What is the role of Gonadotropin-Releasing Hormone (GnRH) agonists or antagonists in hormone therapy for gender transition?

GnRH Agonists in Gender Transition: Role and Clinical Application

GnRH agonists serve two distinct roles in gender transition: as puberty blockers in adolescents to halt irreversible secondary sexual characteristics, and as anti-androgens in adult transgender women to suppress testosterone production when combined with estradiol therapy. 1

Role in Adolescent Gender Transition

GnRH analogues are used in transgender adolescents during early puberty (typically Tanner stage 2) to temporarily suppress testosterone and estradiol production, halting development of irreversible secondary sexual characteristics including breast development, body hair growth, voice changes, and genital development. 1

Key Benefits in Adolescents

• GnRH agonists reduce suicidality and improve psychological function in transgender youth, providing critical mental health benefits during this vulnerable period. 1
• The treatment is reversible, allowing time for the adolescent and family to explore gender identity before committing to masculinizing or feminizing hormone therapy 1
• A 2025 systematic review confirmed GnRH agonists effectively suppress puberty and secondary sex characteristics, with significant improvements in mental health including reduced depression, anxiety, and suicidality 2

Important Adverse Effects to Monitor

• Reduced height velocity and potentially reduced peak bone mass accrual occur during treatment, though height acceleration resumes when gender-affirming hormone therapy is subsequently initiated. 1
• Bone mineral density declines during treatment, particularly in adolescents assigned male at birth, requiring monitoring 2

Role in Adult Transgender Women (Feminizing Therapy)

In adult transgender women who have not undergone orchidectomy, GnRH agonists function as anti-androgens to suppress testosterone production, used in combination with estradiol therapy. 1, 3, 4

Mechanism and Advantages

• GnRH analogues directly suppress FSH and LH production by acting on the hypothalamic-pituitary axis, effectively halting testosterone production at its source—unlike peripheral androgen receptor antagonists (spironolactone, bicalutamide) which may not lower testosterone concentrations. 1, 4
• This allows achievement of target testosterone levels <50 ng/dL while potentially using lower estradiol doses 3, 4

Alternative Anti-Androgen Options

Other anti-androgens commonly used in feminizing therapy include 1, 3:

• Spironolactone (most commonly used, 100-300 mg daily)
• Cyproterone acetate
• Bicalutamide
• Finasteride

The choice between GnRH agonists and other anti-androgens depends on efficacy in achieving testosterone suppression, side effect profiles, cost, and availability—GnRH agonists offer more complete suppression but are typically more expensive than spironolactone. 1

Clinical Monitoring Algorithm

For Adolescents on GnRH Agonists

• Baseline assessment: bone density scan for those at risk of osteoporosis, baseline hormone levels (LH, FSH, testosterone/estradiol), growth parameters 1
• Monitor bone mineral density periodically during treatment 2
• Track pubertal progression (Tanner staging) and growth velocity 1
• Assess mental health outcomes including depression, anxiety, and gender dysphoria 2

For Adults Using GnRH Agonists as Anti-Androgens

• Baseline: testosterone, estradiol, complete blood count, liver function, lipid profile 3, 4
• At 3 months: check testosterone (target <50 ng/dL) and estradiol (cisgender female reference range) 3, 4
• Every 3-6 months during first year, then annually if stable 3, 4

Common Pitfalls to Avoid

• Failing to counsel about bone health implications before initiating GnRH agonist therapy in adolescents—ensure adequate calcium and vitamin D3 intake throughout treatment. 1, 2
• Not providing fertility preservation counseling before starting any gender-affirming hormone therapy including GnRH agonists, as these treatments affect fertility. 3, 4
• Overlooking the initial "flare-up" phenomenon with GnRH agonists, which causes temporary stimulation of gonadotropins before suppression occurs—this is less clinically significant in gender transition than in other applications 5, 6
• Discontinuing GnRH agonists or other gender-affirming hormones perioperatively without individualized risk-benefit discussion—the psychological consequences of cessation may outweigh surgical risks in most cases. 1

Comparison: GnRH Agonists vs. Antagonists

• GnRH agonists cause initial gonadotropin stimulation ("flare-up") lasting <5 days before achieving suppression through receptor desensitization 5, 6
• GnRH antagonists provide immediate suppression without flare-up by competitive receptor blockade 5, 6
• Despite theoretical advantages of antagonists, GnRH agonists remain the established treatment for puberty suppression in transgender adolescents, with decades of safety data and proven efficacy. 1, 2