Conclusions Not So NICE: A Critical Analysis of the NICE Evidence review of puberty blockers for children and adolescents with gender dysphoria

A critical look at the UK’s National Health Service-commissioned review of transgender youth health services and the harm it has caused.

Author’s Note: This article was originally published on Science-Based Medicine.

AJ Eckert on October 17, 2021

Around a year ago, the UK’s National Health Service (NHS) announced that Dr. Hilary Cass, former President of the Royal College of Paediatrics and Child Health, would conduct an independent review of transgender youth healthcare services for the National Institute for Health and Care Excellence (NICE), the institute in the NHS responsible for evaluating the base evidence behind diagnostic modalities and treatments and then making recommendations regarding which of them should be offered by the NHS. In the UK, transgender medical services are primarily administered through the Gender Identity Development Service (GIDS) for Children and Adolescents, which is managed by the Tavistock and Portman NHS Foundation Trust.

NICE reported its intention to focus on key aspects of care and inform clinical decisions around youth with gender dysphoria. Its review was commissioned specifically to address the “significant increase in the number of referrals [to GIDS] at a time when the service has moved from a psychosocial and psychotherapeutic model to one that also prescribes medical interventions by way of hormone drugs”. Per the terms of reference for review of GIDS, “this has contributed to growing interest in how the NHS should most appropriately assess, diagnose and care for children and young people who present with gender incongruence and gender identity issues”.

The NICE Review of gonadotropin-releasing hormone analogues (GnRHa), medications that block the production of the sex hormones testosterone and estrogen and are used to treat gender dysphoria in adolescents, was published in March 2021. The review included nine observational studies published no later than October 14, 2020: five retrospective studies, three prospective longitudinal studies, and one cross-sectional study. Authors of the NICE Review evaluated the studies for what they deemed to be “critical outcomes”, including the impact of puberty blockers on gender dysphoria, mental health, and quality of life, and “important outcomes”, defined for purposes of the review as impact on body image, psychosocial health, extent of and satisfaction with surgery, engagement with health care services, and the rate of treatment cessation. Reviewers also examined the evidence base for the short- and long-term safety of GnRHa. These outcomes were used to estimate the clinical effectiveness of treatment with GnRHa medications, which in addition to their roles in treating certain hormone-sensitive cancers (e.g., breast and prostate) also used as puberty blockers in patients with precocious puberty. They also may be used to block puberty in trans adolescents.

The following is an overview of the nine studies examined by the NICE Review authors:

  1. Vlot et al. 2017: This was a retrospective study of 56 youths on puberty blockers that reported a decrease in bone marrow apparent density (BMAD Z)-scores with GnRHa treatment. An initial decrease of bone mineral density (BMD) scores was observed, followed by normalization or increase of the BMD. BMD assesses bone quality, and a low BMD correlates with an increased risk of bone fracture, while BMAD is a measure of bone mineral density that is primarily used in children, since it accounts for their shorter stature. A Z-score compares your bone density with the average for a person of the same age and sex. According to the International Society for Clinical Densitometry (ISCD), the Z-score in trans youth should be compared with the average for a person of the same age and the gender conforming with the trans youth’s gender identity. In the Vlot et al. study, BMAD remained stable, and the Z-score decrease was expected: GnRHa treatment causes a decrease in bone turnover which coincides with a decrease of BMAD Z-scores.
  2. Klink et al 2015: This was a longitudinal observational study that followed the treatment of 34 subjects from pubertal blockade to young adulthood. The study reported that trans people treated with GnRHa medications during puberty had lower lumbar spine bone mineral apparent density (BMAD) Z-scores compared with pretreatment levels. Absolute bone mass decreased during puberty blocker monotherapy but increased after the start of gender-affirming hormones. The relevance of this observation to fracture risk was characterized as being unclear.
  3. Joseph et al 2019: This was a retrospective review of 70 subjects between 12–14 years of age who underwent yearly DXA scans, imaging tests that measure bone density. A progressive decline in BMD and BMAD Z-scores was noted, showing that bone mass does not accrue according to age when puberty is halted. The authors of this study note that it is debatable whether Z-scores remain a valid comparator between youth on blockers and cis youth in puberty given that GnRHa treatment interrupts the rapidity of bone size increase. Be that as it may, no significant change in the absolute values of hip or spine BMD or lumbar spine BMAD over 3 years on puberty blockers was observed, and this result aligns with results of Klink et al. 2015 and Vlot et al 2017.
  4. Khatchadourian et al. 2014: This was a retrospective review of 84 youth, 27 of whom were treated with puberty blockers. In the study, suicide attempts and emergency room visits for suicidal ideation decreased from 12% at baseline to 5% after the commencement of treatment, which suggested a decrease in suicidality and emotional problems associated with the start of gender-affirming treatment. The authors concluded:
  1. Schagen et al 2016: This was an observational prospective study of 116 patients evaluating the efficacy and safety of puberty blockers. None of the youths discontinued GnRHa treatment because of side effects. Observations included small increases in BMI, with no renal or hepatic complications, consistent with prior studies. An observed decrease in alkaline phosphatase was judged as likely due to decreased bone turnover since no other liver enzyme changes were noted. The authors concluded that Triptorelin, the GnRHa medication reviewed in this study, is effective in suppressing puberty in trans youths, and routine monitoring of liver and kidney function and sex hormone levels is not necessary during treatment.
  2. Brik et al. 2020: This was a retrospective study of 143 youths undergoing GnRHa treatment. 6% of those who started GnRHa medications discontinued treatment, with 3.5% no longer desiring gender-affirming treatment. None of the subjects discontinued treatment due to potential long-term side effects or lack of information on side effects.
  3. Costa et al. 2015: This was a longitudinal study of 201 youths at GIDS in London evaluating the effects of puberty suppression on global functioning. The study reported improved global functioning in all subjects who received psychological support and further significant improvement in those who also received GnRHa treatment, observing:
  1. de Vries et al. 2011: This was a longitudinal observational descriptive cohort study of 70 youths on puberty blockers that assessed psychological functioning and gender dysphoria at baseline prior to treatment and shortly before starting gender-affirming hormones. The investigators reported statistically significant decreases in behavioral and emotional problems over time, with less depression, and significant improvement in general functioning. No changes in gender dysphoria, body satisfaction, or feelings of anxiety and anger were reported, leading to the following conclusion:
  1. Staphorsius et al. 2015: This was a study examining the impact of puberty blockers on executive functioning in 41 trans youths using the ‘Tower of London’ (TOL) task. The TOL task is widely utilized to test executive function, specifically the mental process that enables one to plan. Dysfunction in this area is associated with the frontal lobe of the brain. 8 trans girls on puberty blockers were compared to 10 trans girls not on blockers and 12 trans boys on puberty blockers were compared to 10 trans boys not on blockers. These groups were also compared to controls consisting of 21 cisgender boys and 24 cis girls. The NICE review states that “statistical analysis (of this study) is unclear” and “this study provides very low certainty evidence (with no statistical analysis) on the effects of GnRH analogues on cognitive development or functioning in sex assigned at birth males (transfemales). No conclusions could be drawn.”The results section of this research paper does include statistical analyses on accuracy and reaction times. The authors of this study observed no significant effect of GnRHa treatment on ToL reaction times and accuracy performance scores compared to untreated trans youth with gender dysphoria.The study notes:

Of note, the NICE Review omitted several studies examining the efficacy and safety of puberty blockers when utilized as part of gender-affirming treatment of transgender youths:

Beyond the above omissions (plus more recent data that make the NICE Review assessment of evidence already out of date), it is important to note that, though considered a critical outcome in the review, puberty blockers in and of themselves are unlikely to alleviate gender dysphoria. There are societal and cultural factors that contribute to gender dysphoria, such as bullying at school, barriers to medical care, and family rejection. What puberty blockers do is prevent is the further progression of secondary sex characteristics that develop during puberty, which can ease the distress of trans adolescents regarding their body. As the Gender GP writes, “The pain and distress in adolescents who face prejudice and barriers to living in their authentic gender identity cannot be alleviated by a three-monthly injection alone”.

This is echoed in the one study the NICE Review included that assessed the impact of puberty blockers on gender dysphoria and body image:

As expected, puberty suppression did not result in an amelioration of gender dysphoria. Previous studies have shown that only gender reassignment consisting of CSH (cross sex hormone) treatment and surgery may end the actual gender dysphoria.

An uncontrolled prospective observational study released after the NICE Review, Carmichael et al 2021, examined GnRHa treatment as monotherapy in 44 youths, and found little change in psychological function and BMD changes consistent with suppression of growth. Subjects on blockers reported more happiness and better peer relationships. The researchers noted that gender dysphoria did not improve, which is consistent with the findings of the NICE Review. They explain:

GnRHa does not change the body in the desired direction, but only temporarily prevents further masculinization or feminization. Other studies suggest that changes in body image or satisfaction in GD are largely confined to gender affirming treatments such as cross-sex hormones or surgery.

One of outcomes deemed important in the NICE Review was engagement in healthcare services. Of course, there are many reasons why trans youths, indeed trans people in general, might be reluctant to engage in healthcare services or, having first engaged, choose to disengage from healthcare altogether, including fear of discrimination, exposure to homophobic and transphobic language by staff at clinics, provider prejudice, inappropriate and invasive questions, and being deadnamed or misgendered (called the wrong name or pronoun). One study reviewed noted a large overall loss of patients to follow-up over time but did not report any reasons for the phenomenon. The NICE review also states that there is no evidence for surgical outcomes and gender dysphoria in youths, neglecting a 2018 study on chest dysphoria and surgical outcomes in youths aged 13 to 25 that found statistically higher chest dysphoria scores in those who had not undergone chest reconstruction. More recent studies have yielded similar results.

The NICE review also considers stopping treatment as an important outcome “because there is uncertainty about the short- and long-term safety and adverse effects of GnRH analogues in children and adolescents with gender dysphoria”. This statement ignores history. Puberty blockers have been used to treat precocious puberty for years in children as young as 6 years old, and long-term effects have been studied, with research concluding that GnRHa treatment is effective and safe. Studies on blockers in trans youths have been conducted since the 1980s. In other words, treatment of trans youths with puberty blockers can no longer be considered “experimental”.

The authors of the July 2021 editorial “Access to Care for Transgender and Nonbinary Youth: Ponder This, Innumerable Barriers Exist” posed the following important question:

Given that endocrinologists do not require a mental health assessment prior to using the same medications for other conditions (such as precocious puberty) why should we for transgender and nonbinary youth?

The NICE Review points to a lack of “reliable comparative studies” and “clear, expected outcomes” with GnRHa treatment, citing little change in gender dysphoria and mental health. Other changes attributable to gender-affirming puberty blockers were concluded to be of “questionable” value, with potential for bias and confounding; “…studies all lack appropriate controls who were not receiving GnRH analogues”, according to the NICE Review. Here’s the problem with these statements. There are years of guidelines for gender-affirming puberty blockers in trans youth, such as those used by UCSF, that meet the criterion of evidence-based and are graded according to the GRADE system, a globally recognized measure of evidence based on quality of available studies. This is the same measure that the NICE Review utilized to assess the studies examined. Since gender-affirming treatment is known to be effective in alleviating gender dysphoria, assigning trans youths to a control group who do not receive treatment would arguably be at least ethically dubious, if not outright unethical (e.g. there is a lack of clinical equipoise). Several groups have commented on this very issue with clinical trials in this patient group, including De Vries 2011, a study included in the NICE Review, whose authors observed:

Finally, this study was a longitudinal observational descriptive cohort study. Ideally, a blinded randomized controlled trial design should have been performed. However, it is highly unlikely that adolescents would be motivated to participate. Also, disallowing puberty suppression, resulting in irreversible development of secondary sex characteristics, may be considered unethical.

Dr. Rosenthal notes in his 2014 academic paper, “Furthermore, randomized controlled trials for hormonal interventions in gender-dysphoric youth have not been considered feasible or ethical”. A 2020 study reports that this “particular use cannot be investigated by a RCT”.

One study examined in the NICE Review noted:

A randomized controlled trial in adolescents presenting with gender dysphoria, comparing groups with and without GnRHa treatment, could theoretically shed light on the effect of GnRHa treatment on gender identity development. However, many would consider a trial where the control group is withheld treatment unethical, as the treatment has been used since the nineties and outcome studies although limited have been positive. In addition, it is likely that adolescents will not want to participate in such a trial if this means they will not receive treatment that is available at other centers. Mul et al. (2001) experienced this problem and were unable to include a control group in their study on GnRHa treatment in adopted girls with early puberty because all that were randomized to the control group refused further participation”.

In April 2021, Dr. Helen Webberley reached out to NICE to provide the names and qualifications of the authors of the Evidence Review. The request was refused. As a result, it is impossible to know the identities of the experts who were consulted in composing, assessing, and reviewing the evidence. This is especially concerning given the emergence of trans health ‘experts’ who actively work to remove protections and support for trans people and an utterly unacceptable state of affairs for a review or report produced by a government agency.

Even though no professional organization with trans healthcare expertise opposes the use of puberty blockers to treat trans adolescents, there are those who have interpreted the science of treating trans youths with puberty blockers as experimental and unethical, and those who have noted that “clinicians should proceed with caution,” (p.9, Dahlen et al. International clinical practice guidelines for gender minority/trans people: systematic review and quality assessment). The latter source has unfortunately been cited by those who wish to add roadblocks to gender-affirming care, including Stephen B. Levine, a well-known opponent to gender-affirming care. SEGM, the Society for Evidence-Based Gender Medicine, a transphobic group thatpushes flawed science has claimed:

“Further, the WPATH and Endocrine Society guidelines recently were assessed for quality by a systematic review, which deemed them very low quality and unfit tools for clinical decision-making. Specific to WPATH, the reviewers noted the difficulty of even extracting clear recommendations, describing it as “incoherence within WPATH SOCc7.”*

The NICE Review and the High Court in London consider the evidence base for youth gender affirmation to be “highly uncertain“. As a result, trans youth in England are in crisis. In addition, there is the question of resources. The GIDS, the UK’s primary trans healthcare service, has only one funded clinic in England and Wales, with a minimum 20 month wait list. Once a youth is established at the clinic, they are subjected to an arduous assessment process lasting a minimum of 3 months and often much longer before treatment begins.

Following the latest legal rulings of the UK High Court, access to puberty blockers has become much more difficult for trans adolescents. All youth under 16 have their cases reviewed on an individual basis by a multidisciplinary clinical review to assess if a referral to GIDS is appropriate. Since the Bell v. Tavistock case in December 2020, GIDS has paused care for new puberty blocker referrals and those assessed to be appropriate for blockers since November 2020 are still waiting to be started on GnRHa treatment.

The WPATH and its international branches released a statement condemning the Bell v. Tavistock ruling that children under 16 are unable to consent to taking puberty blockers. There is hope, however. On September 17th, the Court of Appeal reversed the judgement in Bell v. Tavistock, forcing the NIH to review its current guidance on puberty blockers and consent. Puberty doesn’t wait, and neither does the high risk of suicide and self-harm in trans youth. Blocking and/or denying access to puberty blockers for trans youth is not a neutral option, as pointed out by Fisher et al., who wrote:

…omitting or delaying treatment is not a neutral option. In fact, some GD (gender dysphoric) adolescents may develop psychiatric problems, suicidality, and social marginalization. With access to specialized GD services, emotional problems, as well as self-harming behavior, may decrease and general functioning may significantly improve. In particular, puberty suppression seems to be beneficial for GD adolescents by relieving their acute suffering and distress and thus improving their quality of life.

The totality of evidence shows that gender-affirming treatment with puberty blockers significantly decreases distress, depression, emotional and behavioral problems and suicidality, while improving global functioning, psychological and psychosocial functioning, quality of life, satisfaction and happiness. There are expected decreases in Z-scores but bone mineral density remains stable on puberty blockers, as does executive function. Adrenal androgen levels change but yield no negative effects at follow-up. Body changes that occur are aligned with the blocked youth’s affirmed gender. Obesity is more common in trans youth, but treatment with blockers does not increase cardiovascular risk factors. More studies are needed on the neurodevelopmental impact of blockers, though the effect of blockers on mental health improvement can be neuroprotective. Research studies continue to confirm that puberty blockers are safe and effective with minimal complications, and that youth do not discontinue blockers due to side effects.

The NICE reviewers fail to account for the studies that explain why gender dysphoria does not improve with puberty blockers, instead considering it a critical outcome of treatment. They omit several important studies that contribute to the knowledge base on trans youth and puberty blockers, and do not acknowledge the many factors that inform engagement of trans people in healthcare services. The NICE review glosses over the extensive history and study of puberty blocker use and ignores the societal, political, and ethical barriers to a robust database of trans health research. As Deutsch et al. note:

…the absence of high-quality evidence should not serve as an immutable barrier to developing meaningful consensus guidelines in a field where societal stigmas have served as the principal underlying reason for the lack of quality evidence.

Those of us involved in transgender healthcare agree that guidelines should meet the same high-quality standards followed by other fields of medicine. For this to happen, we need resources and funding for trans healthcare research, regular and consistent data collection on gender identity, and destigmatization of the trans community. Trans children deserve love, support, and thoughtful medical care as much as cis children do. Trans children are targets in the current political and culture wars; the tide should shift to supporting and protecting this vulnerable population.

*Footnote: This passage was edited by the author on 12/1/2021 for purposes of clarity and disambiguation at the request of the authors of this article that was cited in the original.

The original passage stated: “Even though no professional organization with trans healthcare expertise opposes the use of puberty blockers to treat trans adolescents, there are those who have interpreted the science of treating trans youths with puberty blockers as “experimental” and “unethical”.

Author

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AJ Eckert (they/he) is Connecticut’s first out nonbinary trans doctor and Medical Director of Anchor Health’s Gender and Life-Affirming Medicine (GLAM).

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AJ Eckert (they/he) is Connecticut’s first out nonbinary trans doctor and Medical Director of Anchor Health’s Gender and Life-Affirming Medicine (GLAM).