address that person.

The evaluation procedure in children and adolescents is similar. In accordance with the recommendations of the World Professional Association for Transgender Health (APMST) and the Dutch quality standard for mental health in transgender care (www.richtlijnendatabase.nl), at the first joint consultation with the child and Their parents discuss specific goals. Subsequently, general diagnostic sessions are carried out with the child/adolescent and her parents separately.

Sessions with the child/adolescent are focused on obtaining a general perspective of psychosocial, cognitive and emotional development and investigating beliefs regarding their gender identity expression. Furthermore, in adolescents, their psychosexual development is addressed. The diagnostic evaluation focuses on family history and general and gender-specific dynamics.

Gender dysphoria is a formal diagnosis in the DSM-5 classification and is defined separately for children (302.6), adolescents (302.85), and adults (302.6). It is defined as a difference between experienced and assigned gender, with significant stress or functioning problems lasting at least 6 months (https://www.psychiatry.org/patients-families/gender-dysphoria/gender dysphoria). and intense and persistent anxiety about one’s assigned gender, manifested before puberty.

Psychiatric problems, internalizing problems, anxiety and depression, increased incidence of suicidal behaviors and autism spectrum disorders [1, 3] are more common in children and adolescents with IG [17]. Therefore, diagnostic sessions also aim to address these possible coexisting problems. Internalizing problems are believed to be reactive to IG feelings and/or arise in response to social stigma.

Many children report a history of problems with their peers in terms of bullying [4]. The cause of the relationship between autism spectrum disorders and gender dysphoria is still under debate and it has been suggested that it could be related to brain and hormonal functioning, or the ability to mentalize [16, 17].

There is no evidence-based guideline for the psychological support of children and adolescents. Treatments aimed at changing gender identity have not been shown to be effective and are currently considered unethical. Still, the optimal processes and outcomes of psychological interventions are under debate and range from supporting social transition to supporting feelings in line with sex assigned at birth [18].

Support focuses on psychoeducation, for example, explaining to parents that the exploration of gender expressions is part of a developmental process and that, in most children, it does not lead to persistent gender dysphoria in adolescence. In children with GI findings, an important goal is the balance between watchful waiting and progress toward gender-affirming interventions [19].

During childhood , much attention is paid to reducing distress as a result of gender incongruence and to preparing/supporting the child and parents in exploring and developing possible steps when the endogenous development of puberty begins. The medical and mental care of transgender people is a long-term process during which the child/adolescent with IG and their parents are advised to make decisions about their social, medical and legal transition.

In adolescents , medical interventions are possible and psychological counseling aims to guide and support the adolescent and their parents during this process. After the initial diagnostic phase as described above, treatment possibilities including hormone therapy, surgery and fertility preservation, are discussed and balanced with the expectations of the adolescent and parents.

During the medical interventions phase, they should receive continued support until the desired medical steps are completed. Since peer support has been shown to be a valuable tool during medical transition [20], contact with support groups or self-help organizations is advisable.

> Pubertal suppression

The development of biological secondary sexual characteristics is generally a very distressing experience for adolescents with IG/DG that can lead to serious issues of psychological functioning and behavior. Therefore, pubertal suppression (PS) has been introduced in several expert centers to prevent or arrest pubertal development [21]. It is well known that the use of long-acting GnRH analogues (GnRHa) to suppress gonadotrophins can effectively prevent the progression of puberty.

There is a long experience with the use of this treatment in young children with central precocious puberty (CPP) [15]. In this group, pubertal suppression is completely reversible. For adolescents with IG/DG, this treatment offers the opportunity to create more time for diagnosis and mental health evaluation.

The current consensus establishes that pubertal suppression should not begin before Tanner stage 2 (in females Tanner 2 breasts, in males testicular volume of 6 to 8 ml) to allow boys to experience the changes of their own pubertal development, since The withdrawal of GI during puberty has been described.

The most commonly used GnRH is an intramuscular injection every 3 months but longer-acting versions and also surgically implanted antagonists are also available.

The criteria for initiating SP are: (1) confirmed diagnosis of GD/IG by an experienced mental health professional (see previous section), (2) written informed consent, (3) minimum Tanner 2, and (4) preferably , sufficient parental support and absence of interfering health problems. In the decision to treat, the presence

Additional risk factors/interfering health problems must be balanced against the possibility that discontinuation of treatment will cause harm to the patient.

After starting treatment, some secondary sexual characteristics that have already developed may decrease, such as breast size and testicular volume. Additionally, withdrawal bleeding may occur in individuals with IG who were assigned female at birth.

GnRHa is generally well tolerated with the exception of episodes of flushing at the beginning of treatment and local reactions such as redness and pain [22, 23]. Additionally, emotional lability and mood changes are described [24]. So far, high blood pressure has been reported as an adverse event in transgender youth in only 3 cases out of a cohort of 138 subjects. Hypertension reversed upon discontinuation of triptorelin [22, 25-27].

In early puberty, the epiphyseal plates are still open and height gain and final size can be influenced. Since little is known about growth patterns during and after treatment, the patient should be counseled about possible effects on growth, but data based on height gain and final height cannot be provided.

Despite the positive effect on pubertal suppression, there is still an ongoing debate on early medical intervention [26]. Opponents suggested that, especially in the younger group, there is an unstable pattern of gender variations with reversible gender incongruence in most children [26].

So far, there are limited data on the effect of pubertal suppression on mental health, all showing improved mental health and quality of life [10, 28–31]. However, long-term studies are necessary to confirm these results in larger cohorts.

> Gender reaffirming hormonal treatment

Following GnRHa treatment, synthetic sex steroids are added to induce the development of sexual characteristics of the identified gender. There are generally two treatment regimens. When GnRHa treatment has been initiated at an early Tanner stage, the “new” puberty is induced with a dosing schedule that is also common in prepubertal hypogonadal adolescents.

Alternatively, when GnRHa treatment has been initiated in physically mature individuals and the duration of the hypogonadal state was limited, the hormones can be initiated at higher doses and increased more rapidly.

An additional advantage of GnRHa treatment is that the hormones do not have to be administered in supraphysiological doses, which would otherwise be necessary to suppress endogenous sex steroid production [32].

• Individuals with GI who were assigned male at birth: Natural 17-beta estradiol is preferred over synthetic estrogens that have a more thrombogenic profile. For pubertal induction, the recommended initial dose is 5 mcg/kg/day, followed by 6 monthly increments of 5 mcg/kg until a maintenance dose of 2 to 4 mg is reached.

In transgender women who started GnRHa when they were Tanner stage 4/5, estrogens can be administered at a daily starting dose of 1 mg after a period of gonadal suppression ranging from 3 to 6 months. This dose can be increased to 2 mg after 6 months. Feminization includes breast development, which usually begins within 3 months after the start of treatment, and alteration of body shape with an increase in hip and a decrease in waist circumference [33, 34]. .

Trans women require gonadal suppressive treatment regardless of estrogen dose until gonadectomy has been performed. GnRHa is preferred over other anti-androgens such as cyproterone acetate or spironolactone. Since there are no data available on how efficient exogenous synthetic sex steroids can be in suppressing the gonadal axis during puberty, GnRHa should be continued until gonadectomy when initiated in early puberty.

• Individuals with GI who were assigned female at birth: For pubertal induction, the use of testosterone ester injections is recommended. The starting dose is 25 mg/m2 every 2 weeks intramuscularly (IM) with increments of 25 mg/m2 every 6 months. Maintenance doses range from 200 mg for 2 weeks for testosterone monoesters, such as testosterone enanthate, to 250 mg IM for 3-4 weeks for mixed testosterone esters.

For transgender boys who started treatment late in puberty, testosterone can be initiated at a dose of 75 mg IM every 2 weeks, followed by the maintenance dose after 6 months.

It is recommended to continue GnRHa at least until the maintenance dose of testosterone is achieved and it is preferred to continue until gonadectomy. With androgens, virilization of the body occurs: changes in the voice; increased muscle development, particularly in the upper body; facial and body hair growth; and clitoral growth [24, 32].

> Surgical interventions

Surgery can address primary or secondary sexual characteristics with the goal of establishing greater congruence with experienced gender. Not all transgender or GI people seek surgical interventions to change their sexual characteristics (Table 1). The desire for surgery is different for each transgender individual. There are a wide variety of combinations of possible operations. Each person must have an individual approach to suit their surgical needs.

Follow-up studies have shown a positive effect of gender-affirming surgery on postoperative outcomes such as well-being, outward appearance, and sexual function. Surgeons in the field of gender surgery usually come from different specialties, depending on the type of operation.

Surgical specialties are common in gender surgery: ENT, maxillofacial surgery, plastic surgery, urology, gynecology and general surgery. Given the low volume within their core specialty, surgeons in the field of gender surgery need training and must be closely linked to a specialized gender team.

Surgery candidates must not have medical or mental health problems.

In preparation for surgery, it is useful to assess the candidate’s resilience to prevent decompensation when complications occur or to help individuals cope with postoperative self-care efforts. Therefore, a thorough informed consent process prior to surgery is desirable.

The goal of gender affirmation surgery is to achieve the appearance and function of experienced sexual characteristics and a genital appearance that is as "natural" as possible. However, the results of gender affirmation surgery can range from surprising and satisfying to disappointing, as complete authenticity is certainly unattainable.

Prior to surgical interventions, it is preferred that the person have lived in the self-identified gender role for a substantial period of time. The intention of this suggested sequence is to give adolescents sufficient opportunity to experiment and socially adapt to their new gender role.

Most gender-affirming surgical procedures are irreversible or, if reversible, result in extensive scarring. These procedures should not be performed if someone is under the legal age to consent to a medical procedure in a given country.

Mastectomy for transgender men is considered a less invasive procedure and can be performed on people below the legal age of consent to reduce gender dysphoria, especially in the case of extensive female breast development that cannot be easily hidden. with a bra [35].

Most transgender children usually want a mastectomy, followed by a hysterectomy. Genital operations, especially the construction of a neophallus (metoidioplasty/phalloplasty) are not as common due to the unpredictability of the results and the complication rates of the surgery [36].

In transgender girls, vaginoplasty is the most favored operation performed followed by breast augmentation using implants [37].

No true long-term outcome studies are currently available, but studies have been published within a cohort of young adults aged 22 years who were treated in their adolescence. Regarding bone health, bone mass was reported to be in the normal range but not at the pretreatment level for both transgender men and transgender women. However, only in transgender women, few had a T score <-2.5 [38].

Compared to their age-matched peers, young adult transgender women showed greater similarity to cis women than to cis men with respect to body shape and composition [34]. BMI was only slightly higher, but the increase in obesity prevalence in trans women was greater compared to cis women. Therefore, a subset of transgender women was shown to be more prone to excessive weight gain [39].

In transgender men, body shape and body composition were within the reference values ​​for cis women and cis men. An early Tanner stage at the start of treatment appeared to be associated with closer resemblance of body shape to the asserted sex [34].

Pretreatment obesity prevalence was already higher compared to the population, but the increase in prevalence was comparable to cis men. For both men and transgender women, other cardiovascular risk factors such as fasting blood glucose, lipid profile, and blood pressure were similar or more favorable [39]. Additionally, the psychological benefits of early medical intervention for young transgender adolescents have been established [30, 31].

One year after surgery, GD was relieved, psychological functioning had steadily improved, and well-being was similar or better than in age-matched young adults in the general population [31].

To meet the needs of young people with GI, a multidisciplinary team is necessary and, therefore, it is recommended that children and adolescents be followed by an experienced and well-trained team of health professionals, including psychologists, psychiatrists, endocrinologists, gynecologists, surgeons and other health care providers.

A phased trajectory beginning with a psychological evaluation, followed by medical interventions, is generally preferred. Endocrine treatment consists of two phases: first, the initiation of GnRHa to prevent the development of puberty (a fully reversible intervention) followed by the addition of gender-affirming hormones, leading to irreversible changes.

Although many details and aspects of this approach are still unknown, it is of great importance that young people with GI are provided with care that improves their well-being. As steps are taken in this process, the benefits and potential harms of each intervention must be carefully balanced.

Table 1. Summary of surgical procedures for the treatment of transgender people with GI.