Is there a standard multidisciplinary protocol for initiating puberty suppression with GnRH (gonadotropin‑releasing hormone) agonists in adolescents with gender dysphoria at early puberty (Tanner stage 2), including required assessments and monitoring?

Puberty Suppression Protocol for Gender Dysphoria

Yes, there is a well-established multidisciplinary protocol for initiating puberty suppression with GnRH agonists in adolescents with gender dysphoria, beginning at Tanner stage 2, with specific diagnostic criteria, pre-treatment assessments, and ongoing monitoring requirements. 1, 2

Eligibility Criteria for Initiating Puberty Suppression

Diagnostic Requirements:

• The adolescent must meet DSM-5 and/or ICD-11 diagnostic criteria for gender incongruence 2
• Long-lasting, intense gender dysphoria that worsens with puberty onset must be documented 2
• Pubertal development must have reached at least Tanner stage 2 before GnRH agonists can be started 1, 2, 3

Pre-Treatment Mental Health Assessment:

• Address any co-existing mental health issues before initiating treatment 2
• The adolescent should participate in mental health therapy to explore gender identity without the distress of progressing puberty 3
• Evaluate for depression, anxiety, self-harm behaviors, and suicidality, which are elevated in this population 3

Required Pre-Treatment Counseling and Consent

Fertility Preservation Discussion:

• The Endocrine Society mandates counseling about fertility preservation prior to initiation of puberty suppression 1
• The World Professional Association for Transgender Health emphasizes this discussion must occur "before starting hormone therapy or undergoing surgery to remove/alter reproductive organs" even at younger ages 1
• Currently, no established techniques exist for preserving gonadal function in pre-pubertal or pubertal adolescents who will never develop reproductive function in their natal sex due to blockers 1

Informed Consent Requirements:

• Both the adolescent and caregiver must provide informed consent after comprehensive counseling on probable reproductive effects 2
• Discuss that puberty suppression temporarily pauses oocyte/sperm maturation 2
• Explain that adolescents starting blockers may never develop reproductive function in their natal sex 1

Treatment Protocol and Medication Administration

GnRH Agonist Options:

• Triptorelin is commonly used and effectively suppresses puberty 4
• Administration routes include intramuscular or subcutaneous injections, or an implant inserted in the upper arm 3
• Treatment should ideally begin in the first stages of pubertal development (Tanner stage 2) 1, 3

Mechanism and Timeline:

• GnRH agonists shut down the hypothalamic-pituitary-gonadal axis through continuous stimulation that desensitizes gonadotrophs 1, 3
• Gonadotropins and sex steroid levels are suppressed within 3 months of treatment initiation 4
• Treatment halts development of irreversible secondary sexual characteristics including breast development, body hair growth, voice changes, and genital changes 1

Monitoring Protocol During Treatment

Initial Monitoring (First 6 Months):

• Physical examination including Tanner staging every 3 months 4
• Blood samples at 0,3, and 6 months to confirm hormonal suppression 4
• Measure gonadotropins (LH, FSH) and sex steroids (testosterone or estradiol) to verify axis suppression 4

Ongoing Monitoring (After 6 Months):

• Blood samples every 6 months 4
• Physical examination every 3 months 4
• Note: Recent data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function may not be necessary during triptorelin treatment, as no sustained abnormalities were encountered in studies 4

Bone Health Assessment:

• Monitor bone mineral density, as 2-year treatment with GnRH agonists may result in bone mass accrual retardation (decreased BMD/BMAD z-scores) 2
• This is a reversible adverse effect; height appears to accelerate when gender-affirming hormone therapy is subsequently commenced 1

Growth Monitoring:

• Track growth velocity, as treatment causes deceleration (decreased height SDS) 2, 4
• Alkaline phosphatase decreases, related to slower growth velocity 4

Body Composition Changes:

• Lean body mass percentage significantly decreases during the first year in both sexes 4
• Fat mass percentage significantly increases 2, 4
• Monitor for weight gain as a potential side effect 3

Expected Physical Changes and Efficacy

In Assigned Males (Transwomen):

• Testicular volume decreases in the majority (43 of 49 subjects in one study) 4
• Prevents development of masculine secondary characteristics 1

In Assigned Females (Transmen):

• Breast development may completely regress if treatment begins at Tanner stage 2 (occurred in 1 of 4 subjects) 4
• Prevents further breast development and menstruation 1

Common Side Effects and Management

Expected Side Effects:

• Hot flashes, mood fluctuations, fatigue, and headache are the most common 2
• These are usually mild and rarely lead to discontinuation 2
• Injection site problems may occur 3
• Emotional instability has been reported 3

Serious Adverse Effects to Monitor:

• Reduced height velocity and potentially reduced peak bone mass accrual 1
• Temporary pause in reproductive cell maturation 2
• Increased fat mass 2

Psychological Benefits and Outcomes

Short-Term Benefits:

• Reduces suicidality and improves psychological function 1
• May improve dysphoria, quality of life, and psychological functioning 1
• Decreases emotional and behavioral (especially internalizing) problems and depressive symptoms 2
• Extends the diagnostic period and gives adolescents time to explore gender identity 2
• May decrease the need for feminization/masculinization surgery later 2

Long-Term Outcomes:

• Young adults who received puberty suppression followed by cross-sex hormones and gender reassignment surgery showed alleviated gender dysphoria and steadily improved psychological functioning 5
• Well-being was similar to or better than same-age young adults from the general population 5
• Improvements in psychological functioning were positively correlated with post-surgical subjective well-being 5

Critical Considerations and Controversies

Evidence Limitations:

• Published studies are inadequate in number, small in size, uncontrolled, and relatively short-term 2
• It is difficult to draw definitive conclusions on long-term efficacy and safety 2
• Large long-term randomized controlled trials are needed 2

Age-Related Concerns:

• Lowering the age threshold for medical intervention remains controversial 6
• Children with gender dysphoria are more likely to express an unstable pattern of gender variance compared to adolescents and adults 6
• Concerns exist regarding the child's ability to make decisions and provide informed consent 6

Irreversibility of Subsequent Steps:

• While GnRH agonists themselves are reversible, adolescents who proceed to cross-sex hormones will never develop reproductive function in their natal sex 1
• This makes pre-treatment fertility counseling absolutely essential 1

Transition to Cross-Sex Hormones

Timing:

• Cross-sex hormones are typically introduced after puberty suppression, at a mean age of approximately 16.7 years 5
• Gender-nonconforming youth who remain gender dysphoric after puberty suppression can proceed to cross-sex hormones for phenotypic gender transition 3

Masculinizing Therapy (for Transmen):

• Testosterone therapy achieves serum concentrations in the typical cisgender male reference range 1
• Hemoglobin increases to male reference range within 3 months 1

Feminizing Therapy (for Transwomen):

• Involves estradiol therapy and anti-androgen medications (spironolactone, cyproterone acetate, bicalutamide, finasteride, or continued GnRH analogues) 1

Common Pitfalls to Avoid

• Do not start GnRH agonists before Tanner stage 2 is reached 1, 2, 3
• Do not skip fertility preservation counseling—this is mandated by major guidelines and must occur before treatment initiation 1
• Do not assume all adolescents with gender variance will persist—careful diagnostic assessment is essential 6
• Do not neglect bone health monitoring during treatment 2
• Do not fail to address co-existing mental health issues before starting treatment 2