Recent evidence suggests that 3a-diol is a ligand for ERs (preferentially ERp) and that it acts to regulate AR levels in the rat prostate. Whether or not 3a-diol regulates AR levels in any other regions of the male reproductive tract has not been investigated, but because one of the major effects of neonatal DES administration is the virtual abolition of AR protein expression in the epididymis, the potential involvement of 3a-diol is a possibility. Studies of the male rat anterior pituitary have shown that the conversion of DHT to 3a-diol is reversible and that 3a-hy-droxysteroid dehydrogenase (3a-HSD) can convert 3a-diol back into DHT.
3a-HSD is expressed in neonatal epididymides and may catalyze the local conversion of 3a-diol from the circulation into DHT, thus promoting the development of H+-ATPase-rich cells. It is possible that this metabolite is capable of acting as a potent androgen via conversion to DHT by 3a-HSD or as an estrogenic ligand with ERa or ERp. Because 3a-HSD, ARs, and ERs are all present in the pubertal epididymis, it is not possible to determine whether 3a-diol acts in one or all of these roles. The potential dual role of this metabolite reinforces how intimately the actions of androgens and estrogens may be linked. The data presented in our study demonstrate that DES can reduce H+-ATPase expression but to the same level as neonatal treatment with GnRHa. So, whereas our findings do not exclude direct estrogenic effects on the epididymis, they imply that this role is secondary to, and can be overcome by androgens.