Ea. Kurzrock et al., Urethral development in the fetal rabbit and induction of hypospadias: A model for human development, J UROL, 164(5), 2000, pp. 1786-1792
Purpose: To determine whether the development of the rabbit phallus would b
e an appropriate model of human phallic development, we evaluated the forma
tion of the fetal rabbit phallus and attempted to induce hypospadias pharma
cologically.
Materials and Methods: New Zealand rabbit fetuses were obtained on gestatio
nal days 20 to 24, 26, 28 and 31. Sex was determined by gonadal morphology,
and 6 fetuses were obtained at each age. The perineum was dissected, fixed
, sectioned and stained with hematoxylin and eosin, and monoclonal antibodi
es against neuronal specific enolase. Two pregnant rabbits were treated wit
h 10 mg./kg. finasteride orally daily between gestational days 19 and 28. T
he development of the external genitalia was compared in treated and untrea
ted control rabbits.
Results: The rabbit phallus contains 2 corpora cavernosa and dorsolateral n
erves similar to the human. In male and female fetuses fusion of the urethr
al folds progressed in a proximal to distal sequence forming a seam at the
point of ventromedial fusion. In male fetuses urethral fold and ventral pre
putial fusion continued more distally toward the glans compared to females.
Thus, in mature males the urethral meatus and ventral prepuce extended to
the tip of the phallus, whereas in females the urethral meatus opened on th
e proximal phallus and the prepuce was deficient ventrally forming a dorsal
hood. Male offspring had a significantly larger anogenital distance postna
tally than female offspring. In male fetuses exposed to finasteride urethra
l fusion did not extend distally and the prepuce was deficient ventrally. A
lso, male offspring exposed to finasteride in utero had a significantly sho
rter anogenital distance than females and untreated control males at all ag
es (p <0.05).
Conclusions: Fetal development of the rabbit phallus and urethra is homolog
ous to the human. Although the gestational period is significantly shorter,
the temporospatial pattern of external genitalia development is analogous
in these species. Feminization of the rabbit urethra, hypospadias, can be i
nduced by inhibiting 5 alpha-reductase. Use of this animal model will allow
further study of molecular mechanisms involved in urethral fusion and the
evaluation of the pathophysiological processes of hypospadias.