The Dutch protocol: origins and follow-up data

Where did puberty blockers for adolescents come from, and what did the Amsterdam follow-up studies actually show?

Puberty blockers did not originate as a treatment for adolescent gender distress. Gonadotrophin-releasing hormone agonists, usually abbreviated to GnRH agonists or GnRHa, were already used in paediatric endocrinology to suppress unusually early puberty, and in other branches of medicine for hormone-sensitive conditions. The Dutch innovation was to apply these drugs to adolescents diagnosed with gender identity disorder, later termed gender dysphoria, as part of a staged pathway towards medical transition.

Background

Puberty blockers did not originate as a treatment for adolescent gender distress. Gonadotrophin-releasing hormone agonists, usually abbreviated to GnRH agonists or GnRHa, were already used in paediatric endocrinology to suppress unusually early puberty, and in other branches of medicine for hormone-sensitive conditions. The Dutch innovation was to apply these drugs to adolescents diagnosed with gender identity disorder, later termed gender dysphoria, as part of a staged pathway towards medical transition.

The central figures were psychologist Peggy Cohen-Kettenis and colleagues working first in Utrecht and then in Amsterdam. The first published account, by Cohen-Kettenis and van Goozen in 1998, was a case report of one 13-year-old female patient given an LHRH agonist and psychotherapy before later sex reassignment. A later 22-year follow-up described the same case as the first published use of this approach. It was a clinical innovation built around an individual patient, not the result of a randomised clinical trial (Cohen-Kettenis and van Goozen, 1998; Cohen-Kettenis et al., 2011). ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/9879847/?utm_source=openai))

By 2006, Henriette Delemarre-van de Waal and Cohen-Kettenis had set out what became known internationally as the Dutch Protocol. Its original safeguards were notably restrictive: a DSM-IV-TR diagnosis, lifelong and intense gender dysphoria, psychological stability, parental or environmental support, and careful exploration of the wish for sex reassignment. Blockers were presented as support for diagnosis rather than the final treatment. If the young person no longer sought transition, puberty suppression could be stopped; if the wish persisted, cross-sex hormones could be introduced from age 16 (Delemarre-van de Waal and Cohen-Kettenis, 2006). ([pure.amsterdamumc.nl](https://pure.amsterdamumc.nl/en/publications/clinical-management-of-gender-identity-disorder-in-adolescents-a-/))

What the documents say

The intervention was a pathway, not a stand-alone treatment

The Dutch documents describe a sequence: psychological assessment, suppression of endogenous puberty from approximately Tanner stage B2–3 or G3–4, then cross-sex hormones, followed in many cases by surgery after adulthood. This matters when reading the outcome literature. The best-known Amsterdam follow-up did not test blockers against ordinary puberty, psychotherapy, watchful waiting, or another treatment. Nor did it test blockers alone. It examined outcomes after a package of interventions administered over several years.

The 2006 protocol itself recorded uncertainties. Its authors reported reduced height velocity and bone maturation during suppression. They stated that total bone density remained in roughly the same range during blockade and increased after cross-sex hormones. They also proposed suppression as a diagnostic aid: a period in which the adolescent could continue or abandon the transition pathway. Those claims were clinical expectations and preliminary observations, not proof of long-term safety or efficacy (Delemarre-van de Waal and Cohen-Kettenis, 2006). ([pure.amsterdamumc.nl](https://pure.amsterdamumc.nl/en/publications/clinical-management-of-gender-identity-disorder-in-adolescents-a-/))

The 2011 study: improvements in some measures, not resolution of dysphoria

De Vries and colleagues’ 2011 prospective study reported on the first 70 eligible adolescents who received GnRHa between 2000 and 2008. Participants were assessed before blockers and again shortly before cross-sex hormones. Behavioural and emotional problems and depressive symptoms decreased, while clinician-rated general functioning improved significantly. However, anxiety and anger did not significantly change, and gender dysphoria did not resolve during puberty suppression. The study was before-and-after: every participant received the intervention, so changes cannot confidently be attributed to blockers rather than time, family support, clinical attention, selection of unusually stable patients, or other factors (de Vries et al., 2011). ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/20646177/?utm_source=openai))

The 2014 study: favourable outcomes after the whole pathway

The 2014 paper followed 55 young adults assessed at three points: before blockers, when cross-sex hormones began, and at least one year after surgery. Their mean ages were 13.6 years at baseline, 16.7 years at hormone initiation and 20.7 years at final follow-up. The authors found improved psychological functioning over time, reduced gender dysphoria after subsequent hormones and surgery, and wellbeing scores comparable with or better than reference samples on several measures. They concluded that a multidisciplinary protocol offered selected young people an opportunity to become well-functioning adults (de Vries et al., 2014). ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25201798/?utm_source=openai))

That conclusion needs careful wording. The final assessment came after puberty suppression, cross-sex hormones, social transition and surgery. It therefore supports the proposition that these 55 selected completers reported favourable outcomes after the full Dutch pathway. It does not establish that blockers themselves caused those outcomes, that the pathway benefits a wider contemporary referral population, or that comparable outcomes would not have occurred with different care.

The 2022 continuation study

Van der Loos and colleagues used Dutch clinical and prescription data to examine continuation of gender-affirming hormones among people who had first received puberty suppression before age 18 and then progressed to hormones. Of 720 people in that defined group, 704, or 98%, were still using hormones at the end of data collection. This is an important record of treatment continuation, but it is not a measure of overall desistance, detransition, regret, physical health, fertility, sexual function or comparative mental-health benefit. By design, it excludes young people who received blockers but did not proceed to hormones (van der Loos et al., 2022). ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36273487/?utm_source=openai))

The positions

Supporters of the Dutch approach argue that puberty suppression was developed precisely for a narrow group: adolescents with early, persistent and severe distress, assessed by experienced multidisciplinary teams. They regard the 2011 and 2014 findings as evidence that carefully selected patients can do well, and they argue that unwanted pubertal development may itself cause serious and lasting distress. Amsterdam UMC responded to the Cass Review in April 2024 by welcoming its call for multidisciplinary provision and further research, while disagreeing that the evidence for blockers was insufficient. The Dutch Health Council’s 2026 advisory report similarly stated that available data are limited but saw no reason to withhold hormonal treatment within the Netherlands’ extensive assessment pathway (Amsterdam UMC, 2024; Health Council of the Netherlands, 2026). ([amsterdamumc.org](https://www.amsterdamumc.org/nl/vandaag/een-reactie-van-amsterdam-umc-op-de-cass-review-over-transgenderzorg.htm?utm_source=openai))

Critics accept that puberty can be suppressed pharmacologically, but dispute the claim that this establishes a favourable risk-benefit balance for gender-distressed adolescents. They emphasise that the Dutch studies were small, observational and conducted in a highly selected cohort, while the most prominent positive findings were measured after later hormones and surgery. The University of York systematic review found no basis for conclusions about effects on gender dysphoria, mental health, psychosocial health or cognitive development; it found evidence that bone health and height may be compromised during treatment (Taylor et al., 2024). Sweden’s SBU reached a similar conclusion in 2022: the evidence was insufficient to determine effects on dysphoria, psychosocial outcomes or cognitive function. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/38594047/))

Interpretation

Beyond Gender’s reading is that the Dutch Protocol has often been represented as though it were validated by decisive evidence for a reversible “pause”. The primary documents show something more limited. It began with a case report, then a carefully managed clinical pathway for a small and unusually selected group. Its best-known follow-up studies found improvements in some outcomes and favourable adult functioning among patients who completed a sequence of blockers, hormones and surgery. Those are observations worth recording, not proof that the first step was independently beneficial or low-risk for all adolescents.

The high progression from blockers to hormones is also open to more than one reading. Supporters may see it as confirmation that clinicians selected persistent cases accurately. Critics may see it as evidence that suppression rarely operated as a neutral period for reconsideration in practice. The figure alone cannot resolve that disagreement. It demonstrates continuation among those who entered the hormonal pathway; it does not demonstrate informed satisfaction, absence of regret, or the counterfactual outcome had puberty not been medically interrupted.

Open questions

Several questions remain unanswered by the Amsterdam record. What were the long-term physical, sexual, reproductive and psychological outcomes for all adolescents offered assessment, including those declined, those who stopped blockers, and those lost to clinical follow-up? How did outcomes differ between the original early-onset, psychologically stable cohort and later referral populations? What proportion experienced regret, detransition or treatment-related harm after leaving specialist services?

There is also a basic causal question. What would have happened to comparable adolescents given comprehensive psychological and family support without medical suppression? Since the Dutch studies did not include such a comparison group, neither benefit nor harm can be estimated with the confidence normally expected before a paediatric intervention becomes established practice. The Dutch Protocol remains historically influential, but its evidential limits should be stated as clearly as its reported successes.

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