Partial rejuvenation of the spermatogonial stem cell niche after gender-affirming hormone therapy in trans women.

Sertoli cells in trans women undergoing GAHT showed partial dedifferentiation, marked by co-expression of androgen receptor (AR) and anti-Müllerian hormone (AMH), mirroring the situation in peripubertal boys.

• In adult male controls, AMH expression was absent while AR was expressed; in trans women, both AR and AMH were co-expressed.
• This co-expression pattern is characteristic of immature/peripubertal Sertoli cells rather than mature adult Sertoli cells.
• The study included 106 trans women who underwent standardized GAHT comprising estrogens and cyproterone acetate.
• Histological and transcriptomic analyses were used to characterize this dedifferentiation.

Leydig cells in trans women exhibited a distribution analogous to peripubertal tissue, accompanied by reduced insulin-like factor 3 (INSL3) expression.

• INSL3 is a marker of mature Leydig cell function and its reduced expression indicates functional immaturity.
• The Leydig cell distribution pattern resembled that seen in peripubertal boys rather than adult males.
• This finding was identified through both histological analysis and transcriptomic profiling.
• The changes in Leydig cells are consistent with the testosterone suppression induced by cyproterone acetate and estrogen therapy.

Peritubular myoid cells in trans women showed disturbed expression patterns of alpha-smooth muscle actin 2 (ACTA2) despite most cells still expressing the marker.

• Most peritubular myoid cells expressed alpha-smooth muscle actin 2 (ACTA2), a marker of contractile peritubular myoid cells.
• However, the expression pattern was disturbed compared to adult male controls.
• Peritubular myoid cell changes occurred alongside fibrosis particularly evident in the tubular wall.
• Tubular lumen was collapsing in most participants, suggesting structural compromise of the seminiferous tubules.

A complete spermatogenic arrest was observed in all 106 trans women included in the study.

• Spermatogenic arrest was observed in all participants regardless of duration of GAHT.
• The study cohort comprised 106 trans women who underwent standardized GAHT.
• Fibrosis was particularly evident in the tubular wall and lumen collapse was observed in most participants.
• These structural changes in the seminiferous tubules are consistent with the observed spermatogenic arrest.

Transcriptomic profiling of transgender testicular tissue confirmed partial rejuvenation of the spermatogonial stem cell niche and detected active inflammation processes.

• The transcriptomic profile confirmed a loss of mature characteristics in the spermatogonial stem cell niche, described as 'partial rejuvenation.'
• Inflammation processes were detected in the transcriptomic analysis of trans women's testicular samples.
• The transcriptomic findings corroborated the histological observations of dedifferentiation of somatic cells.
• The combination of rejuvenation and inflammatory signals represents a distinct testicular environment created by GAHT.

The study characterized the testicular environment of trans women using both histological and transcriptomic analysis of samples from 106 participants on standardized GAHT.

• GAHT consisted of estrogens and cyproterone acetate as a standardized protocol.
• Orchidectomized testes obtained as medical waste material were used for analysis.
• Both histological and transcriptomic approaches were employed to characterize the spermatogonial stem cell niche.
• The sample size of 106 trans women represents a substantial cohort for this type of analysis.