December 2025

The clinical trial on the effects of puberty blockers, which is due to start in January 2026, was one of 32 recommendations in the Cass Review. That four-year review was published in March 2024, and found that the evidence in support of medical intervention, for children who are said to be mentally the opposite sex, is weak.

Eighteen months later, the US Department for Health and Human Services published its own review of treatment for ‘paediatric gender dysphoria’. It found that the assumed benefits of child medical ‘transition’ are profoundly uncertain, while the risks are significant.

The announcement of the puberty blocker trial and the protests against it have brought a new focus on these treatments - but the number of health journalists who’ve historically gone near the issue is tiny. Many of them will be coming to it fresh, and will consequently struggle to digest, critique and compare these two wide-ranging reports.

So we are pleased to host this resource for those who’d find a line by line ‘compare and contrast’ helpful. Biology in Medicine compiled the bulk of this analysis, alongside their own commentary, notes and positions, which are clearly marked.

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Cass v HHS on child transition - comparing the findings

HHS - Department of Health and Human Services Report CR - Cass Review BiM - Biology in Medicine

The aims of each review

HHS: ‘The Review is intended for policymakers, clinicians, therapists, medical organizations and, importantly, patients and their families’. ‘This Review assesses the existing literature on best practices for promoting the health of children and adolescents with gender dysphoria (GD; serious distress at one’s sexed body and associated social expectations) or milder forms of such distress.’

CR: The Review was commissioned by NHS England for commissioners and service providers to make recommendations on how to improve both the current clinical approach and the NHS gender identity service model.

‘This Review is not about defining what it means to be trans, nor is it about undermining the validity of trans identities, challenging the right of people to express themselves, or rolling back on people’s rights to healthcare. It is about what the healthcare approach should be’

HSS description of Cass: ‘The Cass Review was not a Clinical Practice Guideline: it was an ‘independent review’. This is a UK-specific process of conducting a service-level evaluation intended to inform policy, not prescriptive clinical decisions. Such processes are invoked when an area of clinical care begins to operate in ways that compromise care quality and threaten patient safety.’

Exceptionalism

‘Natural course’ of gender dysphoria

HHS: The condition’s natural course (that is, what happens when the condition remains untreated) appears to tend toward resolution, absent medical and/or social transition interventions for a significant number of affected youths’ (Chapter 4).

CR: ‘While a diagnosis of gender dysphoria has been the basis for initiating medical treatment..this is not predictive that the individual will go on to have longstanding trans identity.’

2. Governance

HHS: Discusses that this speciality (‘gender’ medicine) practices under a governance that no other specialty does or could.

‘Firstly, the diagnostic criteria for gender dysphoria are based fully on subjective reports and behavioural observations in patients with no objective physical pathology

‘Secondly, the treatments recommended by the medicalised approach are invasive, usually irreversible, and their purported benefits are based on poor quality evidence.

‘When taken separately, none of these features is unique in medicine. What makes Paediatric General Medicine exceptional is not any one of these features, but their combination.

The stated rationales for these interventions have shifted over time, following decades of research which failed to provide credible evidence of benefit (Chapter 5). This unclarity surrounding the treatments’ fundamental aims is another way in which paediatric gender medicine is exceptional.

In contrast, there is broad consensus about the purpose of medical intervention for conditions like appendicitis, diabetes, or severe depression.

BiM note: The UK has no national training for specialists working within Gender Identity Clinics (unlike other specialities such as cardiology or GU medicine). No other speciality in the UK would be enabled to practice under poor clinical governance where medicine is used off licence, causes long term irreversible harms and where there is a lack of robust medical evidence.

History lessons

HHS: Warns about ‘mass’ mistakes clinicians have made in the past, such as over-prescription of opioids and the resultant crisis of dependence. ‘While physicians are often capable of remarkable healing, they are not immune to human error or bias. However well-intentioned, doctors are not infallible. Even the consensus of professional medical associations can, at times, be mistaken. Consensus does not guarantee correctness—in fact, it can sometimes entrench error. Nor should it be assumed that all treatment recommendations are motivated by altruism, as the opioid crisis has starkly demonstrated.’

BiM: please see our own piece analysing these similarities including

external influence: the gender affirmation model is heavily influenced by external influences, such a lobby groups and activists, rather than clinical evidence: marketing by Pharmaceutical manufacturer Purdue shaped prescribing habits in the US

suppression of evidence: Purdue suppressed evidence about the addictive property of OxyContin: WPATH suppresses evidence that does not support gender affirmative care. Both compromise patient safety.

Activist language

CR: ‘The Review tries as far as possible to use language and terms that are respectful and acknowledge diversity, but that also accurately describe the complexity of what we are trying to articulate..The terms used may not always feel right to some; it is important to emphasise that the language used is not an indication of a position being taken by the Review.

Some activist terms and conventions are seen, including acceptance of the concept of the trans child and the non-binary child.

HHS: ‘The choice of words can affect medical decision-making. In this context, the understandable desire to avoid exclusionary or pathologising language—combined with beliefs firmly embedded in the field—has led to a vocabulary and a mode of communicating that is scientifically ungrounded, that presupposes answers to ethical controversies, and that is in other ways misleading’.

Examples:

the surgical removal of breasts (mastectomy) in physically healthy females is often called ‘gender-affirming chest surgery’ or ‘top surgery’.

HHS disputes the terminology of a transgender child. It is often claimed that gender identity is ‘innate or fixed at a young age’ and so ‘cannot be changed’. ombined with the definition of ‘transgender’, the result is the assumption of a a close-to-immutable trait. In this framework, a ‘trans’ child is one whose unalterable gender identity does not align with their sex, while ‘cisgender’ children are the other kind.

Once this binary paradigm of ‘trans kids’ and ‘cis kids’ is accepted, therapeutic exploration of the underlying causes of a child’s discomfort with his or her sexed body is readily dismissed as ‘conversion therapy’ - an allegedly unethical attempt to interfere with the development of the child’s authentic self

proponents of medicalisation go to lengths to avoid the plain use of ‘sex’, ‘male’, ‘female’ and related words such as ‘boy’ and ‘girl’.

When there is an attempt to define sex, the definition is rarely correct. The Royal College of GPS uses the WHO definition of sex in its guidance : ‘referring to the different biological and physiological characteristics of females, males and intersex persons, such as chromosomes, hormones and reproductive organs.’ This is inaccurate. Sex is binary and gamete based.

BiM: Accurate terminology is indispensable if the medical and ethical issues are to be discussed responsibly. The use of activist language in guidelines from professional bodies in the UK is documented: this can mislead clinicians towards prescription protocols.

‘Non-binary’ patients

CR: ‘Most guidelines recommend that gender is viewed as a spectrum, but only three discuss treatment for those who identify as non-binary. Sweden and Norwegian guidelines do not recommend treatments in this group due to a lack of evidence’

HHS: ‘Non-binary identities now feature prominently in contemporary clinical settings and research populations. In 2020 the Trevor Project found that 63% of 11,914 survey respondents identified as non-binary. In a study of youth who received mastectomies, 11% identified as non-binary or ‘other’. This creates a new set of ethical challenges, as patients seek interventions that have never before been contemplated, including keeping patients in puberty-suppressed states for extended periods of time to allow them to maintain a sex-ambiguous appearance. The risks of such interventions may be considerable.’

BiM: This area is more experimental, and has [even] less evidence of any kind than other ‘gender care’. Many gender clinic shared care agreements have protocols for treating non-binary patients.

This is a move further from the belief that some boys are girls and vice versa, and we believe it demonstrates that the foundation for a radical intervention is based on an ideology and overvalued ideas. This would class interventions as extreme body modification rather than medical care. We believe the risks involved in prescribing for ‘non-binary’ patients are considerable, and the CR should have warned about them.

Suicide

CR: The suggestion that medical ‘transition’ reduces the elevated risk of suicide was not supported by evidence.

‘In summary, the evidence does not adequately support the claim that gender affirming treatment reduces suicide risk. However the distress is real for these children and young adults…… Thus, fear that delayed access to medical treatment may lead to suicidal thoughts’.

[Note: since CR the Appleby report has further debunked the claim that there was an increase suicide risk for those on the waiting list at the Tavistock]

HHS: ‘Some physicians recommending paediatric medical transition have urged anxious parents to consent to irreversible interventions for their distressed children, warning that not doing so may increase the risk of suicide.

‘Such claims are not supported by the evidence and have been criticised as unethical. Moreover there is no evidence that elevated suicidality can be attributed solely to gender dysphoria, as it frequently co-occurs with other mental health conditions.

A 2020 report by the Swedish National Board of Health and Welfare (Socialstyrelsen) concluded that “people with gender dysphoria who commit suicide have a very high rate of co-occurring serious psychiatric diagnoses, which in themselves sharply increase risks of suicide … it is not possible to ascertain to what extent gender dysphoria alone contributes to suicide.

‘Consequently, claims that paediatric medical transition is ‘lifesaving’ appear to be unsupported by the evidence. These findings also have been confirmed by the Appleby Report.. which reviewed suicides among young people with gender dysphoria. The report strongly criticised the way suicide and gender dysphoria have been discussed on social media, characterising it as insensitive, distressing, dangerous, and in violation of established guidance on the safe reporting of suicide.

‘Appleby emphasised that many of the public claims made about suicide do not meet basic standards for statistical evidence. The report also urged a shift away from viewing puberty blockers as the primary marker of supportive care, warning that such a narrow focus oversimplifies complex clinical needs.’

Appleby stated: ‘Data does not support the claim that there has been a large rise in suicide in young gender dysphoria patients at the Tavistock. The way that this issue has been discussed on social media has been insensitive, distressing and dangerous, and goes against guidance on safe reporting of suicide.’

Support for a puberty blocker trial

CR: Identified significant limitations in the evidence base for puberty blockers and cross sex hormones, and recommended that puberty blockers be offered only as part of a clinical trial.

Said psycho-social approaches for children with gender-related distress should be the first line of treatment, and research should be done to find out what happened to the 9,000 children estimated to have been treated at GIDS

‘Following our earlier recommendation to establish a puberty blocker trial, which has been taken forward by NHS England, we further recommend a full programme of research be established. This should look at the characteristics, interventions and outcomes of every young person presenting to the NHS gender services. The puberty blocker trial should be part of a programme of research which also evaluates outcomes of psychosocial interventions and masculinising/ feminising hormones.’

HHS: Does not support a puberty blockers trial

‘As the FDA emphasises: when the risks of a treatment are serious, anticipated effects must be proportionate. In cases where serious risks are anticipated, it is important to consider whether the risk can be outweighed by a benefit of sufficient certainty, magnitude, and clinical relevance to patients.

‘Some of the plausible harms of paediatric medical transition are serious. The likelihood of infertility when puberty blockers are provided at the early stage of puberty, and followed by cross-sex hormones, does not have to be demonstrated in a clinical trial.

‘This is because the mechanism is well-understood and conducting a trial would amount to an unethical ‘parachute test’.

Further notes and links: the links are not exhaustive

Concern has been expressed that ‘pubertal suppression may alter the course of gender identity development, essentially ‘locking in’ a gender identity that may have reconciled with biological sex during the natural course of puberty.”

In 2024, the European Academy of Pediatrics cautioned that puberty suppression may undermine long-term autonomy by creating a path dependency that leads to cross-sex hormones and surgery

Several studies have suggested continuation rates from puberty blockers to cross-sex hormones exceed 90%. The perception of PBs has shifted—from being seen as a reversible “pause button” to more like a “gas pedal” that accelerates medical transition.

Concern has been raised about the unknown or potentially harmful effects of suppressing normally timed puberty on adolescent physical and mental health, especially with regard to bone mineralization and brain development.

Systematic reviews have not found credible evidence that they lead to meaningful improvement in mental health

There is high certainty evidence that puberty blockers exert physiological effects (such as sex hormone suppression) and often cause infertility when followed by CSH, depending on the patient’s pubertal stage and sex. Low certainty evidence suggests that PBs may compromise bone health

The evidence is particularly limited regarding long-term outcomes related to fertility, growth, and neuro-cognitive development.

As a result, there is little data on what happens after treatment ends, and the assumption that the effects of PBs are reversible remains largely untested.

Overall there is an absence of long-term, high certainty evidence on critical outcomes, including suicides, fractures, fertility, growth, and neuro-cognitive development, and substantial uncertainty about the effects of puberty blockers.

HHS: ‘There is low quality evidence suggesting that PBs compromise bone health. However, the quality of evidence for outcomes such as gender dysphoria, mental health, quality of life, and regret remains very low across all intervention types.’

‘Ultimately, medical interventions should be used when the balance of benefits clearly outweighs the risks. Every public health authority that has conducted a systematic review of the evidence has concluded that the benefit/risk profile of paediatric gender transition is either unknown or unfavourable’

Existing evidence from science and physiology on the risks associated with puberty blockers

HHS: ‘When clinical studies provide insufficient information about harms, and therefore systematic reviews are unable reliably to collate information about harms, other types of evidence should be integrated. Trustworthy evidence from other sources, including basic sciences, should be considered to arrive at a more informed understanding of the plausible effects of intervention’

‘The consideration of such evidence aligns with the core requirement of evidence-based medicine: the judicious use of the ‘best available’ evidence’

It says science and physiology give us enough evidence of harm

cross sex hormones and puberty blockers are unlicensed for dysphoria

absence of safety data

‘Patients are maintained in a prepubertal or early pubertal stage while their peers developmentally progress. This has potential sequelae for the adolescent’s psychosocial development.’

Bone density. ‘Sex steroid hormones play an essential role in the mineralization of the skeleton. Failure to reach peak bone density may lead to increased risk of osteopenia, osteoporosis, and fractures later in life, including debilitating fractures of the spine and hip’

Cognitive function. ‘The human brain undergoes substantial reorganisation during adolescence, including synaptic pruning and myelination, processes that are influenced by sex steroid. Research suggests that sex steroid hormones impact brain regions associated with executive function, emotion regulation, and social cognition.’

Infertility. ‘Puberty blockers interrupt the maturation of reproductive anatomy and function. Suppression of the Hypothalamic-Pituitary-Gonadal Axis can impair gametogenesis, potentially resulting in permanent infertility if cross-sex hormones are started thereafter.’

Sexual dysfunction. ‘The extent to which individuals have experienced endogenous puberty could influence later sexual functioning. Puberty blockers inhibit sex steroid exposure of genitalia, which are highly sensitive to androgens during the typical pubertal timeframe ... Interference through puberty blockers affects genital growth and development during a possibly critical period, with potential effects on subsequent sexual function.’

Cross-sex hormones

CR: There are uncertainties about the increased risk of bone health and cardio metabolic adverse effects.

‘Treatment with masculinsing/feminising hormones is not without long term problems and side effects, But to those who have undergone a successful transition, the physical costs are dramatically outweighed by the long term harms.’

‘Understanding side effects and longer-term complication are important for the health of the transgender community, but in terms of patient choice are unlikely to have a major impact on treatment decisions’.

BiM: We find these statements concerning. They suggests that patient autonomy can override non-maleficence and beneficence.

have patients consented for long term risks such as cancer and early mortality

are they informed that there are many unknown risks because of the low quality studies and the lack of long term data

HHS: Discusses the supra-physiological dosages used in cross-sex hormone prescriptions, comparing doses to levels produced by hormone secreting tumours. Links to evidence of irreversible harms and more long term harms.

‘When hormone levels rise beyond the typical reference range for a person’s sex, they are considered supraphysiologic.’

Long-term harms mentioned in HHS:

Testosterone: vaginal atrophy, pelvic floor dysfunction pelvic pain, stroke

both cross-sex hormones raise risk of heart attack and cardio-vascular mortality (discusses the physiology behind it)

structuring remodelling of testosterone in women could increase the risk of breast and ovarian cancers

‘The risk of anabolic androgenic steroid [synthetic variation of testosterone] abuse can lead to serious cardiovascular and psychiatric adverse reactions. These effects have been reported in males and females, including adolescents.’

‘Research on anabolic steroid misuse has demonstrated associations with severe psychiatric problems, including mood instability, psychosis, and dependence. The most frequently observed symptoms include irritability, aggression, euphoria, inflated self-perception, impulsivity, and risk-taking behaviours.’

Evidence for increased mortality risk. A 2023 cohort study from the UK found that compared to their natal sex peers, transgender people had higher risk of mortality (34 % higher for females, 60% higher for males)’

World Professional Association for Transgender Health

Many Gender Identity Clinics use WPATH to justify guidelines, and many regulatory bodies and GICs actively quote WPATH in guidelines.

CR: WPATH lacks developmental rigour and overstates the strength of its evidence. ‘Given the lack of evidence-based guidelines, it is imperative that staff working within NHS gender services are cognisant of the limitations in relation to the evidence base and fully understand the knowns and the unknown’

HHS: Lists reasons it considers WPATH is not reputable

suggests WPATH suppressed studies that might contradict its model

says it therefore promoted the idea that children could consent to treatment, and that treatment was beneficial, despite knowing that evidence supported neither claim

says its guidance relies on insufficient evidence

says it misrepresents of psychotherapy by equating it with so-called ‘conversion therapy’

BiM notes: We believe the Cass Review should have issued a warning about using WPATH to construct guidelines. WPATH does not require its members to be medical professionals. Internal WPATH communications reveal that the ‘medical necessity’ framing in SOC-8 was constructed to remove key safeguarding criteria and centre patient desires in treatment decisions. Example: WPATH reworded patient ‘wishes’ as patient ‘needs.

Silencing of dissent and the impact on whistleblowing

CR: The toxicity of debate around gender means professionals are ‘afraid’ to openly discuss their views

‘The knowledge and expertise of experienced clinicians who have reached different conclusions about the best approach to care are sometimes dismissed and invalidated…There are few other areas of healthcare where professionals are so afraid to openly discuss their views, where people are vilified on social media, and where name-calling echoes the worst bullying behaviour. This must stop. Polarisation and stifling of debate do nothing to help the young people caught in the middle of a stormy social discourse’

HHS: ‘This Review also finds evidence of extreme toxicity and polarisation surrounding this field of medicine. (“There are few other areas of healthcare where professionals are so afraid to openly discuss their views … where name-calling echoes the worst bullying behaviour.”).’

‘In recent years, however, whistleblowers with firsthand experience working in gender clinic environments have come forward with compelling counterexamples. Their testimonies have often been dismissed, ignored, marginalized, or disparaged by colleagues. Several have also faced retaliation because of their disclosures

BiM: Most of us at BiM are anonymous because of fear of retaliation.

Finally, HHS discusses ethics in some detail, including the established principles of biomedical ethics (as laid out by Beauchamp and Childress).

HHS: ‘Importantly, the physician’s duties of non-maleficence and beneficence are not overridden by the patient’s desire for a particular course of treatment.’