New Research Raises More Doubts About Safety and Benefits of Gender Transition Treatments for Minors

A pair of major new analyses of research into providing gender-transition drugs to adolescents and young adults have indicated that a prevailing orthodoxy in the American medical community — that such treatments are safe and effective for gender-distressed minors — is largely based on “very uncertain” scientific evidence.The most rigorous such analyses of their kind to date, these new academic papers are the latest reports to cast doubt on the transgender movement’s battle, now on the defensive, to protect minors’ access to ultimately irreversible gender-transition treatments. The new analyses reach the damning conclusion that almost all the research assessing such treatments is decidedly unreliable at anticipating risks and benefits alike, thanks to consistently weak study designs that leave the door wide open for biased and unreliable results.This sweeping finding echoes the four-year independent assessment of the field of pediatric gender medicine, called the Cass Review, that was commissioned by Britain’s National Health Service and published to great fanfare in April. The nearly 400-page report was anchored on the finding that the field was based on “remarkably weak evidence.” These critical assessments of the controversial medical practices — which in recent years have been banned for minors in 24 states — stand in direct conflict with a nearly united front among American medical associations who endorse the prescribing of puberty blockers and cross-sex hormones for minors experiencing gender dysphoria, which is distress stemming from a conflict between an individual’s sex and gender identity. Prominent societies such as the American Academy of Pediatrics and the American Medical Association have touted such treatments as effective and even life saving — since, advocates claim, gender treatments prevent suicides. A physician and professor at McMaster University in Ontario, Dr. Gordon Guyatt, effectively begs to differ, having found that there is no such clear-eyed certainty about the impacts of these treatments on young people. Known as the “godfather of evidence-based medicine,” Dr. Guyatt on Thursday published in the Archives of Disease in Childhood a pair of systematic review papers of pediatric gender medicine that are the first of their kind to pool study findings and conduct meta-analyses regarding particular outcomes among young people who have received these interventions. One of the analyses examined studies on puberty blockers given to youth with gender dysphoria. The other looked at studies of cross-sex hormones to treat gender dysphoria in adolescents and young adults.Dr. Guyatt and his colleagues concluded in both papers that there is “considerable uncertainty regarding the effects” of each intervention, given that the available research almost entirely yielded evidence of “very low certainty.” Regarding hormone treatment in particular, the authors concluded that “we cannot exclude the possibility of benefit or harm.” The only research finding they considered to be of “high certainty” was that a small percentage of people who started cross-sex hormones subsequently experienced cardiovascular health events.“These papers come to the same conclusion as many other evidence syntheses — which is that we do not have a good evidence base to suggest that these treatments are effective,” a consultant general pediatrician at London, Dr. Ronny Cheung, said. Dr. Cheung is the lead author of a recent peer-reviewed rebuttal to a white paper spearheaded by Yale University pediatrician Meredithe McNamara that sharply criticized the Cass Review. The publication of these two papers from Dr. Guyatt is certain to provoke a chorus of disapproval among the many fierce defenders of pediatric gender medicine in America in particular, given their response to the Cass Review. That report has led the UK to ban puberty blockers outside of a promised clinical trial; and it has been broadly cited in litigation in the U.S. by opponents of these interventions for minors. Striking back, a coterie of academics such as Dr. McNamara has mobilized to cast doubt upon the report’s methodology and conclusions. These champions of pediatric gender medicine have asserted in a string of recent publications, most of which have not been peer reviewed, that, for example, Cass has held these medical interventions to an exceptionally and impossibly high evidentiary standard. Pediatric treatments for all sorts of conditions, some of these champions have pointed out, are routinely based on low-certainty or very-low-certainty evidence (as opposed to moderate- or high-certainty evidence).“It is true that many treatments in medicine have been, and are, used without a satisfactory evidence base. Sometimes this has led to belated evidence gathering in terms of clinical trials, which have subsequently shown benefit,” Dr. Cheung said in an email. “Equally, others have resulted in disastrous outcomes for patients despite the best intentions and biological plausibility. But it is a logical fallacy to say that because many treatments are given without sufficient evidence base, therefore any treatment without sufficient evidence base should be given.”An associate professor of philosophy at Colorado State University, Moti Gorin, said that given the “complexity and vulnerability” of pediatric gender dysphoria cases, “our standards should be very high.” The Sun asked the lead authors of all of the recent Cass critiques to comment on Dr. Guyatt’s new papers. The sole respondent was a lecturer in psychology at the University of Galway, Chris Noone, who argued that the new papers comment “on already identified limitations of research on these interventions related to sample size and comparison groups that are inevitable due to the small population, the impossibility of blinded comparison groups, and the ethics of preventing access to these interventions.” As he has previously, Dr. Noone criticized the particular tool Dr. Guyatt’s team used to score the quality of the evidence, which he said, “given the aforementioned limitations will automatically lead to a judgment of very low certainty in the evidence.” “The authors fail to articulate how a study of puberty blockers or hormone therapy for young people with gender dysphoria could ever produce evidence that is considered certain” by this tool, Dr. Noone said.Dr. Guyatt was not available for comment.The Trans Turning PointThe stakes have never been higher for the beleaguered and politicized medical field of pediatric gender medicine. The Supreme Court is set to rule, probably in June, on the constitutionality of state bans on gender treatments for minors in a case, first marshalled by the ACLU, in which the Biden Administration challenged Tennessee’s law. And while Donald Trump has yet to make good on his campaign promise to further restrict access to pediatric gender-transition treatment, within hours of his inauguration on Tuesday he signed a sweeping executive order attacking what his administration calls “gender ideology” throughout federal law. This turning point in the history of transgender advocacy writ large follows a decade of dramatic growth in the population of young people diagnosed with gender dysphoria or otherwise identifying as trans, both in the United States and across the Western World. A research letter out of Harvard published in JAMA Pediatrics on January 6 found about one in 1,000 privately insured 17-year-olds received cross-sex hormones between 2018 and 2022; and recent trends suggest this figure was likely considerably higher at the end of that period, especially among biological girls.Another paper published Thursday in the Archives of Disease in Childhood reported that between 2011 and 2021, diagnoses of gender dysphoria among adolescents in primary care practices in England surged by more than 50-fold. Following a pattern well documented in the United States, diagnosis rates were similar between biological boys and girls until 2015, at which point they split, until the rate among natal girls was nearly twice that of boys in 2021. By that time, about one in 250 youths had such a diagnosis at age 18. Levels of anxiety, depression, and self-harm were high among this overall population, especially the girls.The 2020s has seen the publication of a slew of systematic literature reviews – the gold standard of scientific evidence – assessing the quality of research and the resulting reliability of the evidence it produces among studies of gender-transition treatments for youths. All these papers have reached essentially the same conclusion: that the evidence backing prescribing gender-transition medications to minors is wanting and highly uncertain. Such critical findings have led the health authorities in a swath of Northern and Western European nations, including the UK, to reclassify such treatments as experimental and to sharply restrict access to minors — or to at least consider pulling back on such access. In America, which lacks a comparable centralized health authority, medical-practice standards tend to be set by medical associations; and with the exception of one group representing plastic surgeons, those societies have overwhelmingly held firm in their support of such interventions. The Evidence-Based Medicine Revolution Confronts Pediatric Gender MedicineWith Dr. Guyatt as one of its talismen, the field of evidence-based medicine emerged during the 1990s as a movement to hold scientific evidence to a higher standard. The goal was to assess the likelihood that the findings of research on any particular subject would actually bear out in clinical practice and that the recommendations based on that evidence were arrived upon in a rigorous and transparent way. The field, for example, sought to confront the fact that, even if multiple studies reach similar findings, this might be due to the fact that they were all biased in a similar way and not because the results were valid. The type of analyses pioneered by Dr. Guyatt are meant to identify potential sources of bias in scientific research and to separate the evidentiary wheat from the chaff.“Systematic review procedures block opportunities for cherry-picking studies that support only one side of an issue and help ensure all relevant studies are included,” said James Cantor, a Toronto psychologist and sex researcher who has often served as a paid expert hired by states to aid in defending their bans of this treatment. (Dr. McNamara has conversely often served as a paid expert for the other side. Both she and Dr. Cantor have been criticized for never having treated gender dysphoria in a minor.)“The methods also work to ensure that all studies get evaluated with the same standards, minimizing opportunities to be more critical or favorable with studies on one side,” Dr. Cantor continued. “Because so many authors have been engaging in exactly these kinds of biased tactics when claiming what the science says about the effects of medicalized transition, the anti-bias methods of systematic reviews are even more important than usual.” For the new paper on puberty blockers published Thursday, Dr. Guyatt and his colleagues scoured the relevant medical literature and settled on 10 key studies to analyze. Those papers, they concluded, “provided very low certainty evidence,” meaning the investigators had very little confidence the findings reflected the true impact of the treatment on gender dysphoria, global function (how well a person functions in daily life), depression, and bone mineral density.Dr. Guyatt’s puberty blocker paper also highlighted a review paper out of England that recently called into question the veracity of the oft-repeated claim that the treatments are “fully reversible.” The cross-sex hormone analysis examined 24 studies in which the average participant was younger than age 26 upon starting treatment (the average age ranged from age 15 to 25). These papers, the authors concluded, largely provided very low certainty evidence regarding such treatment’s impacts on gender dysphoria, global function, depression and bone mineral density changes. One study, which had an untreated comparison group, provided simply “low certainty” evidence—meaning the investigators had merely “limited confidence” it reflected the true effect of the treatment—that taking hormones was linked to a somewhat lower odds of having depression.The only outcome the investigators considered to be of “high certainty,” meaning they were “very confident” it was close to reflecting the treatment’s true impact in clinical practice, was that there was a 4% rate of cardiovascular events among biological females 7 to 109 months after they started testosterone. That was due to a 2019 research letter by Dutch investigators that found that estrogen use in patients who were born male, with a median age of 30, was tied to a nearly doubled rate of stroke and a greater than fourfold higher rate of blood clots; and that testosterone use in biological females, with a median age of 23, was tied to an almost quadrupled heart attack rate.Dr. Noone said that particular study could not isolate the impact of hormones on such outcomes, and that the heart disease events might have been driven by higher rates of tobacco smoking among trans people or the impacts of anti-trans stigma.Overall, the design of the puberty blocker and cross-sex hormones studies meant they could provide insights into the quality of life of youth on the drugs, the study authors concluded. But the analyses could not answer questions about the impacts of the drugs, such as whether quality of life or global function is better among those receiving the medications compared with others who were not. The Battle Over Research StandardsMany advocates of pediatric gender medicine have insisted that randomized controlled trials, or RCTs, of gender-transition treatments for minors are not ethical—because, they argue, the benefits of these interventions are already so well established. There is broader consensus among research experts that RCTs might not be feasible. For one, it would be impossible to blind such a study, since it soon becomes obvious to any young person whether they are experiencing physical changes indicative of being on hormones or off of blockers. And youth randomized to an untreated control group might be disinclined to remain in a study they saw as providing them no benefit.All that said, Dr. Guyatt and his colleagues wrote in their new papers that to understand the impacts of both puberty blockers and cross-sex hormones on young people, “methodologically rigorous studies,” such as those that follow a population over time “are needed to produce higher certainty evidence.” They noted that this includes “RCTs (if ethical)” for blockers in particular. Thus, the study authors did not insist on “high certainty” evidence, as many critics of the evidence-based approach to assessing pediatric gender medicine often attest, accurately or not, is the topline argument stemming from systematic literature reviews of the field; they called for higher certainty. Similarly, despite a recent editorial in the New England Journal of Medicine suggesting that the Cass Review set the standard at the RCT level, the British report actually made a more general call for improved methodological rigor in studies of these treatments. Dr. Guyatt’s papers further argued that physicians counseling young people about receiving these interventions have an obligation to communicate to these patients and their caregivers about the very low certainty of the supporting scientific evidence. Acknowledging the crucial role that patients’ so-called values and preferences play in such clinical decision-making, the investigators called upon the authors of clinical guidelines and policy makers to be transparent about “whose values they prioritize when developing treatment recommendations and policies.”Supporters of minors’ access to these medications often claim that the rate of regret-based detransitioning — in which someone stops gender-transition drugs and reverts to identifying and presenting as their birth sex — among those who started treatment as minors is extremely low. The Cass Review, though, found that due to limited patient follow-up, the true detransitioning rate is unknown. Approximately two dozen detransitioners have filed lawsuits against their care providers, often claiming to have suffered irreversible harms to their body. Many of these plaintiffs are represented by a Texas firm established by a quartet of former white-shoe attorneys who set up their practice for the sole purpose of representing detransitioners — a population that they anticipate will only grow given the recent surge in trans identification among adolescents. The authors of the two new analyses found they could reach no conclusions about rates of regret, anxiety or pelvic pain tied to receiving puberty blockers or hormones. Nor could they reach any conclusions about whether cancer was connected to hormone use or whether puberty blockers were linked to the suicide death rate. The analysis on hormones referenced one two-year U.S. study, published in 2023, in which, among 315 persons who started cross-sex hormones between ages 12 and 20, two died by suicide. Dr. Guyatt’s team deemed this association based on very low certainty evidence. Nor did these analyses provide any substantial insights into a key concern: fertility. Concerns that providing treatment for childhood gender dysphoria with blockers and hormones might cause infertility have motivated many critics of this medical field to call for a higher quality of evidence than might otherwise be acceptable for pediatric medical interventions. Leor Sapir, a fellow at the Manhattan Institute who studies pediatric gender medicine, praised Dr. Guyatt’s new analyses as the most “methodologically rigorous systematic reviews” in this field to date. He said that a notable shortcoming of the papers was the limited information they provided about various potential harms of these treatments — a fault he attributed to the wider medical field.“Gender clinics and clinicians are usually the ones who study medical interventions in this area,” Dr. Sapir said, “And they have little interest or incentive to conduct rigorous, longitudinal studies on the harms of the interventions they adamantly support.” Following the ScienceDr. Guyatt’s papers are likely to impact ongoing litigation over pediatric gender medicine. Alabama’s attorney general, Steve Marshall, made that evident in a statement to the Sun, when he praised the new papers and said they confirmed “that states like Alabama are on firm footing in restricting these treatments for minors and by encouraging the medical community to finally follow the science itself.”The papers did not, however, call for such bans, rather for better research. Some of the nation’s major pediatric gender care research hubs are in states that have passed such bans, which threaten to end their research entirely.As Mr. Marshall’s scathing amicus brief to the Supreme Court for the case over Tennessee’s ban laid bare, records that the attorney general subpoenaed from the World Professional Association for Transgender Health, a prominent transgender medical-activist group, revealed that WPATH suppressed publication of systematic reviews it had commissioned from evidence-based medicine experts at Johns Hopkins University as it developed its 2022 revision to its widely referenced trans-care guidelines.“It is no great mystery why WPATH acted the way it did,” said Mr. Marshall. In a nod to Dr. Guyatt’s advice for guidelines committees, Mr. Marshall continued: “As these latest systematic evidence reviews confirm, there is woefully insufficient evidence to support WPATH’s strong recommendation that kids be given puberty blockers, cross-sex hormones, and surgeries to treat their gender-related distress.”Dr. Guyatt’s papers are likely to be attacked due to their funding source. The research was commissioned by the Society for Evidence-based Gender Medicine, or SEGM, which is a collective of physicians and researchers who are skeptical of the evidence supporting pediatric gender medicine and are regarded as an adversary by the transgender rights movement. The Southern Poverty Law Center has gone so far as to brand SEGM a hate group that traffics in pseudoscience. (The SPLC has itself faced heavy criticism from the right in recent years for expanding its label of hate groups to apply broadly to religious conservatives and other groups that oppose liberal orthodoxy.) However, a three-day conference SEGM held in New York City in the fall of 2023 was almost entirely lacking in politics or any trace of prejudice or animus against transgender people. Instead, it offered a trenchant crash course in evidence-based medicine principles and their application to this field. That said, SEGM’s critics assert that the organization leans on such intellectual principles as a mere pretext to sow doubt among the public and policymakers alike and, above all, to lend academic credibility to efforts to outright ban these interventions.In an interview, SEGM cofounder Zhenya Abbruzzese, a health researcher, firmly denied any such political motivation. She further said that Dr. Guyatt’s team kept her organization “at arm’s length” throughout the work on the review papers, and, unlike the Johns Hopkins team’s ultimate arrangement with WPATH, the academic team had full right to publish regardless of the findings. Speaking to the effort in modern medicine to treat gender dysphoria in young people with blockers and hormones, Ms. Abbruzzese said, “We are operating in the dark. But we don’t have to be.” She pointed to the robust national health databases in many European nations, in particular in Scandinavia, and argued that researchers could reach at least moderately certain conclusions about the potential impacts of these treatments by conducting research based on those health records. “It’s time to look at that data in a very rigorous way,” Ms. Abbruzzese said. Researchers have already conducted such health-database analyses regarding gender transition surgery’s association with mental health outcomes in Swedish adults and cross-sex hormones’ link to suicide deaths in Finnish youths. Both studies found the interventions were tied to no such benefits.

New Research Raises More Doubts About Safety and Benefits of Gender Transition Treatments for Minors

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