{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:44:32Z","timestamp":1791931472015,"version":"4.3.4"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction and Objectives<\/jats:title><jats:p>About 30-75% of infertile men are diagnosed with idiopathic infertility, thereby lacking major causative factors to explain their impaired fertility status. In this study, we used a large cohort of idiopathic infertile men to determine whether subgroups could be identified by an unbiased clustering approach and whether underlying etiologic factors could be delineated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p>From our in-house database Androbase<jats:sup>\u00ae<\/jats:sup>, we retrospectively selected patients (from 2008 to 2018) with idiopathic male infertility (azoo- to normozoospermia) who fit the following selection criteria: FSH \u2265 1 IU\/l, testosterone \u2265 8 nmol\/l, ejaculate volume \u2265 1.5 ml. Patients with genetic abnormalities or partners with female factors were excluded.<\/jats:p><jats:p>For the identified study population (n=2742), we used common andrologic features (somatic, semen and hormonal parameters, including the <jats:italic>FSHB<\/jats:italic> c.-211G&amp;gt;T (rs10835638) single nucleotide polymorphism) for subsequent analyses. Cluster analyses were performed for the entire study population and for two sub-cohorts, which were separated by total sperm count (TSC) thresholds: Cohort A (TSC \u2265 1 mill\/ejac; n=2422) and Cohort B (TSC &amp;lt; 1 mill\/ejac; n=320). For clustering, the <jats:italic>partitioning around medoids<\/jats:italic> method was employed, and the quality was evaluated by average silhouette width.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The applied cluster approach for the whole study population yielded two separate clusters, which showed significantly different distributions in bi-testicular volume, FSH and <jats:italic>FSHB<\/jats:italic> genotype. Cluster 1 contained all men homozygous for G (wildtype) in <jats:italic>FSHB<\/jats:italic> c.-211G&amp;gt;T (100%), while Cluster 2 contained most patients carrying a T allele (&amp;gt;96.6%). In the analyses of sub-cohorts A\/B, two clusters each were formed too. Again, the strongest segregation markers between the respective clusters were bi-testicular volume, FSH and <jats:italic>FSHB<\/jats:italic> c.-211G&amp;gt;T.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>With this first unbiased approach for revealing putative subgroups within a heterogenous group of idiopathic infertile men, we did indeed identify distinct patient clusters. Surprisingly, across all diverse phenotypes of infertility, the strongest segregation markers were <jats:italic>FSHB<\/jats:italic> c.-211G&amp;gt;T, FSH, and bi-testicular volume. Further, Cohorts A and B were significantly separated by <jats:italic>FSHB<\/jats:italic> genotype (wildtype vs. T-allele carriers), which supports the notion of a contributing genetic factor. Consequently, <jats:italic>FSHB<\/jats:italic> genotyping should be implemented as diagnostic routine in patients with idiopathic infertility.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.780403","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T13:09:26Z","timestamp":1640092166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["FSHB Genotype Identified as a Relevant Diagnostic Parameter Revealed by Cluster Analysis of Men With Idiopathic 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