Yes, our evidence is weak

A leading gender clinician acknowledges the low-quality evidence base and says he no longer regards puberty blockers as a "pause" button for children

Photo by Katie Rainbow 🏳️‍🌈 on Unsplash

The gist

A leading Australian gender clinician, Dr. Stephen Stathis, has acknowledged that the evidence base for medicalised gender change with minors is of low quality and admitted there are questions about the reversibility of puberty blocker drugs.

In frank remarks to a psychiatry conference Dr. Stathis also said he no longer believed that puberty blockers offered children a “pause.”

“I’ve changed my mind based on the evidence; it’s really not a pause for the vast majority of young people,” he said.

Dr. Stathis, who is medical director of Child and Youth Mental Health Service at Children’s Health Queensland, was referring to Dutch and English data showing that almost all of the young patients started on blockers went on to cross-sex hormones, which have irreversible effects.

Blockers have often been promoted as a “no regrets” option giving a child time to mature and consider the weighty decision whether to progress to lifelong hormones.

Dr. Stathis, a child and adolescent psychiatrist who founded the gender clinic at the Queensland Children’s Hospital where patient numbers rose from 48 in 2014 to 635 in 2021, made the remarks on July 23 during a lengthy presentation at a conference of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) in Cairns, Queensland.

His commentary is likely to sharpen debate at a time of increasing global scrutiny of the “gender-affirming” treatment approach, an emerging campaign for an inquiry into Australian gender clinics, and a contested review of the RANZCP’s cautious 2021 policy on gender care, which gender-affirming advocates claim “pathologises” transgender people.

Dr. Stathis appears to be one of the first gender-affirming clinicians to publicly accept the findings of systematic reviews in Finland, Sweden and the United Kingdom since 2019 that the evidence base for medical transition of minors is of low quality and very uncertain.

These reviews challenging the mantra that “the science is settled in favour of gender-affirming care” have been ignored by gender-affirming clinicians, who rely instead on low-quality treatment guidelines and position statements by medical societies open to activist capture.

In his conference presentation Dr. Stathis did not embrace the European policy conclusion that poorly evidenced gender medicine—especially puberty blockers—should be tightly restricted rather than first-line treatments as they still are in countries such as Australia, New Zealand, Canada and the United States.

Dr. Stathis argued that if youth gender medicine were to be criticised as “experimental”, that label should also be applied to most treatments used by child and adolescent psychiatry because low-quality evidence was the norm.

He said Australia had failed to build a national network for gender medicine research and hinted at an imminent proposal for multi-clinic experimental trials, but the idea appeared to be that these trials would run in tandem with continued routine use of hormonal gender change for minors.

In a 2019 protocol for its Trans20 study, Australia’s most influential gender clinic at the Royal Children’s Hospital Melbourne (RCH) said there was “limited empirical data” on the rapidly growing number of teenage gender patients and “an urgent need for more evidence to ensure optimal medical and psychosocial interventions.”

Early suppression of puberty with blocker drugs, around age 10-12, followed by synthetic oestrogen or testosterone is expected to lead to infertility and for male patients, sexual dysfunction as adults.

In his talk, Dr. Stathis conceded there were “questions about the reversibility” of blockers, which are used off-label (without regulatory approval) to suppress unwanted sexual development in children who identify as trans or non-binary.

Low bone density potentially leading to early osteoporosis has been a well-known risk of hormone suppression, but the unknown effects of blockers on the adolescent brain are the subject of growing international concern.

Dr. Stathis noted evidence that suppression of natural sex hormones in sheep affected their cognitive function and said there was also data showing cognitive decline in men under hormone suppression for advanced prostate cancer.

He said he was unaware of any evidence—“at this point in time… it might change”—that puberty blockers could harm cognitive development or executive function in children being treated for the distress of gender dysphoria.

The detail

To make sense of the struggle over gender clinics, Dr. Stathis invoked an unlikely figure—American psychiatrist Stephen Levine, an expert witness in support of U.S. state bills to restrict medicalised gender change with minors. Professor Levine saw his first patient with gender distress in 1973 and the following year founded a gender identity clinic at Case Western Reserve University.

Dr. Stathis said he did not “see eye to eye [with Prof. Levine] on a lot of things” but agreed with him that the gender clinic conflict involved “a clash of values.”

On the divide over the value of beneficence, for example, Prof. Levine wrote:

“Each side claims they are pursuing beneficence, but sharply disagree on the solution: one side insists that the most benefit is derived by undergoing a transition as early in puberty as possible to achieve the best possible cosmetic outcomes, while the other asserts that achieving cognitive maturity, emotional stability, and obtaining life experiences (including sexual experiences) prior to making the decision to undergo irreversible transition will provide the most long-term benefit for affected individuals.”

Prof. Levine said clinical decisions were driven by core values in the absence of quality data that unambiguously showed the optimal treatment for the many teenagers presenting with gender dysphoria.

Asked about the key unanswered research questions, Dr. Stathis said: “I think we really need to know, first of all, the number of children that are going to progress through into adolescence [with gender dysphoria], and also the rates of desistance [whereby a child gives up an opposite-sex identity and is reconciled to birth sex].

“You see, if nobody desisted, we would say it doesn’t matter—we should treat [everybody]. If high numbers desist, we have to go back and [ask], what are we doing here?”

Sign here, please

The informed consent document for puberty blockers at the Queensland Children’s Hospital clinic claims these drugs “can greatly improve mental health and quality of life”

The document says the effects of blockers are “reversible”, meaning that if the child stops treatment “pubertal progression will start again”

It says some “adverse effects” of puberty suppression—including hot flushes, headache, joint pain and mood changes—are “usually reversible”

The side-effect of low bone density is cited, but not listed in the “usually reversible” category

There is no mention of any risk to the brain

A general warning says “the medical effects and safety of long-term use” of blockers with gender dysphoric minors “are not fully understood”

Mrs Gillick’s legacy

In his presentation, Dr. Stathis highlighted dilemmas around informed consent to gender medicine by patients navigating the turbulence of adolescence.

A key medico-legal concept is “Gillick competence”, a test for the capacity of a child to give informed consent deriving from an English court case involving access to birth control for a 15-year-old without the knowledge or approval of her mother, Mrs Gillick.

The Gillick test requires the child to understand fully the treatment proposed.

Dr. Stathis said: “I’ve asked QCs [senior barristers], what does it mean for an adolescent to fully understand what is proposed, particularly for lifelong treatment? No one can give me an answer.

“I would say I don’t believe, based on the definition of Gillick, that an adolescent does have the capacity to understand.  

“Adolescents [maybe] don’t know what they’re going to do next week, let alone being able to understand the consequences of long-term treatment in the years to come.

“I’m not persuaded most lawyers would be in a position to fully understand the implications of irreversible hormonal changes over their entire lifespan.”  

Dr. Stathis cited the 2016 Family Court case, re Darryl, involving a 17-year-old deemed competent to consent to irreversible hormone treatment.

The judge said: “I do not accept that the words ‘understand fully’ requires a child to have achieved the maximum understanding which later years may give them when their brain and personality are fully developed.

“Rather, what is required is, as the High Court said… ‘the capacity to make an intelligent choice, involving the ability to consider different options and their consequences’.”

To determine competence to consent, Dr. Stathis said he used a seven-point test elaborated in another 2016 gender medicine case, re Lincoln, involving trans mastectomy for a 15-year-old.

Point six of the test, for example, requires “acknowledgement [by the patient] that the treatment would not necessarily address all of the psychological and social difficulties that the patient had before its commencement.”

Dr. Stathis said he and colleagues struggled with some of the implications of an adolescent being judged competent to consent.

“We feel deeply the need to speak up for the competent adolescent, but if you determine that an adolescent is competent to consent to treatment, you must allow them to consent to that treatment, even if you don’t believe it’s in their best interests—because they’re competent,” he said.

He said the go-ahead for puberty blockers “is always based on parental consent, because we believe that the young people are too young to consent to [blockers].

“Consent for gender-affirming [cross-sex hormone] medication has been confirmed consistently by the Family Court in Australia, that adolescents do have the capacity to consent to such treatment.”

However, the fact that beginning with blockers will almost inevitably lead to cross-sex hormones calls into question the idea that the young patient is in truth weighing the pros and cons of irreversible hormones as a second, distinct stage on the treatment pathway.

In other remarks, Dr. Stathis said—

The gender-affirmative model of care “has almost become a four-letter word” for its critics

This model was simply “respectfully affirming what a young person is currently feeling”

It holds that “gender identity may be fluid… people aren’t locked in to some type of gender identity”

“It’s affirmative, but it’s also exploratory—my job is to seek to understand why this child is coming to see me at this point in time”

The gender-affirming way was “not an ideology, or some unthinking acceptance of a child’s gender identity”

“The reasons behind the increasing numbers of children and adolescents identifying as transgender [are] unclear”

Possible causes included positive media coverage and less stigma encouraging more young people to be open about trans or non-binary identity

Some schoolchildren were “pushing the boundaries” by identifying as trans or non-binary for a while

Patients at the Queensland gender clinic confirmed this, telling Dr. Stathis that the boundary-pushers were “not really trans, Dr. Steve, because I know that I’m trans, and I’m different from them”

Notwithstanding high rates of suicidal ideation and self-harm among trans-identifying youth, suicide remains “a rare, tragic event”

Gender clinics did a lot of psycho-education with young people, impressing upon them the need to continue lifelong hormone treatment, but non-compliance was a problem

“The transgender model of care, in my opinion, provides the strongest evidence base for treatment, but the quality of evidence remains weak to very weak, much like the rest of child and adolescent psychiatry”

Weak evidence all around

Dr. Stathis drew a parallel between gender medicine and treatment for depression to explain his view of the evidence debate.

Apart from a 1996 double-blind placebo controlled trial justifying the use of the anti-depressant Fluoxetine with children, he said other treatments for children including psychotherapy rested on low-quality evidence.

“So let’s not have an argument about the fact that the treatment of gender dysphoria is experimental based on weak and very weak data, unless you want to acknowledge that everything we do in child and adolescent psychiatry... is experimental,” he said.

He said there was little or no evidence supporting less invasive responses to gender dysphoria—the “watchful-waiting” approach or purely exploratory psychotherapy—for patients diagnosed with gender dysphoria.

(He argued that this diagnosis, used since 2013, caught a different patient group than the former diagnosis of “gender identity disorder”. He did not discuss the dramatic flip in sex and age profile among gender clinic patients since 2010.)

Dr. Stathis said observational trials, a low-quality data source, reported no deterioration in patients given puberty blockers, improvement or better outcomes than an untreated comparison group.

“Now, non-deterioration [patients got no worse] is important because of the stigma these young people are already exposed to,” he said.

“So non-deterioration, I don’t think, is a reason not to treat. You may be just holding that young person, while they move through it.”

He said cross-sex hormone treatment for minors also relied on low-quality observational trials, which suggested benefits and “certainly no deterioration.”

“Patients with severe coexisting mental health conditions do often continue with their problems, despite gender-affirming medical treatment. But guess what, that happens all the time in CYMHS [the Child and Youth Mental Health Service] as well.

“Yes, I accept the evidence [for youth gender medicine] is weak. And yes, a number of these young people don’t improve, but they don’t deteriorate—it’s not a reason not to do [medical transition].”

Dr. Stathis praised the new gender care guidelines issued in 2020 by Finland—the first country to undertake a systematic review of the evidence base—but the Finnish approach seems at odds with the gender-affirming treatment model.

The 2018 gender-affirming treatment guideline issued by the Royal Children’s Hospital Melbourne—followed by Queensland’s clinic and counterparts in other states—says that psychiatric co-morbidities such as depression, anxiety and psychosis “should not necessarily prevent medical transition”.

There are anecdotal reports of gender-affirming clinics internationally transitioning very unwell young people on the assumption that their poor mental health was secondary to gender dysphoria and would improve with medical transition.

The driver of change in Finland was the realisation by clinicians that adolescents with such problems were not getting the good outcomes promised by the original Dutch studies which inspired the international trend for paediatric transition.

“In light of available evidence, gender reassignment of minors is an experimental practice,” the 2020 Finnish guideline says.

“In adolescents, psychiatric disorders and developmental difficulties may predispose a young person to the onset of gender dysphoria.

“These young people should receive treatment for their mental and behavioral health issues, and their mental health must be stable prior to the determination of their gender identity.”

Finland’s internationally renowned psychiatrist Professor Riittakerttu Kaltiala, the leading figure in her country’s shift to a more cautious treatment policy, told GCN last year: “I consider it is of utmost importance that severe psychiatric disorders first be treated into remission [before any thought of medicalised gender change].”

In his Cairns talk, Dr. Stathis argued that the low certainty of evidence in the field cut both ways, undermining not only claims of mental health benefits from medical treatment but also claims of adverse side effects.

Setting himself the task to identify the “best evidence we’ve got” to guide clinical practice, he cited Sweden’s new guideline.

That country’s 2021 systematic review of the evidence began with almost 10,000 potential studies. After screening, 195 were selected for reading.

After checks for bias, 24 studies were left—eight on puberty blockers alone, 13 on blockers and cross-sex hormones and three on cross-sex hormones alone. And these were observational studies “limited by methodological weaknesses”.

Lead author of the review paper Professor Jonas F Ludvigsson, from the Karolinska Institute, said: “I am surprised by the shortage of studies in this field. We found no randomised trials, and only 24 relevant observational studies.”

Corresponding author Professor Mikael Landén, from the University of Gothenburg, said: “Against the background of almost non-existent long-term data, we conclude that [puberty blocker] treatment in children with gender dysphoria should be considered experimental treatment rather than standard procedure.

“This is to say that treatment should only be administered in the context of a clinical trial under informed consent.”

Consistent with his claim of little difference between Australian gender medicine and European reformed practice, Dr. Stathis said: “Actually, the gender clinics across Australia… follow all but one of the recommendations of the Cass review.”

British paediatrician Dr. Hilary Cass was appointed to lead an independent review of youth gender care after the controversy at the world’s largest gender clinic, the London-based Tavistock service, which was commissioned by England’s National Health Service (NHS).

In her 2022 interim report, Dr. Cass expressed concerns about gaps in the evidence for gender medicine and profound uncertainty about the rationale, effects and safety of puberty blockers—including whether they might interfere with a critical time window for development of the adolescent brain.

In June this year, as expected, NHS England announced that puberty blockers would only be available within formal clinical trials, reflecting their experimental status.

The post-Tavistock model appears starkly different from the business-as-usual approach of countries, such as Australia, with gender-affirming clinics still offering puberty blockers as routine treatment.

In April 2022, two authors of the RCH gender-affirming treatment guideline used across Australia criticised the caution of the Cass review in the pages of the medical journal BMJ.

The authors argued that gender clinics could not wait for the missing long-term data, and should keep giving puberty blockers and cross-sex hormones based on existing low-quality evidence and clinical consensus.

Dr. Cass’s interim report contained statements “questioning an affirmative approach to gender-affirming care”, according to the Australian Professional Association for Trans Health, which is a gender-affirming lobby.

Most commentators see the developments in Finland, Sweden and England as a radical break with the confident gender-affirming approach.

Note: GCN sought comment from Children’s Health Queensland. Its communications office has a policy of refusing to respond to questions on the basis that GCN is not a “recognised media outlet”. GCN does not dispute that gender-affirming clinicians genuinely believe their interventions help vulnerable young people