The Ethics of a Puberty Blocker Trial

Should the proposed NHS clinical trial proceed?

Photo by Louis Reed on Unsplash

The Final Report of the Cass Review recommended that new prescriptions of puberty blockers for gender dysphoria be halted except in the context of a clinical trial. The NHS stopped new prescriptions of puberty blockers in March, 2024 and the government has now imposed an indefinite ban on private prescriptions based on advice from the Commission on Human Medicines that prescriptions pose an “unacceptable safety risk.”

However, the Cass Review also recommended that a new clinical trial of puberty blockers be conducted and the NHS has announced that one will be commenced in 2025. The details of the trial have not yet been finalized but the proposal has aroused controversy. Dr. Cass has said that she believes a further trial is justified. Genspect and the Clinical Advisory Network on Sex and Gender have argued that a further trial is unnecessary and that research should prioritize the existing data on puberty blockers and the development of non-invasive approaches to gender dysphoria. Meanwhile, groups like WPATH the Mermaids Gender have demanded that the ban be lifted so that routine prescriptions can continue without the need for further research.

The NHS has not yet announced the details for the proposed trial but a BBC article discusses some possible designs. The main question the article considers is what kind of control group the trial will have. Previous studies of puberty blockers have not had a control group who did not receive the treatment so it is not possible to say whether any improvements noted would have happened without treatment or are attributable to some other treatment such as psychotherapy. However, a randomized control trial would be difficult to implement because participants assigned to the control group would see the physical changes of puberty and would have less incentive to continue in the trial

The Ethics of Clinical Trials

However, the ethical concerns around a clinical trial for puberty blockers go much deeper than the issue of the control group. There are serious concerns about whether a further trial is justifiable or even legal. These concerns have been raised by Keira Bell and James Esses, who are threatening to bring legal action to block the trial. Both are familiar with the legal system. Bell is a detransitioner who was one of the applicants in the Bell v. Tavistock case. Although the case was dismissed by the Court of Appeal, it raised public awareness on the problems with the gender affirming model and was a factor in the decision to close the youth gender identity development service at the Tavistock Clinic. Esses is a psychotherapist who brought a successful legal challenge when he was expelled from a masters program for gender critical views.

A solicitor acting for Esses and Bell has sent a letter to the Health Research Authority, which is responsible for approving clinical trials in the UK, setting out their objections to the proposed trial. The letter points out that the UK Policy Framework for Health and Social Care Research has strict requirements for research. The first of these principles is:

The safety and well being of the individual prevail over the interests of science and society.

Research must be scientifically sound and ethical. Any anticipate benefits to individual participants and future recipients of care must be weighed against foreseeable risks. There are also specific requirements for research involving children.

These principles are based on the Helsinki Declaration of the World Medical Association, which is considered the world standard for ethics of medical research on human subjects.

The solicitors’ letter outlines concerns that Bell and Esses have about the proposed clinical trial.

“The anticipated benefits do not begin to outweigh the foreseeable risks”

The solicitor’s letter notes that there are documented risks to the use of puberty blockers which include reduced bone density and possible brain swelling. There are also potential risks to fertility, cognitive development and future sexual function. They note that the National Health Service, in its decision to impose an indefinite ban on puberty blockers, refers to an “unacceptable safety risk in the continued prescription of puberty blockers to children.”

The letter goes on to say “there is no clear medical evidence to support any potential benefits of puberty blockers.” They point out that research does not support the claim the puberty blockers are effective in reducing suicidality.

The limited research suggests that some of the harm for puberty blockers could be serious. Puberty is an important developmental window in brain development and sex hormones play a significant role in this process. There are both animal and human studies which have found that blocking the flow of hormones during puberty may have negative effects on brain development which cannot be reversed after the developmental window has closed. One case study of a transgender identified male found a 10 point reduction in IQ after 22 months of puberty suppression.

Puberty is also the period at which bone density increases most rapidly and puberty blockers stop or slow this process. Some but not all of this lost density may be recovered when patients proceed to cross-sex hormones but they will still be left with below normal bone density and increased risk of early onset osteoporosis.

The effect of puberty blockers on fertility remains uncertain. While it appears that puberty blockers do not affect fertility when used to treat precocious puberty it is not clear that their effect is reversible when used during the normal window for puberty. Since almost all of the children treated with puberty blockers for gender dysphoria proceed to cross-sex hormones, which does lead to sterility, it has not been possible to collect evidence on this issue.

In order to justify exposing more children to the risks of puberty blockers there needs to be evidence of potential benefits that will outweigh these risks. However, there is no consensus as to what the potential benefits of puberty blockers are supposed to be. The rationale for prescription of puberty blockers is constantly shifting.

One of the initial stated purposes for puberty suppression is that it would act as a pause button which would provide gender dysphoric children more time to reflect on their gender identity prior to undergoing the irreversible changes of puberty. However, existing research has found that nearly all children with gender dysphoria who are treated with puberty blockers proceed to cross-sex hormones. This has given rise to an alternative hypothesis that puberty blockers actually prevent resolution of gender dysphoria by disrupting the process of puberty, which is an essential part of identity formation.

A second rationale is that puberty blockers promote improvements in mental health, including reduced suicidality. All of the systematic reviews to date have found that the evidence that puberty blockers lead to improved mental health is low certainty. Better research might provide more certainty but, before proceeding, it is necessary to consider whether there are alternative interventions available which would improve mental health with lower risks.

A third rationale is that puberty blockers make it easier from transpeople to “pass” as adults by preventing irreversible changes of puberty. This is a concern for boys since some changes of male puberty, such as a deeper voice, cannot be reversed. In order to prevent these changes, it would be necessary to start puberty suppression at Tanner Stage 3 or earlier but this carries risks. Boys whose puberty is blocked early do not develop a large enough penis for a penile inversion vaginoplasty so they require a more complex and risky procedure which uses a section of the colon. Blocking puberty earlier than Tanner Stage 3 also prevents the development of mature sperm and therefore leads to sterility.

The appearance rationale is much less important for teen girls, who are the majority of gender clinic patients. Testosterone and surgery can create a reasonably convincing male appearance at any age.

Another factor which needs to be considered when evaluating a clinical trial is how the risks an benefits of the proposed treatment compare to the risks and benefits of no treatment or alternative treatment. There is evidence that childhood onset gender dysphoria will desist in 65-95% of cases if the child is not affirmed in their identity. While many researchers have claimed that gender dysphoria which persists into adolescence is likely to persist, the supporting evidence for this claim is weak. There is also a growing cohort of detransitioners who deeply regret receiving puberty blockers.

Puberty blockers have significant risks for everyone who takes them. They may offer some benefits to patients whose gender dysphoria is likely to persist but the evidence of benefit is low certainty. They offer not benefit but harm to those whose gender dysphoria would otherwise desist. A problem the Cass Review identified is that there is no way if determining which patients are likely to persist in their gender dysphoria, and may therefore receive some benefits from puberty blockers, and those who would otherwise desist and will receive only harm.

The ethical rules for clinical trials are clear that considerations of risk and benefit to patients must take priority over advancement of knowledge. The fact that systematic reviews have found that existing evidence on a treatment is low certainty and more research is needed does not mean that more research is necessarily justified.

Approving a clinical trial is premature where alternative research methodologies which do not pose a risk to children have not been fully explored

Research which involves risk to human subjects should not be undertaken when there are alternatives which do not involve risk. These alternatives include animal studies, research into psychotherapy for gender dysphoria and long term follow up of children who have already been treated with puberty blockers.

The Cass Review recommended a data linkage study which would trace the health outcomes of children and adolescents treated at the Tavistock into adult gender services. This study did not proceed because adult gender clinics refused to release data. They have now been ordered to do so by the NHS and this study should be completed before a new cohort of children is exposed to risk.

There is also a major study of puberty blockers in the United States where the results have not been published because the lead investigator, Joanna Olson-Kennedy, was concerned that they would be used to support the legal case against medical transition of minors.

Thousands of children have been prescribed puberty blockers for gender dsyphoria over the last ten years. Many of them are now young adults but we know very little about the impact of puberty suppression on their mental and physical health. Filling this gap in knowledge should be a first priority before still more children are put at risk.

Approving a clinical trial is premature where alternative treatment options exist.

Esses and Bell say that the systematic reviews conducted by the University of York “show that less invasive psychotherapeutic interventions are associated with no negative side effects and with improvements in mental health in a comfortable majority of gender distressed patients.”

This is somewhat of an overstatement. The University of York systematic review of psychosocial interventions found that there were only a few low-quality studies and it was not possible to draw any conclusions about benefits from treatment. However, the review did find that there was no evidence of any adverse effects.

However, it is not surprising that there is very little recent research on psycho-social interventions in young people. For the last ten years, psycho-social interventions for gender dysphoria have been discouraged both by heavy patient loads in gender clinics and laws and policies which have labelled any approach other than unquestioning affirmation as “conversion therapy.” Psychotherapy has been found to be an effective treatment for a range of mental health conditions but has not been systematically evaluated for treatment of gender dysphoria in young people.

The Cass Review recommended a comprehensive research program which would include both medical and non-medical interventions for gender dysphoria. There is no justification for prioritizing research on a treatment such as puberty blockers, which has significant known risks, over a non-invasive treatment such as psychotherapy.

“[We] query how the proposed trial could possibly achieve a strong evidence base.”

Bell and Esses say that the proposed trial is unlikely to have a sufficient number of participants to produce meaningful results. They claim that participants in the study would have to be limited to male patients at Tanner stage 3 or below with a documented history of childhood onset gender dysphoria. This, they say, would eliminate the majority of patients on the current waiting list.

However, the NHS has not yet announced who will be eligible for the study. If they want to make it consistent with the original Dutch study, participants would be limited to patients of either sex with childhood onset gender dysphoria and no co-morbid mental health conditions. However, even these criteria would likely exclude a large part of the young people who are currently seeking medical transition.

The size issue is only one small problem with the proposed trial. The NHS has not yet described what outcomes, negative or positive, the study will measure. The proposed study period is only two years. This is reasonable, since puberty blockers should not be used for a longer time, but it means that the study will not provide information on the long-term effect of puberty blockers.

“There are considerable issues with the giving of adequate informed consent.”

This is an understatement. The Health Research Authority has strict standards for informed consent in research involving children. Children under 16 cannot take part in a clinical trial of an investigative medical product without consent of their parents or guardians. This raises the question of why parents who have been fully informed on desistance, regret, detransition, bone health, cognitive development, fertility and all of the potential medical complications, would ever consent to giving puberty blockers to their children.

There are vocal activist parents who are absolutely convinced that gender affirming care is lifesaving and will be clamouring to have their children included. These parents will include a toxic subgroup driven by Munchausen’s by Proxy or homophobia.

However, it is likely that the vast majority of parents who have agreed to gender affirming treatments for their children in past have done so reluctantly, prodded by clinicians who understated the risks of transition and exaggerated the risk of suicide. The threat of involvement of the child protection authorities loomed in the background. All of this was enabled by mainstream media which presented an entirely one-sided pro-transition view.

Times have changed, at least in the UK. The risks of medical transition have been widely discussed in the media. Transgender activists no longer have the same ability to mislead and intimidate parents. There is at least a faint hope that a proposed clinical trial will fail from lack of interest.

Time to Move On

There has been more than enough research on the effects of puberty blockers for gender dysphoria. Their use is based on a single low quality study from Amsterdam with questionable methodology, a short follow up period and a very high loss to follow up. One of the 77 patients in the study died of necrotizing cellulitis as a result of complications from a vaginoplasty. A death rate of over 1% in a patient population which started off physically healthy would have been the end of many research programs.

All of the particpants in the received regular pyschotherapy as well as medical transition. There was no control group so it is not possible to say how much improvement resulted from psychotherapy alone.

The main outcome which the Amsterdam study measure was reduction in gender dysphoria according the the Utrecht Gender Dsyphoria scale. However, when they evaluated children at the start of the trial they used the questionnaire for the child’s natal sex. At the end of the study they switched the questionnaire to the one for the child’s desired sex. This switching of scales might have contributed most of the measured improvement.

It is unlikely that any pharmaceutical regulator would have licensed puberty blockers for use in children on the basis of the Amsterdam study. In a normal drug approval process a small scale human trial like the Amsterdam study would have been preceded by animal studies and followed by a larger study with a proper control group.

However, since the drugs had already been licensed for use in precocious puberty, gender clinics were able to start prescribing them on a routine basis without the need for further research. A study at the Tavistock clinic, which was published only in the aftermath of the judicial review brought by Keira Bell, did not provide any benefits of improvements in psychological functioning. The results of a study in the United States has not yet been published.

Another study of puberty blockers will not contribute to resolving the outstanding debate on their use, which no longer depends on evidence. Activists have responded to the weak evidence supporting the use of puberty blockers by moving the goal posts. The Yale “Integrity Project” critique of the Cass Review claims that because puberty blockers do not change it current physical characteristics it is unreasonable to expect them to lead to reduced gender dysphoria or increased body satisfaction. They argue that evidence that puberty blockers contribute to stability in mental health should be sufficient justification for their use. A group from the Amsterdam gender clinic goes even further and rejects the “logic of improvement” entirely. In their view the only meaningful outcome for gender affirming care is satisfaction of patient desire.

The push for pediatric transition was driven by political activism rather than evidence. There is no need to expose still more children to irreversible harm to collect evidence that will resolve nothing.

Postscript

Some further information on the trial has just been published. The details are still vague and Hannah Barnes has serious concerns. The follow up period will only be two years and everyone participating in the trial will received psychosocial support. There are no details about selection criteria, control groups or randomization. A two year trial will not do anything to address the major knowledge gap indentified in the Cass Review which is the lack of long term follow up.