Жодне нове дослідження препаратів, що блокують статеве дозрівання, не відповіло критеріям якості після NICE

За межами NICE: Оновлений систематичний огляд наявних доказів застосування фармакологічних засобів блокади статевого дозрівання та перехресних статевих гормонів у неповнолітніх з ґендерною дисфорією

Систематичні огляди доказів Блокатори статевого дозрівання Клінічні настанови та політика

Authors: Florian D. Zepf, Laura König, Anna Kaiser, Carolin Ligges, Marc Ligges, Veit Roessner, Tobias Banaschewski, Martin Holtmann
Journal: Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie
Year: 2024
Source: pubmed.ncbi.nlm.nih.gov/38410090

Summary

In 2020 England's NICE found the evidence on puberty blockers and cross-sex hormones for under-18s with gender dysphoria to be of very low quality. This German team repeated NICE's search method for studies published from July 2020 to September 2023. No new puberty-blocker study met NICE's standards. Only two small hormone studies qualified. Both were brain-scan studies of trans boys, not designed to test whether treatment helps, and both were rated low quality. Many other studies were left out because they had no comparison group. The authors conclude the evidence does not show that dysphoria or mental health improve much with treatment. They suggest talking therapy for distress, and say any hormone treatment should happen within research. This matches other reviews. But the 'no new studies' result depends on strict rules, and several authors had publicly opposed Germany's guideline.

Key findings

Команда шукала в чотирьох великих дослідницьких базах даних дослідження, опубліковані між липнем 2020 і вереснем 2023 року, використовуючи ті самі питання й результати, що й NICE у 2020 році: дисфорія, психічне здоров'я, якість життя, образ тіла та повсякденне функціонування.
Жодне нове дослідження блокаторів пубертату, опубліковане після NICE, не відповідало його стандартам за жодним із головних результатів.
Лише два нові дослідження гормонів протилежної статі відповідали: одне дослідження мозку за допомогою сканування, що порівнювало 19 трансхлопців на тестостероні з 23 не на ньому, і друге подібне. Обидва були малими, включали лише трансхлопців і були оцінені як низької якості.
Ще 29 досліджень гормонів і 25 оглядів було знайдено, але виключено, головно через те, що вони не порівнювали молодь, яка отримувала лікування, з тією, що ні.
Автори повторно перевірили 12 досліджень, які, за словами критиків, NICE помилково виключив, і погодилися з NICE. Ці дослідження не ставили чіткого питання порівняння, не повідомляли результатів блокаторів окремо або повторно використовували вже вивчені групи пацієнтів.
Автори роблять висновок, що наявні докази не показують, що гендерна дисфорія чи психічне здоров'я значно покращуються від блокаторів чи гормонів і що довгострокових досліджень бракує.
Вони рекомендують психотерапію для полегшення дистресу. Будь-яке використання блокаторів чи гормонів має слідувати за ретельною оцінкою та лікуванням інших проблем психічного здоров'я і відбуватися в рамках досліджень, як в Англії.

Abstract

Beyond NICE: Updated Systematic Review on the Current Evidence of Using Puberty Blocking Pharmacological Agents and Cross-Sex-Hormones in Minors with Gender Dysphoria Abstract: Objective: The suppression of physiological puberty using puberty-blocking pharmacological agents (PB) and prescribing cross-sex hormones (CSH) to minors with gender dysphoria (GD) is a current matter of discussion, and in some cases, PB and CSH are used in clinical practice for this particular population. Two systematic reviews (one on PB, one on CSH treatment) by the British National Institute for Clinical Excellence (NICE) from 2020 indicated no clear clinical benefit of such treatments regarding critical outcome variables. In particular, these two systematic NICE reviews on the use of PB and CSH in minors with GD detected no clear improvements of GD symptoms. Moreover, the overall scientific quality of the available evidence, as discussed within the above-mentioned two NICE reviews, was classified as "very low certainty" regarding modified GRADE criteria. Method: The present systematic review presents an updated literature search on this particular topic (use of PB and CSH in minors with GD) following NICE principles and PICO criteria for all relevant new original research studies published since the release of the two above-mentioned NICE reviews (updated literature search period was July 2020-August 2023). Results: The newly conducted literature search revealed no newly published original studies targeting NICE-defined critical and important outcomes and the related use of PB in minors with GD following PICO criteria. For CSH treatment, we found two new studies that met PICO criteria, but these particular two studies had low participant numbers, yielded no significant additional clear evidence for specific and clearly beneficial effects of CSH in minors with GD, and could be classified as "low certainty" tfollowing modified GRADE criteria. Conclusions: The currently available studies on the use of PB and CSH in minors with GD have significant conceptual and methodological flaws. The available evidence on the use of PB and CSH in minors with GD is very limited and based on only a few studies with small numbers, and these studies have problematic methodology and quality. There also is a lack of adequate and meaningful long-term studies. Current evidence doesn't suggest that GD symptoms and mental health significantly improve when PB or CSH are used in minors with GD. Psychotherapeutic interventions to address and reduce the experienced burden can become relevant in children and adolescents with GD. If the decision to use PB and/or CSH is made on an individual case-by-case basis and after a complete and thorough mental health assessment, potential treatment of possibly co-occurring mental health problems as well as after a thoroughly conducted and carefully executed individual risk-benefit evaluation, doing so as part of clinical studies or research projects, as currently done in England, can be of value in terms of generation of new research data. The electronic supplement (ESM) 1 is an adapted and abreviated English version of this work.

Conclusion

The currently available studies on the use of PB and CSH in minors with GD have significant conceptual and methodological flaws. The available evidence on the use of PB and CSH in minors with GD is very limited and based on only a few studies with small numbers, and these studies have problematic methodology and quality. There also is a lack of adequate and meaningful long-term studies. Current evidence doesn't suggest that GD symptoms and mental health significantly improve when PB or CSH are used in minors with GD. Psychotherapeutic interventions to address and reduce the experienced burden can become relevant in children and adolescents with GD. If the decision to use PB and/or CSH is made on an individual case-by-case basis and after a complete and thorough mental health assessment, potential treatment of possibly co-occurring mental health problems as well as after a thoroughly conducted and carefully executed individual risk-benefit evaluation, doing so as part of clinical studies or research projects, as currently done in England, can be of value in terms of generation of new research data.

Methodological limitations

Strict rules about comparison groups: Studies were only counted if they compared treated young people with untreated ones or another treatment, so 29 hormone studies were left out. 'No new studies' partly reflects these rules, not a total lack of new research.
Copies a disputed method: The review uses NICE's 2020 method, which critics (for example Eckert, 2021) said wrongly left out relevant studies. The authors re-checked and agreed with NICE's choices, but the dispute remains.
The studies that counted weren't built to test benefit: Both hormone studies that qualified were small brain-scan studies of trans boys only. They say very little directly about dysphoria or mental health.
No publicly registered plan: The review was not registered in advance, and details such as whether two people checked each study separately are only in extra files. This makes it harder to judge whether others could repeat it.
Limited search and language: Only four databases were searched, with no search of reports outside journals. The main text is in German with only a short English summary, so fewer international readers can check it.
Quality ratings done by the same team: The authors rated how trustworthy the evidence was themselves, and no outside group repeated those ratings.
Authors' earlier public stance: Lead author Zepf left Germany's treatment-guideline group in 2022 over ethical concerns and later led a public statement opposing the draft guideline. Readers should know the review was written during that dispute, though its findings agree with independent reviews such as York and the Cass Review.
Journal editor is a co-author: Co-author Martin Holtmann is chief editor of the journal that published the review and is paid by its publisher, Hogrefe. The paper does not explain how the review was kept independent during editing.
Drug-company fees: Several authors report consulting or speaking fees from drug companies such as Takeda and Medice. They say none related to puberty blockers, but Zepf gave two Takeda-supported talks on the evidence for blockers and hormones.
'No evidence of benefit' is not 'proof of no benefit': The conclusion reflects uncertainty, not a shown lack of effect. The review also does not measure harms.

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Summary

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Abstract

Conclusion