Klinefelter syndrome is a genetic condition in which a person is born with an extra X chromosome: a 47,XXY karyotype instead of the usual 46,XY. That extra copy usually goes hand in hand with an attenuated male sexual development and a low testosterone production, what doctors call hypogonadism. And here a question with direct clinical implications arises: when a person with Klinefelter also presents gender incongruence and seeks feminizing affirmation therapy, is the same treatment regimen needed as in other people? A new study from the Center of Expertise on Gender Dysphoria in Amsterdam, published in Andrology, provides a practical answer that had been little explored until now.
A genetic condition that complicates the hormonal equation
Klinefelter syndrome is characterised, among other things, by testes that produce less testosterone than normal. Precisely because of that, some small studies suggested that gender incongruence might be somewhat more frequent in these people. However, feminizing hormone therapy in this group had barely been described in the medical literature: a gap the Dutch team set out to fill.
Half a century of clinical history reviewed
The authors reviewed the data of every person with Klinefelter syndrome who had attended the Center of Expertise on Gender Dysphoria at Amsterdam UMC between February 1972 and May 2025. They found 8 people with the condition, which amounts to 0.12% of the total cohort seen in that period. The median age at Klinefelter diagnosis was 25.3 years, and at arrival at the gender clinic, 45.3 years.
The central finding: estradiol alone can be enough
Of the 8 people, 6 were using estradiol as part of their feminizing therapy. Most striking is that none of the 5 who kept their testes needed testosterone blockers, with a median follow-up of 5.4 years. The reason is elegant and biologically sound: because Klinefelter already causes a low testosterone production at baseline, estradiol on its own is enough to suppress it, with no need to add blocking drugs.
Fewer drugs, same goal
The authors’ conclusion is that, in people with Klinefelter syndrome and gender incongruence, estradiol monotherapy may be a suitable first-line treatment, avoiding the systematic use of testosterone blockers. It is a clinical nuance that simplifies treatment, reduces the pharmacological burden and tailors affirmation therapy to each person’s biological particularities. The study also finds that the prevalence of Klinefelter in its cohort does not exceed that of the general population.
Why it matters
This work illustrates how genetics —an extra X chromosome— modulates the way hormonal affirmation treatment should be approached. Every chromosomal or sex development condition has its own rules, and recognising them allows for more precise, safer and personalised care for people with gender incongruence. The authors call, in any case, for studies with larger and more diverse samples to confirm these findings.
Source: Kroon M, Klooker TK, Hannema SE, Den Heijer M. Feminizing Therapy in People With Klinefelter Syndrome and Gender Incongruence: Considerations for Treatment Without Testosterone Blockers. Andrology. 2026. doi:10.1111/andr.70290.
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