The German Guidelines for Diagnosis and Treatment of Gender Incongruence and Gender Dysphoria of Childhood and Adolescence

• Youth Social Gender Transition (SGT) is a benign act of self-expression that should be child-led.
• The decision to undergo SGT should be made based on the child’s wish for self-expression. The parents should remain open to future identity changes. Mental health providers can help the family accept the child’s decision and manage adverse societal reactions.

• Youth Social Gender Transition (SGT) is an active intervention with potential for benefit and harm.
• Complete SGT is generally discouraged, especially for prepubertal children. If undertaken, it should involve the parents, and be done in consultation with a mental health provider who can advise on the benefits, risks and long-term consequences.

• Benefits: “There is evidence that an affirmatively supported role change can have a positive effect on social integration and the child's self-confidence through the development of the child's personality in the course of prepubertal development… There is evidence that an affirmatively supported role change before the onset of puberty can have a positive effect on socio-emotional development.”

• Benefits: “For example, two studies suggest there may be some benefit associated with use of chosen name in adolescence. However, in another study lifetime suicide attempt and past-year suicidal ideation was higher among those socially transitioning as adolescents compared with those socially transitioning in adulthood.”

• Harms: “There was no evidence of increased psychosexual confusion, identity insecurity or otherwise conspicuous gender-related cognitions in a group of children with GI who had undergone a social role change with the support of their parents.”

• Harms: “In this review, two studies suggest that children who socially transition are more likely to continue to experience gender dysphoria/incongruence in adolescence, though one study found differences by birth-registered sex. One of these studies also reported that the majority of those who socially transitioned progressed to medical interventions.”

• Harm-benefit ratio: Based on the presumption of benefits of social gender transition and the absence of harm, the child’s right to self-determination was used as the guiding principle in making the recommendation in favor of SGT.

• Harm-benefit ratio: Potential harms of changing “sex of rearing” on long-term development, and heightened risk of future medicalization are weighed heavier than the potential benefits.

• The guideline methods “Leitlinienreport” referenced a systematic evidence search. The systematic search was stopped in September 2017.
• The analysis, including non-systematic search after 2017, identified and discussed 12 studies, but did not appear to conduct any structured appraisal of the studies for risk of bias.

• Commissioned a systematic evidence review for SGT. The systematic search was stopped in April 2022.
• The systematic review assessed 3,181 studies for eligibility, yielding 11 eligible studies, which were subsequently assessed for risk of bias using the modified Newcastle-Ottawa Scale.

• Over 50% of the studies in the UK SGT systematic review — 6 out of 11 — were not included in the German SGT analysis. Five of the six omitted studies were published after the German team suspended its systematic evidence search for SGT in 2017.
• The non-systematic nature of the literature search and appraisal after September 2017 led to an apparent bias. For example, while the review included Olson et al. 2022, accepting the study's conclusion that social transition is beneficial, it overlooked the Sievert et al. 2021 study, which came to a different conclusion. This omission is all the more surprising since the data came from a German clinical sample of children with gender dysphoria; the topic was directly related to SGT and the article was descriptively titled “Not social transition status, but peer relations and family functioning predict psychological functioning in a German clinical sample of children with Gender Dysphoria”; and the review team discussed the study's other findings unrelated to SGT in other sections of the guidelines.
• The German review displays a preference toward a positive interpretation of uncertain outcomes. For example, it interprets the Olson et al. 2022 finding that over 90% of youth who underwent early SGT continued to identify as transgender five years later, with the majority initiating medical transition, as a sign of long-term stability of trans identities that emerge before puberty. The alternative interpretation — that early social gender transition may create a potential “lock-in” effect of transgender identity — is not considered.
• These issues would be mitigated by a systematic evidence search, synthesis of evidence, and appraisal of quality of evidence in regard to each recommendation question. The lack of transparent evidence synthesis and appraisal is concerning.

• PBs for gender dysphoria (GD) are indicated upon commencing puberty and obtaining ICD-11 diagnosis of “gender incongruence” or DSM-5 diagnosis of “gender dysphoria” of adolescence/adulthood. Youth with a cross-sex identification as well as non-binary are similarly eligible for puberty blockade.
• No requirement of distress beyond “anticipatory fear” of developing secondary sexual characteristics. Explicitly states that the DSM-5 “gender dysphoria” diagnosis is no longer required.
• No requirement of childhood-onset of gender incongruence: While “lasting” incongruence is mentioned, it is not defined beyond “weeks to months” of assessments prior to starting PBs.
• Psychiatric assessment is recommended but PBs can be provisionally prescribed without assessment. The high rate of co-occurring mental illness that can complicate the diagnosis, and the difficulty in determining future persistence of trans identity, are cited as main reasons to have “weeks to months” of assessments prior to starting PBs. However, endocrinologists can prescribe PBs provisionally, ahead of the psychiatric assessment, if the pubertal changes are creating an urgency.
• Ongoing psychotherapy not required if no mental health problems are apparent. Gender incongruence is seen as a healthy identity variation which, in and of itself, warrants no additional exploration.
• Parental disagreement may lead to involvement of child protective services. If the child desires PB but parents do not agree, and if counseling cannot reconcile the disagreement, child protective services and court systems may be called on to protect “best interests of the child.”

• PBs for gender dysphoria (GD) are no longer allowed in medical practice. Clinical research trials may be approved at a later point for narrow indications.
• If distress is present, standard evidence-based treatments should be used: “standard evidence based psychological and psychopharmacological treatment approaches should be used to support the management of the associated distress and cooccurring conditions. This should include support for parents/carers and siblings as appropriate.”

• Benefits: UK NICE systematic reviews indicate “favorable outcome of the measured parameters” for psychological benefits of pubertal suppression:

“The systematic reviews of the British NICE (National Institute for Health and Care Excellence (NICE), …on the state of the evidence on puberty-blocking .. in adolescence state that the studies available at the time of the reviews point overall in the direction of a favorable outcome after medical interventions for the mental health of adolescents with gender dysphoria.”

SEGM fact-check note: the actual conclusion of the referenced NICE review, and the subsequent Cass Report recommendation to decommission the use of PBs, contradicts this assertion — see SEGM fact-check 1 at the end of the table.

• Also discusses individual studies that suggest positive outcomes. Specifically, the guidelines describe the positive findings of the original Dutch study but fail to acknowledge the highly relevant UK study from the largest pediatric gender clinic in the world, Carmichael et al., 2021, which failed to replicate the Dutch study’s positive results — see SEGM fact-check 6 at the end of the table.

• Benefits: There is no trustworthy evidence of psychological benefits from systematic evidence reviews from either NICE or the updated York systematic evidence reviews:
• The 2020 NICE systematic review “found no evidence that puberty blockers improve body image or dysphoria, and very limited evidence for positive mental health outcomes, which without a control group could be due to placebo effect or concomitant psychological support.”
• The 2024 York systematic review found a “lack of high-quality research assessing puberty suppression in adolescents experiencing gender dysphoria/incongruence. No conclusions can be drawn about the impact on gender dysphoria, mental and psychosocial health or cognitive development.”

• Harms:
• There are no concerns about psychological harms:
• Does not consider the risk of permanently altering gender identity and sexual development credible. Notes high rate of initiation of cross-sex hormones following puberty blockade but attributes this to excellent diagnostic/prognostic ability of the clinicians, rather than to puberty blocker potential to permanently alter gender and sexual identity.
• Does not consider negative impact of neurocognitive development significant. Recognizes research that points to possible problems in cognitive development, but points to research that suggests high levels of educational attainment post-transition.

• Harms:
• There are serious concerns about psychological harms:
• Raises the possibility of permanently altering the trajectory of development of sexuality and gender identity. “Blocking natal sex hormone production means that young people have to understand their identity and sexuality based only on their discomfort about puberty and a sense of their gender identity developed at an early stage of the pubertal process.”
• Considers negative impact on neurocognitive development. “Adolescent sex hormone surges may trigger the opening of a critical period for experience dependent rewiring of neural circuits underlying executive function… Brain maturation may be temporarily or permanently disrupted by the use of puberty blockers, which could have a significant impact on the young person’s ability to make complex risk-laden decisions, as well as having possible longer term neuropsychological consequences.”

• There are no serious concerns about physical harms:
• Recognizes potential physical harms of PBs, for example bone development challenges, insufficient penile tissue for future gender-affirming surgery, sexual side-effects, negative fertility-preservation implications, BMI increase, and menopausal symptoms, but does not consider any significant effects besides to bone health.
• Specific to bone density concerns, recommends limiting the duration of puberty blockade.

• There are serious concerns about physical harms:
• The York review notes that “bone health and height may be compromised during treatment.”
• Discusses the risk of other adverse effects, including metabolic health and weight, insufficient penile tissue, etc.

• There are no accepted alternatives: “In particular, psychotherapy alone cannot be regarded as a suitable treatment to effectively reduce or avert gender dysphoria in cases of diagnosed persistent gender incongruence.”

• Urges the development of evidence base for alternative treatment approaches: “An explicit clinical pathway must be developed for non-medical interventions, as well as a research strategy for evaluating their effectiveness.”

• Harm-benefit ratio: Because most teens place a higher value on preventing “irreversible progression of the development of secondary sexual characteristics” over avoiding uncertain long-term harms, puberty blockade use is justified — see SEGM fact-check 5 at the end of the table.

• Harm-benefit ratio: Because of the uncertain benefits and because the harms could be significant, PBs can only be used in clinical research settings with “very narrow indication,” i.e., for natal males as an explicit start of a transition pathway in order to stop irreversible pubertal changes, and subject to standard ethics approvals.

• Systematic evidence reviews:
• The guideline methods “Leitlinienreport” stated that a systematic evidence search was conducted which included search terms specific to the topic of PBs. However, the systematic search was stopped in August 2017, with non-systematic surveillance up until 2023. The body of evidence that was appraised has not been presented.
• The guideline also referenced the UK systematic review of puberty blockers. However, it inaccurately represented its key finding — see SEGM fact-check 1 at the end of the table.
• In practice, most of the recommendations were supported by primary studies, but the studies were not formally appraised for risk of bias — see SEGM fact-check 6 at the end of the table.

• Systematic evidence reviews:
• Original NICE systematic evidence review of puberty blockers conducted in 2020.
• New York systematic evidence review for PBs through April 2022, with non-systematic surveillance through January 2024.
• The York systematic review assessed 3,181 studies for eligibility, yielding 50 eligible studies, which were subsequently assessed for risk of bias using the modified Newcastle-Ottawa Scale.

• Consideration of other guidelines and recommendations:
• The review relied on WPATH Standard of Care 8 (SOC8) after 2017, asserting that SOC8 meets the German S3-level evidence-based guidelines, the highest possible level. This is not accurate — see SEGM fact-check 2 at the end of the table.
• The review also references the Endocrine Society 2017 (ES2017) guidelines, asserting that ES2017 meet the German S3-level evidence-based guidelines, the highest possible level. This is questionable — see SEGM fact-check 3 at the end of the table.
• The guideline also references the Cass Review and implies that it would concur with the German recommendation. This is inaccurate — see SEGM fact-check 4 at the end of the table.

• Consideration of other guidelines and recommendations:
• Analyzed 23 guidelines and clinical recommendations in two systematic reviews. Conducted two systematic reviews. Concluded, “Two international guidelines (World Professional Association for Transgender Health and Endocrine Society) formed the basis for most other guidance, influencing their development and recommendations.”
• For WPATH Standards of Care 8 (SOC8) and the Endocrine Society 2017 (ES2017) concluded, “Most clinical guidance lacks an evidence-based approach and provides limited information about how recommendations were developed. The WPATH and Endocrine Society international guidelines, which like other guidance lack developmental rigour and transparency have, until recently, dominated the development of other guidelines. Healthcare professionals should consider the lack of quality and independence of available guidance when utilising this for practice.”

1. NICE Systematic Evidence Review. The German guideline does not accurately describe the conclusion of the referenced NICE review. Rather than concluding that there are psychological benefits of puberty blockade, the review concluded just the opposite — “little change” — noting that the small reported changes are likely the result of poor study designs:

   “The results… suggest little change with GnRH analogues [PBs] from baseline to follow-up Studies that found differences in outcomes could represent changes that are either of questionable clinical value, or the studies themselves are not reliable and changes could be due to confounding, bias or chance.” “Evidence review: Gonadotrophin releasing hormone analogues for children and adolescents with gender dysphoria”, 2020, p. 13.

2. WPATH SOC8 Guidelines. Contrary to the assertion in the German guideline, WPATH SOC8 is not an evidence-based guideline for adolescents. The Adolescent section of SOC8 explicitly states that it was based on a narrative, rather than systematic, review. A recent systematic review commissioned by the Cass Review assessed SOC8 using AGREE II, a tool widely used by AWMF, which oversaw the guideline, and concluded that these guidelines “lack developmental rigor and transparency.” The guideline attained 35 out of 100 possible points on the “methodological rigor” domain, and 24 out of 100 possible points in the “applicability” domain. The German process also appraised SOC8 using AGREE II and gave it somewhat higher ratings, 55/100 for methodology and 28/100 for applicability.

   If properly appraised, WPATH SOC8 is unlikely to meet S3 guideline, highest possible level, due to failure to meet several of the current S3 requirements, e.g., DOLBI item 8 “systematic methods were used in the search for evidence”; item 9 “the criteria for the selection for the evidence are clearly described”; item 12 “the link between the recommendations and the underlying evidence is presented”; and a number of other criteria. A recent BMJ article concurred that SOC8 cannot be considered an evidence-based guideline.

3. The Endocrine Society 2017 guidelines (ES2017). Contrary to the assertion in the German guideline, the Endocrine Society 2017 guideline cannot be considered an evidence-based guideline for puberty blockade because it did not use a systematic review of evidence for pubertal suppression. S3 guidelines require that systematic methods were used to search for evidence, AGREE criterion 8.
   • Neither of the two ES2017 commissioned systematic reviews of evidence focused on adolescents or pubertal suppression.
   • The first systematic review, Maraka et al., 2017, analyzed the effects of cross-sex hormones on cardiometabolic outcomes of adults and is not applicable to the population of youth or the question of pubertal suppression.
   • The second systematic review, Sing-Ospina et al., 2017, analyzed the effects of gender-affirming endocrine interventions on bone health, but of the total of 13 studies, only 1 study dealt with pubertal suppression in youth. The rest of the studies were for cross-sex hormone use by adults. The one study, Klink et al., 2015, concluded that there were adverse effects of pubertal suppression on bone health of youth that were not attenuated even after initiation of cross-sex hormones. However, because the other 12 studies concerned mature adults’ use of cross-sex hormones and found no adverse effects on bone, the review concluded no adverse effects on bone, which the ES2017 recommendation for puberty suppression for youth ultimately relied upon.
   • Of note, no systematic evidence reviews of psychological effects of pubertal suppression on youth were conducted despite psychological benefits being the primary indication for puberty blockade in gender-dysphoric youth.
   • A recent systematic review commissioned by the Cass Review assessed ES2017 using AGREE II, a tool widely used by AWMF, which oversaw the guideline, and concluded that these guidelines, like WPATH, “lack developmental rigor and transparency.” The guideline attained 44 out of 100 possible points in the “methodological rigor” domain, and 22 out of 100 possible points in the “applicability” domain. The German process also appraised ES2017 using AGREE II and gave it similar ratings, 40/100 for methodology and 22/100 for applicability.
   • If properly appraised, ES2017 recommendations for adolescents are unlikely to meet the S3 level requirements, highest possible level, due to failure to meet key requirement 8: “systematic methods were used in the search for evidence.” This requirement was demonstrably not met for the population of adolescents, as no specific literature search of the literature about benefits or harms for adolescents was conducted. A recent BMJ article concurred that ES2017 recommendations cannot be considered evidence-based.
4. Cass Review. The German guideline appears to suggest that the Cass Report supports the notion that puberty blockers should be prescribed based on consensus since the evidence is of very low certainty: “The clinical recommendations derived from [UK NICE systematic review] have so far not included any proven clinical experience expertise, although this is explicitly formulated as a requirement in the Cass Review. There it is stated that as long as the evidence is uncertain, the broadest possible consensus of clinical experts should be sought as a basis for preliminary treatment recommendations.” The Cass Report did not support the use of puberty blockers based on “consensus,” and in fact strongly recommended decommissioning their use for gender dysphoria — the recommendation that NHS England recently accepted.
5. Patient values and preferences research into how patients and caregivers trade off benefits and risks of pubertal suppression in the short and long term has not been conducted. High-quality values and preferences research should be established on the basis of understanding the benefits, harms, and other desirable and undesirable consequences of different alternative interventions. Lack of evidence on the benefits and harms of interventions is one major hurdle for understanding values and preferences. Another concern is the cognitive development of children and adolescents, and their ability to appreciate benefits and harms of aspects of their lives that often do not typically come into consideration until later in life, e.g., desire for children and sexual function. The lack of quality research into this complex area makes the argument of teen “preference” for immediate physical changes over avoiding long-term harms deeply problematic.
6. Interpretation of individual study findings. Instead of relying on systematically appraised body of evidence, the review relies on findings from individual non-systematically searched studies. It does not appear that a structured appraisal of risk of bias of individual studies has been conducted. The discussion of study findings show a preference toward a positive interpretation of uncertain outcomes of youth transitions. For example:
   • The guidelines reference the Dutch research, de Vries et al., 2014, as evidence of no/low regret of youth transitions, by stating “Of the 55 people reported, no case of regret and/or detransition was reported.” It fails to mention the very short follow-up, average two years after surgery. It also does not mention several adverse affects among the original cohort of 70 which became reclassified as “non-completers,” including one transition-associated death, three instances of patients developing severe diabetes and obesity, and at least one apparent “stopped treatment” which could signal detransition.
   • The guidelines' analysis of several US studies, Tordoff et al., 2022 and Turban et al., 2020, fails to critically appraise the studies for methodological flaws, and does not discuss notable studies that contradict the conclusions of benefit of pubertal suppression, e.g., Carmichael et al., 2021, McPherson & Freedman, 2023.
   • This preference for positive interpretation could be mitigated by systematic search and synthesis of the relevant evidence for each outcome in question, and appraisal of quality of evidence using a widely accepted tool such as the GRADE system. The lack of transparent evidence synthesis and evidence appraisal is concerning.

• Cross-sex hormone treatment is indicated for any adolescent with the ICD-11 diagnosis of gender incongruence (GI) who experiences a “long-term desire” for the “physical changes expected as a result of hormone treatment.” No minimum age is specified.
• The DSM-5 “distress” criterion no longer applies, and distress appears to be understood not as impairment in functioning, but as the “desire to develop the gender-specific physical changes” not associated with natal puberty.
• No requirement of childhood-onset of gender incongruence: While “long-standing” gender incongruence is required, the minimum duration is deliberately not specified. The timing of the onset, pre-pubertal vs post-pubertal, appears unimportant; it is sufficient that the “distress developed or intensified after the onset of puberty.”
• A mental health assessment is required to establish “stable/persistent gender incongruence.” However, the guideline acknowledges a lack of “empirically validated individual criteria for the determination of a permanent stability/persistence of gender incongruence or gender dysphoria.”
• Ongoing psychotherapy not required. The decision of psychotherapy should be made on a case-by-case basis and prioritized with the patient. Treatment of other mental disorders is recommended but should not interfere with the body-modifying treatment.
• Parental involvement and co-consent are recommended. If the child desires cross-sex hormones but parents do not agree, and if counseling cannot reconcile the disagreement, child protective services and court systems may be called on to protect “best interests of the child.”

• Cross-sex hormone treatment for those diagnosed with Gender Dysphoria is currently available but with a new qualification of “extreme caution.” The minimum age is 16.
• Psychotherapy and psychosocial support should be the first line of treatment. There should be a clear clinical rationale for providing hormones for minors rather than waiting until an individual reaches 18.
• A new centralized team not directly involved in care of the young person would need to approve the medical necessity.
• NHS England will use the Cass recommendations to develop a policy on masculinizing/feminizing hormones for those aged 16 and older.

• Benefits:
• Claims systematic reviews show “favorable outcome of the measured parameters.”

“The systematic reviews of the British NICE (National Institute for Health and Care Excellence (NICE), …on the state of the evidence on puberty-blocking and gender reassignment hormone treatment.. in adolescence state that the studies available at the time of the reviews point overall in the direction of a favorable outcome after medical interventions for the mental health of adolescents with gender dysphoria.”

SEGM fact-check note: This is an inaccurate representation of the findings of the NICE review. See SEGM fact-check 1 at the end of the table.

• Quotes individual studies to assert there is evidence of benefit for the “overall package” of treatments, rather than evidence for benefits of cross-sex hormones:

“The reported data from previous non-controlled clinical cohort studies on hormonal interventions in adolescents with diagnosed gender incongruence or gender dysphoria provide consistent evidence for a favorable outcome of the measured parameters for mental health and life satisfaction if gender reassignment hormone treatment was at least part of the treatment.”

SEGM fact-check note: It is not appropriate to analyze results of individual studies. Instead, conclusions must be drawn from the entire body of evidence which was systematically searched and appraised for quality at each outcome level. See SEGM fact-check 2 at the end of the table.

• Benefits:
• Concludes there is no trustworthy evidence of psychological benefits of cross-sex hormone treatments, quoting the 2024 York systematic review:
• “There is a lack of high-quality research assessing the outcomes of hormone interventions in adolescents experiencing gender dysphoria/incongruence, and few studies that undertake long-term follow-up. No conclusions can be drawn about the effect on gender-related outcomes, body satisfaction, psychosocial health, cognitive development or fertility. Uncertainty remains about the outcomes for height/growth, cardiometabolic and bone health.”
• The evidence also did not support the notion that hormone treatment decreases risk of death by suicide.
• Notes about the small effect sizes and the possibility that the improvements may be short-lived:

“When a young person has been on puberty blockers, a short-term boost in mental wellbeing is to be expected when sex hormones are introduced....The start of long anticipated physical changes would be expected to improve mood, at least in the short term, and it is perhaps surprising that there is not a greater effect size. However, much longer term follow-up is needed to understand the full psychological impact of medical transition.”

• Harms:
• Physical harms: The recommendations for cross-sex hormone treatment are not accompanied with the evidence on the probability and severity of potential harms although a number of potential harms are mentioned, e.g., increased BMI, decreased HDL, increased risk of thrombosis, etc. The harm to fertility is also recognized.

• Harms:
• Physical harms: Systematic reviews evaluated a range of physical health outcomes. It found only one high-quality study that examined side effects. Inconsistent results were observed for height/growth, bone health and cardiometabolic effects. There was insufficient evidence to assess impact on fertility; no study assessed fertility in birth-registered females. Most studies included adolescents who received puberty suppression, making it difficult to determine the effects of hormones alone.

• Psychological harms from overtreatment:
  • Diagnostic reliability: Acknowledges a lack of predictive validity of the ICD-11 diagnosis of gender incongruence, and a lack of validated criteria to predict persistence. However, it is not viewed as a risk for overtreatment.
  • Gay youth: Acknowledges sexual orientation may be related to persistent gender incongruence in some adolescents, but recommends cross-sex hormone treatment regardless of sexual orientation.
  • Autistic youth: Although the guidelines recognize a high rate of co-occurrence between autistic diagnosis and gender incongruence, there is no apparent concern over potential overdiagnosis or overtreatment of autistic youth.

• Psychological harms from overtreatment:
  • Diagnostic reliability: Recognizes that the diagnoses of “gender dysphoria” (DSM-5) or “gender incongruence” (ICD-11) lack predictive validity. It is unknown whether that young person will have longstanding gender incongruence in the future, or whether medical intervention will be the best option for them.
  • Gay and autistic youth who frequently exhibit gender non-conforming behaviors and are susceptible to developing GD/GI. There is a concern with inappropriately treating such youth with gender transition.

• Youth with fluid/evolving identities: Though the guidelines recognize the rise of a non-binary identity and a lack of understanding how such identities may develop, the guidelines still recommend cross-sex hormone treatment for children reporting non-binary gender identity.

• Youth with fluid/evolving identities: Recognizes that nonbinary identities are on the rise, and that identity in youth is still developing, which raises questions about medical interventions.

• Detransition is recognized as a phenomenon but assumed to be rare and not a signal of overtreatment/harm.

• Detransition: The percentage of people treated with hormones who subsequently detransition remains unknown due to the lack of long-term follow-up studies, although there is suggestion that numbers are increasing.

• Issues related to consent: Recognizes that the irreversible nature of many hormone-induced changes, including risk to fertility and sexual function, make it imperative that the young person is capable of consent. In the event that a minor cannot consent, legal guardians should not be allowed to consent on the minor's behalf. Instead, the minor's own capacity to consent should be developed.

• Issues related to consent: Recognizes a key barrier to informed decision making, since poor evidence basis makes it challenging to provide adequate information on which a young person and their family can make an informed choice.

• There are no accepted alternatives to hormone treatment: “there is a lack of a justifiable evidence-based alternative treatment option in the sense of a previously established and proven treatment.”
• Because adolescents have associated desire to develop “the gender-specific physical changes expected as a result of hormone treatment” over avoiding uncertain long-term harms, cross-sex hormone treatment is justified.

• Urges the development of evidence base for alternative treatment approaches: “An explicit clinical pathway must be developed for non-medical interventions, as well as a research strategy for evaluating their effectiveness.”

• Harm-benefit ratio: While the evidence is recognized as uncertain, the benefits are assumed to outweigh harms, while the principles of self-determination of minors should guide the decision to treat with cross-sex hormones, as long as minors are deemed capable of consent.

• Harm-benefit ratio: There is insufficient and/or inconsistent evidence about the risks and benefits of hormone interventions in this population.

• Systematic evidence reviews:
• The guideline methods “Leitlinienreport” referenced a systematic evidence search which included search terms specific to the topic of hormone treatment. The systematic search was stopped in August 2017.
• The guideline discussed a number of studies but did not formally appraise them for risk of bias.
• The guideline references the evidence of “whole package”, which included psychotherapy and hormone treatment, rather than evidence on hormone treatment.

• Systematic evidence reviews:
  • The Cass Review commissioned a systematic evidence review for cross-sex hormones, systematically searching for studies through April 2022.
  • The systematic review assessed 3,181 studies for eligibility, yielding 53 eligible studies, which were subsequently assessed for risk of bias using the modified Newcastle-Ottawa Scale.

• Consideration of other guidelines and reviews:
• The review relied on WPATH Standard of Care 8 (SOC8) after 2017, asserting that SOC8 meets the German S3-level evidence-based guidelines, the highest possible level.
• The review also references Endocrine Society 2017 (ES2017) guidelines, asserting their equivalence to German S3-level evidence-based guidelines, the highest possible level.
• The guideline also references Cass Review, with the incorrect implication that Cass Review would concur with the German recommendation.

See SEGM fact-check notes 3–5 at the end of the table.

• Consideration of other guidelines and recommendations:
• Analyzed 23 guidelines and clinical recommendations in two systematic reviews. Conducted two systematic reviews. Concluded, “Two international guidelines (World Professional Association for Transgender Health and Endocrine Society) formed the basis for most other guidance, influencing their development and recommendations.”
• For WPATH Standards of Care 8 (SOC8) and the Endocrine Society 2017 (ES2017) concluded, “Most clinical guidance lacks an evidence-based approach and provides limited information about how recommendations were developed. The WPATH and Endocrine Society international guidelines, which like other guidance lack developmental rigour and transparency have, until recently, dominated the development of other guidelines. Healthcare professionals should consider the lack of quality and independence of available guidance when utilising this for practice.”

1. NICE systematic evidence review. The German guideline does not accurately describe the conclusion of the referenced 2020 NICE review for cross-sex hormones. Rather than concluding “favorable outcomes,” the 2020 NICE cross-sex hormones review noted:

   “The key limitation to identifying the effectiveness and safety of gender-affirming hormones for children and adolescents with gender dysphoria is the lack of reliable comparative studies. All the studies included in the evidence review are uncontrolled observational studies, which are subject to bias and confounding and were of very low certainty using modified GRADE. A fundamental limitation of all the uncontrolled studies included in this review is that any changes in scores from baseline to follow-up could be attributed to a regression-to-the mean...Any potential benefits of gender-affirming hormones must be weighed against the largely unknown long-term safety profile of these treatments in children and adolescents with gender dysphoria.”

2. Using results from individual studies: The recommendations on cross-sex hormone treatment should be informed by systematically appraising the entire body of evidence regarding each specific outcome. Further, discussing individual findings from studies, without assessing the study for risk of bias, is not appropriate, as any given study's result may not be trustworthy.

3. WPATH SOC8 Guidelines. Contrary to the assertion in the German guideline, WPATH SOC8 is not an evidence-based guideline for adolescents. The Adolescent section of SOC8 explicitly states that it was based on a narrative, rather than systematic, review. A recent systematic review commissioned by the Cass Review assessed SOC8 using AGREE II, a tool widely used by AWMF, which oversaw the guideline, and concluded that these guidelines “lack developmental rigor and transparency.” The guideline attained 35 out of 100 possible points on the “methodological rigor” domain, and 24 out of 100 possible points in the “applicability” domain. The German process also appraised SOC8 using AGREE II and gave it somewhat higher ratings, 55/100 for methodology and 28/100 for applicability.

   If properly appraised, WPATH SOC8 is unlikely to meet S3 guideline, highest possible level, due to failure to meet several of the current S3 requirements, e.g., DOLBI item 8 “systematic methods were used in the search for evidence”; item 9 “the criteria for the selection for the evidence are clearly described”; item 12 “the link between the recommendations and the underlying evidence is presented”; and a number of other criteria. A recent BMJ article concurred that SOC8 cannot be considered an evidence-based guideline.

4. The Endocrine Society 2017 guidelines (ES2017). Contrary to the assertion in the German guideline, the Endocrine Society 2017 guideline cannot be considered an evidence-based guideline for puberty blockade because it did not use a systematic review of evidence for pubertal suppression. S3 guidelines require that systematic methods were used to search for evidence, AGREE criterion 8.
   • Neither of the two ES2017 commissioned systematic reviews of evidence focused on adolescents.
   • The first systematic review, Maraka et al., 2017, analyzed the effects of cross-sex hormones on cardiometabolic outcomes of adults and is not applicable to the population of youth.
   • The second systematic review, Sing-Ospina et al., 2017, analyzed the effects of gender-affirming endocrine interventions on bone health, but of the total of 13 studies, only 1 study dealt with cross-sex hormones in youth; the rest of the studies were for cross-sex hormone use by adults. The one study, Klink et al., 2015, concluded that there were adverse effects of pubertal suppression on bone health of youth that were not attenuated even after initiation of cross-sex hormones. However, because the other 12 studies concerned mature adults’ use of cross-sex hormones and found no adverse effects on bone, the review concluded no adverse effects on bone, which the ES2017 recommendations for endocrine interventions for youth ultimately relied upon.
   • A recent systematic review commissioned by the Cass Review assessed ES2017 using AGREE II, a tool widely used by AWMF, which oversaw the guideline, and concluded that these guidelines, like WPATH, “lack developmental rigor and transparency.” The guideline attained 44 out of 100 possible points in the “methodological rigor” domain, and 22 out of 100 possible points in the “applicability” domain. The German process also appraised ES2017 using AGREE II and gave it similar ratings, 40/100 for methodology and 22/100 for applicability.
   • If properly appraised, ES2017 recommendations for adolescents are unlikely to meet the S3 level requirements, highest possible level, due to failure to meet the S3 level key requirement 8: “systematic methods were used in the search for evidence.” This requirement was demonstrably not met for the population of adolescents, as no specific literature search of the literature about benefits or harms for adolescents was conducted. A recent BMJ article concurred that ES2017 recommendations cannot be considered evidence-based.
5. The Cass review revealed that most included studies on cross-sex hormones included adolescents who received puberty suppression, making it difficult to determine the effects of hormones alone. It is not appropriate to draw conclusions about cross-sex hormone treatment based on the “whole package” of treatment, which included various steps of medical transition, and was confounded by psychological interventions.