Ofner P, Bosland M C, Vena R L
Tufts University School of Medicine, Boston, Massachusetts 02111.
Toxicol Appl Pharmacol. 1992 Feb;112(2):300-9. doi: 10.1016/0041-008x(92)90200-c.
Treatment of Noble rats with separate silastic implants containing testosterone (T) and estradiol-17 beta (E2) for 16 weeks has previously been shown to induce multifocal epithelial dysplasia, a putative preneoplastic lesion, consistently in the dorsolateral prostate (DLP) but not in the ventral prostate (VP). We now studied effects of diethylstilbestrol (DES) substituted for E2 on these prostate lobes under the same conditions of exogenous androgen support. Three-week treatments with one 1-cm-long silastic implant of E2 or DES were approximately equipotent in changing target-organ weights and plasma prolactin. Accordingly, rats received for 16 weeks one 1-cm-long E2 or DES implant and two 2-cm-long T implants. In contrast to T + E2, T + DES induced widespread multifocal VP dysplasia and less or no DLP dysplasia. A serum-free explant-culture assay was used to determine uptake and metabolic disposition of 3H-labeled 5 alpha-dihydrotestosterone (DHT), T, and E2. Dysplastic VP explants incubated with 1.7 microM 1 beta-3H-labeled DHT and T accumulated more 3H-labeled steroid, metabolized 69 and 50% less substrate to terminal hydroxylated metabolites, and thereby formed and retained up to eight times as much estrogenic metabolite 5 alpha-androstane-3 beta,17 beta-diol (3 beta-androstanediol) and its lipoidal derivative than control VP. Experimental DLP explants did not form or retain more 3 beta-[3H]androstanediol than control DLP irrespective of treatments. Control VP metabolized [2-3H]E2 more actively to estrone than DLP. Dysplastic VP, however, metabolized one-half and accumulated five times as much E2 as VP and did not release more 3H as a marker of the 2,3-catechol estrogen pathway. These data suggest that differential target-tissue bioavailability of the estrogen component of the protracted dual-hormone stimulus determines in which prostate lobe dysplasia develops.
先前的研究表明，用含有睾酮（T）和雌二醇 - 17β（E2）的单独硅橡胶植入物处理雄性大鼠16周，可在背外侧前列腺（DLP）中持续诱导多灶性上皮发育异常，这是一种假定的癌前病变，但在腹侧前列腺（VP）中则不会。我们现在研究了在相同的外源性雄激素支持条件下，用己烯雌酚（DES）替代E2对这些前列腺叶的影响。用一个1厘米长的E2或DES硅橡胶植入物进行为期三周的治疗，在改变靶器官重量和血浆催乳素方面大致等效。因此，大鼠接受了一个1厘米长的E2或DES植入物和两个2厘米长的T植入物，持续16周。与T + E2相反，T + DES诱导了广泛的多灶性VP发育异常，而DLP发育异常较少或没有。使用无血清外植体培养试验来测定3H标记的5α - 二氢睾酮（DHT）、T和E2的摄取和代谢情况。与1.7 microM 1β - 3H标记的DHT和T一起孵育的发育异常的VP外植体积累了更多的3H标记类固醇，将底物代谢为末端羟基化代谢物的量分别减少了69%和50%，因此形成并保留的雌激素代谢物5α - 雄甾烷 - 3β，17β - 二醇（3β - 雄甾二醇）及其脂类衍生物比对照VP多八倍。无论治疗如何，实验性DLP外植体形成或保留的3β - [3H]雄甾二醇都不比对照DLP多。对照VP比DLP更活跃地将[2 - 3H]E2代谢为雌酮。然而，发育异常的VP代谢的E2量是VP的一半，但积累量是VP的五倍，并且作为2,3 - 儿茶酚雌激素途径标记物的3H释放量并不更多。这些数据表明，长期双激素刺激中雌激素成分的靶组织生物利用度差异决定了发育异常发生在哪个前列腺叶。
