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Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood-testis barrier and a subtherapeutic effect of cysteamine in testis.

ABSTRACT: Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease-modifying treatment. We aimed at unraveling the origin of azoospermia in cysteamine-treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns^-/- mouse model compared with wild type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact, an enlarged caput epididymis and reduced levels of seminal markers for obstruction neutral α-glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Histopathological examination in human and mouse testis revealed a disturbed blood-testis barrier characterized by an altered zonula occludens-1 (ZO-1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, but showed that cystine accumulation in the testis is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testis.

SUBMITTER: Reda A

PROVIDER: S-EPMC9291572 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Non-obstructive azoospermia (NOA) is the most severe form of male infertility. Currently, known causative factors, including congenital and several acquired causes only account for approximately 30% of NOA cases. The causes for NOA remain unclear for most patients, which is known as idiopathic (iNOA). However, whether iNOA is due to congenital defects or acquired abnormalities is a confusing problem due to the delayed diagnosis of this frustrating condition until the childbearing age. Therefore, we collected several cases with "secondary idiopathic NOA" and detected the altered mRNAs profiles in the testicular tissues to explore the possible molecular basis. Materials and Methods: In this study, several patients with a previous history of natural pregnancy with their partners before, who were diagnosed as iNOA based on the outcomes of routine semen analysis and multiple testis biopsies now, were enrolled. Some known risk factors and genetic factors were excluded. Therefore, we defined this phenotype as "secondary idiopathic NOA." To explore the possible molecular basis of this disease, we performed mRNA expression analysis through next-generation sequencing on three cases and other three patients with obstructive azoospermia as controls. Bioinformatics analyses were conducted to assess differentially expressed genes and possible biological mechanisms involved in the disease. Quantitative real-time reverse transcription polymerase chain reaction assays were applied to confirm the results in several selected mRNAs involved in stages and metabolism of Sertoli cells. Results: A series of mRNAs were found to be altered in testicular tissues between patients with "secondary idiopathic NOA" and controls, including 6,028 downregulated and 3,402 upregulated mRNAs. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses revealed a range of GO and KEGG terms, such as cellular process involved in reproduction, protein degradation, and absorption. Conclusion: The present study introduces a novel classification called "secondary idiopathic NOA." We provide a global view of the altered mRNAs involved in spermatogenetic failure in these cases. Regarding the limited samples, further studies should be taken to understand this new classification.

Project description:PURPOSE: Non-obstructive azoospermia (NOA) is one the many causes of male infertility (10 %) resulting from testicular failure. Multiple testicular biopsies fail to find mature sperm in at least 50 % of cases Therefore; hunting for sensitive and specific biomarkers of spermatogenesis that could better determine the fertility status in NOA can lead to improved management of male infertility. Therefore, we evaluated sperm production through analyses of germ cell-specific transcripts (DAZ, TSPY1, SPTRX3 and SPTRX1) in semen and testicular biopsies of men with azoospermia. METHODS: We collected semen (N=83) and testis biopsies (N=31) from men with non-obstructive azoospermia. We later extracted RNA and synthesized cDNA using washed semen precipitate and testicular tissues. We also performed semi-nested PCR with designed specific primers. Using H&E method, an expert pathologist performed the histopathological evaluation. Having categorized the patients into three groups based on histopathological results, we calculated the agreement between molecular results of semen and tissues with histopathological findings for each patient using Kappa statistical test. RESULTS: Molecular findings of precipitated semen and testicular tissues were in disagreement with histopathological results in most cases. Molecular analysis of testis biopsies showed significant difference (Kappa coefficient=0.009, P value=0.894) with histopathological results; TSPY1, DAZ, SPTRX3 and SPTRX1 were respectively detected in 94 %, 94 %, 17.6 % and 52.9 % of men diagnosed with germ cell aplasia. CONCLUSIONS: Molecular analysis of semen does not provide sufficient sensitivity and specificity to be used as a screening test at the present time, but it is a useful adjunct to histopathological methods in men with NOA. Spermatid/sperm specific transcripts indicated the possibility to find mature sperm following repeated multiple testicular sperm extraction (TESE) or microdisection TESE (mTESE).

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Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood-testis barrier and a subtherapeutic effect of cysteamine in testis.

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