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• Response to authors
  Roberto D'Angelo, Shirley Prager, George Halasz, Juan C d'Abrera, Ron Spielman and Philip Morris
  Published on: 23 February 2020
• Authors' reply
  Ken C Pang, Michelle A Tollit, Carmen C Pace and Michelle M Telfer
  Published on: 17 February 2020
• What constitutes informed consent in the treatment of childhood gender dysphoria?: some comments on the Trans20 study
  Roberto D'Angelo, Juan C d'Abrera, George Halasz, Philip Morris, Shirley Prager and Ron Spielman
  Published on: 14 December 2019

• Published on: 23 February 2020

  Response to authors

  • Roberto D'Angelo, Psychiatrist and Psychoanalysi Institute of Contemporary Psychoanalysis, Los Angeles
  • Other Contributors:
    • Shirley Prager, Psychiatrist
    • George Halasz, Adjunct Senior Lecturer
    • Juan C d'Abrera, Psychiatrist
    • Ron Spielman, Retired Psychiatrist and Psychoanalyst
    • Philip Morris, Psychiatrist

  A recent article in The Times asks: "How will this play out in the next decade, as the first cohort on puberty blockers come to terms with their probable infertility? Such experimental paediatric medicine has been politicised and shrouded in secrecy for too long. It is time to ask serious questions.”1

  In the spirit of asking serious questions of the RCHGS Trans20 study, we stand by our previous claims and respond to the author’s comments, which clearly misrepresented our concerns. Based on our reading of the data, we are of the view that gender-affirming interventions, be they psychosocial or medical, do not have an adequate evidence base to warrant their widespread use as routine medical care in children and adolescents. In fact, the paper’s authors acknowledge this lack of evidence and highlight the “urgent need for more evidence to ensure optimal medical and psychosocial interventions”.

  In their response to our comments, the authors justify their claim that the Trans20 study is an observational study by referring to the NIH definition that an observational study is one in which “participants may receive interventions that are part of their routine medical care”. We do not agree that gender affirmative treatments, particularly medical interventions, constitute “routine medical care”, especially when there are only two small follow-up studies that report short term outcomes of young people who have undergone puberty blockade.2,3 This view is supported...

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  A recent article in The Times asks: "How will this play out in the next decade, as the first cohort on puberty blockers come to terms with their probable infertility? Such experimental paediatric medicine has been politicised and shrouded in secrecy for too long. It is time to ask serious questions.”1

  In the spirit of asking serious questions of the RCHGS Trans20 study, we stand by our previous claims and respond to the author’s comments, which clearly misrepresented our concerns. Based on our reading of the data, we are of the view that gender-affirming interventions, be they psychosocial or medical, do not have an adequate evidence base to warrant their widespread use as routine medical care in children and adolescents. In fact, the paper’s authors acknowledge this lack of evidence and highlight the “urgent need for more evidence to ensure optimal medical and psychosocial interventions”.

  In their response to our comments, the authors justify their claim that the Trans20 study is an observational study by referring to the NIH definition that an observational study is one in which “participants may receive interventions that are part of their routine medical care”. We do not agree that gender affirmative treatments, particularly medical interventions, constitute “routine medical care”, especially when there are only two small follow-up studies that report short term outcomes of young people who have undergone puberty blockade.2,3 This view is supported by the Australia Council of Therapeutic Advisory Groups which recommends that off-label medication use in children and adolescents should only occur if there is high-quality evidence supporting its use in paediatric populations.4 In 2019, BMJ Evidence Based Medicine concluded that significant problems with the research into puberty blockade and cross-sex hormones prevent definitive conclusions being drawn and that these treatments should be regarded as experimental.5

  The Trans20 study in fact meets the NIH definition of a clinical trial, namely “clinical research studies involving human participants assigned to an intervention in which the study is designed to evaluate the effect(s) of the intervention on the participant and the effect being evaluated is a health-related biomedical or behavioral outcome”6. We therefore stand by our position that this is an interventional study investigating what we and others consider to be an experimental treatment.

  The “step-wise progression” we refer to is outlined in the paper itself. The RCH’s Multidisciplinary Assessment Clinic’s function is to provide: information, assessment, psychosocial support, puberty blockers and gender-affirming hormones. We did not assert that all patients being treated at the RCH Gender Clinic receive all of these interventions. We are also perplexed that we were understood to be stating that children as young as 3 could receive medical interventions, when it is clear that puberty blockade could only be administered just before or during puberty. When we argue that the Trans20 study will intervene in the developmental trajectories of trans-identifying youth, we see all steps in the RCH’s protocol, be they psychosocial or medical, as parts of a very particular intervention, namely gender-affirmation. We stand by our conclusion that this study will not be able to document the natural history of gender dysphoria in young people as this natural history is being altered by gender-affirming interventions.

  We were very pleased to read the percentages of patients who receive puberty blockade and cross sex hormones. We have attempted to obtain this information from the RCH via Freedom Of Information and are still waiting for a response. Given that there are approximately 250 new referrals to the RCH gender clinic each year, the numbers of patients receiving puberty blockade (23%) and cross-sex hormones (20%) are substantial. It would be helpful to know how these percentages were derived. Do 23% of all patients referred to the clinic (including those who drop out) receive puberty blockers? Or is it 23% of patients who remain in contact with the clinic? Each of these present very different scenarios. Given that these figures represent averages over the last 10 years, it would be interesting to know whether the proportion of patients receiving medical treatment has increased in recent years.

  Regarding the desistance data, we suspect the authors would be aware that there are several studies that document desistance rates, which largely replicate the findings of the Singh study.7 We also assume the authors are aware of the 2011 study by Dhejne et al,8 one of the most robust studies looking at outcomes of gender-affirming treatment in adults, which documents a very high suicide rate post-transition. The authors are correct in stating that robust suicide data for young people receiving gender-affirming treatments is lacking. Sadly, the paper by Turban which the authors refer to suffers from serious methodological limitations, including the use of a non-generalisable convenience sample and a failure to correlate psychiatric comorbidity with reports of suicidal ideation and attempts.

  We continue ask: “what constitutes informed consent in the treatment of childhood gender dysphoria” and in the Trans20 study. The paper says very little about the informed consent procedure, other than that it is a “multistep process”. In our view, for any informed consent to be valid, it must include detailed information about the desistance rates (even if disputed by some), the unknown suicide risks, and the lack of long-term outcome data for gender-affirming interventions in young people. Further, Trans20 appears to be studying the outcome of what we and others believe are experimental treatments. Pang et al have made clear that these treatments are not intended or understood by the participants at the RCH Gender Clinic to be part of a clinical trial. This adds to our ethical concerns about the Trans20 study.

  1. Janice Turner for The Times, “Giving Puberty Blockers to Children is a Leap into the Unknown” https://www.thetimes.co.uk/article/giving-puberty-blocker-to-trans-child... accessed 23/02/2020
  2. DeVries A, McGuire J, Steensma T, Wagenaar E, Doreleijers T, Cohen-Kettenis P. Young adult psychological outcome after puberty suppression and gender reassignment. Pediatrics 2014, 134:1-9
  3. Costa R, Dunsford M, Skagerberg E, Holt V, Carmichael P, Colizzi M. Psychological support, puberty suppression, and psychosocial functioning in adolescents with gender dysphoria. J Sex Med 2015,12:2206-2214,
  4. Council of Australian Therapeutic Advisory Groups, Guiding Principles for the Quality Use of Off-Label Medicines. http://www.catag.org.au/wp-content/uploads/2012/08/OKA9963-CATAG-Rethink... accessed 23/02/2020
  5. Heneghan C, Jefferson T., Gender Affirming Hormones in Children and Adolescents. BMJ Evidence Based Medicine blog Feb 19 2020. https://blogs.bmj.com/bmjebmspotlight/2019/02/25/gender-affirming-hormon... accessed 23/02/2020
  6. NIH Grants and Funding, NIH Definition of a Clinical Trial https://grants.nih.gov/policy/clinical-trials/definition.htm accessed 23/02/2020
  7. Cantor, J, Sexology Today, “Do Trans Kids Stay Trans When They Grow Up?” http://www.sexologytoday.org/2016/01/do-trans-kids-stay-trans-when-they-... accessed 23/02/2020
  8. Dhejne, C. et al. Long-term follow-up of transsexual persons undergoing sex reassignment surgery: Cohort study in Sweden. PLoS ONE 2011; 6, e16885 http://doi.org/10.1371/journal.pone.0016885

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  Conflict of Interest:
  None declared.

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• Published on: 17 February 2020

  Authors' reply

  • Ken C Pang, Clinician Scientist Fellow and Team Leader Murdoch Children’s Research Institute, Melbourne, Victoria, Australia
  • Other Contributors:
    • Michelle A Tollit, Research Officer
    • Carmen C Pace, Research Officer
    • Michelle M Telfer, Paediatrician and Head

  We appreciate the opportunity to address the concerns raised by D’Angelo and colleagues in relation to our recently published protocol for the Trans20 study [1]. While we certainly welcome feedback on our study, D’Angelo and colleagues focus much of their commentary on the clinical care of young people with gender dysphoria rather than on the Trans20 study protocol itself. In addition, the letter contains a number of inaccuracies and misconceptions that we feel must be clarified.
  Firstly, the authors claim not only that the study “intervenes in the developmental trajectories of all 600 expected participants” and that the model involves “a uniformly stepwise progression through the social and biological stages of transition”, but also that The Royal Children’s Hospital (RCH) Gender Service offers biological interventions to children as young as three. These assertions are incorrect. While patients and families attending the RCH Gender Service routinely receive mental health input to assess, explore and support their gender identity, the use of medical interventions occurs in only a minority of patients, reflecting the highly individualised approach to care. More specifically, a recent 10-year audit of the service from 2007-16 (up until the inception of Trans20) revealed that only 23% of patients received puberty blockers, while an even lower figure of 20% received gender-affirming hormones, and no patient under 10 years of age received either of these medical interven...

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  We appreciate the opportunity to address the concerns raised by D’Angelo and colleagues in relation to our recently published protocol for the Trans20 study [1]. While we certainly welcome feedback on our study, D’Angelo and colleagues focus much of their commentary on the clinical care of young people with gender dysphoria rather than on the Trans20 study protocol itself. In addition, the letter contains a number of inaccuracies and misconceptions that we feel must be clarified.
  Firstly, the authors claim not only that the study “intervenes in the developmental trajectories of all 600 expected participants” and that the model involves “a uniformly stepwise progression through the social and biological stages of transition”, but also that The Royal Children’s Hospital (RCH) Gender Service offers biological interventions to children as young as three. These assertions are incorrect. While patients and families attending the RCH Gender Service routinely receive mental health input to assess, explore and support their gender identity, the use of medical interventions occurs in only a minority of patients, reflecting the highly individualised approach to care. More specifically, a recent 10-year audit of the service from 2007-16 (up until the inception of Trans20) revealed that only 23% of patients received puberty blockers, while an even lower figure of 20% received gender-affirming hormones, and no patient under 10 years of age received either of these medical interventions (Tollit et al, unpublished data).
  Secondly, the authors assert that “good data” already exists “on the natural history of gender confusion which shows that a majority of children desist at puberty”. To support this claim, the authors reference a doctoral dissertation [2] based on data originating from a controversial gender clinic in Toronto that was shut down by Canadian health authorities in 2015. A key aim of that clinic was to “help children feel more comfortable with their biological sex” [2], which led to suggestions that it was practising “conversion therapy” and questions over the validity of natural history data from this clinic [3]. Moreover, Kenneth Zucker himself, who led the Toronto clinic and oversaw these studies, has subsequently stated that their results are unlikely to generalise to contemporary cohorts of transgender children, and he instead predicts that persistence rates will become “extremely high” [4]. Consistent with this, Professor Zucker has also written that “we require more comparative data to draw conclusions about the natural history of GID [gender identity disorder] in children and its relation to contextual factors” [5]. This is precisely one of the aims of Trans20.
  Thirdly, D’Angelo and colleagues appear to conflate observational studies with clinical trials. As defined by the US National Institutes of Health, an observational study is one in which participants may receive interventions that are part of their routine medical care; these interventions are not assigned to them by the research team as occurs in a clinical trial [6]. At the RCH Gender Service, hormonal interventions are initiated on a case-by-case basis by a patient’s clinicians, and the Trans20 study simply observes the resultant outcomes. In this way, the authors’ assertion that Trans20 “more closely resembles an ‘interventional’ clinical trial” is inaccurate and misleading.
  Fourthly, the authors refer to high suicide rates and psychiatric morbidity post-transition. This is disingenuous, since meaningful interpretation of such rates requires either longitudinal analysis and/or comparison to a suitable control group given the high rates of suicidality and psychiatric morbidity in young transgender individuals pre-transition [7]. Unfortunately, such data are lacking, although a recent study by Turban et al from Harvard Medical School’s Department of Psychiatry indicates that puberty suppression in transgender adolescents is associated with a significantly lower odds ratio (0.3) in lifetime suicidal ideation compared to transgender individuals who were unable to access this intervention [8].
  Lastly, the authors raise concerns and questions regarding the process of informed consent. It is clear that their comments pertain to the consent process that occurs as part of clinical care at the RCH Gender Service and is distinct from consent to participate in the Trans20 research study, the process for which is clearly detailed in our protocol [1].
  References
  1 Tollit MA, Pace CC, Telfer M, et al. What are the health outcomes of trans and gender diverse young people in Australia? Study protocol for the Trans20 longitudinal cohort study. BMJ Open 2019;9.
  2 Singh D. A follow-up study of boys with Gender Identity Disorder. Doctoral dissertation, University of Toronto.
  3 Temple Newhook J, Pyne J, Winters K, et al. A critical commentary on follow-up studies and “desistance” theories about transgender and gender-nonconforming children. Int J Transgenderism 2018;19:212–24.
  4 Zucker KJ. The myth of persistence: Response to “A critical commentary on follow-up studies and ‘desistance’ theories about transgender and gender non-conforming children” by Temple Newhook et al. (2018). Int J Transgenderism 2018;19:231–45.
  5 Zucker KJ, Wood H, Singh D, et al. A developmental, biopsychosocial model for the treatment of children with Gender Identity Disorder. J Homosexuality 2012;59:369–97. doi:10.1080/00918369.2012.653309
  6 Learn About Clinical Studies - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/about-studies/learn#ObservationalStudies (accessed 14 Jan 2020).
  7 Olson J, Schrager SM, Belzer M, et al. Baseline physiologic and psychosocial characteristics of transgender youth seeking care for gender dysphoria. J Adolesc Health 2015;57:374–80.
  8 Turban JL, King D, Carswell JM, et al. Pubertal suppression for transgender youth and risk of suicidal ideation. Pediatrics 2020;145:e20191725.

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  Conflict of Interest:
  KCP is a member of the Australian Professional Association for Transgender Health (AusPATH) and on its research subcommittee. MAT and CCP are both members of AusPATH. MMT is a member and President of AusPATH.

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• Published on: 14 December 2019

  What constitutes informed consent in the treatment of childhood gender dysphoria?: some comments on the Trans20 study

  • Roberto D'Angelo, Psychiatrist Institute of Contemporary Psychoanalysis, Los Angeles
  • Other Contributors:
    • Juan C d'Abrera, Consultant psychiatrist
    • George Halasz, Adjunct senior lecturer, psychiatrist
    • Philip Morris, Psychiatrist
    • Shirley Prager, Psychiatrist
    • Ron Spielman, Psychiatrist and Psychoanalyst

  We wish to express concerns about the Trans20 longitudinal cohort study of transgender and gender diverse (TGD) youth from Melbourne’s Royal Children’s Hospital Gender Service (RCHGS) presented in the BMJ (Tollit et al BMJ Open 2019:9).

  While we agree with the authors that in regard to the management of TGD youth there is ‘’urgent need for more evidence to ensure optimal medical and psychosocial interventionsi”, we have grave reservations about the ethical underpinnings and methodology of the study as described.

  The Trans20 study aims to “document the natural history of gender diversity presenting in children”. It is not clear to us how the methodological design could allow observation of the ‘natural’ history of TGD youth when it intervenes in the developmental trajectories of all 600 expected participants. Given that a vast majority of young people who commence puberty blockers proceed to cross-sex hormonesii, it may well be the case that early intervention ‘locks’ a child into a persistent gender incongruence, closing them off to future choices in identity. We already do possess good data on the ‘natural history’ of gender confusion which shows that a majority of children desist at puberty and return to a gender identity congruent with their natal sexiii. Is this fact presented to concerned families?

  The RCHGS adopts an exclusively gender-affirming model of care, offering psychosocial and biological interventions to children as young as 3. Although...

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  We wish to express concerns about the Trans20 longitudinal cohort study of transgender and gender diverse (TGD) youth from Melbourne’s Royal Children’s Hospital Gender Service (RCHGS) presented in the BMJ (Tollit et al BMJ Open 2019:9).

  While we agree with the authors that in regard to the management of TGD youth there is ‘’urgent need for more evidence to ensure optimal medical and psychosocial interventionsi”, we have grave reservations about the ethical underpinnings and methodology of the study as described.

  The Trans20 study aims to “document the natural history of gender diversity presenting in children”. It is not clear to us how the methodological design could allow observation of the ‘natural’ history of TGD youth when it intervenes in the developmental trajectories of all 600 expected participants. Given that a vast majority of young people who commence puberty blockers proceed to cross-sex hormonesii, it may well be the case that early intervention ‘locks’ a child into a persistent gender incongruence, closing them off to future choices in identity. We already do possess good data on the ‘natural history’ of gender confusion which shows that a majority of children desist at puberty and return to a gender identity congruent with their natal sexiii. Is this fact presented to concerned families?

  The RCHGS adopts an exclusively gender-affirming model of care, offering psychosocial and biological interventions to children as young as 3. Although the Trans20 subjects are administered ostensibly different types of intervention, the therapeutic pathway in that model is a uniformly stepwise progression through the social and biological stages of transition.

  The authors state that the information will be analysed under a “’clinical audit framework”. To us this study more closely resembles an ‘interventional’ clinical trial (lacking an untreated control group) rather than an observational study. We wonder if this distinction was made explicit to the participants and their families during the recruitment phase and formed part of the ‘informed consent’ process.
  Our specific ethical concerns centre on whether the ‘informed consent’ offered to parents and their children reflect the rapid advances in complexity and uncertainty that have been reported in recent studiesiv,v,vi. It would be reasonable to expect a more detailed discussion of the consent process given the controversial nature of the treatments and the vulnerability of the participants. The report noted that consent was obtained through a ‘multi-step’ procedure. What does this mean? Are parents fully informed about the biological and psychological risks associated with delaying puberty through hormone blockers? Which aspects of gender dysphoria are and are not moderated by medical intervention? Are families dispassionately appraised of the high suicide rates and psychiatric morbidity post-transition? What supports, psychiatric or otherwise, are provided to subjects who, in the course of the study a) wish to revert to their natal gender (given the ostensibly fluid nature of gender) or b) are assessed as being dysphoric for reasons other than gender incongruence?

  We welcome additional clinical and research data from the RCHGS Trans20 cohort study to clarify their ethical guidelines, including a detailed nature of the informed consent protocol so others might learn to maximize the safety/risk ratio for these vulnerable young people and their families.

  Dr Roberto D’Angelo, FRANZCP
  Dr Juan Carlos d’Abrera, FRANZCP
  Dr George Halasz, FRANZCP
  Dr Shirley Prager, FRANZCP
  Dr Philip Morris, FRANZCP
  Dr Ron Spielman, FRANZCP

  Tollit, M.A., Pace, C.C., Telfer, M., Hoq, M., Bryson, J., Fulkoski, N., Cooper, C. and Pang, K.C., 2019. What are the health outcomes of trans and gender diverse young people in Australia? Study protocol for the Trans20 longitudinal cohort study. BMJ open, 9(11).

  Steensma, T.D., Kreukels, B.P., de Vries, A.L. and Cohen-Kettenis, P.T., 2013. Gender identity development in adolescence. Hormones and behavior, 64(2), pp.288-297.

  Singh, D., 2012. A follow-up study of boys with gender identity disorder (Doctoral dissertation, University of Toronto).

  Littman, L., 2018. Rapid-onset gender dysphoria in adolescents and young adults: A study of parental reports. PloS one, 13(8), p.e0202330.
  Chew, D., Anderson, J., Williams, K., May, T. and Pang, K., 2018. Hormonal treatment in young people with gender dysphoria: a systematic review. Pediatrics, 141(4)

  Landen, M., 2019. Dramatic increase in adolescent gender dysphoria requires careful consideration. Lakartidningen, 116.

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  Conflict of Interest:
  None declared.

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