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Experts comment on the PATHWAYS trial of puberty suppression in young people with gender incongruence having received all necessary regulatory and ethics approval
Dr Hilary Cass, paediatrician and Chair of the Cass independent review of gender services for children and young people, said:
“My review uncovered a very weak evidence base for benefits from the use of puberty blockers for children and young people with gender dysphoria. In fact some children had more negative than positive effects.
“However, given that there are clinicians, children and families who believe passionately in the beneficial effects, a trial was the only way forward to make sense of this.
“I am really pleased that Professor Simonoff and the team at KCL are undertaking the work. They are one of the best in the country for this kind of trial.
“Although a lot of media attention has focused on the trial, they have a much broader research programme. Following the outcomes for young people who do not elect for a medical pathway will be just as important as following those who do.”
Prof Dougal Hargreaves, Professor of Paediatrics & Population Health, Imperial College London; and Honorary Consultant Paediatrician, said:
“To improve care and outcomes for children and young people with gender incongruence, we need a joined-up approach that combines the best possible use of existing knowledge and experience, with high-quality studies to address outstanding research gaps. The PATHWAYS clinical trial of puberty suppression in young people with gender incongruence is a robustly-designed new study that has potential to make an important contribution to the evidence base in this area.”
Prof Sara Fovargue, Professor of Law and Deputy Chair of the University Research Ethics Committee, University of Sheffield, said:
“Involving children and young people in clinical trials may be ethically contentious, but if we don’t include them then they will be prescribed medicines that have not been tested on bodies like theirs. Consent is obviously a key legal and ethical concern and the protocol set out consent processes involving the children and young people, their parents or legal guardians, and with space for other family members and caregivers too. The team have rightly recognised the importance of giving time in those processes to developing understanding, processing information, and discussing what is being proposed. Providing information in a variety of formats, dependent on the needs of the individual child or young person, shows that the team takes their legal and ethical obligations seriously.”
Prof Sir Jonathan Montgomery, Professor of Health Care Law, UCL, said:
“The PATHWAYS TRIAL has been carefully designed in accordance with the requirements of research ethics so as to ensure that no one is invited to participate unless they have requested treatment for puberty suppression after receiving other care for gender incongruence, unless their treating clinician considers that there is a reasonable prospect that the individual would benefit from drugs to supress the onset of their puberty, and unless that young person has sufficient understanding of the known advantages and disadvantages of treatment. These factors will initially be considered by the young person’s own clinician independently of the research team and only later confirmed by them. This ensures that participation follows detailed clinical consideration rather than a desire to recruit into the trial. It also makes sure that assessments of competence to consent are clinical judgments not prejudged by rules. This complies with the guidance given by the Court of Appeal in the Tavistock litigation. Parental consent provides an additional protection for the interests of children. In this way the legal and ethical rights of young people are respected and the researchers have complied with the requirements of research ethics, as confirmed by regulatory scrutiny in the approvals process.”
Prof Rod Mitchell, Professor of Developmental Endocrinology, Centre for Reproductive Health, University of Edinburgh; and Consultant Paediatric Endocrinologist, Royal Hospital for Children and Young People, Edinburgh, said:
“In 2024, the UK government introduced regulations to prevent medical practitioners from prescribing GnRH analogues (puberty suppression) to children and young people with gender incongruence who were below the age of 18.
“By making the management of young people with gender incongruence part of an ethically approved clinical trial, it is possible to collect evidence that can improve care.
“The study is primarily focused on the short-term impacts of puberty suppression on psychological wellbeing and it is not designed to determine long-term impacts of these medications on physical health.
“Puberty suppression has been used for many years in children who have entered puberty at a very young age. In these children with ‘precocious puberty’ treatment has been shown to be effective in preserving growth potential, whilst also having a good safety profile in this patient group.
“The main difference between using puberty suppression in precocious puberty and gender incongruence is the age at which they are prescribed.
“The aim of treatment of precocious puberty is to delay puberty so that it is in the normal age-range, whereas prescribing puberty suppression in gender incongruence will often delay beyond the typical age for puberty.
“The study does include scans that will measure bone strength after puberty suppression, although longer-term follow-up would still be required to determine whether bones reach maximum strength as this usually does not occur until 20-30 years of age.
“The study is limited by the relatively short follow-up period, which makes it difficult to determine the impact of puberty suppression on physical development, including bone health.
“Given that this study has now been approved to determine the short-term effects of puberty suppression in gender incongruence, the opportunity to invite this group to join longer-term follow-up studies should not be missed.”
Dr Ronny Cheung, NHS Consultant Paediatrician, and Honorary Senior Lecturer, King’s College London, said:
“As a practicing paediatrician, I strongly welcome this study which addresses an area of conflicting, poor quality evidence.
“Practicing clinicians are always at pains to understand that the treatments we give (and withhold) may appear to be beneficial to the individuals we treat, but without robust evidence we are prone to human biases which overplay the benefit and underestimate the harms. Biological plausibility is not sufficient cause for treatment, as history has shown (note the harm caused to thousands of premature babies rendered blind from excess oxygen therapy). Even in life and death scenarios such as childhood cancers, treatments delivered as part of a robust clinical trial process has been routine for decades, and improved our understanding of how to save countless more lives as a result.
“This trial has the potential to do help us navigate care for children and young people with gender incongruence in the same sea of uncertainty that once characterised cancer care.
“That analogy may also be helpful to understand the decision not to include a placebo arm, which would be ethically difficult and pragmatically impossible to recruit to. Instead, the choice of immediate or delayed treatment elegantly provides a solution which should still give sufficient information in a real world context. Within this robust trial framework, we will at least be able to glean more reliable information about the potential benefit and risks associated with treatment at different points in development to be able to inform clinical decision making in a positive way.
“Furthermore, I applaud the use of the an overall quality of life metric as the primary outcome. It would have been easy to focus on gender-related distress, physical and psychological benefits and complications which form the basis of so much of the nuanced debate around these therapies. These are, quite rightly, included in the secondary outcomes, but it is crucial that we focus on the overall wellbeing of these children and young people in the round, and the choice of a primary outcome that focuses on their overall wellbeing is crucial.
“There will no doubt be criticisms around the high bar set for entry into the trial – the minimum duration of two years of gender incongruence, the need for consent from both child and parent, the exclusion based on potentially subjective assessments of the family’s ability to adhere to treatment and so on. However, these reflect standard practice in trials involving children and young people, particularly those where there is unquantified risk/benefit in treatment, and are important safeguards to protect this deeply vulnerable group of children, young people and their families.”
* Protocol title: ‘Puberty Suppression and Transitional Healthcare with Adaptive Youth Services (PATHWAYS): PATHWAYS TRIAL, PATHWAYS CONNECT and PATHWAYS HORIZON-INTENSIVE’.
This was published at 00:01 UK time on Saturday 22 November 2025.
Declared interests
Dr Hilary Cass: “Independent advisor to DHSC on CYP gender services.”
Prof Dougal Hargreaves: “I don’t have any competing interests to declare.”
Prof Sara Fovargue: “I don’t have any interests to declare.”
Prof Sir Jonathan Montgomery: “Sir Jonathan Montgomery is Professor of Health Care Law at University College London and a former Chair of the Health Research Authority. He has been providing advice to the study team on how to ensure compliance with legal and ethical requirements on an unremunerated basis and is not one on the investigators in receipt of the grant.”
Prof Rod Mitchell: “Received honoraria for invited lectures and publications – none of which are related to the subject of gender incongruence.”
Dr Ronny Cheung: “I should declare that I have published a narrative literature review (not original research) on gender care in Archives of Disease in Childhood (published by BMJ publishing), and that I am a clinical colleague of Dr Michael Absoud, who is the Deputy Chief Investigator of the study. I do also hold a part-time role with NHS England working with the children and young people’s transformation team. Otherwise I have no other declarations of interest.”