ArticleProceedings of the National Academy of Sciences of the United States of America2015
Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers, 2 of them syntheses that pooled it.
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Who cites it
76 citing papers in PubMed, 2 syntheses or guidelines pooled it, 130 citations in OpenAlex.
- Congenital penile curvature treatments in adults: a systematic review of techniques and outcomes.International journal of impotence research · 2026Pooled it
- Unraveling the Androgen Receptor's Role in Hypospadias: A Systematic Review and Meta-Analysis.International journal of molecular sciences · 2026Pooled it
- The genetic landscape of hypospadias: clinical insights into inherited and de novo risk factors.Science China. Life sciences · 2026Article
- Revisiting the dual role of androgens and oestrogens in mammalian sex differentiation with a focus on genitalia.Nature reviews. Urology · 2026Review
- The periodical formation of the vaginal closure membrane in guinea pigs is a regeneration process maintained by a special stem cell niche.Research square · 2026Article
- A long non-coding RNA Leat1 mediates the hormone responsiveness of EfnB2 during male urogenital development.Communications biology · 2025Article
- Causal links between congenital malformations, birth weight, and neuroblastoma: insights from Mendelian randomization.BMC pediatrics · 2025Article
- Developmental basis of male nipple loss and retention in mammals.Research square · 2025Article
- Genetic disruption of the baculum compromises the ability of male mice to copulate.PLoS genetics · 2025Article
- NR2F2 regulation of interstitial cell fate in the embryonic mouse testis and its impact on differences of sex development.Nature communications · 2025Article
- Article
- Androgen receptor antagonist flutamide modulates estrogen receptor alpha expression in distinct regions of the hypospadiac rat penis.Frontiers in endocrinology · 2025Article
- Suspected Ovotesticular Disorders of Sexual Differentiation in a Phenotypic Male With Ambiguous Genitalia, Light Menstrual Flow, and Synchronous Bilateral Dysgerminoma: A Case Report From Ethiopia.Case reports in pediatrics · 2025Article
- Navigating Ambiguous Genitalia: A Case of Dysgerminoma in an Afghan Boy.International medical case reports journal · 2025Article
- Assessing placental transfer and in utero reproductive effects in rats of a short-chained paraffin withCurrent research in toxicology · 2025Article
- MAFB-mediated CEBPA regulated human urothelium growth through Wnt/β-catenin signaling pathway.Genes & diseases · 2025Article
- An extragenital cell population contributes to urethra closure during mouse penis development.Science advances · 2024Article
- SOX9 regulates epithelial-mesenchymal transformation by mediating the Wnt/Pediatric discovery · 2024Article
- Characterization of urethra closure in female neonatal mice at histological and molecular levels.Reproduction (Cambridge, England) · 2024Article
- The association and underlying mechanism of the digit ratio (2D:4D) in hypospadias.Asian journal of andrology · 2024Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Congenital penile anomalies (CPAs) are among the most common human birth defects. Reports of CPAs, which include hypospadias, chordee, micropenis, and ambiguous genitalia, have risen sharply in recent decades, but the causes of these malformations are rarely identified. Both genetic anomalies and environmental factors, such as antiandrogenic and estrogenic endocrine disrupting chemicals (EDCs), are suspected to cause CPAs; however, little is known about the temporal window(s) of sensitivity to EDCs, or the tissue-specific roles and downstream targets of the androgen receptor (AR) in external genitalia. Here, we show that the full spectrum of CPAs can be produced by disrupting AR at different developmental stages and in specific cell types in the mouse genital tubercle. Inactivation of AR during a narrow window of prenatal development results in hypospadias and chordee, whereas earlier disruptions cause ambiguous genitalia and later disruptions cause micropenis. The neonatal phase of penile development is controlled by the balance of AR to estrogen receptor α (ERα) activity; either inhibition of androgen or augmentation of estrogen signaling can induce micropenis. AR and ERα have opposite effects on cell division, apoptosis, and regulation of Hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling in the genital tubercle. We identify Indian hedgehog (Ihh) as a novel downstream target of AR in external genitalia and show that conditional deletion of Ihh inhibits penile masculinization. These studies reveal previously unidentified cellular and molecular mechanisms by which antiandrogenic and estrogenic signals induce penile malformations and demonstrate that the timing of endocrine disruption can determine the type of CPA.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.