Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism

TLDR

Male phenotypic determination depends on androgen‑induced masculinization, yet the mechanisms underlying common disorders such as hypospadias, cryptorchidism, and testicular dysgenesis syndrome remain unclear. The authors exposed rat fetuses to anti‑androgens or androgens and demonstrated that masculinization of all reproductive tract tissues is programmed by androgen action during a common fetal window. They found that blocking androgen during this window caused hypospadias, cryptorchidism, and reduced penile length in male rats—correlated with anogenital distance—while androgen exposure in females had the same effect, suggesting that AGD measurement could predict reproductive disorders.

Abstract

Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation.