Testis Molecular Pathways in CAIS Unveil Testosterone/Estradiol on Germ Cell Tumor Risk in Non-Obstructive Azoospermia.
Academic Article
Overview
abstract
CONTEXT: Non-obstructive azoospermia (NOA) is the most severe form of male infertility affecting 1% of all men, with a clinical picture characterized by no sperm production, hyalinization of the basal membrane of the seminiferous tubules, primary hypogonadism and earlier onset of age-related comorbidities compared with fertile men. NOA is also characterized by etiologic heterogeneity and the non-genetic form has higher incidence of testicular germ cell cancer (TGCC) compared to the forms with genetic abnormalities. OBJECTIVE: We aimed to establish molecular pathways in the testicular somatic cells that are either shared or specific for non-genetic and genetic forms of NOA, as Complete Androgen Insensitivity Syndrome (CAIS) and Klinefelter Syndrome (KS). METHODS: Single cell RNAseq of the testicular somatic cells of an individual with CAIS, and data integration with published scRNA-seq datasets of testis with normal spermatogenesis, NOA, KS and germinal testicular cancer. Detailed clinical data of the CAIS patient, Testosterone and Estradiol levels in age-matched men (120 fertile, 155 infertile, 116 NOA, 18 KS, and 343 with TGCC). RESULTS: In all conditions, Leydig cells are immature and senescent, but those of NOA associated with primary hypogonadism depict the highest expression of transcripts associated with the seminoma microenvironment, including estrogen-responsive genes. An oncological transcriptional signature in the Leydig cells has been confirmed at the systemic levels by showing a prognostic role of the decreasing Testosterone/Estradiol ratio for TGCC in men with non-genetic NOA. CONCLUSION: This study offers molecular insights into the prediction of TGCC in persons with NOA and eligibility for the use of aromatase inhibitors.
