Testis Molecular Pathways in CAIS Unveil Testosterone/Estradiol on Germ Cell Tumor Risk in Non-Obstructive...

Area of Science:

• Reproductive Endocrinology
• Oncology
• Male Infertility Research

Background:

• Non-obstructive azoospermia (NOA) is a severe male infertility form impacting 1% of men, characterized by absent sperm production and primary hypogonadism.
• NOA exhibits etiological heterogeneity; non-genetic forms have a higher incidence of testicular germ cell cancer (TGCC) than genetic forms.

Purpose of the Study:

• To identify shared and specific molecular pathways in testicular somatic cells for non-genetic and genetic forms of NOA.
• To investigate molecular differences between non-obstructive azoospermia (NOA), Complete Androgen Insensitivity Syndrome (CAIS), and Klinefelter Syndrome (KS).

Main Methods:

• Single-cell RNA sequencing (scRNAseq) of testicular somatic cells from a CAIS patient.
• Integration of scRNAseq data with existing datasets from normal spermatogenesis, NOA, KS, and TGCC testes.
• Analysis of clinical data and hormone levels (Testosterone, Estradiol) in age-matched men.

Main Results:

• Leydig cells in all studied conditions were immature and senescent.
• Leydig cells in NOA with primary hypogonadism showed high expression of seminoma microenvironment transcripts, including estrogen-responsive genes.
• A decreasing Testosterone/Estradiol ratio in men with non-genetic NOA was identified as a prognostic indicator for TGCC.

Conclusions:

• The study provides molecular insights for predicting TGCC risk in individuals with NOA.
• Findings suggest potential eligibility for aromatase inhibitor therapy in specific NOA patient groups.