Can proteomic analysis help us understand the molecular events in men with idiopathic germ cell aplasia?

Can proteomic analysis help us understand the molecular events in men with idiopathic germ cell aplasia?

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Go to the profile of Alfano Massimo
almost 4 years ago

We thank Dr. Arora for his insightful comment to our publication (1). We agree that retinoic acid (RA) has been shown to play a key role in steroidogenesis, spermatogonial proliferation and the initiation of meiosis in the adult gonads (2-7); conversely, little is known about the effect of RA on the modulation of the human testis extracellular matrix (ECM). More in details, it is a novel finding of our study that the increased RA signaling in the Sertoli cells is a feature associated with complete idiopathic germ cell aplasia, despite normal systemic levels of retinol. This piece of information would suggest that treating infertile men with retinoic acid to improve spermatogenesis (8) might be tricky. Similarly, several authors already pointed out that either a deficit or an excess of RA resulted in testicular lesions and spermatogenetic disorders thus contributing to testicular dysgenesis syndrome (9-12).

Second novelty from our study is the association between the increased RA signaling of Sertoli cells and the decreased levels of expression of few of the basal membrane components (i.e., HSPG2 and NID2) of the seminiferous tubules in idiopathic germ cell aplasia. Moreover, we showed for the first time a decreased signaling of vitamin K in Leydig cells, which was associated with the decreased level of the ECM regulator Factor IX. Altogether, these novel findings highlight the relevance of vitamin A and vitamin K signaling in the process of modulation of the testis ECM composition in idiopathic germ cell aplasia, regardless of the systemic levels of those two vitamins.

From a pathophysiological standpoint, our study provides novel insights in terms of the dysregulation of the human testicular microenvironment in idiopathic germ cell aplasia, identifying the potential role of a local impairment of vitamin A and K metabolic pathways in men with non-obstructive azoospermia. Thereof, as it has been correctly stated by Dr. Arora in his editorial, we actually hope that our findings can help in the identification of non-invasive, clinically useful biomarkers and new therapeutic targets for non-obstructive azoospermic patients.

1.         M. Alfano, F. Pederzoli, I. Locatelli, S. Ippolito, E. Longhi, P. Zerbi, M. Ferrari, A. Brendolan, F. Montorsi, D. Drago, A. Andolfo, M. Nebuloni, A. Salonia. Impaired testicular signaling of vitamin A and vitamin K contributes to the aberrant composition of the extracellular matrix in idiopathic germ cell aplasia. Fertil Steril 2018;(present manuscript).

2.         Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S et al. Retinoid signaling determines germ cell fate in mice. Science 2006;312:596-600.

3.         Chen Y, Ma L, Hogarth C, Wei G, Griswold MD, Tong MH. Retinoid signaling controls spermatogonial differentiation by regulating expression of replication-dependent core histone genes. Development 2016;143:1502-11.

4.         van Pelt AM, de Rooij DG. Synchronization of the seminiferous epithelium after vitamin A replacement in vitamin A-deficient mice. Biology of reproduction 1990;43:363-67.

5.         van Pelt AM, de Rooij DG. Retinoic acid is able to reinitiate spermatogenesis in vitamin A-deficient rats and high replicate doses support the full development of spermatogenic cells. Endocrinology 1991;128:697-704.

6.         Chung SS, Wang X, Roberts SS, Griffey SM, Reczek PR, Wolgemuth DJ. Oral administration of a retinoic Acid receptor antagonist reversibly inhibits spermatogenesis in mice. Endocrinology 2011;152:2492-502.

7.         Zhang J, Eto K, Honmyou A, Nakao K, Kiyonari H, Abe S. Neuregulins are essential for spermatogonial proliferation and meiotic initiation in neonatal mouse testis. Development 2011;138:3159-68.

8.         Clavijo RI, Arora H, Gibbs E, Cohen S, Griswold A, Bakircioglu E et al. Whole Exome Sequencing of a Consanguineous Turkish Family Identifies a Mutation in GTF2H3 in Brothers With Spermatogenic Failure. Urology 2018;120:86-9.

9.         Livera G, Rouiller-Fabre V, Pairault C, Levacher C, Habert R. Regulation and perturbation of testicular functions by vitamin A. Reproduction 2002;124:173-80.

10.       Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proceedings of the National Academy of Sciences of the United States of America 2006;103:2474-9.

11.       MacLean G, Li H, Metzger D, Chambon P, Petkovich M. Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice. Endocrinology 2007;148:4560-7.

12.       Jorgensen A, Nielsen JE, Perlman S, Lundvall L, Mitchell RT, Juul A et al. Ex vivo culture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development. Human reproduction 2015;30:2351-63.


Alfano Massimo, Pederzoli Filippo, Salonia Andrea