Unraveling the Androgen Receptor's Role in Hypospadias: A Systematic Review and Meta-Analysis

Androgen signaling is critical for male sex differentiation and proper penile development. Disruption of this pathway results in congenital malformations of the male external genitalia, such as hypospadias. Hypospadias is a malformation of the penis, where the urethral opening is located along the ventral shaft rather than the tip. Although the molecular link between androgen signaling, penile differentiation, and proper urethra closure has been established for over 70 years, most hypospadias cases do not have a defined etiology. To clarify how the androgen receptor contributes to human hypospadias, we conducted a quantitative meta-analysis comparing androgen receptor expression in hypospadias patients and healthy boys. Due to substantial heterogeneity and imprecision in both mRNA and protein assays, no consistent direction of androgen receptor expression could be demonstrated, suggesting that hypospadias etiology may be more complicated than just the sole expression of the androgen receptor. To contextualize these results, we complemented the meta-analysis with a mini-review summarizing the various mechanisms through which androgen receptors can be regulated in the developing penis. This review aims to provide a framework for future investigations of androgen signaling and urethral closure mechanisms during penile development.