Diagnosing gender dysphoria in minors

Gender identity is apparent in early childhood, with children as young as 2–3 years able to correctly label their own genders. According to Kohlberg’s stage theory of gender development, by age six children have developed gender consistency, the understanding that gender is fixed and independent of external features such as hair or clothing . In spite of the evidence that gender identity develops early and is durable once established, prepubertal gender dysphoria/incongruence is notoriously difficult to diagnose. True gender dysphoria can be mistaken for other types of gender-nonconforming behavior in childhood. Given the concern about gender dysphoria “desisting” after puberty , the current understanding is that gender dysphoria can only be reliably diagnosed after the onset of puberty.

The diagnosis of gender dysphoria/incongruence is defined by the DSM-V. Individuals meet the criteria for gender dysphoria when they exhibit the following for at least 6 months’ duration:

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  A strong desire to be of a gender other than one’s assigned gender,

  
  
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  A strong desire to be treated as a gender other than one’s assigned gender,

  
  
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  A significant incongruence between one’s experienced or expressed gender and one’s sexual characteristics,

  
  
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  A strong desire for the sexual characteristics of a gender other than one’s assigned gender,

  
  
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  A strong desire to be rid of one’s sexual characteristics due to incongruence with one’s experienced or expressed gender, and

  
  
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  A strong conviction that one has the typical reactions and feelings of a gender other than one’s assigned gender.

The diagnosis of gender dysphoria/incongruence in an adolescent has historically been made in a multidisciplinary manner with the input of an experienced mental health provider.

Gender dysphoria/incongruence is thought to be due to a poorly understood combination of biological, environmental, and cultural factors. Studies of individuals with differences of sexual development suggest that early exposure to androgens plays a role in the development of a male gender identity . Meanwhile, twin studies suggest that gender dysphoria has a hereditary component . While these studies give us fascinating insight into the development of gender identity, untreated adults with gender dysphoria/incongruence will typically have sex steroid profiles consistent with their assigned sex. Currently, there are no available genetic or laboratory tests that can predict or confirm a diagnosis of gender dysphoria.

Monitoring for puberty onset

An adolescent’s reaction to puberty has diagnostic value in terms of confirming the diagnosis of gender dysphoria/incongruence . For this reason, children suspected of having gender dysphoria/incongruence should be monitored for early signs of puberty. Pubertal patients with gender dysphoria/incongruence should be evaluated for treatment with gonadotropin-releasing hormone agonists (GnRHa) to reversibly prevent the development of undesired secondary sex characteristics. Pubertal suppression accomplishes two essential goals: (1) relieving patients of the distress caused by puberty and (2) allowing for self-exploration prior to starting cross-sex hormone treatment .

Empirical evidence supports the use of GnRHa in transgender adolescents. In one prospective follow-up study from The Netherlands, 55 transgender adolescents were assessed at three time points: (1) prior to GnRHa use, (2) at the start of gender-affirming hormone use, and (3) 1 year after gender-affirming surgery . Gender dysphoria persisted in patients throughout puberty suppression, but mental health improved and depression was reduced. Subsequent treatment with gender-affirming hormones and gender-affirming surgeries was associated with resolution of gender dysphoria and improved psychological functioning. The well-being of this group was similar to their age-matched peers, and none of the study participants regretted treatment.

The onset of puberty is mediated by an increase in GnRH pulsatile activity and correlates clinically with Tanner stage II. For natal females, the earliest sign of puberty is breast bud formation; for natal males the earliest sign of puberty is testicular enlargement >4 mL with change in scrotal skin texture . Although pubertal onset often occurs in tandem with the appearance of pubic hair, the presence of pubic hair reflects adrenarche and is due to a surge in adrenal androgen production. Adrenarche, as opposed to puberty, is not mediated by the hypothalamic-pituitary-gonadal axis. Pubertal onset typically occurs between age 8 and 13 years in cisgender females, and between 9 years 6 months and 13 years 6 months in cisgender males, although these ranges vary somewhat by ethnicity .

The onset of puberty can be confirmed clinically with physical examination or by hormonal measurement. The gold standard for the biochemical evaluation of puberty onset is the measurement of luteinizing hormone (LH) after the administration of GnRH or GnRHa . A stimulated LH concentration of 5–10 IU/L is suggestive of puberty . Alternatively, LH can be measured randomly and concentrations above 0.3 IU/L are suggestive of pubertal onset .

Beginning pubertal suppression

GnRHa are currently considered the first-line therapy for puberty suppression . GnRHa provide continuous stimulation to the pituitary gonadotrophs, resulting in desensitization and preventing the release of LH [and, to a lesser extent, follicle-stimulating hormone (FSH)]. By suppressing LH and FSH, GnRHa reversibly “turns off” the hypothalamic-pituitary-gonadal axis and prevents further pubertal development.

GnRHa should be initiated at the earliest sign of puberty. While early evidence of puberty may regress, advanced pubertal changes (such as beard growth or breast development) are irreversible . Currently, several GnRHa are commercially available. The available options and their dosing schedules can be seen in Table 17.2 .

Adverse effects of GnRHa frequently include headaches and hot flushes. Patients may also have local injection site reactions such as pain, redness, or sterile abscesses . Hypertension has been reported as an adverse effect in a few natal girls treated with GnRHa for precocious puberty . For this reason, blood pressure monitoring before and during treatment is recommended.

The Endocrine Society clinical guidelines for the treatment of gender-dysphoric/gender-incongruent individuals suggest monitoring clinical pubertal development every 3–6 months and laboratory parameters every 6–12 months during treatment . Specifically, the following follow-up protocol is recommended during treatment:

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  Every 3–6 months : anthropometry: height, weight, sitting height, blood pressure, Tanner stages;

  
  
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  Every 6–12 months : laboratory: LH, FSH, estradiol, testosterone, 25-OH vitamin D;

  
  
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  Every 1–2 years : bone density using DXA, bone age on X-ray of the left hand (if clinically indicated).

Initiating gender-affirming hormones

Adolescents with gender dysphoria will eventually make the transition from pubertal delay with GnRHa to the initiation of gender-affirming hormone therapy. There is some debate as to the ideal age to start this process. The Endocrine Society clinical guidelines currently recommend initiating cross-sex hormones at 16 years of age. This starting point is reasonable for many adolescent patients because it is an age at which many (although not all) will have developed the capacity to make complex medical decisions. It also happens to be the age at which teenagers are granted medical autonomy in certain countries . However, because adolescents ultimately develop capacity at their own rate, this must be assessed on an individual basis.

There may be persuasive reasons to initiate gender-affirming hormone therapy earlier than age 16. One of the most compelling arguments for initiating earlier hormonal therapy is to prevent osteopenia or osteoporosis later in life. Maximum bone density is accrued by age 25, and this process is largely sex steroid–mediated . For this reason, there are major concerns about the effect of a prolonged delay in puberty on long-term bone health. A recent study of 19 transgender males and 15 transgender females suggests that there is suboptimal bone mineral accrual during GnRHa treatment . During the treatment period (a median duration of 1.5 years for transgender males and 1.3 years for transgender females) there was a decrease in areal bone mineral density (BMD) z- scores and of bone mineral apparent density z -scores, although not all changes were statistically significant. There was incomplete catch up at age 22, and unfortunately there are no available long-term follow-up studies to reassure that long-term bone health is not impacted.

There is concern about the social, emotional, and cognitive impact of prolonged pubertal delay. To date, there are no data comparing the social and emotional well-being of adolescents started on gender-affirming hormone regimens at 16 years old versus at earlier ages. While scant, there are some data available regarding the effect of puberty suppression with GnRHa on cognitive development. Executive functions, such as managing emotions and memory retrieval, are generally thought to develop with chronological age independently of puberty status. Reassuringly, one cross-sectional study suggests that pubertal delay with GnRHa does not compromise cognitive functioning; however, animal data suggest that there may be an impact .

Fertility concerns

GnRH agonists temporarily and reversibly affect spermatogenesis and oocyte maturation. When GnRH agonists are discontinued, these processes resume. In a study of cisgender males treated for precocious puberty, spermarche was reported 0.7–3 years after cessation of GnRHa .

Because there is a paucity of data regarding the effects of hormone therapy on future fertility, it is currently recommended that all patients who are pursuing hormone therapy be offered the opportunity for fertility preservation prior to initiation. However, presently, endogenous puberty is required for fertility preservation. Oocyte and spermatocyte cryobanking require the presence of mature gametes. Although in vitro methods of fertility preservation are being investigated that involve the collection of immature gamete, these methods are currently experimental. Patients must be counseled about a possible loss of fertility if they proceed directly from pubertal suppression to gender-affirming hormone therapy without undergoing endogenous puberty.

Laboratory : There is very little in the medical literature indicating regular laboratory testing for transgender youth. Assessment of puberty is generally accomplished phenotypically by Tanner stage . If GnRHa are used the sex hormone concentrations should remain within the prepubertal reference interval. Estradiol, testosterone, FSH, and LH can be measured to monitor puberty suppression, as needed . Before initiating transition-related medical therapies in adolescence The Endocrine Society guidelines specify that providers should confirm that there are no medical conditions for which hormone therapy would contraindicate. This may require some amount of laboratory workup, but would be personalized to the individual. During transition there are reports of fluxes in liver enzymes, hemoglobin and hematocrit, prolactin, coagulation factors, and lipid panels . Abnormalities generally resolved naturally over time. Regular monitoring of these labs is not recommended.