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Cryptorchidism is the most common cause of non-obstructive azoospermia in man. In contrast to the general belief that temperature-dependent effects on the undescended gonad damage cryptorchid testes before sexual maturation is complete, molecular pathology strongly supports the theory that impaired mini-puberty is responsible for azoospermia and infertility in cryptorchidism.

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Cryptorchidism is the most common cause of non-obstructive azoospermia in man. In contrast to the general belief that temperature-dependent effects on the undescended gonad damage cryptorchid testes before sexual maturation is complete, molecular pathology strongly supports the theory that impaired mini-puberty is responsible for azoospermia and infertility in cryptorchidism. Molecular biological observations favor LH deficiency, with EGR4 as a master regulatory gene in Leydig cell dysgenesis, as the reason for impaired mini-puberty, and recent evidence supports the idea that infertility in cryptorchidism is a consequence of alterations in the Piwi pathway.
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Spermatogonia contain processing bodies that harbor P-element-induced wimpy testis (Piwi) proteins. Piwi proteins are associated specifically with Piwi-interacting RNAs to si-lence transposable DNA elements. Loss-of-function mutations in the Piwi pathway lead to derepression of transposable elements, resulting in defective spermatogenesis.

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Spermatogonia contain processing bodies that harbor P-el-ement-induced wimpy testis (Piwi) proteins. Piwi proteinsare associated specifically with Piwi-interacting RNAs to si-lence transposable DNA elements. Loss-of-function muta-tions in the Piwi pathway lead to derepression of transpos-able elements, resulting in defective spermatogenesis. Fur-thermore, deletion of gametocyte-specific factor 1 (GTSF1),a factor involved in Piwi-mediated transcriptional repres-sion, causes male-specific sterility and derepression of LINE-1 (L1) retrotransposons. No previous studies have examinedGTSF1, L1 and PIWIL4 expression in cryptorchidism. We ex-amined transposon-silencing genes and L1 transposon ex-pression in testicular biopsies with Affymetrix microarraysand immunohistology. Seven members of the Tudor genefamily, 3 members of the DEAD-box RNA helicase family, andthe GTSF1 gene were found to show significantly lower RNAsignals in the high-infertility-risk group.
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Spermatogonia contain processing bodies that harbor P-element-induced wimpy testis (Piwi) proteins. Piwi proteins are associated specifically with Piwi-interacting RNAs to silence transposable DNA elements. Loss-of-function mutations in the Piwi pathway lead to derepression of transposable elements, resulting in defective spermatogenesis.

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Furthermore, deletion of gametocyte-specific factor 1 (GTSF1), a factor involved in Piwi-mediated transcriptional repression, causes male-specific sterility and derepression of LINE-1 (L1) retrotransposons. No previous studies have examined GTSF1, L1 and PIWIL4 expression in cryptorchidism. We examined transposon-silencing genes and L1 transposon expression in testicular biopsies with Affymetrix microarrays nd immunohistology. Seven members of the Tudor gene family, 3 members of the DEAD-box RNA helicase family, and he GTSF1 gene were found to show significantly lower RNA signals in the high-infertility-risk group. In the immunohistochemical analysis, patients from the low-infertility-risk group showed coherently stronger staining for GTSF1 and PIWIL4 proteins and weaker staining for L1 transposon when com-pared to the high-infertility-risk samples. These new findings provide first evidence consistent with the idea that infertility in cryptorchidism is a consequence of alterations in the Piwi pathway and transposon derepression induced by the impaired function of mini-puberty.
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