Induction of atypical hyperplasia, apoptosis, and type II estrogen-binding sites in the ventral prostates of Noble rats treated with testosterone and pharmacologic doses of estradiol-17 beta.

BACKGROUND

We have previously shown that combined administration of testosterone (T) and a low dose of estradiol 17 beta (T+LDE2) for 16 weeks induces an atypical proliferative lesion, termed dysplasia, in the dorsolateral prostates of intact Noble rats (1, 2). The lesion was accompanied by increases in the levels of a moderate affinity, high capacity, estrogen-binding site (type II sites) found exclusively in dorsolateral prostates of these animals (1, 3). In contrast, a proliferative response and type II sites were not observed in the ventral prostates (VP) of the same rats treated with this hormonal regimen. In the current study, rats were treated with a higher dose of E2 (4 x LDE2) but the same dose of T (T+HDE2) for 16 weeks. Our aims were to determine how the VP would respond to the T+HDE2 treatment.

EXPERIMENTAL DESIGN

Intact Noble rats were treated with T+HDE2 for 16 weeks. Prostatic tissues were removed for histology, electronmicroscopy, and type II site measurements. Proliferating cells were identified by the histochemical detection of proliferating cell nuclear antigen and colcemid-arrested mitotic figures. Apoptotic cells were recognized by their characteristic histologic and ultrastructural features and by in situ detection of nuclear DNA fragmentation. Data were compared with results previously obtained from VP of rats treated with T+LDE2.

RESULTS

The VP of T+HDE2-treated animals contained focal atypical hyperplasia and wide-spread apoptosis. Proliferating cell nuclear Ag-positive-stained epithelial cells and mitotic figures were only present in foci of atypical hyperplasia. Total DNA content of the VP was significantly increased, but the tissue wet weight was not augmented. Nuclear type II sites, never observed in untreated or T+LDE2-treated rats, were detected in the VP of the majority of T+HDE2-treated animals.

CONCLUSIONS

The administration of a high dose of E2 with T produced a unique lesion in the VP, characterized by simultaneous occurrence of apoptosis and proliferation. The synergy between androgens and estrogens, via type II site induction, likely produces the proliferative response. On the other hand, inhibition of intracellular androgen activation pathways, leading to reduction in cell survival factors, may be the cause for the apoptotic development. Our model, thus, provides a unique opportunity to further study the balance/switch between cell proliferation and apoptosis that is often disturbed during cancer development.