Unraveling a Subgroup of Men with Unexplained Male Infertility - Men with Normogonadotropic Nonobstructive Azoospermia

Abstract

Context Nonobstructive azoospermia (NOA) constitutes male infertility with complete absence of sperm in the ejaculate. NOA can originate in testicular malfunction or in endocrine dysregulation. Elevated follicle-stimulating hormone (FSH) levels are diagnostically valuable for NOA. Objective An azoospermic patient cohort comprising 79 men and exhibiting no obstruction but normal FSH levels was identified. Focusing on this normogonadotropic nonobstructive azoospermic (NNOA) group, the study aimed to characterize these patients in depth. Methods Whether the missing FSH upregulation in patients with NNOA is due to testicular or pituitary/hypothalamic malfunctions was examined by analyzing somatic, endocrine, and testicular parameters compared with 87 men with hypergonadotropic NOA and 88 normozoospermic men. Results Testicular phenotypes of patients with NNOA and NOA were compared in histologically stratified subgroups (most advanced germ cell type). Using flow cytometry, the samples were evaluated for testicular cell composition by ploidy analysis. Concerning the distinct histological classification (hypospermatogenesis, spermatogenic arrest, Sertoli cell only, tubular atrophy) NNOA men produced more elongated spermatids and showed higher sperm retrieval. Testicular tissue composition between patients with NNOA and patients with NOA only differed after meiosis. Conclusion The missing FSH upregulation in NNOA might be due to a testicular malfunction, as both FSH and testosterone were normal and NNOA spermatogenesis differed only after meiosis. Two explanations are possible: NNOA represents a phenotype in which spermatogenesis fails - different from NOA - only at the postmeiotic level, leaving FSH regulation unaffected, or the same mechanism underlies both NNOA and NOA, but the groups are at different stages of progression of the same disorder.