From concept to protocol: iterative approach of a target trial emulation on GnRH analog safety in transgender and gender diverse youth
Authors' conclusion
This discussion paper serves as a methodological example of target trial emulation with observational data to study long-term safety of GnRHa in TGDA. By transparently addressing methodological challenges and incorporating expert input, this approach offers a feasible and ethically sound alternative to RCTs, and contributes to the evidence base needed for informed clinical and policy decisions in transgender healthcare.
Study context
- Population
- Transgender and gender diverse adolescents (TGDAs), observational data from national healthcare registries
- Exposure
- Gonadotropin-releasing hormone analog (GnRHa) treatment vs late-presenting TGDA individuals
- Outcome
- Long-term safety of GnRHa treatment
Methodological detailstarget trial emulation protocol, national healthcare registries, expert review, Independent experts in causal inference reviewed the concept design; feedback systematically summarized and discussed
- Target trial emulation protocol
- National healthcare registries
- Expert review
- Independent experts in causal inference reviewed the concept design; feedback systematically summarized and discussed
Main finding
As reported in the abstract
Study design
- Main methodological challenges: selection of the control group and definition of time zero
- Design will select late-presenting TGDA individuals as control group; time zero is GnRHa initiation in the intervention group and the equivalent age in controls
- Sensitivity analyses with alternative control groups and time zero definitions will assess robustness
Observational data: associations, not effects.
Original publication
From concept to protocol: iterative approach of a target trial emulation on GnRH analog safety in transgender and gender diverse youth. Eur J Endocrinol. Published 17 June 2026. doi:10.
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