INDUCTION OF ATYPICAL HYPERPLASIA, APOPTOSIS, AND TYPE-II ESTROGEN-BINDING SITES IN THE VENTRAL PROSTATES OF NOBLE RATS TREATED WITH TESTOSTERONE AND PHARMACOLOGICAL DOSES OF ESTRADIOL-17-BETA

BACKGROUND: We have previously shown that combined administration of t estosterone (T) and a low dose of estradiol 17 beta (T+LDE(2)) for 16 weeks induces an atypical proliferative lesion, termed dysplasia, in t he dorsolateral prostates of intact Noble rats (1, 2). The lesion was accompanied by increases in the levels of a moderate affinity, high ca pacity, estrogen-binding site (type II sites) found exclusively in dor solateral prostates of these animals (1, 3). In contrast, a proliferat ive response and type II sites were not observed in the ventral prosta tes (VP) of the same rats treated with this hormonal regimen. In the c urrent study, rats were treated with a higher dose of E(2) (4 x LDE(2) ) but the same dose of T (T+HDE(2)) for 16 weeks. Our aims were to det ermine how the VP would respond to the T+HDE(2) treatment. EXPERIMENTA L DESIGN: Intact Noble rats were treated with T+HDE(2) for 16 weeks. P rostatic tissues were removed for histology, electronmicroscopy, and t ype II site measurements. Proliferating cells were identified by the h istochemical detection of proliferating cell nuclear antigen and colce mid-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 resul ts previously obtained from VP of rats treated with T+LDE(2). RESULTS: The VP of T+HDE(2)-treated animals contained focal atypical hyperplas ia and widespread apoptosis. Proliferating cell nuclear Ag-positive-st ained epithelial cells and mitotic figures were only present in foci o f atypical hyperplasia. Total DNA content of the VP was significantly increased, but the tissue wet weight was not augmented. Nuclear type I I sites, never observed in untreated or T+LDE(2)-treated rats, were de tected in the VP of the majority of T+-HDE(2)-treated animals. CONCLUS IONS: The administration of a high dose of E(2) with T produced a uniq ue lesion in the VP, characterized by simultaneous occurrence of apopt osis and proliferation. The synergy between androgens and estrogens, v ia type II site induction, likely produces the proliferative response. On the other hand, inhibition of intracellular androgen activation pa thways, leading to reduction in cell survival factors, may be the caus e for the apoptotic development. Our model, thus, provides a unique op portunity to further study the balance/switch between cell proliferati on and apoptosis that is often disturbed during cancer development.