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Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism
Michelle Welsh, … , Lee B. Smith, Richard M. Sharpe
Michelle Welsh, … , Lee B. Smith, Richard M. Sharpe
Published March 13, 2008
Citation Information: J Clin Invest. 2008;118(4):1479-1490. https://doi.org/10.1172/JCI34241.
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Research Article Development Article has an altmetric score of 135

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

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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.

Authors

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

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Figure 6

Characterization of windows of androgen action in phallus development during fetal life.

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Characterization of windows of androgen action in phallus development du...
Reproductive tracts were examined at P25 from male rats exposed to flutamide (A) or at P17 from female rats exposed to testosterone (B) in utero during EW (E15.5–E17.5), MW (E17.5–E19.5), LW (E19.5–E21.5), or FW (E15.5–E21.5), compared with control male and female rats. (A) Phallus weight was reduced in male rats by exposure to flutamide during any window between E15.5 and E21.5, compared with that in control males. (B) Testosterone exposure during any window between E15.5 and E21.5 increased phallus weight in female rats, compared with that in control females, but not with male weight. (C) Images of P25 male penis histology showing that EW, but not LW, flutamide affected ossification of the os penis (arrow), indicated by the absence of osteoid cells (stained red by Goldner stain) in the os penis after exposure to EW flutamide. Note also the failure of the urethral folds to fuse in the EW flutamide penis (*), compared with the formation of a patent urethra in the control and LW flutamide male. Original magnification, ×20. Values are mean ± SEM (n = 5–28 rats from 2–5 litters per treatment group). ***P < 0.001 compared with control male values; †P < 0.001 compared with control female values. Blue dotted line highlights mean male level; red dotted line highlights mean female level.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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