Is puberty delaying treatment ‘experimental treatment’?

In 2019 five clinicians working at the Gender Identity Development Service (GIDS) at the Tavistock and Portman NHS Foundation Trust in London in the United Kingdom (UK) resigned (The Times, 2019), and one of the governors of the Trust also resigned (The Guardian, 2019b). Among other reasons, they adduced that puberty ‘blockers’¹ are prescribed experimentally to gender diverse youth, without sufficiently robust evidence around efficacy and safety, and without sufficiently robust diagnosis.

One issue that has emerged from these disputes is that there seems to be lack of clarity around whether or not clinicians, patients, families, and policy-makers should consider puberty delaying intervention as experimental, and, if so, in what ways. This concern has also been raised in the academic literature (Biggs, 2019; Henegan & Jefferson, 2019).

In this editorial we unpack and analyze the claim that prescribing puberty delaying medications is experimental and we show that provision of puberty delaying medications to adolescents with gender dysphoria is not experimental, or at least not any more experimental than standard pediatric practice when there are no licensed² treatment options for a pediatric patient population.

We will analyze three issues in particular: 1) Does the fact that the drugs used for inducing and maintaining puberty delay are prescribed ‘off label’ make the use experimental?; 2) does the fact that the drugs do not have market authorization for puberty delay in gender diverse children make the use experimental?; and 3) does the fact that there are no randomized controlled trials of puberty delay in gender diverse children make the use experimental?

We should note at the outset that the question concerning whether the use of a pharmaceutical product is experimental is different from the question concerning whether it is ethically provided. A drug could be used experimentally and yet it could be clinically indicated and ethically provided. The UK courts have, for instance accepted that a completely novel, experimental use of a drug can be in the best interest of a patient, even if the only evidence for possible efficacy is from small animal studies (Simms v An NHS Trust, 2002).

The treatment of gender diverse children involves a range of interventions and our analysis here is restricted to puberty delaying pharmaceutical products and in particular gonadotropine releasing hormone analogs (GnRHa).

Who is prescribed puberty delaying treatment?

Puberty delaying hormones are typically only prescribed to adolescents who suffer strong and persistent gender dysphoria (Hembree et al., 2017). The treatment is not normally prescribed either to young children, or to those who identify as simply gender diverse, and is even less likely to be prescribed to those who might just be perceived as gender diverse by others.

Gender dysphoria is defined as distress caused by the discrepancy between a person’s gender identity and a person’s sex assigned at birth (and the associated gender role and/or primary and secondary sex characteristics) (WPATH, 2011).

Not all children who have non-congruent gender expression also suffer dysphoria and there is significant variability in gender expression, both in cisgender children and transgender children (Gülgöz et al., 2019). Many cisgender children express behaviors that are perceived as gender non-congruent in the culture of belonging. These are not the children who would typically be treated medically.

Since the mid 1990s, puberty delaying medications have been prescribed to some adolescents (not prepubertal children) with severe and persistent gender dysphoria, in cases in which such distress was aggravated by pubertal development.

The Royal College of Psychiatrists (RCP), in 1998, recommended delaying puberty in young adolescents who experienced strong and persistent “cross-sex identification” and distress around the physical body that intensifies with the onset of puberty. The RCP added:

In order for adolescents and those with parental responsibility to make properly informed decisions, it is recommended that they have experience of themselves in the post-pubertal state of their biological sex. Where, for clinical reasons, it is thought to be in the patient’s interest to intervene before this, this must be managed within a specialist service with paediatric endocrinological advice and more than one psychiatric opinion³. (Royal College of Psychiatrists, 1998)

The Harry Benjamin International Gender Dysphoria Association’s Standards of Care for Gender Identity Disorders (now the World Professional Association for Transgender Health (WPATH) similarly stated in 2001 that:

Adolescents may be eligible for puberty-delaying hormones as soon as pubertal changes have begun. In order for the adolescent and his or her parents to make an informed decision about pubertal delay, it is recommended that the adolescent experience the onset of puberty in his or her biologic sex […]. In order to provide puberty delaying hormones to an adolescent, the following criteria must be met:

1. through childhood the adolescent has demonstrated an intense pattern of cross-sex and cross-gender identity and aversion to expected gender role behaviors;

2. sex and gender discomfort has significantly increased with the onset of puberty

3. the family consents and participates in the therapy (Harry Benjamin Standards of Care, 2001, p. 10).

These older recommendations have fed into more recent international guidance.

Advice has evolved; however, these guidelines have historical importance: they show that puberty blockers are not ‘novel’ treatment. They were recommended by prominent bodies of medical opinion in the UK and internationally over two decades ago, and have thus been part of standard medical treatment for many years. Interestingly, the Royal College of Psychiatrists expected situations in which blockers might be in a patient’s best interests even before they had experienced life in the post-pubertal state.

The guidelines currently recognized as most authoritative are the WPATH Standards of Care (2011) and the US Endocrine Society guidelines (2017) (Hembree et al., 2017).

Claims that ‘transgender children’ have their puberty blocked (Reed, 2018) are thus in some ways misleading. They might lead readers to think that puberty delaying hormones are routinely prescribed to young children who are gender diverse. Instead, endocrine treatment is unlikely to be prescribed to anyone unless they have experienced gender dysphoria, and clinically significant distress after the onset of puberty. The clinical consensus is that only adolescents who suffer from severe gender dysphoria, and whose dysphoria persists or is aggravated by pubertal development, should be prescribed puberty delaying hormones. Moreover, puberty is not ‘suppressed’; the intervention is temporary and thus puberty is being delayed, rather than suppressed.

The problems of off label use

The medications that are most commonly used to delay puberty in adolescents with gender dysphoria are gonadotropine releasing hormone analogs (GnRHa). There are a number of different GnRHas on the market in the UK with market authorisations for the treatment of prostate cancer, uterine fibroids, endometriosis, and as part of the ovulation induction regime used in the context of assisted reproduction (BNF, 2019). In pediatrics one product (Triptorelin) is licensed in the UK for the treatment of central precocious puberty and the unlicensed use for adolescent endometriosis is mentioned in the BNF for Children for several of the marketed GnRHa (BNF, 2019). No GnRHa has market authorization for puberty suppression in gender diverse children in the UK.

The GnRH analogs act on the pituitary gland and they suppress the endogenous production of sex hormones temporarily. There is little doubt that GnRHa administration is effective as a puberty delaying treatment: it does temporarily suspend pubertal development during the time of administration. When the medication is withdrawn, puberty is thought to restart as normal (but see discussion of possible long-term side-effects below).

GnRHa has been used in the treatment of gender dysphoria since the mid 1990s, and their efficacy in delaying puberty in adolescents is documented by numerous studies and scientific publications (Cohen-Kettenis, Schagen et al., 2011; Cohen-Kettenis, Steensma et al., 2011; De Vries & Cohen-Kettenis, 2012; Coleman et al., 2012; Desforges et al., 1991; Costa et al., 2015; Delemarre-van de Waal & Cohen-Kettenis, 2006; Kreukels & Cohen-Kettenis, 2011; De Vries et al., 2011, 2014; Edwards-Leeper & Spack, 2012; Hembree et al., 2009; Hembree, 2013; Hewitt et al., 2012; Khatchadourian et al., 2014; Nakatsuka, 2012; Shumer & Spack, 2013; Spack, 2013; Vrouenraets et al., 2015, 2016; Wylie et al., 2016).

Thus the puberty delaying efficacy of GnRHa in adolescents with severe gender dysphoria is well evidenced and not experimental.

However, GnRHa is not expressly licensed by the EMA (European Medicine Agency) or the MHRA (Medicines and Healthcare products Regulatory Agency) for the treatment of gender dysphoria in adolescents (Fisher et al., 2014) and this is one of the reasons why it has been argued that GnRHa is provided experimentally (The Times, 2019).

The use of a drug for an indication that is different from the one for which the drug is licensed, usually referred to as ‘off label use’ or ‘off label prescription’ is common in many areas of medicine, but we will focus here on pediatrics. Off label prescription is both common and necessary in pediatrics, because many drugs have only been tested on adults as part of the development process leading to licensing and are therefore only licensed for use in an adult population (Balan et al., 2018; Cuzzolin et al., 2003; Magalhães et al., 2015). Off-label prescribing in pediatrics is endorsed in general by the Royal College of Pediatrics and Child Health (RCPCH), and even for a sensitive area such as pediatric psychiatry by the British Association for Psychopharmacology (Sharma et al., 2016) which states that:

Health-care professionals have a responsibility to prescribe the most effective and safe treatments for their patients. For children and adolescents, this may mean choosing an off-label medication in preference to a licensed one, a non-pharmacological treatment or no treatment at all. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term off-label does not imply an improper, illegal, contraindicated or investigational use. (p. 420)

The EU and the USA have put in place schemes in order to incentivise the pharmaceutical industry to do more pediatric research on new molecular entities in order to enable licensing for pediatric use, but these schemes do not apply to old, already licensed products (Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for pediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004; Penkov et al., 2017). GnRHa were first licensed in the 1980s when there was no requirement for, or incentives to conduct pediatric research for licensing purposes (Conn & Crowley, 1994). It would be possible for a pharmaceutical firm to apply for the licensing of their GnRHa for puberty delay in adolescents with gender dysphoria, but there is very little incentive for the firm to do so. Having a licensed product would not necessarily lead to increased sales, even if it was the only licensed product on the market. If the product is already the market leader for the new licensed indication there would be little extra sales, and if it is not the market leader doctors could still go on prescribing the unlicensed competitor products off label.

It is not primarily the lack of research that prevents the licensing of GnRHa for puberty delay in adolescents with gender dysphoria. It is likely that GnRHa could be licensed based on already existing research, but no one has an incentive to use the necessary resources to submit a license application. If we look at the licensing of GnRHa for puberty suppression in children with central precocious puberty that use has been licensed in Europe and the US based on relatively short open-label studies with small groups of patients (MHRA), because it is impossible and unethical to perform a Randomized Controlled Trial (RCT) for this indication. The same would apply to puberty delay in adolescents (see below). It is worth noting that GnRHa is only licensed for this indication because there are so few patients with central precocious puberty that the condition is classified as an orphan condition (IPSEN), which provides specific financial incentives in terms of market exclusivity for the first firm obtaining a license. The mere fact that a drug is used ‘off label’ therefore does not show that it is used experimentally. The first time it is prescribed off label, especially if it is for a different condition than that for which it is licensed the prescription may be said to be experimental (but, as noted earlier, that would not necessarily mean that the use is unethical). However, as the knowledge about the effects and side-effects of the treatment builds up over time and is documented in the academic literature, the use becomes less and less experimental and may eventually become routine and standard, especially if the knowledge is generated through well designed follow up studies and not just as an accumulation of unsystematic clinical experience.

Why not a randomized controlled trial?

One of the claims found in the recent literature is that the use of GnRHa for puberty delay is experimental because it has not been tested in a randomized controlled trial (RCT) (NHS, 2019). In a typical two-armed RCT patients are allocated by randomization to either a treatment arm where they receive the new treatment or a control arm where they do not receive the new treatment, but may receive a placebo if it is necessary to maintain blinding. Both arms receive whatever else is part of standard treatment, e.g. counseling etc.

These types of trials are normally taken as providing the highest level of scientific and medical evidence that can be derived from a single study (Elamin & Montori, 2012; Evans, 2003), and are, in cases where they are possible, usually a requirement for the licensing of a pharmaceutical product. In the case of puberty delay with GnRHa it is, however, practically impossible to conduct a RCT, and it might be unethical to try to do it. There are two main practical problems that preclude conducting a RCT.

First, patients who approach clinics for help because of distress caused by the first signs of puberty will be unlikely to accept to be a part of a RCT. Medications are needed within a relatively short period of time, at pain of treatment being less effective or ineffective. Recruitment would thus be hard if not impossible.

Second, the ideal RCT is either double blind, i.e. neither researchers nor participants know who gets the active drug, or it assesses outcomes using blinded observers when treatment allocation cannot be hidden from participants. Blinding is necessary in order to reduce bias in outcome assessments. But, a RCT of puberty delay could not maintain blinding. Because GnRHa are effective in delaying puberty it would soon become evident to participants, researchers and outcome assessors who was in the active treatment arm and who was not. This breakdown of blinding would mean that there would be potential bias in the outcome assessments, both in relation to biological and psychological outcomes. It would also mean that participants allocated to the non-treatment arm of the study would be likely to either withdraw from the study at a much higher rate than in the treatment arm introducing potential bias, and/or be more likely not to adhere to the trial but seek puberty delaying treatment outside of the trial thereby adding a confounder. It is also not clear that a RCT would provide answers to the questions that are still outstanding in relation to puberty delay with GnRHa in the relevant group of patients. We already know that the treatment is effective in delaying puberty and that puberty restarts when GnRHa is withdrawn. The questions that still need answering are about the medium- and long-term effects of puberty delay. We can divide these in two categories, that is questions about 1) negative side-effects, e.g., in relation to bone density or other long term biological risks, and; 2) effects on gender dysphoria and gender transition.

We will discuss both types of questions in separate sections below, but in this section on the putative need for RCTs it is important to note two things. First, that both types of questions require long-term follow up that extends well into adulthood and much longer than in a typical RCT. Second, that in those patients who eventually continue transition with cross sex hormones⁴ and in some cases surgery or other gender affirming medical interventions, the effects of puberty delay will become entangled with the effects of later treatments and will become difficult to assess because of confounding. The absence of RCT evidence, which could in reality not be obtained, does not make the prescription of GnRHa for puberty delay in adolescents with gender dysphoria experimental.

GnRHa have unknown long term side effects

Another worry around GnRHa relates not perhaps to prescription off label but to the potential unknown side effects in the medium and long term. In this interpretation prescribing a drug is ‘experimental’ as long as there is uncertainty about it medium and long term side effects. But, the fact a drug or medical intervention have unknown side effects does not entail that prescribing the drug or performing the intervention can be described as experimental in any meaningful way. This can be shown in two different ways. The first follows from the current drug development pathway. A new drug will go through a series of trials in humans before being licensed. However, even the pivotal Phase 3 randomized clinical trials that may involve hundreds or thousands of patients and which are the basis for licensing are not powered to detect even moderately rare side effects (Sonal & Loke, 2012; Wahab et al., 2013). It is not uncommon for a drug to be marketed and then later withdrawn from the market because serious side effects are discovered. This shows that at the point of marketing there are still significant remaining uncertainties about the side effects of a drug, but we would not say that a doctor who prescribed a recently marketed drug for its registered indication was prescribing ‘experimental treatment’. Furthermore, the follow up period in the pivotal Phase 3 trials is usually not long enough to detect late, long term side effects even if they are not rare. But, that again does not entail that prescribing drugs that have not been on the market for many years allowing for the detection of late side effect is ‘experimental’.

Second, we are rarely in a position where we can predict an individual’s response to a particular drug with absolute certainty. Most drugs have side effects, and most have some rare but serious ones, but our inability to predict whether this particular patient will experience a serious side effect does not make the prescription ‘experimental’. If it did all prescription, even of Aspirin would be experimental. What drives clinical decisions is the risk/benefit ratio using a probabilistic calculation, which includes elements such an assessment of the risks of the condition if left untreated, the expected benefits of the intervention, the expected risks, the potential more remote risks, their likelihood. From this a conclusion is drawn concerning whether the intervention is overall clinically appropriate. However, in response to the concerns around the medium and long term side effects of GnRHa, we will briefly summarize the current understanding of its long-term effects and then discuss the general problems in researching possible side-effects of GnRHa treatment of transgender adolescents.

Broadly the concerns can be divided in the following categories:

1. Effects on bone density (risk of osteoporosis later in life);

2. Effects on reproductive capability;

3. Increased odds of later medical transition.

1. Effects on bone density and risk of osteoporosis

A major concern is the impact of GnRHa on bone development. Administration of GnRHa slows the pubertal growth spurt. This can represent an advantage for natal males, as it reduces their likely final height and makes it more likely for them to achieve an ultimate height within the normal female range. However, the question is whether reduction of the rate of growth has any effects on bone formation and metabolism and whether these effects persist after the end of the treatment (Haraldsen et al., 2007). GnRHa inhibits the production of endogenous sex hormones and thereby impacts negatively on the formation of bone mass, by delaying the increase in bone mass during the pubertal growth spurt. There is some evidence from follow up studies that adolescents treated with GnRHa and later cross sex hormones may not reach the same peak bone mass as they would have reached if untreated (Klink et al., 2015) and this issue has been identified as one of the priority issues for further research (Olson-Kennedy et al., 2016). The findings are difficult to interpret, since the available evidence on bone density and mass in transgender persons receiving gender-affirming hormonal treatment as adults is ambiguous (Wiepjes et al., 2019).

If it can be substantiated in larger studies that peak bone mass is affected by GnRHa treatment it will obviously become an important consideration in the general risk/benefit calculation prior to offering this treatment.

2. Effects on reproductive and sexual capability

Additional concerns regarding puberty delaying treatment relates to its effects on reproductive capability (De Sutter, 2005; De Sutter, 2009).

There are two most likely scenarios. In one, the adolescent proceeds with the transition to the other gender, and eventually in adulthood receives full genital surgery. In these cases, natural conception is not possible. However, it might still be possible to have genetically related children with assisted reproduction technologies. In this scenario, one concern is that the use of blockers in early puberty might prevent the extraction and storage of sperm (for males assigned at birth) and of ova (for females assigned at birth). However, the suppression of spermatogenesis in natal males is temporary and can be restored by interrupting treatment. A male assigned at birth whose puberty has been suppressed before spermatogenesis has occurred could decide to stop treatment long enough for spermatogenesis to start if they wish to collect and store sperm for reproductive purposes (this of course would mean that they would have to accept the masculinizing effects of endogenous testosterone on the body during this period). They can then continue with treatment for transition to female gender.

Collection of ova in natal females is less problematic. The treatment has little impact on the already formed ova. They may be collected and stored at the time of oophorectomy (Cheng et al., 2019; De Sutter, 2005). The other possible scenario is one in which the person does not need or requests genital surgery. A person with a penis and functioning testes and a vagina and functioning ovaries and womb can in principle reproduce naturally. There are in fact reports of trans men who have conceived naturally and have given birth (The Guardian, 2019a; Obedin-Maliver & Makadon, 2016). What impact cross sex hormones and the previous provision of GnRHa have on fertility in this scenario is unknown.

3. Increased odds of later medical transition

There is also a worry that delaying puberty may lead to increased odds of later medical transition, i.e., that a larger proportion of adolescents treated with GnRHa choose to transition than would have chosen to transition if their puberty had not been delayed. The problem here is due to the fact that GnRHa has multiple purposes: on the one hand, it has a therapeutic purpose (reduce distress and prevent or reduce the need for future surgeries, making transition easier); on the other hand, it has a diagnostic purpose (in delaying puberty, the adolescent is given time to elaborate their gender identity without the distress of the fast developing body). Because gender identity might fluctuate in puberty and after puberty (Wallien & Cohen-Kettenis, 2008), it is difficult to conceptually differentiate the diagnostic aims from the therapeutic aims. If we had clear early indicators of persistence, clinicians could in principle limit provision of GnRHa only to prospective persisters, thus reducing the risk of offering the treatment to adolescents who will not apply for gender affirming treatment later on. But it is not clear that GnRHa only benefits those who will transition. If a child is anxious or distressed at the development of sex characteristics, it may be difficult for them to explore their gender identity, due to the anguish that the developing body causes. They might benefit from puberty delay regardless of whether they choose to transition at a later stage. This seems coherent with earlier clinical recommendations. GnRHa prescription has since the late 1990s also been considered as a diagnostic intervention: by giving time to the adolescent without the distress of the changing body, GnRHa may facilitate the exploration of gender identity (Cohen-Kettenis & Van Goozen, 1998). Hypothetically, one could argue that the prescription of drugs may crystallize in the significant others or others at large the idea that the adolescent is transgender, when in actual fact they are not. The social expectations might result in psychological pressure for the adolescent to continue on the path to transition. However, this would be a problem not with GnRHa per se, but with the expectations that significant others form or might form around an adolescent’s gender identity development. To deny beneficial treatment because others might form unrealistic expectations around the patient would be ethically problematic: medical treatment is to serve the interests of the patient, not of others. However, there is no evidence that GnRHa induces people to cross genders. There is for example no evidence in those treated for precocious puberty that they are more likely than others to identify as transgender. Whereas there is a clear correlation between being on GnRHa and later medical transition, the cause of the later medical transition is unlikely to be GnRHa provision in itself. GnRHa is only provided after puberty has commenced, and to those adolescents who have strong and persistent dysphoria: only a minority of those who continue to experience strong dysphoria and cross gender identification after the onset of puberty revert to the original birth gender, regardless of GnRHa provision (Steensma et al., 2013). Another related potential risk is that GnRHa provision (but also social transition) might alter the cognitive representation of self, that is, might induce a person to internalize the idea of one self as transgender. However, developmental psychology shows that many factors contribute to shape the cognitive representation of ourselves and our gender (our names, the way parents interact with us since birth, the attitudes of our environment of belonging, prenatal exposure to hormones and so on (Gross, 2015, pp. 609–619), and it is difficult, if not impossible, to assess the impact that one individual factor might have.

General problems in researching possible side-effects

The health care journey of gender diverse youth does not begin or end with GnRHa treatment. Before GnRHa treatment is initiated there will usually be long, exploratory diagnostic process. Before, during and after GnRHa treatment there will be counseling and potentially other psychological interventions. And after GnRHa treatment has ended those who go on to transition will have cross-sex hormones and perhaps gender affirming surgery. And, the health care journey is just one part of the complex social journey that gender diverse youth have to navigate on the way to becoming adults. For those who go on to transition the long term effects will be determined by the totality of all of the medical and psychological interventions they have received. And, in addition by their response to the supportive or less supportive social environment in which they have grown up. This entails that even large, well conducted follow-up studies may not be able to provide definitive answers to questions about the biological, psychological and social long term effects of GnRHa treatment seen in isolation. Even if long term follow up shows a particular set of effects of the ‘whole package’ of interventions, it will be close to impossible to disentangle the specific effects of GnRHa treatment. This is the case even for seemingly hard biological outcomes like peak bone mineral density. This may be influenced by GnRHa treatment, but also by dose and duration of cross sex hormone treatment, by surgery and reconvalescence, by level of physical activity etcetera.

This means that it is unlikely that in this area of care we can achieve the sort of evidence-base that can lead to whole-ranging clinical guidance applicable to all patients in all contexts. It is therefore important that, while furthering understanding and collating additional evidence around gender identity development and GnRHa, clinicians retain sufficient discretion to use current evidence and current international guidelines as guidance for clinical practice, while also remaining flexible and sensitive to the particular needs of individual patients and to the specific circumstances in which they live.

Conclusions

Puberty delaying medications are currently provided off label to adolescents affected by gender dysphoria and this particular use cannot be investigated by a RCT. We have shown that this does not mean they are experimental drugs or are provided experimentally. Whether or not these (or even approved drugs) are ethically prescribed depends on whether they are likely to serve the patient’s health interests based on the evidence available at the time of prescription.

The published literature provides insight into the likely benefits of GnRHa. In summary, they reduce the patient’s dysphoria (Cohen-Kettenis & Pfäfflin, 2003, p. 171; Kreukels & Cohen-Kettenis, 2011, p. 467), reduce the invasiveness of future surgery (for example, mastectomy in trans men; treatment for facial and body hair, thyroid chondroplasty to improve appearance and cricothyroid approximation to raise the pitch of the voice in trans women) (Cohen-Kettenis & Pfäfflin, 2003, p. 171); GnRHa is correlated with improved psychosocial adaptation (Cohen-Kettenis & Pfäfflin, 2003, p. 171; Kreukels & Cohen-Kettenis, 2011, p. 467) and reduced suicidal ideation and attempts. Hembree noted increased suicidal ideation where blockers were not given (Hembree, 2011; see further, Imbimbo et al., 2009; Kreukels & Cohen-Kettenis, 2011; Murad et al., 2010; Spack, 2008).

In light of the collected and published evidence, it seems that the international clinical community has found a sensible point of balance: GnRHa can be prescribed to adolescents who experience strong and distressing dysphoria. GnRHa is not usually recommended for prepubertal children, when there is still significant uncertainty around the future gender identity development trajectory. The reaction to pubertal development will be part of the clinical assessment. In this way, most likely GnRHa will only be given to those who most likely will choose to continue to transition, but should the patient change their mind, then no permanent changes will have been effected (whereas, should an untreated person transition, permanent changes of pubertal development will only be partially reversible surgically). Parents, clinicians and significant others should continue to be open to the idea that the gender identity development of an adolescent might fluctuate even after puberty and therefore that the provision of gender affirming medical treatment is a separate decision from the earlier provision of puberty delaying treatment.

Simona Giordano
Hub Leader Centre for Social Ethics and Policy (CSEP)/Reader in Bioethics, The University of Manchester Law School, Manchester, UK
simona.giordano@manchester.ac.uk

Søren Holm
Centre for Social Ethics and Policy, The University of Manchester Law School, University of Manchester, UK
Center for Medical Ethics, HELSAM, Faculty of Medicine, University of Oslo, Norway

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Declaration of interest

No potential conflict of interest was reported by the authors.