Consensus Report on Symposium in May 2005

Developing Guidelines for Endocrinological Intervention in the Gender Identity Development Treatment of Adolescents


The aim of this project is to develop an expert consensus among the clinicians engaged in the treatment of adolescents experiencing gender variance. This should lead to improved guidelines for endocrine intervention in this patient group. Currently there are no agreed guidelines being applied consistently amongst paediatric and adolescent endocrinologists in this complex area of medical intervention and little published research evidence to inform practice, which varies greatly between and within countries. This project raises complex ethico-legal issues relating to respect for patient autonomy, competence in the minor to give properly informed consent and promotion of the welfare and best interests of the minor.

As most adolescents experiencing gender variance, and their families, go through an acutely stressful time linked to pubertal development, the perceived lack of consistency in approaching these issues by professionals may add to their distress. This also makes it difficult for the multidisciplinary professional teams involved in their care to help these adolescents deal with their feelings and may increase the risk of unwanted acting out and self-harm. It is therefore highly desirable that there are commonly agreed guidelines for medical intervention endorsed by professional bodies, throughout the world, such as the professional medical colleges and, in the UK, the National Institute of Clinical Excellence (NICE). Moreover, such guidelines could be used to convince insurers to cover the cost of the most effective medication, even if expensive. The team’s work may influence existing guidance from the UK Royal College of Psychiatrists (RCPsychs) (1998), the British Society for Paediatric Endocrinology & Diabetes (BSPED) (2005) and the World Professional Association for Transgender Health (WPATH ) (2001).

The Gender Identity Research and Education Society (GIRES) is administering the current project and, together with Mermaids, is partially funding it. The substantial majority of the funding is provided by two medical charities, The Nuffield Foundation and King’s Fund, and also the Servite Sisters Charitable Trust Fund, all based in the UK.

The project team met in London, at the Institute of Child Health, for a two-day Symposium on 19 and 20 May 2005. It was agreed that Domenico Di Ceglie and Michael Besser should jointly chair the team, of which the members are:

  • Michael Besser, St Bartholomew’s Hospital, London, UK
  • Caroline Brain, Great Ormond Street Hospital for Children & Middlesex Hospital, London, UK
  • Polly Carmichael, Great Ormond Street Hospital for Children, UK
  • Peggy Cohen-Kettenis, VU University Medical Centre, Amsterdam, The Netherlands
  • Henriette Delemarre-van de Waal, VUUniversity Medical Centre, Amsterdam, The Netherlands
  • Petra De Sutter, Ghent University, Belgium
  • Domenico Di Ceglie, The Tavistock and Portman NHS Trust, London, UK
  • Simona Giordano, University of Manchester Medical School, UK
  • Wylie Hembree, Columbia University College of Physicians and Surgeons, New York, USA
  • Peter Lee, Penn State College of Medicine, Hershey, Pennsylvania, USA
  • Walter Meyer, University of Texas Medical Branch, Galveston, Texas, USA
  • Bernard & Terry Reed, GIRES, UK
  • Veronica Sharp, Mermaids, UK
  • Norman Spack, Children’s Hospital, Boston, Massachusetts, USA
  • Russell Viner, Great Ormond Street Hospital for Children & Middlesex Hospital, London, UK
  • Garry Warne, Royal Children’s Hospital, Parkville, Victoria, Australia

The endocrine interventions to be considered included:

A – use of GnRH (gonadotrophin releasing hormone) analogues to suppress gonadal sex hormone production by inhibition of pituitary gonadotrophin secretion. Important issues are the start-time of this intervention in relation to pubertal development, the length of time over which it is safe to continue the medication and the immediate options regarding reproduction, together with their future implications. Issues regarding licensing, cost and availability are also important.

B – the use of sex hormones to initiate the development of secondary sex characteristics, which are in accord with the adolescent’s gender identity when this is well established. Important issues are the appropriate start-time of this intervention, in relation to the prior use of GnRH analogues, and the immediate options regarding reproductive potential together with their future implications.

C – to consider the value of this staged approach, initial use of GnRH analogue alone followed by the addition of sex hormones, as compared to using high dose sex hormone intervention alone, or with the concurrent use of the GnRH analogue.

D – the use of other endocrine agents e.g. medroxyprogesterone acetate and anti-androgenic agents including cyproterone acetate and spironolactone.

Caroline Brain presented a review of the scant published evidence on treatment and the clinical risks in the adolescent population. She advised that current treatment is based upon theoretical or anecdotal considerations rather than evidence obtained from the outcomes of controlled research trials. The team members currently treating this group of patients then presented summaries of their own somewhat varied protocols and experiences (Henriette Delemarre-van de Waal, Peggy Cohen Kettenis, Peter Lee, Wylie Hembree, Norman Spack, Walter Meyer, Garry Warne and Caroline Brain). Petra De Sutter described the reproductive options available now, and those likely to become available, to adolescents prior to the commencement of medication to block pubertal development or administration of cross-sex hormones. Veronica Sharp described users’ and parents’ views of the available treatments, and the anguish they may experience when hormone blocking is delayed. Polly Carmichael described the psychological and legal issues relating to the ability of both adolescents and their parents/guardians to give properly informed consent. Simona Giordano described the ethical issues.

During the discussion of each presentation and in the final review of the proceedings, the Team broadly supported the philosophy of a staged approach to management, which involves the progression from reversible interventions to partially reversible ones, and finally to irreversible interventions. The following broad principles were agreed:

1 – In Holland, where clinicians use careful screening and selection tools and criteria, young trans persons, at times earlier than current practice in some centres dictates, appear to benefit from prevention of the experience of pubertal development in the undesired sex beyond Tanner Stage Two. This is as recommended under the existing HBIGDA Standards of Care and allowed, subject to a second opinion, under the existing RCPsychs guidance. This approach enables children to experience how it is to feel their ‘own’ hormones and is diagnostically relevant. Then, it provides more time for continuing careful assessment without committing children irrevocably to pubertal developments that can only be reversed with difficulty, or even not at all. The Dutch clinicians provide a fuller description of their approach in the first Appendix to this Report. However, undervirilised genitalia in trans girls would provide less material to be used if vaginoplasty were eventually performed. Although there are surgical means to deal this difficulty, the patient and her parents or guardians should be fully informed about its implications. In the UK, it is thought that patients might benefit from the reduction in ambivalence that the experience of pubertal development in the undesired sex to Tanner Stage 4/5 could bring. The BSPED Guidance recommends that this is continued in all cases until the development of secondary sex characteristics is complete, final height has been achieved and peak bone mass has been accrued. The British clinicians provide a fuller description of their approach in the second Appendix to this Report. Selection criteria will eventually differentiate these two types of persons. A task that other centres may consider, for the future, is to use the Dutch experience (and any other published data) to select those who are most likely to benefit from the use of GnRH analogues or medroxyprogesterone acetate to block further pubertal development after Tanner Stage Two.

2 – No validated research data were presented to support either approach. There has not been sufficient time to evaluate the long- term effects of starting the analogue at an earlier stage of puberty. It is necessary that a research project, ideally involving two or more centres sharing a common assessment protocol (to be developed), explores the benefits and drawbacks of these two approaches, before evidence based guidelines can be written. The research project would require ethical approval, which should facilitate the willingness of the clinical organisations involved to endorse the local research. The clinics in London, Amsterdam and Boston have embarked on a collaborative research project, as described below.

3 – GnRH analogues are the best available treatment to block pubertal development, with medroxyprogesterone acetate as a less desirable agent, which may have to be used in some circumstances. Clearly, medroxyprogesterone acetate may work but has to be more thoroughly monitored for its side effects and may require some combination with other blockers. Periodic monitoring of endogenous sex steroids is necessary to ensure efficacy of the protocol utilized. There appears to be the potential for reduction of bone density with any regimen that gives rise to prolonged periods of no sex steroids during what would normally be the years of pubertal development. However, this will reverse with gonadal steroid replacement, or with the cessation of blockers and the resumption of the previous pubertal development, accompanied by the production of endogenous sex steroids, if the adolescent were no longer affected by acute cross gender identification. Adolescents need standardised monitoring and testing throughout any endocrine treatment. The Dutch experience indicates how bone formation and height should be prudently monitored and regulated. The results, so far, are reassuring.

4 – Having achieved suppression of the endogenous hormone production, androgens or estrogens can be administered at a dosage that mimics normal pubertal development. The use of physiological gonadal steroids, e.g. estradiol, rather than equine or synthetic estrogen, permits accurate measurement of blood levels. This approach eliminates the use of medications that cannot be monitored and of anti-androgens, a group of drugs whose use is unnecessary and may be responsible for much of the morbidity experienced by trans people during transition management.

5 – More attention than hitherto should be given, by clinicians, users and parents, to the reproductive options available to the adolescent, which, with the benefit of new research, may continue to evolve. There is helpful information that can be provided for them to consider. The time constraints on these options differ between trans boys (FtM) and trans girls (MtF). Use of blockers in early puberty will prevent the storage of sperm for trans girls.

6 – Informed consent should be the outcome of a sustained educational process, rather than a single consultation, in order to achieve detailed understanding by the competent minor, and usually the parents or guardians, regarding the benefits, risks and side effects of any hormone blocking or cross-sex hormone intervention. While the ethico-legal issues that bear on this project are being explored by all the experts involved, clinicians may only wish to consider treating adolescents who are legally able to give informed consent. In cases where the competent patient is still a minor, clinicians may also consider it appropriate to have (or require) the consent of the parents or guardians. Whilst highly desirable, the consent of the latter is not an absolute legal requirement in some jurisdictions.

7 – Guidance on ethics and the law may help to clarify the ethico-legal grounds for peri-pubertal interventions. These could be: (a) respect for autonomy and (b) promotion of the adolescent’s best interests. Psychological and physical harm are certainly caused by natural puberty that results in the development of secondary sex characteristics that have to be reversed, by means of costly, invasive and, in some cases, only partially successful procedures, because they are in conflict with an established core gender identity. Clinicians need to balance the potential for such harm against that potentially caused by interventions to delay natural pubertal development (which might include denying adolescents the opportunity to experience that development in a manner that is consistent with their phenotype). It has to be clarified in each individual case whether the adolescent experiencing atypical gender identity development can be autonomous and legally competent to ask for endocrine treatment.

8 – It could never be in the young person’s best interest to commence cross-sex hormones at a peri-pubertal stage without informed consent. Guidance must include discussion of any largely irreversible effects of cross-sex hormones. In the case of an individual who later regrets transition, this may cause problems that can be severe, in both FtM and MtF patients, and may also require costly and invasive procedures that, in some cases, result in only partial reversal.

9 – In the light of the above considerations, and pending the outcome of the proposed research project, the team will work to develop interim amendments to the existing HBIGDA, BSPED and RCPsychs guidance for those organisations to consider. Approvals will, as necessary, be sought from other state and professional regulatory bodies. In addition, individual members of the team are preparing papers on these topics for submission to the academic journals and for presentation at the professional conferences relating to this field.

Meeting in Amsterdam – 31 March 2006

As agreed at the Joint Project Team’s Symposium, held in London in May 2005, work has started on collaborative research. This involves the treatment centres in Amsterdam, Boston and London. On 31 March 2006, the clinicians from those centres met in Amsterdam. The Project Team members present were:

  • Peggy Cohen-Kettenis
  • Henriette Delemarre-Van de Waal
  • Norman Spack
  • Caroline Brain
  • Polly Carmichael
  • Domenico Di Ceglie
  • Russell Viner

The design of the study and the measures to be used were discussed. As a first step, it was agreed that each centre will begin some use of the Dutch psychological screening protocol. The whole protocol is fairly extensive. As a first move, it was agreed that it would be a step forward if each centre would use a number of similar instruments on all its patients at Tanner Stage Two. This is only possible for those who come to the centres before that stage. Patients often come later. Further screening will then be conducted on the selected patients at appropriate intervals, to be determined. The clinicians from the three centres will meet again in October 2006.

Appendix 1 – The Dutch Approach

Most of our patients who apply for sex reassignment, which we begin with GnRH-analogue treatment, are 14 years or older and well into Tanner stage 3 or 4. However, if they are referred to our clinic at a younger age and have been diagnosed according to an extensive procedure and fulfill certain strict criteria, we consider them eligible to start GnRH treatment after they have reached Tanner stage 2. Typically, at the initiation of the physical changes of puberty, gender dysphoria becomes considerably worse. We do not entirely prevent the onset of puberty because we believe that adolescents should experience the beginning of biological pubertal development in order to make a more informed decision about having it curtailed. Also, since there is such individual variation in the timing of pubertal initiation, beginning analogue therapy at Tanner 2 provides a common starting point for all patients, when their physical development is still reversible. Our treatment with GnRH-analogue, triptorelin, is titrated to degree of breast development in girls and the testosterone level in boys.

We are currently treating 50 patients who began analogue therapy at various Tanner stages. Bone metabolism, bone age, growth and hormonal and metabolic parameters are closely followed throughout the years of treatment. We have found no reduction in bone accretion during pubertal suppression with GnRH analogue. The accretion of bone remains prepubertal. When cross-sex steroids are begun at the age of 16, bone density ultimately catches up. After two years on estrogen or testosterone, analogue-treated patients have a normal bone density for age. Final outcome will depend on whether our patients will attain a normal peak bone mass.

None of the patients who began treatment with GnRH analogue has reported regrets about treatment. This difference between the London experience and our own may be due to differences in our eligibility criteria. The most recent data from the largest clinical groups on the persistence of GID into adolescence and young adulthood come from Canada and the Netherlands. Approximately 20% of the children who have been diagnosed with GID when they were under 12 appear to suffer from GID as adolescents and young adults. However, this finding still implies that the large majority seems to ‘outgrow’ their GID before puberty. Precisely because of this finding, we believe that the diagnostic phase should be performed extensively and repetitively by highly skilled evaluators.

Of course, one should do everything possible to prevent harm caused by treating the ‘wrong’ adolescents. But harm may also come from not treating the ‘right’ adolescents or postponing treatment. Many of these patients may exhibit self-destructive behaviors and require heavy doses of psychotropic medication to deal with depression and anxiety. Their irreversible secondary sex characteristics will remain visible and contribute to life-long stigmatization.

From several studies of our group it appears that young adolescent GID patients function psychologically healthier than adult patients. In order to prevent the damage we have observed in our adult patients, and as a result of a number of follow-up studies, we have adjusted our treatment policy in recent years. We continue to evaluate our current treatment in prospective studies. This does not mean that we reject or do not see the value of other policies. In fact, the differences between the London and Amsterdam policies offer a unique opportunity to evaluate the long-term outcome of patients who have been treated according to the two protocols.

Appendix 2 – The British Approach

The analogue is prescribed at a later stage of pubertal development following the RCPsychs and BSPED guidelines, which recommend that adolescents have some experience of themselves in the post pubertal biological sex. Currently the criteria used by the British team for commencing analogue treatment include the following principles:

i. Significant level of distress associated with secondary sex characteristics and experience of being in “the wrong body”.
ii. Serious level of conviction about cross gender identification both in statements and also in living in other gender role.
iii. Some therapeutic exploration has taken place.
iv. The use of the hypothalamic blocker should be considered as a treatment in its own right and should not be described as the pre-cursor to opposite sex hormones. The next stage of treatment, if any, should be left open for further exploration.
v. The importance of continuing regular meetings and ongoing therapeutic exploration should be emphasised.
vi. The assessment of the biological environment and physical development by the paediatric endocrinologist must precede the use of the hypothalamic blockers.

For specific endocrinological recommendations, see BSPED guidance.