Blood Testis Barrier and Somatic Cells Impairment in a Series of 35 Adult Klinefelter Syndrome Patients.

Giudice Giudice,Vermeulen Vermeulen,Wyns Wyns

doi:10.3390/ijms20225717

Abstract

Klinefelter Syndrome (KS) is the most common genetic cause of infertility in men. Degeneration of the testicular tissue starts in utero and accelerates at puberty with hyalinisation of seminiferous tubules, spermatogonia apoptosis and germ cell maturation arrest. Therefore, fertility preservation in young KS boys has been proposed, although this measure is still debated due to insufficient knowledge of the pathophysiology of the disease. To better understand the underlying mechanisms of testicular failure and germ cell loss, we analysed functional and morphological alterations in the somatic compartment of KS testis, i.e., Sertoli cells, including the blood–testis barrier (BTB) and Leydig cells (LC). We compared three populations: 35 KS 47,XXY non-mosaic patients, 28 Sertoli-cell-only (SCO) syndrome patients and 9 patients with normal spermatogenesis. In KS patients the expression of BTB proteins connexin-43 and claudin-11 assessed with a semi-quantitative scoring system appeared significantly reduced with a disorganised pattern. A significant reduction in seminiferous tubules expressing androgen receptors (AR) was observed in KS compared to normal spermatogenesis controls. INSL3 expression, a marker of LC maturation, was also significantly reduced in KS compared to patients with normal spermatogenesis or SCO. Hence, the somatic compartment impairment in KS could be involved in degeneration of seminiferous tubules.

Highlights

Klinefelter Syndrome (KS) is the most frequent sexual chromosomal aneuploidy in men, characterised by the presence of an extra “X” chromosome
We focused on Sertoli cells (SCs) and Leydig cell (LC) maturation and function, as well as on main blood–testis barrier (BTB) proteins, in a large cohort of KS patients compared to: (1) Sertoli-cell-only (SCO) patients with normal karyotype and anatomopathological features similar to KS, and (2) to a group of patients with normal spermatogenesis (NSP) and normal karyotype
A mean of 5% ± 10% seminiferous tubules (STs) in KS presented a score 2 corresponding to a well-organised distribution of the protein, which was lower in KS than in NSP and SCO (Figure 1a,b)

Summary

Introduction

Klinefelter Syndrome (KS) is the most frequent sexual chromosomal aneuploidy in men, characterised by the presence of an extra “X” chromosome. Almost 40% of patients have some remaining foci where mature sperm may be recovered by testicular sperm extraction (TESE) during early adulthood and so far knowledge on molecular mechanisms involved in degeneration of seminiferous tubules (STs) and on the reproductive potential of spermatogonia in KS is very limited and uncertain (for review see Giudice et al [9]). While physiologically the release of anti-Müllerian hormone (AMH) by SCs decreases during puberty and is arrested when SCs achieve maturation, in KS a delay in disappearance of AMH expression during puberty and a decline of circulating AMH in adulthood have been described, probably as a result of disrupted regulatory mechanisms in the pituitary–gonadal axis [11,12]. A reduced SC expression of nuclear androgen receptors (AR) whose signalling is essential for spermatogenesis [13] was shown in KS boys [12]

Methods

Results

Discussion

Conclusion