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The Cass Review -- of which an interim report changed youth gender-affirming care services in England -- has been published in full, concluding that there's no high-quality evidence supporting puberty blockers and hormones in gender care for young people.

It also concludes that clinical guidelines currently in use are not backed by scientific evidence, but rely on expert consensus.

Review leader Hilary Cass, MD, and colleagues have suggested a more "holistic" assessment of youths with gender dysphoria, one that's provided in a broader pediatric setting by a multidisciplinary team.

"This generation ... has a much more flexible view about gender, in some ways a healthier view, less gender stereotyped than [what we grew up with]. And young people are expressing their genders in many different ways, so that's potentially breaking down many different barriers," Cass said .

"But the tricky question is whether and when the right thing is to medicalize that," she continued. "Certainly some of the young adults we've spoken to -- because medication is binary, but their gender expressions are often not -- have said to us, 'We wish we'd known there were more ways of being trans than just binary trans.'"

That doesn't mean puberty blockers and hormones should be withheld from patients who are likely to benefit from them, Cass cautioned. And U.S. experts told MedPage Today that the report should be taken in "totality" and that treatments should be available while the evidence base is enhanced.

The centers around six publications, most of which are published in the Archives of Disease in Childhood. This includes four evidence reviews: one on puberty blockers; one on hormones; and one on clinical guidelines that's divided into two parts. There's also an accompanying editorial in that journal, along with an opinion piece by Cass published in The BMJ.

The report comes amid a very specific context in the U.K., which has seen a sharp increase in referrals among children and adolescents to specialist pediatric gender services. For instance, referrals rose from 201 in 2011-2012 to 3,585 in 2021-2022, according to the report.

Meanwhile, this population has a high rate of mental health complexity, the researchers said. At the same time, revised treatment protocols have broadened criteria for treatment with puberty blockers and hormones; scrapped a minimum eligibility age; and expanded eligibility from gender dysphoria to gender incongruence.

That confluence of factors led to a long waiting list at the country's sole gender care facility, known as the Tavistock clinic, and Cass subsequently was tasked with reviewing the NHS's treatment protocols for youth gender services. An interim publication of the report led to a restructuring, in which gender care will be provided by regional services and puberty blockers will only be offered as part of a clinical trial. So far, two regional clinics are slated to open, with a third following soon.

All four of the evidence reviews were led by Jo Taylor, PhD, of the University of York in North Yorkshire, England.

On , Taylor and colleagues found no high-quality studies, and concluded there's insufficient or inconsistent evidence about the effects of suppressing puberty on several fronts: gender-related outcomes, mental and psychosocial health, cognitive development, cardiometabolic risk, and fertility.

In her , Cass noted that the "clearest indication" for puberty blockers is in "helping the small number of birth-registered males, whose gender incongruence started in early childhood, to pass in adult life by preventing the irreversible changes of male puberty."

In particular, Cass added, there's a lack of "follow-up data on the more recent cohort of predominantly birth-registered females who frequently have a range of co-occurring conditions including adverse childhood experiences, autism, and a range of mental health challenges."

They did find consistent moderate-quality evidence that bone density and height may be compromised during treatment. Although high-quality research is still needed to confirm these findings, they concluded that "these potential risks should be explained to adolescents considering puberty suppression."

The puberty blocker review included 50 studies: 11 cohort, 8 cross-sectional, and 31 pre-post studies that were published from 2006 to 2022, conducted in the U.S., U.K., the Netherlands, Canada, Belgium, Israel, Brazil, and Germany. One cross-sectional study was of high quality, 25 studies were moderate quality, and 24 were low quality.

The among youths similarly found no high-quality evidence, with insufficient or inconsistent findings on the impact on gender dysphoria, body satisfaction, psychosocial and cognitive outcomes, fertility, height, bone health, and cardiometabolic effects.

Moderate-quality evidence suggests that mental health may be improved during treatment, but this needs more robust study, they said.

Taylor and colleagues reviewed 53 studies on hormones: 12 cohort, 9 cross-sectional, and 32 pre-post studies that were published from 2006 to 2022, from a similar global distribution as the puberty blocker review. One cohort study was high quality, 33 were moderate quality, and 19 were low quality.

The researchers tackled the guideline reviews in two parts: one on , and one on the actual . They identified a total of 23 guidelines published from 1998 to 2022, the majority of which were published in the last 5 years.

They concluded that few guidelines were informed by a systematic review of the evidence, and that they lacked transparency about how the recommendations were developed. They also found limited guidance on how to implement the recommendations.

Most of the guidances were influenced by guidelines from the World Professional Association for Transgender Health (WPATH) and the Endocrine Society, which the review concluded lacked rigor. They only recommended two guidances: one from Finland in 2020 and another from Sweden in 2022, which were the only guidances to publish details about how the writers reviewed and used the evidence base, along with the decision making behind the recommendations, the researchers said.

In an emailed statement to MedPage Today, the Endocrine Society said its clinical practice guidelines are developed using a "robust and rigorous process" that adheres to National Academy of Medicine guidance. "Our guideline development panels spend years developing each guideline based on a thorough review of medical evidence, author expertise, rigorous scientific review, and a transparent process."

Its "cites more than 260 research studies," the statement said, and is set to be updated soon.

After this story published, WPATH and its partner organizations sent a statement to MedPage Today, noting that the Cass review is "rooted in the false premise that non-medical alternatives to care will result in less adolescent distress for most adolescents and is based on a lack of knowledge of and experience working with this patient population."

"It is harmful to perpetuate this notion and does not acknowledge the very real fact that medical pathways are an important treatment option for many young people," the statement continued.

WPATH and its affiliates supported the U.K.'s move away from a single center providing care, which they say will better enable providers to follow its treatment guidance, known as SOC8, "which calls for a comprehensive biopsychosocial assessment and may help increase access to timely transgender adolescent care."

"WPATH also emphasizes the importance of acknowledging the complexity of the human experience and therefore maintains that policies which severely restrict access to physical healthcare, and focus almost exclusively on mental healthcare for a population which the WHO does not regard as inherently mentally ill, are harmful, and have no place in medicine where clinical guidelines exist."

As for the review of guideline recommendations, Taylor and colleagues concluded that while many promote a similar care pathway -- psychosocial care for prepubertal children followed by hormonal interventions for some adolescents, provided by a multidisciplinary team -- there's no consensus about the specific process of assessment or about when psychological or hormonal interventions should be offered, or on what basis.

In her opinion piece, Cass wrote that medical treatment for gender dysphoria is "built on shaky foundations."

She said she took on the review "in full knowledge of the controversial nature of the subject, the polarization and toxicity of the debate, and the weakness of the evidence base."

Nonetheless, she said she believes that gender-questioning children and adolescents should be able to have a broad, holistic assessment provided by a multidisciplinary team of pediatricians, child psychiatrists, and other "allied health experts."

The new regional service program will have research embedded from the start, she wrote, and data collection will be integral to its model. A prospective puberty blocker study is already in development, she added.

"Those young people who the team feel might benefit from puberty blockers will be able to go on them as part of a research trial," Cass said in her interview. "The aim won't be to have a group who never get puberty blockers and those that do. They will go on puberty blockers if it's deemed they may be in that group that will benefit."

In , Camilla Kingdon, MD, outgoing president of the Royal College of Paediatrics and Child Health, wrote, "I believe we are on the cusp of seeing real progress in the care of this patient group."

Christopher Bolling, MD, a retired pediatrician who practiced in Kentucky and Ohio -- states that have banned gender-affirming care -- and who has testified in front of state legislatures on gender-affirming care bans, told MedPage Today that the findings of the Cass Review are "appropriate."

"I think we need data," he said, cautioning, however, that the report needs to be looked at in totality. Unlike banning puberty blockers and hormones for youths, as some U.S. states have done, the report acknowledges the transgender experience and supports these individuals in getting needed healthcare.

He said gender-affirming care in the U.S. already takes a measured approach to treatment. He said Cass's interview with The BMJ appears to conflate "gender-affirming care" with "medications."

"That's not my take on what gender-affirming care is," Bolling said. "Patients in the U.S. already get really thorough mental health screenings. They get lots of counseling. It goes very slowly, and very few of them actually wind up on medications."

Bolling said a number of studies of gender-affirming care are progressing and should be reporting out soon. While it's impossible to do a randomized controlled trial (RCT) in this setting -- and the NHS program will not be an RCT -- there are research methods, such as case matching, that can help deliver quality evidence.

Will experts accept a research base that doesn't include RCTs? "We're going to have to," Bolling said. "I don't know how we do it any other way. There's a research structure you can use to give you meaningful and good data. Maybe not RCT-level, but still pretty good."

England is not the only country to pull back on puberty blockers and hormones for youths. In 2020, Finland's health agency recommended psychotherapy as the main treatment for teens with gender dysphoria, and in 2022, Sweden restricted hormone treatments in youths to exceptional cases, .

Also, in December 2023, Norwegian health officials decided to only provide hormones to adolescents in clinical trials, while new guidelines being finalized in Denmark will limit hormone treatment to those who had gender dysphoria since childhood, the Times reported.