Impaired testicular signaling of vitamin A and vitamin K contributes to the aberrant composition of the extracellular matrix in idiopathic germ cell aplasia

Impaired signaling of vitamin A and vitamin K in the adult human Sertoli and Leydig cells is associated with an unbalanced composition of the testicular extracellular matrix and germ cell aplasia.

Volume 111, Issue 4, Pages 687–698


Massimo Alfano, Ph.D., Filippo Pederzoli, M.D., Irene Locatelli, Ph.D., Silvia Ippolito, M.D., Erika Longhi, B.Sc., Pietro Zerbi, M.D., Maurizio Ferrari, M.D., Andrea Brendolan, Ph.D., Francesco Montorsi, M.D., Denise Drago, Ph.D., Annapaola Andolfo, Ph.D., Manuela Nebuloni, M.D., Andrea Salonia, M.D., Ph.D.



To study pathogenic features of the somatic testicular microenvironment associated with idiopathic germ cell aplasia.


Cross-sectional study.


Tertiary referral center for reproductive medicine.


Testicular specimens from men with idiopathic nonobstructive azoospermia (iNOA) prospectively submitted to microdissection testicular sperm extraction. Of 20 specimens used for histology, 10 were also available for proteomic analysis. Primary Sertoli cells with normal karyotype and phenotype were also used.


Patients with iNOA were dichotomized according to a positive versus negative sperm retrieval at microdissection testicular sperm extraction, and on the isolated extracellular matrix (ECM) the proteomic analysis was performed.

Main Outcome Measure(s)

Proteomic analysis of the ECM from testicular specimens with positive versus negative sperm retrieval. Gene ontology enrichment was used to identify upstream regulators based on the 11 deregulated ECM proteins, which were validated by immunohistochemistry and quantitative polymerase chain reaction. Continuous variables were expressed as medians and interquartile range.


Germ cell aplasia was characterized by an increased signaling of the retinoic acid in Sertoli cells and associated with decreased expression of the basal membrane markers nidogen-2 and heparan sulfate proteoglycan-2. Decreased levels of the interstitial matrisome-associated factor IX and its regulator VKORC1 were, instead, coupled with decreased signaling of vitamin K in Leydig cells. An altered expression of a further eight ECM proteins was also found, including laminin-4 and laminin-5. Peripheral levels of the two vitamins were within the reference range in the two cohorts of iNOA men.


We identified the pathogenetic signature of the somatic human testicular microenvironment, providing two vitamin-related mechanistic insights related to the molecular determinants of the idiopathic germ cell aplasia.

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