Impact of gender-affirming hormone therapy on the endocrine axis and male germ cells

Gender-affirming hormone therapy (GAHT) facilitates the desired phenotypic changes consistent with an individual’s gender identity. However, inter-individual variability in treatment effects has been reported at the endocrine and testicular tissue levels. To address the hypothesis that treatment effects are not homogeneous, we selected 24 persons from a cohort of 453 persons assigned male at birth, based on a similar dose of cyproterone acetate (Androcur®, 10 or 12.5 mg/day). Principal component analysis and hierarchical clustering on principal components were performed considering clinical parameters and identified four distinct clusters. Cluster 1 (n = 3) was characterized by the presence of tubules with round or elongated spermatids, the highest numbers of reserve spermatogonia (Adark) and cells positive for UTF1, PIWIL4, NANOS3 and KIT. Persons in Cluster 2 (n = 4) showed a high percentage of tubules with spermatogonia as the most advanced germ cell type and high testosterone levels that were not suppressed to the desired female values. Persons in Cluster 3 (n = 10) had low testosterone but elevated AMH levels and suppressed spermatogenesis to the spermatogonial level. Finally, persons in Cluster 4 (n = 7) had the highest number of Sertoli cell-only tubules and tubular shadows, as well as the highest person age. Despite homogeneous inclusion criteria, we observed heterogeneous treatment effects. Consultation regarding contraceptives, as well as fertility preservation, therefore has to be considered in counselling, ideally prior to initiation of GAHT.