Transcriptional Crosstalk between INSL3 and Androgen Receptor in Foetal Leydig Cells: Molecular Insights into TDS

Testicular Dysgenesis Syndrome (TDS) encompasses a spectrum of male reproductive disorders that originate during fetal development. Among the critical players in testicular morphogenesis, fetal Leydig cells perform essential functions through the secretion of insulin-like 3 (INSL3) and androgens, which act via their respective receptors, RXFP2 and the androgen receptor (AR). While the individual signalling pathways of INSL3–RXFP2 and AR have been extensively studied, emerging evidence points toward a potential transcriptional crosstalk between these axes that influences gubernacular development and testicular descent. This review consolidates current molecular insights into the expression profiles, signalling cascades, and co-regulatory networks governing INSL3 and AR activity in fetal Leydig cells. We further examine how environmental disruptors and genetic or epigenetic alterations may impair this interplay, thereby contributing to the pathogenesis of TDS. Additionally, we evaluate in vivo and in vitro models that elucidate these mechanisms and consider the clinical potential of INSL3–AR interactions as biomarkers or therapeutic targets. A deeper understanding of this transcriptional crosstalk may offer new avenues for early diagnosis and intervention in male reproductive disorders.