Letter to PATHWAYS trial investigators, Children and Young People’s Gender Dysphoria Research Oversight Board, HRA, MHRA, NIHR, NHSEngland, CHM, Kings College Hospital, SLAM NHS Foundation Trust, Secretary of State for Health and Social Care
March 2025
We are writing on behalf of the Clinical Advisory Network on Sex and Gender (CAN-SG) to express our concerns about the proposed PATHWAYS trial [1] of gonadotrophin-releasing hormone agonists (GnRHa), or ‘puberty blockers’ for children with gender dysphoria/incongruence is unethical. CAN-SG is an established network of over 100 health professionals committed to open discussion and proper consideration of evidence in the field of gender medicine, and with a principle of “first do no harm”.
UK law mandates that clinical trials in children must be designed to minimise any foreseeable risk to a child’s stage of development (Schedule 1 Part 4 Principle 14 of the Medicines for Human Use (Clinical Trials) Regulations 2004) [2]. Given that puberty blockers by definition disrupt a crucial phase of human development, the anticipated benefits of such a trial must be tangible and significant to justify the risk to children. GnRHa use in children with gender dysphoria/incongruence has clearly established and documented risk of serious injurious adverse effects that impact children’s development and health for life.
On the other hand, tangible evidence of any benefit is absent, as demonstrated in the Cass review. There is thus no clinical equipoise, and to proceed counters all international standards of clinical trial ethics, regulation and legislation.
We argue that data already exist to evaluate the question and that other interventions, such as counselling and psychosocial interventions, are likely to be effective with no risk of medical adverse effects: investment and effort in conducting trials on these interventions would be more worthwhile.
In summary, this trial is unethical as a) the intervention with GnRHa will interfere with the child’s development, by definition; b) there are established substantive harms and risks of the intervention; c) the benefits are contested with no evidence-based endpoints for a trial of GnRHa in children that can act as reliable proxies for adult outcomes; d) the information is procurable by other methods.
Details of the argument are outlined in the annex. Members of CAN-SG request a meeting with you to discuss this further.
Yours faithfully
Dr Maria Atkins, Retired Consultant Psychiatrist and former chair Devolved Council for Wales RCPsych 2020-2024
Dr David Bell, Retired Consultant Psychiatrist, Psychoanalyst, former Governor Tavistock Trust
Dr Lenny Cornwall, Consultant Psychiatrist
Dr Paul Garner, Professor Emeritus in evidence synthesis
Dr Sinead Helyar, Registered Nurse working in clinical trials
Dr Chris Holdridge, General Practitioner
Dr Shahana Hussain, Consultant Child and Adolescent Psychiatrist
Dr Louise Irvine, General Practitioner and co-chair CAN-SG
Dr Tessa Katz, General Practitioner
Dr Stella Kingett, Consultant Psychiatrist and co-chair CAN-SG
Dr Jane Martin, retired Consultant Psychiatrist
Dr Aileen O’Brien, Reader in Psychiatry and Education and Honorary Consultant Psychiatrist
Ms Stella O’Malley, Psychotherapist
Dr Hannah Ryan, Specialty Registrar in Clinical Pharmacology and General Medicine
Dr Kiran Sharma, General Practitioner
Ms Sheila Stallard, retired Consultant Breast Surgeon
Mr Bob Withers, Jungian Psychoanalyst
Dr Ellen Wright, General Practitioner and Clinical Academic Fellow, Kings College London
Dr Pamela Yerassimou, Consultant Psychiatrist
cc. PATHWAYS research team
cc. Children and Young People’s Gender Dysphoria Research Oversight Board
cc regulators (HRA, NIHR, NHSE, CHM, MHRA, R&D dept Kings College Hospital)
cc SoS Health and Social Care
Annex.
We remind you of UK legislation governing the conduct of clinical trials (Medicines for Human Use – Clinical Trials Regulations 2004) [3] specifies the following:
- A trial should be initiated and continued only if the anticipated benefits justify the risks and should not be conducted where there is a preceding belief that death or disabling injury will occur.
- A trial must be designed to minimise any foreseeable risk in relation to a child’s stage of development (Schedule 1 Part 4 Principle 14 of the Medicines for Human Use (Clinical Trials) Regulations 2004) [2]
- Trials with human participants must conform to scientific principles.
- The information sought must be unprocurable by other methods.
It should be noted that according to UK law a child or a minor is anyone under the age of 18 (Children Act 1989), so where the research funding agreement repeatedly refers to “young people” instead of “children” it risks obscuring the fact that this research proposal is about children and therefore all laws protecting children in research must apply to all participants in the proposed research.
Our concerns can be summarised as follows:
Anticipated benefits do not justify the risks
GnRHa as prescribed for gender dysphoria/incongruence causes harm to bone development [4,5], and there is evidence of risk of impaired development of cognitive function[6], inadequate development of the sex organs, infertility [7,8] and lack of sexual function [9]. The putative benefit must be tangible and significant to outweigh these risks [10], but observational studies have failed to demonstrate any benefit to short-term well-being (Cass Review, p176).
No trial design could conform to scientific principles
- Given the lack of consensus around the diagnosis and prognosis for gender dysphoria/incongruence in children [11] the point of clinical equipoise lies at the point of enquiry regarding the aetiology, natural history, and causes of the dramatic changes in epidemiology [12] seen in recent decades, about which we know very little.
- As the Cass Review said (p177): “For the more recently presenting population of predominantly birth-registered females who develop gender dysphoria in early to mid-puberty, there is even less understanding of what in medical terms is called the ‘natural history’ of their gender dysphoria”.
- It is premature to consider a drug trial when these questions have not been addressed.
Scientific rationale is flawed
- There is no plausible scientific rationale for the mechanism by which puberty suppression alleviates gender dysphoria/incongruence in childhood and adolescence; rather it was hypothesized their use would enhance cosmetic outcomes in transgender adults and thereby improve adult psychosocial functioning [13,14], or provide time to explore gender identity, which was not borne out by research.
- No studies have demonstrated diagnostic criteria that reliably discriminate between children who will persist with gender dysphoria/incongruence into adulthood and those who will experience spontaneous resolution [11]. A prospective trial will inevitably involve giving GnRHa to a significant number of children who would have simply desisted, as there is no proven way of excluding these children at screening.
- Historical cohorts demonstrate that most children with gender dysphoria will have spontaneous resolution of their symptoms during puberty [15]. Conversely, most children treated with puberty blockers in published cohorts progress to cross-sex hormones [16,17]. It is therefore plausible that puberty suppression could exacerbate rather than remediate gender dysphoria/incongruence.
- As there are no published data of adult outcomes for children treated with GnRHa, there are no evidence-based endpoints for a trial of GnRHa in children that can act as reliable proxies for adult outcomes. For example, we have no idea whether improved social functioning after two years on GnRHa correlates at all with improved social functioning in adulthood. Thus, all proposed outcome metrics for a trial are entirely speculative and may be grossly misleading with regards to long-term benefits.
- GnRHa is the first step in a pathway of interventions for gender dysphoria/incongruence. Studying the effect of GnRHa without studying their real world use where they are almost inevitably followed by cross sex “gender affirming” hormones is likely to underestimate harms significantly, such as risk of permanent infertility.
- We note that the PATHWAYS trial proposes interventions for “gender incongruence” not “gender dysphoria”. (The Cass Review referred to both gender dysphoria and gender incongruence). ICD11 makes clear that “gender incongruence” is not a disorder and does not include mental distress or dysphoria in the diagnosis. It is even further outwith the bounds of ethical research to medicalise the non-disorder of gender incongruence than it would be to medicalise gender dysphoria.
- Ethical considerations stipulate the information sought must be unprocurable by other methods.
- Information about risks and benefits of puberty blockers could be obtained by less risky methods including: data from previous cohorts; animal studies; a systematic review of the safety of GnRHa in all other clinical populations, e.g. prostate cancer and precocious puberty; and research into psychosocial treatments.
Data already available
Observational data from the 9000 children treated by the Gender Identity Disorders Service (GIDS) at the Tavistock and Portman NHS Foundation Trust, including about 2000 who were given GnRHa will likely provide important safety information that should inform decisions around a prospective trial. The retrieval and analysis of this data, including adult outcomes, is still in progress, and given the paucity of long-term outcome data for this intervention and the gravity of the potential risks, we must wait for this information prior to recruiting healthy children to a trial. Any other approach would be to disregard the primacy of participant safety.
Research into psycho-social treatments
The Cass Review recommended a full programme of research including into psycho-social interventions saying it was “important to assess whether other treatments may have a greater effect on the distress that young people with gender dysphoria are suffering during puberty”. (p177). The Review said the lack of research into psychosocial interventions and longer-term outcomes of those who do not access endocrine pathways left “a major gap in our knowledge about how best to support and help young people with gender-related distress”. If the aim of the PATHWAYS study is to find out how the NHS can best support children and young people with gender incongruence, then research into psychosocial treatments should be a priority.
Cass was concerned that “The focus on puberty blockers and beliefs about their efficacy has arguably meant that other treatments (and medications) have not been studied/developed to support this group, doing the children and young people a further disservice.” (p. 179). Prioritising a GnRHa trial over research into psychosocial treatments could reinforce the focus on puberty blockers and beliefs about their efficacy and disincentivise children and their families from participating in therapeutic work. This could undermine the implementation of the Cass Review recommendation for a fundamental shift to prioritising psychosocial care for this group of children and young people.
References
- PATHWAYS funding award https://fundingawards.nihr.ac.uk/award/NIHR167530
- Government of the United Kingdom (2004). Schedule 1, Part 4 -Conditions and principles which apply in relation to a minor. Principles – 14. The Medicines for Human Use (Clinical Trials) Regulations 2004
- Government of the United Kingdom (2004). The Medicines for Human Use (Clinical Trials) Regulations. The Medicines for Human Use (Clinical Trials) Regulations 2004 (legislation.gov.uk)
- Sebastian E E Schagen, S, E. E., Wouters, F., M. Cohen-Kettenis, P. T., Gooren, L. G., Hannema. S. E. (2020) Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming Hormones. The Journal of Clinical Endocrinology & Metabolism, 105 (12) e4252–e4263. https://doi.org/10.1210/clinem/dgaa604
- van der Loos MATC, Vlot MC, Klink DT, Hannema SE, den Heijer M, Wiepjes CM. Bone Mineral Density in Transgender Adolescents Treated With Puberty Suppression and Subsequent Gender-Affirming Hormones. JAMA Pediatr. 2023 Dec 1;177(12):1332-1341. doi: 10.1001/jamapediatrics.2023.4588. PMID: 37902760; PMCID: PMC10616766.
- Baxendale, S. (2024) The impact of suppressing puberty on neuropsychological function: A review. Acta Paediatrica. https://doi.org/10.1111/apa.17150.
- Murugesh V, Ritting M, Salem S, Aalam SMM, Garcia J, Chattha AJ, Zhao Y, Knapp DJ, Kalthur G, Granberg CF, Kannan N. Puberty Blocker and Aging Impact on Testicular Cell States and Function. bioRxiv [Preprint]. 2024 Mar 27:2024.03.23.586441. doi: 10.1101/2024.03.23.586441. PMID: 38585884; PMCID: PMC10996503.
- Cheng PJ, Pastuszak AW, Myers JB, Goodwin IA, Hotaling JM. Fertility concerns of the transgender patient. Transl Androl Urol. 2019 Jun;8(3):209-218. doi: 10.21037/tau.2019.05.09. PMID: 31380227; PMCID: PMC6626312.
- Biggs, M. (2022). The Dutch Protocol for Juvenile Transsexuals: Origins and Evidence. Journal of Sex & Marital Therapy, 49(4), 348–368. https://doi.org/10.1080/0092623X.2022.2121238
- World Medical Association (2022) WMA Declaration of Helsinki – Ethical principles for medical research involving human subjects. WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Participants – WMA – The World Medical Association
- The Cass Review (2024). Independent review of gender identity services for children and young people: Final Report. Final Report – Cass Review
- Griffin, L., Clyde, K., Byng, R., & Bewley, S. (2021). Sex, gender and gender identity: a re-evaluation of the evidence. British Journal of Psychotherapy Bulletin, 45(5), 291–299. https://doi.org/10.1192/bjb.2020.73
- Delemarre-van de Waal, H. A., & Cohen-Kettenis, P. T. (2006). Clinical management of gender identity disorder in adolescents: a protocol on psychological and paediatric endocrinology aspects. European Journal of Endocrinology, 155(suppl 1), S131-S137
- Tavistock and Portman NHS Foundation Trust. (2019) Freedom of Information Act 2000 disclosure log entry. Reference 19-20011. FOI_19-20011_GIDS_Research_Information_with_attachments.pdf – Google Drive
- Ristori, J., & Steensma, T. D. (2016). Gender dysphoria in childhood. International review of psychiatry (Abingdon, England), 28(1), 13-20. https://doi.org/10.3109/09540261.2015.1115754
- Carmichael, P., Butler, G., Masic, U., Cole, T. J., De Stavola, B. L., Davidson, S., Skageberg, E. L., Khadr, S., & Viner, R. M. (2021). Short-term outcomes of pubertal suppression in a selected cohort of 12 to 15 year old young people with persistent gender dysphoria in the UK. PLoS One, 16(2), e0243894. https://doi.org/10.1371/journal.pone.0243894
- Wiepjes, C. M., Nota, N. M., de Blok, C. J. M., Klaver, M., de Vries, A. L. C., Wensing-Kruger, S. A., …den Heijer, M. (2018). The Amsterdam cohort of gender dysphoria study (1972–2015): Trends in prevalence, treatment, and regrets. Journal of Sexual Medicine, 15, 582–590. doi:10.1016/j.jsxm.2018.01.016