To what extent are the purported short-term psychological benefits of “gender-affirming” care, reported by some recent studies conducted by pediatric gender clinics, due to the placebo effect, rather than the hormonal and surgical interventions themselves? This question is the focus of a new tour-de-force peer-reviewed publication in the Archives of Sexual Behavior by Dr. Alison Clayton.

Clayton, a researcher and practicing psychiatrist (who is also affiliated with SEGM), has been a powerful, sober voice in the increasingly heated debates in gender medicine. During the past 24 months, she alerted readers to the “marked asymmetry in outcomes reporting” by gender clinics, where the “findings of positive outcomes of medical interventions are trumpeted in abstracts, while their profound limitations remain behind the paywall, thus, below the radar of busy clinicians.” She was one of the first clinicians to point out that "gender-affirming" practices fall, at best, in the “innovative clinical model” and are not ready for wide-scale use in general medical settings. Her ongoing research into misadventures in medicine that had harmed vulnerable patients—such as prefrontal lobotomy for mentally ill patients—informed Clayton’s concerns about troubling parallels between those eschewed practices of the past, and the currently-celebrated practice of offering mastectomies to gender-distressed female minors.

In her most recent article, Clayton argues that the findings of modest “benefits” of hormonal and surgical “affirming” interventions are compromised by the placebo effect—the expectation of benefits heavily promoted by enthusiastic providers, and indeed the entire cultural narrative.  Clayton poses the next logical question: If the placebo effect is not only in play but is also likely responsible for the reported short-term benefits, is that a problem—as long as the patient gets better? Clayton’s overview of the significant health risks of euphemistically-termed “gender-affirming” interventions is a powerful reminder of why, while the “placebo effect” is a welcome addition to the plethora of ways in which medical treatment may help patients, it should only be called upon when the treatment itself has proven net-beneficial in a controlled trial—something that has never occurred in pediatric gender medicine.

Short-term benefits from placebo effects are common and may even endure, depending on the condition (e.g., they may aid in treatment of heart disease and depression, but do not shrink tumors). However, the price that young gender dysphoric patients will pay for the benefits of the “placebo” effects is unacceptably high, as it involves infertility, sexual side effects, and a growing list of medical health risks—along with the certainty of lifelong medical patienthood and the risk of regret over irreversible interventions. Currently, as many as 30% of individuals (19% of natal males and 36% of natal females) who initiate "gender-affirming" interventions, stop them 4 years later; however the harmful effects of these interventions are often life-long.

Clayton asserts that "gender-affirming" interventions for youth constitute a perfect storm for placebo effects and observes that current research is unable to distinguish benefits resulting from placebo effects from those of specific treatments. Clayton’s in-depth, nuanced analysis and discussion of these issues cannot be reduced to a short summary, and we encourage readers to set aside the time to read the original publication in its entirety. However, we briefly summarize the key points, well-aware that we cannot do justice to the remarkable scholarship of this publication:

• What are placebo effects?

Placebo effects are the beneficial effects (and nocebo effects are deleterious effects) attributable to the mind-body response evoked by treatment context rather than those caused by the specific action of the treatment. Placebo effects can lead to real, measurable improvement in a patient’s clinical condition.

• How are placebo effects distinguished from specific treatment effects?

Typically, prior to their introduction into routine practice, new medical treatments are subject to rigorous research. The double-blind randomized controlled trial is the gold-standard for distinguishing a treatment’s specific efficacy from placebo effects. There have been no randomized controlled trials undertaken of the various "gender-affirming treatments" that are presently routinely provided for gender-dysphoric youth. Other clinical research methods that do not rely on the use of inert “placebos” are also capable of distinguishing and mitigating the placebo effect, but such studies have not been undertaken either.

• Why is it important to differentiate placebo effects from specific treatment effects in gender medicine?

It is vitally important to know whether we are using treatments—especially those carrying significant risk of adverse effects—solely to realize benefits due to placebo effects. 

First, although some placebos such as sugar pills do not have direct adverse effects, this cannot be said of hormonal and surgical gender-affirming treatments. There are numerous potential adverse risks of gender-affirming treatments, including: impaired fertility, sterility, cardiovascular disease, osteoporosis, cancers, impaired brain development, impaired sexual function, surgical complications including mortality and later regret/detransition.

Second, placebo prescribing does not meet modern medicine’s requirements for honesty, medical transparency, and patient autonomy—all of which underpin informed consent. Thus, even prescribing a “harmless” sugar pill to a patient is inconsistent with modern medical ethics and practice.

Ultimately, “a medical profession that does little to distinguish placebo effects from specific treatment effects risks becoming little different from pseudoscience and the quackery that dominated medicine in past times, with likely resulting decline in public trust and deterioration in patient outcomes.”

• Is it unethical to perform comparative quality research capable of mitigating the placebo effect in pediatric gender medicine?

The Dutch researchers, who pioneered the "gender-affirming" hormonal and surgical treatment approach for youth, asserted that such research would have been unethical. However, the ethics of implementing a new treatment without a rigorous evidence base also must be considered. There are many examples of medical practices that have later been shown to be more harmful than beneficial.

For example, through much of the latter half of the twentieth century, most pediatricians and medical organizations recommended, based on clinical wisdom and low quality evidence, the prone sleeping position for infants. They claimed the prone position decreased the risk of death from aspiration of vomit. Subsequently, quality epidemiological research revealed prone sleeping as a major risk factor for  sudden infant death syndrome (SIDS) and parents were advised to use a supine (back) infant sleep position. Prone sleeping is thought to have contributed to the deaths of tens of thousands of infants.

Today, gender-affirming care for gender-dysphoric youth not only lacks any randomized controlled trials but also any high or even moderate-quality prospective observational studies. Thus, there is only very low-quality evidence for the alleged benefits of these interventions in youth. As recent systematic reviews of evidence from the UK demonstrated, the reported mental health benefits, which are the principal rationale offered for implementing these treatments in youth, are likely due to bias, confounding and chance, and placebo effects make a key contribution to the unreliability of these findings.

• What makes youth “gender-affirming” medicine a “perfect storm” for placebo effects?

Youth gender medicine presents a confluence of other elements that make it a “perfect storm” for placebo effects:

It relies on subjective criteria for diagnosis and treatment outcomes. There are no objective diagnostic tests for gender dysphoria and it is assessed largely on the basis of patient self-reports. Placebo effect research has demonstrated that placebo responses are particularly noted in patient-reported symptoms and outcomes–such as anxiety, pain, life satisfaction, mood, and behaviors. The as yet unexplained massive increase in the prevalence of gender-dysphoric youth presenting to clinics and its preponderance of female tweens and teens heightens this concern.

Gender clinics exclusively promote gender-affirming interventions. Child and adolescent gender clinics problematically conflate clinical advocacy and research agendas. Most clinics present gender-affirming interventions as very low risk, high-success interventions. In contrast, they often eschew noninvasive alternatives such as psychotherapy as useless at best, and unethical and harmful at worst. This orientation primes patients to experience positive short-term effects of hormones and surgery due to placebo, negative short-term effects of delaying the “affirmative” treatment due to nocebo (negative self-fulfilling prophecy effect), and generally undermines research performed in gender clinic environments.

Gender clinics and the media propagate ethically-questionable and inaccurate suicide narratives. Gender clinicians and the media often overstate, exaggerate and even falsify suicide-risk among trans-identified youth. For example, claims are made that if children don’t receive puberty blockers they will commit suicide, despite the fact that there is no evidence that puberty blockers decrease suicide rates. These types of narratives pose a dangerous nocebo effect, which may act to increase suicidality and suicide risk.

Societal celebration of the “affirmation” narrative. The celebration of trans rights has been a double-edged sword, both increasing acceptance of gender diversity but also inadvertently signaling to gender dysphoric youth that transition will produce happiness or fulfillment. In part this narrative is fueled by gender clinicians, some of whom are financially motivated and actively promote the interventions on social media popular with minors, such as TikTok. At the same time, balanced coverage that highlights the risks and uncertainties is frequently shut down. This media/social media milieu may foster “emotional contagion,” contributing to the dissemination of gender dysphoria symptoms and behaviors throughout the community, with the placebo effect contributing to the short-term “improvements” due to “gender affirmation.”

Strong pro-transition bias in scientific information shared. Gender clinicians, who typically lead research in pediatric gender medicine, tend to overstate claims about the strength of the evidence and certainty of benefit, while discounting the risks of pediatric gender transition. This contrasts with their more cautious statements, often hidden behind paywalls, in the peer-reviewed literature. This presents a two-faced narrative: a placebo-effect-enhancing overstatement of certainty/strong evidence of benefit displayed to gender-dysphoric youth, their families, and policy makers—and the more realistic face of uncertainty and a dearth of evidence that is available only to the most committed students of the medical literature who have the skills and time to critically assess the existing studies.      

• Is concern about the placebo effect unique to gender medicine?

The challenge of distinguishing placebo from treatment effects is not unique to gender medicine. However, they have been surmounted in other areas of pediatric medicine where the risks of treatments are substantial but are supported by higher quality evidence. In addition, in other areas of medicine, the placebo effect is often discussed and acknowledged (e.g., the role of placebo effect in response to antidepressants). This is in stark contrast to the situation in youth gender medicine where, to date, there has been no discussion of the placebo effect.

Clayton states that “it seems particularly vital to consider the potential role of the placebo effect” of gender-affirming care because the stakes are high.” Medical and surgical interventions, given to vulnerable minors, lead to lifelong medicalization and hold the risk of serious irreversible adverse impacts, such as sterility and impaired sexual function. “Thus, we need strong evidence that they are as efficacious for critical mental health outcomes as claimed and that there are no less harmful alternatives.”

Concluding Thoughts

SEGM welcomes Clayton’s call for greater awareness and discussion of the placebo effect in youth gender medicine. Given the profound risks of gender-affirming interventions, it is imperative that careful thought and debate focus on this issue. From the methods perspective, the placebo effect puts gender medicine studies at a high risk of bias due to both confounding (the anticipation of improvement affects the results, but its effect cannot be separated from the effect of the treatment) and measurement error (if a study participant expects a positive outcome, they will be more likely to make a positive judgement about the outcome, which will bias their self-reported outcome).

SEGM appreciates the challenges of conducting placebo controlled trials in gender medicine, since the effects of the drugs are apparent nearly immediately and thus the use of inert placebos is not feasible. However, other research designs, including comparative research where control groups use other forms of active interventions such as psychotherapy, provide a viable alternative to minimize the placebo effect, as in both instances the study participants may be expecting improvement. SEGM concurs with Clayton's concerns that gender clinic settings, with their strong stated position of superiority of medical and surgical "affirming" interventions, are inherently problematic research sites for generating reliable comparative data on the efficacy of various treatment approaches. We agree that ultimately, “independent reviews by expert clinicians and methodologists" which include gender clinicians as well as those "not currently involved in clinical practice and research in this area (thus, having some emotional distance and minimizing intellectual conflict risk), could helpfully advise further research and clinical strategies.” 

Both clinicians and media must reassess their approach to reporting on “gender-affirming” interventions, focusing on measured and honest statements about what is known and not known about the safety and efficacy of gender-affirming treatments. The uncertain and wholly inadequate evidence base for these treatments must be acknowledged. The full range of treatment options and pathways should be presented, including, as Clayton suggests, “realistic positive stories of those with gender dysphoria who have decided not to transition or have delayed transition until maturity; accounts of patients who have benefitted from ethical psychological approaches; and accounts of those who have had negative transition experiences. Detransition, regret, and harm from transition should be acknowledged and publicized as a significant risk."

Finally, in recent months, we have seen an attempt by the gender-medicine establishment to begin to redefine the “affirmative care” pathway away from the previous focus on social transition, puberty blockers, cross-sex hormones and surgery, as articulated in the American Academy of Pediatrics’ 2018 policy, and toward a broader definition of generally supportive care that affirms a young patient’s confidence and self-worth. SEGM welcomes this definitional shift. In a recent statement, the AAP president went on record stating that only a minority of trans-identified youth need hormones and surgery, while the majority need "just the opposite."

If “gender-affirming care” is redefined as an approach promoting “positive clinician-patient interactions” that respect the young person's experience, decrease anxiety, and increases hope—without infusing undue assurance about the safety and efficacy of hormones and surgery—then we can all get behind the idea of “affirmative care.” After all, this is the very reason why positive patient-clinician interactions are the core of healing, even if some of its effects are placebo-induced.