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

Welsh, Michelle; Saunders, Philippa T K; Fisken, Mark; Scott, Hayley M; Hutchison, Gary R; Smith, Lee B; Sharpe, Richard M


Michelle Welsh

Philippa T K Saunders

Mark Fisken

Hayley M Scott

Lee B Smith

Richard M Sharpe


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.


Welsh, M., Saunders, P. T. K., Fisken, M., Scott, H. M., Hutchison, G. R., Smith, L. B., & Sharpe, R. M. (2008). Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. Journal of Clinical Investigation, 118(4), 1479-1490.

Journal Article Type Article
Acceptance Date Jan 23, 2008
Publication Date 2008
Deposit Date Mar 27, 2014
Publicly Available Date Mar 27, 2014
Print ISSN 0021-9738
Electronic ISSN 1558-8238
Publisher American Society for Clinical Investigation
Peer Reviewed Peer Reviewed
Volume 118
Issue 4
Pages 1479-1490
Keywords androgen-induced masculinization; hypospadias; cryptorchidism; testicular dysgenesis syndrome (TDS); androgen action; anogenital distance(AGD); programming window;
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