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Critical androgen-sensitive periods of rat penis and clitoris development
Michelle Welsh1, David J MacLeod, Marion Walker
1MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, Edinburgh, UK.
Insights
Penile development is predetermined during a critical fetal window. Later androgen exposure influences growth rate but not final adult size, and cannot correct early programming deficits.
Area of Science:
- Reproductive biology
- Developmental endocrinology
- Urology
Background:
- Androgen's role in penis development is not fully understood.
- A critical fetal 'masculinisation programming window' (MPW) in rats influences penile length and hypospadias.
- Understanding these mechanisms has implications for human conditions like micropenis.
Purpose of the Study:
- To determine the timing of androgen action affecting penile development and growth in rats.
- To investigate if early deficits in MPW androgen action can be corrected by postnatal treatments.
- To assess the impact of testosterone propionate (TP) administration during different developmental windows on penile growth.
Main Methods:
- Pregnant rats were treated with flutamide during the MPW, with or without postnatal TP.
- TP was administered to rats in various fetal and postnatal time windows.
- Penile length, weight, morphology, hypospadias, and anogenital distance (AGD) were measured at specific time points.
- Serum testosterone levels were measured in adult males.
Main Results:
- MPW flutamide exposure dose-dependently reduced adult penile length and caused hypospadias, unrescuable by postnatal TP.
- Fetal TP exposure increased female clitoral size but not male penile size.
- Postnatal or pubertal TP increased penile length at day 25 but not in adulthood.
- Combined fetal and postnatal TP increased early penile size but reduced adult size.
- AGD strongly correlated with final penis length.
Conclusions:
- Adult penile size is critically dependent on androgen action during the fetal MPW.
- Subsequent penile growth is influenced by later androgen exposure, but does not alter the predetermined size.
- Postnatal androgen treatment can advance growth rate but not increase ultimate adult penile size.
- Early androgen programming deficits are not reversible with postnatal treatments.
Abstract:
Androgen control of penis development/growth is unclear. In rats, androgen action in a foetal 'masculinisation programming window' (MPW; e15.5-e18.5)' predetermines penile length and hypospadias occurrence. This has implications for humans (e.g. micropenis). Our studies aimed to establish in rats when androgen action/administration affects development/growth of the penis and if deficits in MPW androgen action were rescuable postnatally. Thus, pregnant rats were treated with flutamide during the MPW +/- postnatal testosterone propionate (TP) treatment. To assess penile growth responsiveness, rats were treated with TP in various time windows (late foetal, neonatal through early puberty, puberty onset, or combinations thereof). Phallus length, weight, and morphology, hypospadias and anogenital distance (AGD) were measured in mid-puberty (d25) or adulthood (d90) in males and females, plus serum testosterone in adult males. MPW flutamide exposure reduced adult penile length and induced hypospadias dose-dependently; this was not rescued by postnatal TP treatment. In normal rats, foetal (e14.5-e21.5) TP exposure did not affect male penis size but increased female clitoral size. In males, TP exposure from postnatal d1-24 or at puberty (d15-24), increased penile length at d25, but not ultimately in adulthood. Foetal + postnatal TP (e14-postnatal d24) increased penile size at d25 but reduced it at d90 (due to reduced endogenous testosterone). In females, this treatment caused the biggest increase in adult clitoral size but, unlike in males, phallus size was unaffected by TP during puberty (d15-24). Postnatal TP treatment advanced penile histology at d25 to more resemble adult histology. AGD strongly correlated with final penis length. It is concluded that adult penile size depends critically on androgen action during the MPW but subsequent growth depends on later androgen exposure. Foetal and/or postnatal TP exposure does not increase adult penile size above its 'predetermined' length though its growth towards this maximum is advanced by peripubertal TP treatment.
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