Critical androgen‐sensitive periods of rat penis and clitoris development

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.

‘Idiopathic’ partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?

“…In addition, to our knowledge, there is no report dealing with the association of micropenis and prenatal EDC contamination, whereas in experimental animals (67,68), as well as in our recent clinical experience, this is the malformation most likely to be associated with such exposure. The medical histories actually indicated that within this group of infants with an 'idiopathic' PAIS-like phenotype, 11 newborns/infants -that is, nearly 40% -had parents who reported environmental or occupational exposure to EDCs before/during the patients' fetal life and all patients presented severe forms of micropenis (16.20G5.77 mm; Fig.…”

The relationship between anogenital distance and age

“…Welsh et al, 2010) Human studies have also established that exposure to endocrine disrupting agents can shorten male infant perineal lengths. (Swan et al, 2005) (Torres-Sanchez et al, 2008) Thus, current studies suggest that gestational exposures may play a critical role in male fertility and adult testicular function.…”

Testicular function and physical outcome in young adult males diagnosed with idiopathic 46 XY disorders of sex development during childhood

“…It has been shown that adult penis size in rats is critically dependent on androgen action during the fetal masculinization programming window, during which androgens must act to ensure correct subsequent development. Moreover, postnatal testosterone treatment does not increase the size of the adult penis beyond its 'predetermined' length, though growth toward this maximum is advanced by peripubertal testosterone treatment (29,30).…”