Gender Identity

Prenatal influences

A child's sex development begins in the intrauterine stage. Hormone-induced sexual dimorphism in the growing fetus plays a primary role. It is critical to understand that all human fetuses have the potential to develop either a female gonad (ovary) or a male gonad (testis), depending on the presence of many genes, transcription factors, enzymes, and receptors, as the primary gonad is bipotential. ^[6]

Development occurs in 2 phases: first, “sex determination,” which is the development of the undifferentiated gonad into a testis or ovary and then, “sexual differentiation,” where phenotypic sex develops through the action of gonadal and other hormones. ^[6] During the sixth week of gestation, fetuses with a Y chromosome and a functional locus for the SRY gene product, also called the testis-determining factor (TDF), undergo testicular development of the bipotential gonad. The testes will produce a steadily increasing surge of testosterone.

Further progression toward the eventual male phenotype occurs by signaling through the androgen receptor, which leads to the development of the Wolffian ducts to form the internal genital structures of vas deferens, seminal vesicles, and epididymis during the first trimester. Antimüllerian hormone (AMH) is produced by the Sertoli cells of the testes, inhibiting the formation of Müllerian ducts, which would lead to female internal genital development (ie, uterus, fallopian tubes, upper third of the vagina). Much of the testosterone is converted to dihydrotestosterone, which will lead to virilization of the external genitalia. Along the biochemical pathway of hormone production, multiple other recently identified genes play an additional role in the masculinization of the fetus.

Genes on the X chromosomes, as well as other autosomal genes, lead to ovarian determination of the bipotential gonad. Without testis-produced AMH, the Müllerian ducts persist, and without testosterone, the Wolffian structures regress and female external genitalia develop.   

Early gender development

The environment in which a baby is reared with respect to gender begins to take shape prior to birth. Prenatal ultrasonography now allows the sex of a fetus to be determined quite accurately by the second semester of gestation. Families who receive knowledge of the child's biological sex often use this information to tailor parental planning and reactions. Gender-specific names, items of clothing/toys, and even aspirations for the soon-to-arrive baby may differ depending on the anticipated sex. Thus, a preformed idea of the child's preferences is in place even before the child is delivered.

Upon assignment of sex at birth, a significant environmental role begins in gender development, as the parents usually rear the child as either male or female, with all of the associated social interactions. In recent years, the prevailing notion once fostered by John Money of Johns Hopkins University, that gender identity is malleable during the first years of life, after which it becomes irreversible, has been challenged.

While there may be a number of children who do not clearly fit into a binary model of gender identity in the early childhood years, it is increasingly clear that gender identity is a characteristic that emerges during early development. For the moment, a number of proposed theories appear to have some validity. Note that these theories are neither mutually exclusive nor universally applicable, given the latest evidence. An epidemiologic approach to the human population as a whole cannot be reconciled with the very personal, and often unique, experience of gender identity development. As such, the current state of knowledge remains somewhat incomplete.

Quite possibly, the multifactorial nature of mammalian development allows the inherent brain bias toward a particular gender identity to be molded during the first few years and, in some cases, perhaps even in later years. Clearly though, as gender development progresses in children, an acceptance and personal expression of a gender identity occurs. Traditionally, this has been called the core gender identity. Evidence suggests that this expression usually takes place by age 2–3 years. The gender role may not necessarily be well defined until age 5 years, although in some cases, it is evident earlier. Although this concept and these reference-age ranges have been accepted for several decades, the plasticity of gender identity has not yet been fully elucidated. Whether an absolute final point truly exists after which a gender identity is irrevocably fixed is still unproven.

Eventually, the concept of gender constancy develops in the growing child. This refers to the ability of a child to concretely differentiate between male and female genders, frequently occurring by age 2 years, at which time the first expressions of gender identity are commonly made. Gender constancy is thought to be achieved by age 6 years in nearly all children, barring those with specific variations from the usual pattern.

Continuing gender development

Throughout the rest of childhood and school years, a child's gender identity is typically reinforced by the gender role. A preference for same-sex playmates often manifests by age 3–4 years, and the gender role is better defined by subsequent interactions.

In recent years, significant strides have been made in the awareness of gender-diverse behaviors in both boys (male sex assigned at birth) and girls (female sex assigned at birth). That such gender variance is biologically equivalent in boys and girls, and that it is not necessarily an indicator of gender dysphoria or incongruence in childhood, is growing clearer. However, the converse is also true; insofar as such behaviors have associations with questioning or incongruence of gender identity, both girls and boys may experience such symptoms.

In adolescence, a key period of identity formation, not only gender identity but also one’s overall personal identity, the influential factors of pubertal development, emerging personality traits, peer interaction, and sexuality are important in gender development. Although for many children gender identity may be fixed in early childhood, for others, gender identity may still be evolving and consolidating during early, mid- or late adolescence and early adulthood. ^[7]

Conditions resulting from genetic or hormonal influences

Changes to the usual process of fetal development can cause differences in the development of the fetus. When levels of prenatal hormones are altered, phenotypic progression can also be altered. Some of these conditions may affect the development of a child's gender identity.

Chromosomal alterations

Turner syndrome and Klinefelter syndrome result from chromosomal abnormalities.

Turner syndrome

In Turner syndrome, one X chromosome, or part of the X chromosome, is missing or structurally abnormal. Individuals with Turner syndrome are born with female external genitalia; however, their ovaries characteristically consist of streak gonads, which usually lead to premature ovarian insufficiency and infertility. Other characteristics usually include short stature, neck and chest anomalies, and cardiac and renal anomalies.

Depending on the karyotype (eg, 45X monosomy versus 45X/46, XX mosaic karyotype), various degrees of spontaneous pubertal development can occur. However, many of these youths will require exogenous estrogen supplementation to induce pubertal development.  

Klinefelter syndrome

Klinefelter syndrome occurs when the male fetus possesses a supernumerary X chromosome (47XXY in the vast majority of individuals). ^[8] Because of the presence of the Y chromosome and its components, external genitalia is masculine. Many males with Klinefelter syndrome are often recognized and diagnosed at the age of puberty because they do not begin or complete pubertal development (including failure of testes to grow normally, incomplete virilization [eg, scant pubic and facial hair]) or present with gynecomastia. Low serum testosterone levels can be seen, requiring exogenous testosterone supplementation. Infertility is common.

Gender identity in individuals with Turner or Klinefelter syndrome is usually concordant with sex assigned at birth. Preliminary data suggest that, compared to the general population, a slightly higher number of these individuals identify as gender-diverse. More studies are needed in this area. ^[9]   

Other chromosomal anomalies

Many other chromosomal findings are described in the literature, including XYY individuals (the extra Y chromosome has been linked to increased aggressive or antisocial behavior, with no known association with gender incongruence). Mosaicism of sex chromosomes can also be present, including XX/XY persons who may present with ambiguous genitalia. Another condition is termed gonadal dysgenesis, with abnormally developed gonads. Each of these rare situations requires a separate assessment of the patient's gender identity.

Ovotesticular DSD

Some individuals can present with a gonad that possesses ovarian as well as testicular tissue, with various degrees of ambiguous genitalia. Karyotype is most commonly 46XX. Management of infants with ambiguous genitalia has evolved tremendously in the past decades. Now, allowing intersex children to self-determine their gender identity before having any irreversible genital surgery is the recommended approach by many teams in the field. ^[10]  Some exceptions apply, such as the removal of dysgenetic gonads, which contain a Y chromosome, because these can lead to the development of tumors such as gonadoblastomas.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) in North America has an incidence of 1:12,000–14,200 population. In individuals with CAH, the fetus is exposed to abnormally high levels of androgens produced by its own adrenal gland. An enzyme defect exists in the pathway by which cortisol and aldosterone are produced, which leads to a greater amount of androgenic adrenal hormone production. For XX female fetuses, the prenatal exposure to androgens results in virilization of external female genitalia and ambiguous genitalia at birth.

Various degrees of virilization can occur, ranging from isolated clitoromegaly to completely masculinized genitalia. In such cases, male sex is often mistakenly assigned to the newborn at birth. However, a complete physical examination will reveal absence of palpable gonads bilaterally and should prompt the physician to rule out this potentially lethal condition if undiagnosed. Clinical findings and symptomatology will usually allow to confirm the defect in the adrenal gland and the 46XX genotype of the child. Serious salt-losing adrenal crisis may be the presenting problem in those infants and can lead to death. Exogenous hormonal replacement with corticosteroids and mineralocorticoids are used to treat patients once the diagnosis is known.

Both the gender identity and gender role of individuals with CAH have been the topic of studies. It has been reported that youths with CAH can present a more stereotypically masculine gender role and expression. ^[11] For the most part, gender identity in individuals with CAH seems to remain consistent with the genetic profile. Further longitudinal studies are needed to assess the impact of CAH on gender development.

Androgen insensitivity syndrome

When a normal Y chromosome with a fully functional SRY locus is found in a patient with dysfunctional androgen receptors, as is the case in androgen insensitivity syndrome, which has an incidence rate of 1 per 20,000 population, external virilization of the fetus is incomplete. Although testosterone is produced in utero, it cannot change cells that lack normal receptors. In complete androgen insensitivity, the fetus has a total absence of functional androgen receptors. Therefore, progression in the path toward female external genital differentiation continues uninterrupted. ^{[12, 13]}  In such situations, infants do not present ambiguous genitalia and are assigned female at birth. The testes are undescended, although the vagina is blind-ended with no uterus or ovaries. Subsequent gender identity is most often female

During puberty, the testes produce testosterone, some of which is converted to estradiol. Given that circulating testosterone is unable to exert any virilizing effects, unopposed estradiol allows female secondary sex characteristics to develop, such as breast development. Body hair and other androgen-induced changes that normally occur in females are usually absent.

Once breast development is completed, the testes may be removed because of the risk for malignant conversion in  undescended testicles. Some literature now suggests that surgery may be avoided if consistent and close surveillance of the testes by ultrasonography and serum levels of typical tumor markers (eg, alpha-fetoprotein) are monitored. Testes should not be removed early since hormone replacement therapy will be required to develop female secondary sex characteristics (as described above) because no source would remain for the secretion of sex hormones. Apart from infertility from the female standpoint, this condition has no other clinical sequelae.

In partial androgen insensitivity, on the other hand, variable degrees of receptor function result in differing degrees of external genitalia virilization. Phenotypic presentation at birth will consist of ambiguous genitalia. Testes are normally developed and levels of testosterone will increase normally during puberty, which will allow some masculine secondary sex characteristics to develop. However, because of the conversion of testosterone to estrogen, gynecomastia will develop, and decreased body and facial hair is also well described. For those who were assigned female at birth, normal testes would need to be removed surgically to prevent virilization during puberty. Long-term studies are needed to study gender identity development in these individuals.

5-alpha-reductase deficiency

This condition is also an enzyme defect with effects during prenatal development. The incidence in North America is roughly 1:40,000. Lack of 5-alpha-reductase prevents the conversion of testosterone to dihydrotestosterone in 46XY fetuses. External genital virilization is incomplete leading to various degrees of ambiguous genitalia at birth. Testes are normally functioning and Müllerian ducts are absent. When the testes produce a surge of testosterone at puberty, some masculine secondary sex characteristics occur.

Some individuals, however, do require androgen supplementation to fully complete the virilizing process of puberty. In past studies, notably in kindred studies from the Dominican Republic, affected 46XY youths raised as females during childhood transitioned to male at the time of puberty. ^[14]

Overview

Several terms are used to describe a sentiment of mismatch between gender identity and sex assigned at birth (with or without associated distress), including gender non-conformity, gender incongruence, and gender dysphoria. These terms can be replaced by a more general and less medicalized term, genderdiversity, which can be seen in children, adolescents, and adults. In addition, transgender and non-binary identities are gaining favor as non-stigmatizing terms to better describe those who do not identity with their assigned sex at birth. Social transitioning refers to taking on a gender role to match one’s gender identity.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition-TR (DSM-5-TR) ^[1] describes gender dysphoria as a strong and persistent preference for the status and gender role of another gender than the one assigned at birth (see full criteria below). In an increasing number of cases, this desire is manifested by a desire for medical treatment, where an adolescent or adult may ultimately decide to pursue hormonal and/or surgical sex reassignment to achieve phenotypic congruence with gender identity. In accordance with an emerging body of evidence aiming to move away from a pathological model for gender diversity, the World Health Organization’s International Classification of Diseases 11 (ICD-11) ^[2] has chosen to remove the category of gender identity disorders and has created the new entities of Gender Incongruence of Childhood and Gender Incongruence of Adolescence and Adulthood, which now fall under the category of Conditions related to Sexual Health.

Physicians should distinguish all aspects of gender dysphoria from transvestism or cross-dressing. The specific act of cross-dressing, in the absence of any true confusion about gender identity, is classified as simple gender-variant, diverse, or creative behavior. It is quite common to see school-aged children or teenagers who engage in varying degrees of gender creative behaviors, sometimes in relation to peer group activity or for creative expression. This behavior cannot be equated to gender dysphoria unless other specific criteria are met.

In the diagnosis of gender dysphoria or gender incongruence of childhood, a referral for mental health assessment can be made to address any potential comorbidities and support children and their families. Some children wear clothes of the opposite sex (or express the desire to do so), play with toys typically preferred by the opposite sex, and have difficulty in same-sex peer interaction. Others demonstrate some level of fluidity in their choice of clothing or toys and may identify with both same and opposite sex-associated objects and behaviors. Age of onset is often in children younger than 5 years. Psychologic testing can be useful but is not used alone to make a diagnosis for children.

The etiology of gender dysphoria or gender incongruence of childhood is not fully understood. Several theories have been proposed, all associated with variation from the normative pathways described above. Because much of the existing body of literature on this topic suggests that gender dysphoria or incongruence occurs in otherwise genetically and hormonally normal individuals, psychosocial explanations continue to play a role in theories of causality. However, this approach is being increasingly challenged with strong incentives to de-medicalize and de-pathologize the notion of gender dysphoria to make way for trans-affirmative models of care. ^[15]

Depending on the societal acceptance of gender creative behaviors, some parents and relatives may initially struggle with acceptance of any signs of gender dysphoria or incongruence. Thus, because of this intolerance, children with gender-creative behaviors can experience severe levels of distress as they grow and age. Gender dysphoria or incongruence of childhood of any type has been associated with increased risk for physical or sexual abuse, and post-traumatic stress in youth. It is important to properly explore these issues when evaluating or following a child with issues or questions related to gender identity. ^[16]

A number of studies suggest that some children with gender dysphoria or incongruence may no longer meet diagnostic criteria for these conditions as they become an adult. According to these studies, many develop a gender identity consistent with their anatomic sex. ^{[17, 18]} Some express a homosexual or bisexual orientation, while others may not. In spite of these suggestive findings, the numbers involved in these studies are too small to allow any conclusive statements to be made. In order to counsel families and patients about gender identity development, a very individualized approach must be taken. The entire spectrum of possibilities ought to be discussed, and few predictions about prognosis or outcome should be made quickly or decisively.

Adolescents with gender dysphoria or incongruence usually present similarly to adults. Their movement toward a social and/or medical transition is often more articulated than for younger children. Those who present themselves honestly to physicians should be credited for their courage because the condition of gender dysphoria often remains highly stigmatizing. Many retreat and become isolated, and a significantly higher incidence of suicide has been linked with transgender and non-binary identities. ^{[19, 20]}  

With greater awareness, tolerance, and acceptance of gender-diverse individuals as part of society, some adolescents are able to take first steps into social and medical transition, progressing to gender congruence either with or without surgical/medical interventions. Standards of care have been described and recently revised by the World Professional Association of Transgender Health (see below). ^[15]

ICD-11 diagnostic criteria for Gender Incongruence

Gender incongruence of childhood

Gender incongruence of childhood is characterized by a marked incongruence between an individual’s experienced/expressed gender and the assigned sex in pre-pubertal children. It includes a strong desire to be a different gender than the assigned sex; a strong dislike on the child’s part of his or her sexual anatomy or anticipated secondary sex characteristics and/or a strong desire for the primary and/or anticipated secondary sex characteristics that match the experienced gender; and make-believe or fantasy play, toys, games, or activities and playmates that are typical of the experienced gender rather than the assigned sex. The incongruence must have persisted for about 2 years. Gender variant behavior and preferences alone are not a basis for assigning the diagnosis.

Gender inconguence of adolescence and adulthood

ICD-11 also has a separate definition for gender incongruence in adolescents, which is the same as the definition used for gender incongruence in adults.

Gender Incongruence of Adolescence and Adulthood is characterized by a marked and persistent incongruence between an individual´s experienced gender and the assigned sex, which often leads to a desire to "transition," in order to live and be accepted as a person of the experienced gender, through hormonal treatment, surgery, or other healthcare services to make the individual´s body align, as much as desired and to the extent possible, with the experienced gender. The diagnosis cannot be assigned prior to the onset of puberty. Gender variant behavior and preferences alone are not a basis for assigning the diagnosis.

DSM-5-TR diagnostic criteria for Gender Dysphoria in Children and Adolescents

Gender dysphoria in children

A marked incongruence between one's experienced/expressed gender and assigned gender, of at least 6 months duration and manifested by at least six of the following (one of which must be the first criterion):

• A strong desire to be of the other gender or an insistence that one is the other gender (or some alternative gender different from one’s assigned gender)
• In boys (assigned gender), a strong preference for cross-dressing or simulating female attire; or in girls (assigned gender), a strong preference for wearing only typical masculine clothing and a strong resistance to wearing of typical feminine clothing
• A strong preference for cross-gender roles in make-believe or fantasy play
• A strong preference for toys, games, or activities stereotypically used or engaged in by the other gender
• A strong preference for playmates of the other gender
• In boys (assigned gender), a strong rejection of typically masculine toys, games, and activities, and a strong avoidance of rough and tumble play; or in girls (assigned gender), a strong rejection of typically feminine toys, games, and activities
• A strong dislike of one's sexual anatomy
• A strong desire for the primary and/or secondary sex characteristics that match one's experienced gender

The condition is also associated with clinically significant distress or impairment in social, school, or other important areas of functioning.

Gender dysphoria in adolescents and adults

A marked incongruence between one’s experienced/expressed gender and their assigned gender, lasting 6 months, as manifested, however, by at least two (instead of six) of the following:

• A marked incongruence between one’s experienced/expressed gender and primary and/or secondary sex characteristics (or in young adolescents, the anticipated secondary sex characteristics)
• A strong desire to be rid of one’s primary and/or secondary sex characteristics because of a marked incongruence with one’s experienced/expressed gender (or in young adolescents, a desire to prevent the development of the anticipated secondary sex characteristics)
• A strong desire for the primary and/or secondary sex characteristics of the other gender
• A strong desire to be of the other gender (or some alternative gender different from one’s assigned gender)
• A strong desire to be treated as the other gender (or some alternative gender different from one’s assigned gender)
• A strong conviction that one has the typical feelings and reactions of the other gender (or some alternative gender different from one’s assigned gender)

As is the case in children, the condition is also associated with clinically significant distress or impairment in social, school, or other important areas of functioning.

Gender-diverse behaviors can occur as part of normal gender development but can also be associated with early signs of gender incongruence or gender dysphoria. Depending on the cultural and societal context, this can be a source of distress for youth and families because of caregiver fears of later homosexual or gender-diverse behavior, and have a strong negative impact on a child or adolescent’s wellbeing and mental health.

Current evidence-based guidelines and recommendations exist to guide families, professionals, and physicians with regards to gender diversity. A gender-affirming approach and individualized personalized counseling for patients and families are recommended by experts in the field. ^[5]

Increasingly apparent is the fact that greater information about gender identity as an integral part of personality serves to help in understanding the human condition as a whole. Findings and observations over the past 50 years have allowed gender diversity to be more properly identified, and many clinics have since emerged to provide care for transgender and non-binary individuals. Though the positive impacts of providing comprehensive trans-affirmative medical care for children and youth is well established, ^[21]  more prospective longitudinal studies are needed to assess for long-term outcomes of individuals receiving such care.

In September 2022, the World Professional Association for Transgender Health (WPATH) published the 8th edition of its Standards of Care (SOC 8) for the health of transgender and gender-diverse people. ^{[15, 22]}

The updated version now includes two separate chapters specifically dedicated to the care of children and adolescents.

The new guidelines for children highlight that care for prepubertal youth is primarily social in nature and distinct from that of pubertal adolescents. Social transition includes important elements such as using an affirmed name/pronouns and changing hair style and clothes. It does not include medication treatment, at least, until the first stages of puberty (Tanner stage II-III) are reached. Some recommendations for children include the following:

• Healthcare professionals should provide information to gender-diverse children and their families/caregivers as the child approaches puberty about potential gender-affirming medical interventions, the effects of these treatments on future fertility, and options for fertility preservation.
• Healthcare professionals should consider consultation, psychotherapy, or both for a gender-diverse child and family/caregivers when families and healthcare professionals believe this would benefit the wellbeing and development of a child and/or family.

Similarly, the new chapter of the SOC 8 guidelines on the care of adolescents includes several important points, such as the following:

• Healthcare professionals should involve mental health and medical professionals when determining whether puberty suppression, hormone initiation, or gender-related surgery for gender-diverse and transgender adolescents are appropriate and remain indicated throughout the course of treatment until the transition is made to adult care.
• Providers should consider prescribing menstrual suppression agents for adolescents experiencing gender incongruence who may not desire testosterone therapy, who desire but have not yet begun testosterone therapy, or in conjunction with testosterone therapy for breakthrough bleeding.
• Prior to treatment, healthcare professionals working with transgender and gender-diverse adolescents requesting gender-affirming medical or surgical treatments should inform these patients of the reproductive effects including the potential loss of fertility and available options to preserve fertility within the context of the youth's stage of pubertal development.

Version 7 of the SOC had established a minimum age of 16 years before any partially reversible medications (ie, testosterone or estrogen) were started as part of a patient’s medical transition. SOC 8 removes this minimum age for the initiation of gender-affirming hormone therapy. However, a patient must still have begun their natal puberty before any medication is started and be able to show sufficient maturity to provide informed consent before therapy is initiated.

Similar to SOC 7, SOC 8 continues to stress the importance of a comprehensive, multidisciplinary evaluation of adolescents who seek medical therapy as part of their transition. In all cases, whether with children or adolescents, a thorough evaluation of gender identity, preferred gender role, and a complete psychosocial history is needed to assess the situation and provide optimal care.