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CAIS molecular pathways unveil Testosterone/Estradiol ratio to germ cell tumor risk in non-obstructive azoospermia

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 testis 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298368 | GEO | 2025/07/21

REPOSITORIES: GEO

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Project description:Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray on testis specimens from 47 non-obstructive azoospermia (NOA) and 11 obstructive azoospermia (OA) patients were performed, and 2,611 transcripts that preferentially included genes relevant to gametogenesis and reproduction according to Gene Ontology classification were found to be differentially expressed. Using a set of 945 of the 2,611 transcripts without missing data, NOA was further categorized into three classes using the non-negative matrix factorization method. These three subclasses showed differences in Johnsenâs score, FSH level, and LH level. In addition, the 52 genes showing high statistical difference between NOA subclasses (P < 0.01 with Tukey's post hoc test) were subjected to allelic association analyses to identify genetic susceptibilities in 442 NOA patients and 475 fertile men. After two rounds of screening, SNPs of the ADP-ribosyltransferase 3 (ART3) gene were associated with NOA with highest significance with ART3-SNP25 (rs6836703; P = 0.0025). Haplotypes with 5 SNPs were constructed, and the most common haplotype was found to be under-represented in patients (NOA 26.6 % versus control 35.3 %, P = 0.000073). Subjects having the most common haplotype showed an elevated level of testosterone, suggesting a protective effect of the haplotype on spermatogenesis. Thus, genome-wide gene expression analyses were used to identify genes involved in the pathogenesis of NOA, and ART3 was subsequently identified as a susceptibility gene for NOA. These findings clarify the molecular pathophysiology of NOA and suggest a novel therapeutic target in the treatment of NOA. Experiment Overall Design: Comparative analysis of two disease phenotypes, using testicular biopsy specimens from 47 NOA and 11 OA patients. No experimental replicates.

Project description:Testosterone is essential to maintain qualitative spermatogenesis. Nonetheless, no studies have been yet performed in humans to analyze the testosterone-mediated expression of the sperm proteins and their importance in reproduction. Thus, this study aimed to identify sperm protein alterations in male hypogonadism using proteomic profiling. We have performed a comparative proteomic analysis comparing sperm from fertile controls (a pool of 5 normogonadic normozoospermic fertile men) versus sperm from patients with secondary hypogonadism (a pool of 5 oligozoospermic hypogonadic patients due to isolated LH deficiency). Sperm protein composition was analyzed, after peptide labelling with Isobaric Tags, via liquid chromatography followed by tandem mass spectrometry (LC-MS/MS) on an LTQ Velos-Orbitrap mass spectrometer. LC-MS/MS data were analyzed using Proteome Discoverer. Criteria used to accept protein identification included a false discovery rate (FDR) of 1% and at least 1 peptide match per protein. Up to 986 proteins were identified and, of those, 43 proteins were differentially expressed: 32 proteins were under-expressed and 11 were over-expressed in the pool of hypogonadic patients. Bioinformatic analyses were performed using UniProt Knowledgebase, and the Gene Ontology Consortium database based on PANTHER. Notably, 13 of these 43 differentially expressed proteins have been previously reported to be related to sperm function and spermatogenesis. Western blot analyses for A-Kinase Anchoring Protein 3 (AKAP3) and the Prolactin Inducible Protein (PIP) were used to confirm the proteomics data. In summary, a high-resolution mass spectrometry-based proteomic approach was used for the first time to describe alterations of the sperm proteome in secondary male hypogonadism. A panel of deregulated sperm proteins was identified, including Prosaposin, Ropporin-1B, SERPINA5, SMOC-1, SPANXB1, GSG1, ELSPBP1, fibronectin, 5-oxoprolinase, AKAP3, AKAP4, HYDIN, ROPN1B, ß-Microseminoprotein and Protein S100-A8, which might represent putative physiological in vivo targets for androgen deficiency.

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CAIS molecular pathways unveil Testosterone/Estradiol ratio to germ cell tumor risk in non-obstructive azoospermia

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