A report in April 2024 by Dr Hilary Cass has ignited an ideological war in the UK. On one side are those who support and promote the manipulation of natural biological processes in young people so that they can eventually transition; change their biological sex. On the other side are mostly the rest of us, who have looked on bewildered for 10 years at what was happening to these vulnerable children and asking, ‘is this right?’ The orthodoxy was aggressively pursued by trans-rights activists and groups, and their cult became unchallengeable; to object was tantamount to ‘genocide’ of these tragically disturbed young people; or so we were told. This was a key battle-front in the current culture wars.
I have always taken the view that any adult wishing to change sex should have every right to do so and should never be discriminated against. This is a personal view but should I as a pharmacist have a view? Yes. The puberty blockers children are subjected to are medicines which should be properly assessed for safety and efficacy yet, in young people, it seems they were not.
A number of different puberty blockers are used. These include the Gonadotrophin Releasing Hormone (GnRH) agonists buserelin, histrelin, leuprorelin, nafarelin and triptorelin. GnRH antagonists are also expected to be effective as a puberty blocker, but have not yet been widely studied or used for this indication. Progestogens in high doses have been used, but are not as effectives as GnRH agonists and have more side-effects. The anti-androgen bicalutamide has been used as an alternative puberty blocker in transgender girls.
Treatment options for girls wishing to transition to boys include ketoconazole, the aromatase inhibitors, testolactone, fadrozole, anastrozole and letrozole, and the anti-oestrogens, tamoxifen and fulvestrant. Treatment options for boys transitioning to girls include anti-androgens bicalutamide, spironolactone and cyproterone acetate, ketoconazole, and the aromatase inhibitors testolactone, anastrozole and letrozole.
GIDS
The Gender Identity Development Service (GIDS) was established in the UK in 1989 as the Tavistock and Portman NHS Foundation Trust. Initially, the numbers of children seen were small (fewer than 10 per annum in the first few years). These were generally very disturbed children who were professionally assessed and a holistic approach to therapy was implemented, with a strong emphasis on mental health within a watch-and-wait approach. This was uncontroversial, and what was evident was that this cohort of children were more likely to have autism or suffered trauma from adverse childhood events.
The Dutch Protocol
Things changed with the emergence of ‘the Dutch Protocol’. In 1998, a single case study described a female-to-male transition where puberty blockers started at age 13. The rationale for the approach was two-fold: To support the diagnostic procedure by buying time to think, and to improve the longer-term ability to transition to the preferred gender.
The watching-waiting approach continued in the UK until 2011, when puberty blockers were trialled in an uncontrolled study with inclusion criteria in line with the original Dutch Protocol, and similar outcome measures.
Then the strict inclusion criteria of the Dutch Protocol were no longer followed, and puberty blockers were given to a wider range of adolescents than would have met the inclusion criteria in either the Dutch or UK studies. These included patients with no history of gender incongruence prior to puberty, as well as those with neurodiversity and complex mental health presentations.
Safety
Very little is known about the long-term side effects of puberty blockers in children with gender dysphoria. There is no understanding about the impact of hormone blockers on development factors such as bone density, brain development and fertility in transgender patients. These drugs are unlicenced so used off-label. Drug manufactures have not submitted any of these medicines for regulatory approval as puberty blockers, mainly due to cost, but also because of the politics surrounding the transgender issue. To use off-label is common in paediatric medicine and in itself is not malpractice.
Hilary Cass found that few studies have been undertaken into the effects of puberty blockers, and these studies are generally of poor quality, so the evidence that they provide is also of poor quality. A 2024 systematic review confirmed the conclusion of the National Institute for Health and Care Excellence (NICE) that the currently available studies have significant conceptual and methodological flaws.
Short term side-effects of puberty blockers include headaches, fatigue, insomnia, muscle aches, and change in breast tissue, mood and weight. Adverse effects on bone mineralisation and compromised fertility are potential risks of pubertal suppression in gender dysphoric youth treated with GnRH agonists.
Research on long-term effects on brain development, cognitive function, fertility and sexual function is limited. A 2020 study suggested that pubertal suppression may prevent key aspects of development during a sensitive period of brain organisation and that we need high-quality research to understand the impacts of the treatments — impacts that may be positive in some ways and potentially negative in others.
In 2016, the FDA insisted that manufactures added warnings to puberty blocker drugs labels stating: “Psychiatric events have been reported in patients, including symptoms such as crying, irritability, impatience, anger and aggression.”
Efficacy
The original rationale for the use of puberty blockers was that this would buy ‘time to think’ by delaying onset of puberty and also improve the ability to transition sex in later life. It was suggested that the drugs may also improve body image and psychological wellbeing. A systematic review from the University of York found no changes in gender dysphoria or body satisfaction. There was insufficient/inconsistent evidence about the effects of puberty suppression on psychological or psychosocial wellbeing, cognitive development, cardio-metabolic risk or fertility. Moreover, given that the vast majority of young people started on puberty blockers proceed from puberty blockers to masculinising/feminising hormones, there is no evidence that puberty blockers buy time to think, and some concern that they may change the trajectory of psychosexual and gender identity development.
The University of York also carried out a systematic review of outcomes of masculinising/feminising hormones. Overall, the authors concluded: “There is a lack of high-quality research assessing the outcomes of hormone interventions in adolescents with gender dysphoria/incongruence, and few studies that undertake long-term follow-up. No conclusions can be drawn about the effect on gender dysphoria, body satisfaction, psychosocial health, cognitive development, or fertility. Uncertainty remains about the outcomes for height/growth, cardiometabolic and bone health. There is suggestive evidence from mainly pre-post studies that hormone treatment may improve psychological health, although robust research with long-term follow-up is needed.
But most importantly, it had been stated strongly by transgender activists that hormone treatment reduced the elevated risk of death by suicide in this population, yet the review found there was no support for this conclusion.
Conclusion
The UK right-winged press has understandably jumped on the Cass report as vindication of its view that the increased numbers of vulnerable children treated at the Tavistock Clinic — a part of the National Health Service — was a classic case of mass mania. They have a point. In many cases, parents were not given information on what was being done to their children and GPs were increasingly alarmed at what was being prescribed for their young patients. When anyone protested, they were accused of risking death by suicide in these children; a risk that we now know very likely does not exist.
The NHS has now banned the prescribing of puberty blockers for children, but they will still be available at private clinics. In the NHS, at least common sense has prevailed and we should never again have drug therapy used in support of an orthodoxy, but only where there is good-quality evidence of safety and efficacy and that the medicines demonstrably improve a patient’s quality of life.
