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

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.

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

“…Our data show that, in fetal life, these stem cells increase >17-fold in number from e15.5 to e21.5 in rats when intratesticular testosterone levels are high/increasing (33,40).…”

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

“…Although failure of such androgen exposure induces the defective masculinization, the degree of anomalies depends on the timing of androgen exposure. In rat models, blocking androgen actions in late gestation induces the defective penile growth, but does not induce hypospadias (6,28). Mafb exhibited sexually dimorphic expression during this critical time window.…”

“…These results indicate that Mafb acts downstream of androgen signaling during the embryonic urethral masculinization. Several works have identified the critical time window for masculinization of external genitalia (3,6,27). Exposure to a proper amount of androgen within this period is essential for the induction of its masculinization.…”

“…However, the mechanisms mediating androgen-dependent masculinization processes are largely unknown. Failure of exposure to androgen causes lack of masculinization of male genital tubercles (GTs) (3,6). Therefore, proper timing of embryonic exposure to androgen is essential for inducing GT masculinization.…”

Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report

“…Growing evidence suggests that all these disorders are interlinked in terms of their origins [56] and that this probably involves disruption of androgen production or androgen action during a critical 'masculinization programming window (MPW)', which in humans is localised within the period of 8-12 weeks' gestation [57,58].…”