{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:50:29Z","timestamp":1792788629468,"version":"4.5.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing Natural Science Foundation","award":["7254520"],"award-info":[{"award-number":["7254520"]}]},{"name":"Young Talents Support Program of the China Association of Chinese Medicine","award":["CACM-2024-QNRC2-B17"],"award-info":[{"award-number":["CACM-2024-QNRC2-B17"]}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["GZB20250910, 2025T181076, 2025M784009"],"award-info":[{"award-number":["GZB20250910, 2025T181076, 2025M784009"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Young Elite Scientists Sponsorship Program by the China Association for Science and Technology","award":["YESS20240193"],"award-info":[{"award-number":["YESS20240193"]}],"id":[{"id":"https:\/\/ror.org\/035vmht26","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To identify disproportionality signals linking androgenetic alopecia (AGA) drugs (finasteride, dutasteride, and minoxidil) with male infertility-related adverse events and to explore infertility-related biological features using testicular transcriptomic datasets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A dual-database replication design was employed using FAERS (2004\u20132025) and EudraVigilance (2002\u20132025). Disproportionality analysis with multiple signal detection metrics assessed drug\u2013infertility associations. Multi-level bioinformatic analyses\u2014including toxicity prediction, drug-associated target screening, testicular transcriptomic analysis, single-cell RNA sequencing, intercellular communication analysis, gene set enrichment analysis (GSEA), and immune infiltration analysis\u2014were integrated to explore biological features potentially relevant to male infertility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Disproportionality analyses detected signals for all three drugs, with finasteride demonstrating the most prominent reporting signal, followed by dutasteride and minoxidil. Multi-level bioinformatic analysis identified HIF1A as an overlap-derived candidate under the specified datasets and screening criteria, and HIF1A expression was higher in testicular tissue from patients with male infertility. Single-cell analysis showed higher HIF1A expression in late spermatocytes, Leydig cells, and myoid cells from infertility samples, together with group-dependent inferred communication patterns for selected VEGF-, PDGF-, IGF-, and FGF-related signaling axes. GSEA associated higher HIF1A expression with immune-response-, wound-healing-, and cell-adhesion-related processes, whereas lower HIF1A expression was associated with spermatid-development- and cilium\/flagellum-dependent motility-related processes. ssGSEA-based analysis showed positive correlations between HIF1A expression and several immune-cell signature scores.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study systematically evaluated associations between AGA drugs and male infertility using real-world pharmacovigilance data and integrated bioinformatic analyses. The HIF1A-related transcriptomic findings provide a hypothesis-generating biological context for male infertility but do not establish a shared or drug-specific mechanism linking the three medications to infertility. The pharmacovigilance findings indicate reporting signals rather than incidence or causality.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0357154","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:29:16Z","timestamp":1790270956000},"page":"e0357154","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Androgenetic alopecia drugs and male infertility: Evidence from pharmacovigilance and testicular transcriptomics"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2235-4956","authenticated-orcid":true,"given":"Zhuozhi","family":"Gong","sequence":"first","affiliation":[{"name":"Xiyuan Hospital of China Academy of Chinese Medical Sciences","place":["Beijing, China"],"department":["Department of 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Effects","volume":"7","author":"MC Estill","year":"2023","journal-title":"Georgetown Medical Review"},{"key":"pone.0357154.ref027","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.2147\/DDDT.S214907","article-title":"Minoxidil and its use in hair disorders: a review","volume":"13","author":"P Suchonwanit","year":"2019","journal-title":"Drug Des Devel Ther"},{"issue":"7","key":"pone.0357154.ref028","article-title":"Hypoxia-Inducible Factor 1-Alpha (HIF-1\u03b1): An Essential Regulator in Cellular Metabolic Control","volume":"16","author":"M Basheeruddin","year":"2024","journal-title":"Cureus"},{"issue":"1","key":"pone.0357154.ref029","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s11658-024-00682-7","article-title":"Systematic and comprehensive insights into HIF-1 stabilization under normoxic conditions: implications for cellular adaptation and therapeutic strategies in cancer","volume":"30","author":"J Zhang","year":"2025","journal-title":"Cell Mol Biol Lett"},{"key":"pone.0357154.ref030","doi-asserted-by":"crossref","first-page":"725933","DOI":"10.3389\/fcell.2021.725933","article-title":"Effects of Environmental and Pathological Hypoxia on Male Fertility","volume":"9","author":"Z Li","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"5","key":"pone.0357154.ref031","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s00418-014-1232-z","article-title":"Interleukin-1\u03b2, cyclooxygenase-2, and hypoxia-inducible factor-1\u03b1 in asthenozoospermia","volume":"142","author":"E Salvolini","year":"2014","journal-title":"Histochem Cell Biol"},{"key":"pone.0357154.ref032","doi-asserted-by":"crossref","first-page":"120495","DOI":"10.1016\/j.jep.2025.120495","article-title":"Linggui formula improves asthenozoospermia by modulating seminal plasma exosomes Wnt signaling via the LRP6\/GSK3\/Septin4 pathway","volume":"354","author":"S Liu","year":"2026","journal-title":"J Ethnopharmacol"},{"issue":"10","key":"pone.0357154.ref033","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1111\/and.12400","article-title":"Testicular hypofunction caused by activating p53 expression induced by reactive oxygen species in varicocele rats","volume":"47","author":"M Liang","year":"2015","journal-title":"Andrologia"},{"issue":"3","key":"pone.0357154.ref034","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/and.12449","article-title":"Hypoxia-induced apoptosis and mechanism of epididymal dysfunction in rats with left-side varicocele","volume":"48","author":"K Zhang","year":"2016","journal-title":"Andrologia"},{"issue":"1","key":"pone.0357154.ref035","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1095\/biolreprod.104.027797","article-title":"A dominant-negative isoform of hypoxia-inducible factor-1 alpha specifically expressed in human testis","volume":"71","author":"R Depping","year":"2004","journal-title":"Biol Reprod"},{"issue":"3","key":"pone.0357154.ref036","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s00441-019-03064-0","article-title":"Effect of silencing HIF-1\u03b1 gene on testicle spermatogenesis function in varicocele rats","volume":"378","author":"W Zhao","year":"2019","journal-title":"Cell Tissue Res"},{"issue":"1","key":"pone.0357154.ref037","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/JME-18-0148","article-title":"HIF 1 inhibits STAR transcription and testosterone synthesis in murine Leydig cells","volume":"62","author":"X Wang","year":"2019","journal-title":"J Mol Endocrinol"},{"issue":"6","key":"pone.0357154.ref038","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.cell.2019.01.021","article-title":"VEGF in signaling and disease: beyond discovery and development","volume":"176","author":"RS 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