Notable Publications in Gender Medicine, April-May 2025

SEGM Digest, Issue 1 (April-May 2025)
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May 30, 2025

Introducing the SEGM Digest

This issue is the first installment of the SEGM Digest, a new series that will highlight recent influential publications in pediatric gender medicine. When we first launched our Spotlight series in 2019 the field was producing relatively few publications. As of 2025, however, the volume of published research and guidance documents has surged, now reaching dozens of publications per week. This growth has created a pressing need for broader overviews to help track the rapidly evolving landscape.

The SEGM Digest differs in format from our Spotlight, prioritizing breadth over depth. Nonetheless, our core mission remains the same: to equip researchers, clinicians, policymakers, patients, and advocates with accurate and trustworthy information about the literature and major policy developments shaping youth gender medicine. In the Digest series, the selection of featured publications is necessarily subjective; we apply our best judgment to identify the works that are most worthy of attention. Our Spotlight series will continue to appear roughly once per month and will offer in-depth analyses of select publications that merit closer examination.

We welcome community feedback as we refine our approach to curating the growing body of information relevant to the question at the heart of our work: how to best care for gender-dysphoric and gender-questioning children, adolescents, and young adults. 

SEGM Digest: Issue 1

  1. Treatment for Pediatric Gender Dysphoria (HHS Review) (HHS, 2025). Although many European public health authorities have moved to restrict or ban pediatric gender transition, the U.S. Department of Health and Human Services (HHS) previously supported it. That changed with the May 1, 2025 release of a comprehensive HHS report re-examining the field’s historical, evidentiary, and ethical foundations. The HHS Review's comprehensive evidence and ethics analysis concludes that psychotherapy, rather than hormones and surgery, is currently the most supported treatment. 
     SEGM reviewFull text (external link)
  2. Gender-Affirming Medical Treatments for Pediatric Patients With Gender Dysphoria (Utah Report) (LaFleur et al., 2024). This 2024 report (released in May 2025) was conducted at the request of Utah’s Department of Health and Human Services. Unfortunately, the authors did not conduct an evidence synthesis. As a result, the Report fundamentally fails in the purpose for which it had been commissioned: to provide the Utah legislature with a systematic review of evidence regarding what is known about the safety and efficacy of endocrine interventions in order to inform decisions regarding the state's moratorium on these interventions. There are other irregularities in the report that warrant further analysis. 
    SEGM reviewFull text (external link)
  3. Mastectomy for Individuals With Gender Dysphoria Younger Than 26 Years: A Systematic Review and Meta-Analysis (Miroshnychenko et al., 2025). A new systematic review by McMaster University, an internationally renowned center for evidence-based medicine, finds evidence for psychological outcomes of mastectomy (including quality of life, gender dysphoria, body and chest satisfaction, and depression) is predominantly rated as very-low certainty.  In contrast, the evidence for some physical harms following mastectomy is rated as high certainty. These findings contradict the assertions by WPATH that mastectomies are associated with a "consistent and direct increase in health-related quality of life, a significant decrease in gender dysphoria, and a consistent increase in satisfaction with body and appearance."
    SEGM reviewFull text (external link)
  4. Pediatric Gender Affirming Care is not Evidence-Based (McDeavitt et al., 2025). Over the last two years there has been a surge in research studies and systematic reviews reporting on the use of puberty blockers and cross-sex hormones as treatment for gender-distressed youth. This makes it difficult for the non-specialist to keep on top of the evidence. McDeavitt and colleagues simplify the task of keeping up with the latest systematic reviews by synthesizing their key findings and implications. 
    SEGM reviewFull text (external link)
  5. Fertility Preservation (Laidlaw et al., 2025). Medical transition in children and adolescents can harm their future fertility. When puberty blockers are provided at the onset of puberty and are followed by cross-sex hormones, fertility preservation becomes especially difficult. This new paper focuses on the technical and ethical challenges of applying fertility preservation methods, originally developed in the context of lifesaving pediatric cancer care, to iatrogenically-induced infertility for the purpose of sex-trait modification in gender-dysphoric children and adolescents.
    SEGM reviewFull text (external link)
  6. How to Improve Research Methodology (Van Breukelen, 2025). It is widely agreed that the evidence regarding the benefits and harms of the "gender-affirming" treatment model for youth is inadequate. There is currently considerable discussion on how to improve the quality of this evidence, with both the proponents and opponents of pediatric transitions expressing concerns (albeit for different reasons) about whether randomized controlled trials (RCTs) are either unethical or impossible. The paper provides a thought-provoking discussion of alternatives to RCT designs.
     SEGM reviewFull text (external link)
  7. A Legal Assessment of the Dutch Protocol (Smeehuijzen et al., 2025). Generally, physicians who follow published medical standards of care or clinical practice guidelines have assumed they are protected from medical negligence claims. The paper considers whether this assumption will still hold if widely used clinical guidelines fail to meet accepted standards. The authors conclude that the Dutch Protocol, especially in its current form, has departed from scientific norms and may not be viewed by the courts as the standard of care.
    SEGM reviewFull text (external link)

1. Treatment for Pediatric Gender Dysphoria (HHS Review)

Internationally, a growing number of European countries have retreated from the "gender-affirming treatment model" for children and adolescents due to concerns about a lack of evidence of benefits and increasing evidence of harms of these interventions. These developments have largely been ignored by U.S. medical bodies and health authorities. This changed with the May 1, 2025, release of the Department of Health and Human Services review into pediatric gender dysphoria. 

The HHS report is divided into five substantial sections: background; evidence review; clinical realities; ethics review; and psychotherapy. This comprehensive review demonstrates that: 

  • Pediatric transitions were launched without proper justification. Usually, when an off-label treatment is used in pediatrics without prior clinical research, it is because it has been proven safe and effective in adults. In the case of youth transitions, the opposite has occurred:  gender transitions for older adolescents were launched in response to the failures of the practice of adult transitions to deliver satisfactory outcomes, in the hope that earlier transitions would improve outcomes. The protocol was then extended to children and adolescents as young as 8–12 without scientific or ethical justification.
  • The risk-benefit ratio of pediatric transition is unfavorable. Nearly 20 years after the formal introduction of the Dutch protocol in 2006, the best available evidence in the form of systematic reviews has failed to detect credible benefits. In contrast, harms, such as harms to fertility and a number of other health domains, are much more certain and arise from biological and general scientific knowledge.
  • The evidence for the practice of gender transitions has been manipulated. WPATH and gender clinicians have consistently misrepresented the evidence for pediatric transition. They have also engaged in suppression of debate and disparaged those raising questions about the evidence and ethics of pediatric gender transitions. The U.S. medical establishment has delegated the assessment of the treatment outcomes to small, ideologically driven, WPATH-aligned groups and failed to engage in independent analysis.
  • The U.S. medical establishment has failed to respond to new scientific information. The unfavorable risk-benefit ratio of youth transitions has led an increasing number of European countries to change their treatment approaches accordingly, prioritizing non-invasive interventions such as psychosocial support and psychotherapy. In contrast, the U.S. medical establishment has failed to respond and continues to promote pediatric transitions as the only acceptable treatment model for gender-distressed youth.
  • Medical ethics supports prioritizing psychotherapy over hormones and surgery for youth. Hormones and surgery have uncertain benefits and certain harms, while psychotherapy has uncertain benefits but is not associated with known harms. Clinicians have a duty to protect patients from harm—even when harmful treatments are requested—since the principle of autonomy does not override the obligation to do no harm, particularly in the care of minors. Psychotherapy emerges as the least-harmful treatment, while efforts to conflate psychotherapy with "conversion therapy" are misguided and/or politically motivated.

SEGM comment: Despite the polarized and politicized context in which the HHS Review was commissioned, it stands as a measured and rigorous analysis of the best available evidence and ethical considerations regarding gender transition in minors. It has received favorable coverage from respected outlets such as The Washington Post and The Economist. Although major medical societies have so far avoided engaging with the Review’s findings, its credible analysis and measured tone are likely to have a gradual but lasting impact on clinical practice in the U.S. and abroad. Some cite the political climate to dismiss the Review, but its greatest challenge may simply be its length: 409 pages in the main report, with a 174-page appendix. The 4-page executive summary is useful, but the full report remains essential reading for anyone personally or professionally involved in this field.

2. Gender-Affirming Medical Treatments for Pediatric Patients With Gender Dysphoria (Utah Report)

This review was conducted by the Drug Regimen Review Center at the University of Utah at the request of Utah’s Department of Health and Human Services. It was intended to provide the legislature with recommendations to help determine whether to lift the state’s moratorium on hormonal interventions for minors with gender dysphoria, as described in Section 26B-1-239.  Although dated August 2024, the report was submitted to the state on May 19, 2025 and is now publicly available.

The Utah Report, which spans over 1,000 pages, states that it provides three main deliverables: 

  1. A list of specific hormonal and hormonally active pharmacological agents routinely used as part of gender transition in minors, and their FDA-approved uses (all are being used off-label for gender dysphoria).
  2. A summary of recent clinical practice guidelines relating to the treatment of gender dysphoria
  3. Evidence tables of systematic reviews and/or meta-analyses

The Report includes a list of studies drawn from existing systematic reviews and clinical guidelines, and attempts to assess their quality using the relatively lenient Newcastle-Ottawa Scale. However, the Utah Report inexplicably stops short of performing the most essential step of any systematic review: synthesizing the evidence. Without a formal synthesis—ideally using GRADE, though other transparent methods could suffice—the legislature’s central question of whether the provision of hormones and surgeries to gender-dysphoric minors is justified remains unanswered. The authors attribute the omission of the evidence synthesis to “insufficient resources.” Yet synthesizing evidence is a core requirement of systematic reviews under PRISMA standards, which they claim to follow. Despite the omission of the critical step of evidence synthesis, the Report offers “high-level conclusions” asserting that the hormonal treatments are safe and effective—in apparent contradiction to existing systematic reviews, which consistently find the evidence to be highly uncertain. 

The Report authors also appear to conflate the quantity of available studies with the quality or certainty of the evidence. This is evident in the following statement:

“The conventional wisdom among non-experts has long been that there are limited data on the use of GAHT [gender-affirming hormone treatment[ in pediatric patients with GD. However, results from our exhaustive literature searches have led us to the opposite conclusion. We found more than 277 individual, full-text citations that met eligibility for study design, population, and treatments of interest.” (p. 90). 

Had the authors employed the GRADE approach to evidence synthesis, they would have recognized that despite the large number of studies claiming benefits, the certainty in those findings remains extremely low due to serious limitations in study design. When experts refer to the dearth of evidence supporting pediatric gender transition, they are not referring to the number of studies, but rather to their low methodological quality and the resulting lack of confidence in the findings. The issue is not the quantity of evidence—it is the profound weaknesses within it.

In addition, the authors make a highly unusual statement in the Executive Summary that they do not consider infertility to be an important outcome since "infertility is a known risk of CSHT [cross-sex hormones therapy]" (p. 4). This position is paradoxical. If infertility were not an important harm to patients, there would be no reason for the significant focus in gender-affirming literature on fertility preservation methods. The very existence of efforts to preserve fertility clearly reflects a recognition that fertility is valuable—its loss, therefore, is a key harm that must be balanced against the treatment's hoped-for benefits. 

The Utah Report has a number of other irregularities, such as failure to include well-known systematic reviews (e.g., the NICE and York reviews which had already been published by the time the report was produced in 2024), and a surprising and novel decision to redact parts of publicly available scientific details in its study summaries, making it challenging to scrutinize the work.

SEGM comment: The first part of the Utah report's deliverable—the list of the drugs currently used for gender transitioning of youth, and their current FDA indications—represents a helpful resource. However, the analysis of the treatment guidelines, systematic reviews, and individual studies falls far short of expected professional standards for a systematic review. Due to the decision not to conduct an evidence synthesis, the Review fundamentally fails to achieve the purpose for which it was commissioned: to provide the Utah legislature with a synthesis of what is known about the safety and efficacy of medical interventions used in youth gender medicine.

3. Mastectomy for Individuals With Gender Dysphoria Younger Than 26 Years: A Systematic Review and Meta-Analysis

  • Miroshnychenko, A., Roldan, Y. M., Ibrahim, S., Kulatunga-Moruzi, C., Dahlin, K., Montante, S., Couban, R., Guyatt, G., & Brignardello-Petersen, R. (2025). Mastectomy for individuals with gender dysphoria younger than 26 years: A systematic review and meta-analysis. Plastic and Reconstructive Surgery, 155(6), 915–923. https://doi.org/10.1097/PRS.0000000000011734.

A new systematic review and meta-analysis, undertaken by researchers from McMaster University, addresses the evidence regarding the benefits and harms of one of the most common types of "gender-affirming" surgeries for minors—mastectomy—with a focus on psychological and physical health outcomes in the adolescent and young adult population under age 26. Miroshnychenko et al. adhered to high methodological standards for conducting systematic reviews. The authors conducted a systematic search, assessed primary studies meeting the inclusion criteria, assessed the primary studies for risk of bias using ROBINS-I, and assessed the certainty of evidence using GRADE. Whenever possible,  meta-analyses were undertaken as well.

Of 39 included mastectomy studies, 3 are classified as comparative observational, 2 are before-and-after, and 34 are case series. The studies are frequently rated as being at serious or critical risk of bias (for example, due to confounding, not including all eligible participants, missing data, and outcome measurement inadequacies). Evidence for psychological outcomes (including quality of life, gender dysphoria, body and chest satisfaction, and depression) is predominantly rated as very-low certainty. Evidence for some post-operative outcomes, such as death (0/1000), necrosis (10-40/1000), and hypertrophic scarring (50/1000) is rated as high certainty. Risk of regret is assessed as 10/1000 and is rated as very low certainty. 

The authors conclude that higher-quality evidence—ideally from prospective cohort studies and, where ethically feasible, randomized controlled trials—is needed to understand the impact of "gender-affirming" mastectomy on mental health outcomes. This evidence is essential to ensure that individuals with gender dysphoria, along with their clinicians, guideline developers, and policymakers, can make informed decisions.

As part of the methodological rigor of the review, the author team provided a comprehensive disclosure of interest, including the fact that the review was funded by the Society for Evidence-Based Medicine (SEGM) through a multi-year research agreement between McMaster University and SEGM. The authors detail how potential conflicts of interest (COI) were managed.

SEGM comment: 

This systematic review is significant for three reasons. First, it is the first to conclude that the risk-benefit profile of youth mastectomies is unfavorable: while the harms are well-documented, potential benefits, such as reduced dysphoria or improved quality of life, remain uncertain. Second, it was conducted by a team from McMaster University, an internationally renowned center of evidence-based medicine (EBM), and the author group includes internationally recognized experts in the EBM field. Third, the systematic review was published in Plastic and Reconstructive Surgery, the official journal of the American Society of Plastic Surgeons (ASPS), the surgical specialty most often performing these procedures.

Of note, WPATH’s 2022 Standards of Care, version 8 (SOC-8) claims that 'gender-affirming' mastectomy is a safe and effective treatment and that its efficacy has been “demonstrated in multiple domains, including a consistent and direct increase in health-related quality of life, a significant decrease in gender dysphoria, and a consistent increase in satisfaction with body and appearance” (p. 128). The findings of this published systematic review directly challenge WPATH's assertions regarding the benefit and harms of mastectomy.

Given the weight of the review's findings, it is not surprising that the journal solicited additional commentaries. Foster et al. offered a positive response, praising the systematic review’s methodological rigor. In contrast, Schechter et al. offered a sharply critical response. Some of Schechter et al.’s  critiques warrant further consideration and discussion, while others appear misguided. Unfortunately, Schechter and his two coauthors—all of whom coauthored the WPATH Surgery chapter—present their critiques through a sharply politicized lens, relying on ad hominem attacks to discredit the systematic review. It would be of great assistance to this debate if Schechter and colleagues authorized the publication of the WPATH commissioned Johns Hopkins systematic review of gender-affirming surgery, which, according to the court disclosures discussed in the HHS Review, have been suppressed from publication (HHS Review, p. 163). 

This unfortunate approach to debate reflects a broader pattern often seen when influential figures in transgender medicine are confronted with new evidence that challenges their assumptions, beliefs, and clinical practices. In turn, this dynamic hinders self-correction within the field. Regulatory interventions—including legislative restrictions, as well as actions by medical boards and public health authorities—have become increasingly common as countries around the world work to bring gender medicine in line with the standards expected in other areas of healthcare.

4. Pediatric Gender Affirming Care is not Evidence-Based

Over the last two years there has been a surge in research studies and systematic reviews reporting on the use of puberty blockers and cross-sex hormones as treatment for gender-distressed youth. This makes it difficult for the non-specialist to keep on top of the evidence. The psychiatrist Kathleen McDeavitt and colleagues J. Cohn and Chan Kulatunga-Moruzi provide a comprehensive overview of the current state of the evidence underpinning hormonal treatments for children and adolescents with gender-related distress.

Two tables detail the key clinical research studies on safety/risks and effectiveness/benefits. A third table, assessing the safety/effectiveness of hormone treatments, documents the multiple systematic reviews that have been undertaken. The authors also provide a helpful summary of the principles of evidence-based medicine. 

The authors conclude that puberty blockers and cross-sex hormone treatment for gender-distressed youth carry significant and inevitable risks, and that the evidence for their mental health benefits is lacking. 

SEGM comment: McDeavitt and colleagues’ paper provides an excellent overview of the current literature and the state of the evidence. It will be a helpful go-to resource for anyone seeking a succinct summary of key research in this field.

5. Fertility Preservation

  • Laidlaw, M. K., Lahl, J., & Thompson, A. (2025). Fertility preservation: Is there a model for gender-dysphoric youth? Frontiers in Endocrinology, 16:1386716, 1–11. https://doi.org/10.3389/fendo.2025.1386716. 

Endocrinologist Michael Laidlaw, along with obstetrician and gynecologist Angela Thompson and Jennifer Lahl (R.N., M.A., and President of the Center for Bioethics and Culture) examine the current understandings and ethical issues surrounding fertility preservation (FP) for children and adolescents with cancer and gender dysphoria.

They highlight that FP methods used during early puberty (which can occur as young as eight in females and nine in males) are still experimental, and that there is no evidence that these methods are successful for children and adolescents who start early medical gender-affirming treatment (GAT). 

The authors emphasize the difference between using these experimental FP methods in situations such as childhood cancer, where chemotherapy or radiotherapy is the only option to preserve life, versus using them for gender dysphoria. Laidlaw and colleagues point out that causing infertility or reduced fertility through medical GAT takes away children and adolescents’ “right to an open future,” especially since they cannot provide informed consent for a future loss of their reproductive function at an early stage in their development. 

The authors conclude that it is unethical to cause iatrogenic infertility/subfertility in children and young adolescents through GAT and then offer experimental, invasive fertility preservation as a way to circumvent this issue. 

SEGM comment:  The proponents of pediatric gender transitions emphasize the importance of fertility preservation (FP). This underscores the point that the loss of fertility should be conceptualized as a key harm of the GAT treatment pathway. The early intervention model advocated by the Dutch Protocol — puberty blockers administered at the earliest stage of puberty and later followed by cross-sex hormones — greatly hinders the difficult task of successful fertility preservation due to immaturity or unavailability of the gametes (eggs and sperm). Given the anticipated loss of fertility in gender-transitioned youth, the benefits of the treatment should be commensurate. Unfortunately, no robust evidence to date has been able reliably to demonstrate psychological benefits from pediatric gender transitions.

6. How to Improve Research Methodology

It is widely agreed that the evidence regarding the benefits and harms of the gender-affirming treatment (GAT) model for youth is inadequate. There is currently considerable discussion on how to improve the quality of this evidence. A recent paper by Van Breukelen provides a valuable contribution to this important debate. 

Gerard Van Breukelen, from Maastricht University’s Department of Methodology and Statistics, provides a detailed overview of the problems with current research methodology in youth gender medicine and offers some ideas for advancing the quality of evidence. He begins by outlining why a randomized controlled trial (RCT) is the best study design for comparing different treatments with respect to their beneficial and, potentially, averse effects on health outcomes of interest. He observes that clinicians in youth gender medicine object to RCTs on the basis of claimed ethical and feasibility issues. 

He then explains why the main existing study design in youth gender medicine—a pre-post comparison of a single treated group without a control group—provides only weak evidence due to its susceptibility to many confounding factors, such as natural changes over time, regression to the mean, placebo effects, and selective dropout. Similarly, studies that have compared youth receiving GAT to youth who do not are also subject to unmeasured confounders, loss to follow-up, and are often limited by short-term follow-up only. 

As a potential way to advance the evidence in this field, Van Breukelen suggests a carefully designed and conducted international, multicenter “quasi-experiment,” in which the outcomes of patients from clinics implementing medical GAT are compared with those at clinics that refrain from or restrict such treatments.

SEGM comment: This technical paper covers complex methodological and statistical principles in a way that makes them accessible to those without specific training. It is a helpful addition to the debate regarding how to improve the evidence in this field of medicine.

7. A Legal Assessment of the Dutch Protocol

  • Smeehuijzen L., Smids J. & Hoekstra C. (2025). A legal assessment of the Dutch Protocol for transgender care to children: Evidence, ethics and procedure. Family and Law, 1–21. DOI:10.5553/FenR/.000069.

In this article, two Dutch legal experts (Smeehuijzen  and Hoekstra) and a medical ethicist (Smids) evaluate whether the Dutch Protocol as laid out in the 2018 Dutch guideline for somatic gender care (i.e., medical and surgical interventions) meets the necessary requirements for it to have authority in legal settings be recognized as the standard of care. Of note, the 2018 Dutch Protocol substantively departed from the original Dutch Protocol by reducing lower age limits for puberty blockers, cross-sex hormones, and mastectomy, and by dropping the requirement of pre-existing childhood gender dysphoria as a condition for obtaining medical and surgical interventions in adolescence.

The authors outline the three key criteria required in the Netherlands for a standard of care to be considered legally authoritative, namely: (1) the standard is evidence-based, (2) it is not of an ethical nature, and (3) it was established through a properly designed process. They find that the 2018 Dutch Protocol fails to meet these criteria and thus conclude that courts should not rely on it. 

SEGM comment: Although this article focuses on the Dutch medical and legal situation, it is likely to have considerable cross-over relevance to other countries. The 2018 Dutch protocol's criteria and development bear significant resemblance to the 2017 Endocrine Society guideline and the WPATH Standards of Care, both of which have been identified as the source of all other "affirmative" guidelines. Practitioners relying on such guidelines may find that poorly evidenced and/or inadequate medical treatment protocols and clinical practice guidelines might not be accepted as the medical standard of care in adversarial legal settings.