Puberty Suppression and Transitional Healthcare with Adaptive Youth Services (PATHWAYS): PATHWAYS TRIAL, PATHWAYS CONNECT and PATHWAYS HORIZON-INTENSIVE
Gender incongruence
The PATHWAYS TRIAL is designed as a Randomised Controlled Trial (RCT) comparing immediate vs. delayed start (at 1 year post-randomisation) of GnRHa amongst 226 CYP with primary endpoint at 2 years post-randomisation. Participants will be randomised 1:1 to immediate or delayed treatment with Gonadotropin Releasing Hormone Agonists (GnRHa). Midpoint comparisons determine short-term differences due to receipt of GnRHa while endpoint comparisons determine whether the groups converge or GnRHa timing/duration influences outcome. All participating CYP and their parents/legal guardians will be asked to assent/consent to longer-term follow-up, which in the first instance will be for the life of the funding (total period 5.5 years). HORIZON INTENSIVE is a non-randomised comparison group of CYP (n = 300) not receiving GnRHa who are broadly matched on key participant characteristics: clinical centre, birth-registered sex, presence of a neurodevelopmental disorder or high level of traits and chronological age. They will complete the same physical, physiological and cognitive measures as TRIAL participants, although only at baseline and endpoint. As CYP who experience gender incongruence may differ from the general population of same-aged CYP, these data will provide a comprehensive comparison to aid interpretation of the effects of GnRHa. PATHWAYS CONNECT is a magnetic resonance (MR) brain imaging study to examine whether the use of GnRHa alters the trajectories of brain development. PATHWAYS CONNECT will recruit a subset of CYP enrolled in TRIAL (n = 150) and HORIZON INTENSIVE (n = 100) to participate in serial brain imaging over the same 2-year time course.
Current inclusion criteria as of 17/07/2026: TRIAL Clinical Inclusion Criteria: 1. The child or young person meets diagnostic criteria for gender incongruence according to ICD-11. This diagnosis should be made or confirmed within the CYPGS. Specifically: 1.1. The CYP has a strong desire to be a different gender than the birth-registered sex 1.2. The CYP has a strong dislike of sexual anatomy or anticipated secondary sex characteristics 1.3. The incongruence must have persisted for a minimum of 2 years 1.4. The CYP has a strong desire to ‘transition’, to live and be accepted as a person of the experienced gender 2. The CYP wants puberty suppression for their gender incongruence and this care preference persists after receiving other care deemed appropriate from the CYPGS and other sources prior to the initiation of GnRHa 3. The CYP is confirmed by the CYPGS to be in Tanner stage 2-5 4. Age: At the time of randomisation, for birth-registered females, the CYP is between 11 years and up to the 16th birthday; For birth-registered males, the CYP is between 12 years and up to the 16th birthday 5. The clinician in the CYPGS leading on care for that CYP considers that GnRHa for puberty suppression offers a reasonable prospect of benefit. This benefit might be achieved in relation to quality-of-life parameters (e.g., confidence in peer and family relations, participation in school and/or leisure activities, improved sense of well-being), mental or physical health. 6. The clinician in the CYPGS leading on care for an individual patient considers they have participated sufficiently for their holistic health and well-being in other forms of care for puberty suppression to be considered, in line with NMDT recommendations and this participation is reviewed by the NMDT. 7. The CYP has demonstrated sufficient understanding of the possible advantages and disadvantages of the proposed treatment including immediate psychological and physical impacts and also long-term implications, ben
Current exclusion criteria as of 17/07/2026: TRIAL Clinical Exclusion Criteria: 1. Physical conditions where puberty will not commence or advance in a patient. This may include gonadal failure (e.g. due to genetic disorders such as Turner syndrome) or central hypogonadotropic hypogonadism. 2. Unstable physical health. The purpose of this criterion is to ensure that that the CYP is not undergoing concurrent high-intensity physical interventions which might affect their response to GnRHa or their ability to adhere to the trial protocol. These include but are not limited to: 2.1. Very low or very high BMI (or rapid changes in BMI), particularly if there is a concerning trajectory or associated nutritional or metabolic concerns. This could include eating disorders or body dysmorphic disorder. 2.2. Any poorly controlled medical disorder, such as uncontrolled epilepsy, inflammatory bowel disease, cystic fibrosis. This includes any other condition where participation may pose a risk to the individual’s health or compromise study integrity. 2.3. Concerns about bone health or significant risk of fractures (this may also include a low baseline bone density). 2.4. QTc interval above 470 milliseconds at screening, or concomitant high-risk QT-prolonging drugs that cannot be ceased 3. Hypersensitivity to gonadotropin releasing hormone (GnRH), its analogues, or to any of its excipients 4. Known congenital long QT syndrome 5. Unstable mental health that may impair ability to provide informed assent/consent or lead to risk of serious harm to self or others. Many CYP with gender incongruence experience anxiety and/or depression which they relate to gender dysphoria or distress. It is not the intention to exclude those with mild to moderate levels of mental health symptoms. However, severe or unstable symptoms may affect the ability to engage in all aspects of the clinical protocol. Examples would include (but are not limited to): 5.1. Severe or profound depression with significant ef