Feminizing Therapy in People With Klinefelter Syndrome and Gender Incongruence: Considerations for Treatment Without...

Klinefelter syndrome (KS; 47, XXY) usually involves male sex development and gender identity. Small studies suggest gender incongruence may be more common in KS, but feminizing gender‑affirming hormone therapy in this group has been scarcely reported.

To evaluate current feminizing hormone therapy in individuals with KS and the number of individuals with KS attending our gender clinic.

We conducted a care evaluation of individuals with KS referred to the Center of Expertise on Gender Dysphoria (Amsterdam UMC) between February 1972 and May 2025, collecting data on KS diagnosis, testosterone use, referral age, feminizing hormone therapy, and hormone concentrations.

Eight (0.12%) people had KS. Median age at KS diagnosis was 25.3 years (IQR 16.9-37.5, n = 8), and at gender clinic intake 45.3 years (IQR 34.2-52.2, n = 8). Among estradiol users, median age was 45.7 years (IQR 42.4-57.1, n = 6). None of those retaining their testes use testosterone blockers (follow‑up: median 5.4 years (3.6-7.7), n = 5).

In KS, estradiol alone may sufficiently suppress testosterone. KS prevalence in our cohort does not exceed that of the general population.

Given KS‑related hypogonadism, estradiol monotherapy may be an appropriate first‑line feminizing hormone therapy, avoiding routine use of testosterone blockers.