{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:30:38Z","timestamp":1791419438215,"version":"4.3.3"},"reference-count":71,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"URI-Urological Research Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Non-obstructive azoospermia (NOA) is the most severe form of male infertility, affecting 1% of all men, with a clinical picture characterized by no sperm production, hyalinization of the basal membrane of the seminiferous tubules, primary hypogonadism, and earlier onset of age-related comorbidities compared with fertile men. NOA is also characterized by etiologic heterogeneity and the non-genetic form has higher incidence of testicular germ cell cancer (TGCC) compared to the forms with genetic abnormalities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We aimed to establish molecular pathways in the testicular somatic cells that are either shared or specific for non-genetic and genetic forms of NOA, such as complete androgen insensitivity syndrome (CAIS) and Klinefelter syndrome (KS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed single-cell RNA sequencing of the testicular somatic cells of an individual with CAIS, and data integration with published scRNA-seq datasets of testis with normal spermatogenesis, NOA, KS, and germinal testicular cancer. Detailed clinical data of the CAIS patient, testosterone and estradiol levels in age-matched men (120 fertile, 155 infertile, 116 NOA, 18 KS, and 343 with TGCC) were analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In all conditions, Leydig cells are immature and senescent, but those of NOA associated with primary hypogonadism depict the highest expression of transcripts associated with the seminoma microenvironment, including estrogen-responsive genes. An oncological transcriptional signature in the Leydig cells has been confirmed at the systemic levels by showing a prognostic role of the decreasing testosterone\/estradiol ratio for TGCC in men with non-genetic NOA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study offers molecular insights into the prediction of TGCC in persons with NOA and eligibility for the use of aromatase inhibitors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgaf404","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T14:09:51Z","timestamp":1752502191000},"page":"388-404","source":"Crossref","is-referenced-by-count":5,"title":["Testis Molecular Pathways in CAIS Unveil Testosterone\/Estradiol on Germ Cell Tumor Risk in Non-Obstructive Azoospermia"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6904-9158","authenticated-orcid":false,"given":"Massimo","family":"Alfano","sequence":"first","affiliation":[{"name":"Division of Experimental Oncology\/Unit of Urology, URI, IRCCS Ospedale San Raffaele , Milan 20132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-5490","authenticated-orcid":false,"given":"Anna Sofia","family":"Tascini","sequence":"additional","affiliation":[{"name":"Center for Omics Sciences, IRCCS Ospedale San Raffaele , Milan 20132 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Pederzoli","sequence":"additional","affiliation":[{"name":"Division of Experimental Oncology\/Unit of Urology, URI, IRCCS Ospedale San Raffaele , Milan 20132 ,","place":["Italy"]},{"name":"Department of Urology, Universit\u00e0 Vita-Salute San Raffaele , Milan 20132 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