Hepatocellular alterations after intraportal transplantation of ovarian tissue in ovariectomized rats

The mechanisms of hepatocarcinogenesis by certain synthetic estrogens seem to involve both nongenotoxic and indirect genotoxic effects. However, the n atural estrogen estradiol did not exert any carcinogenic effects in establi shed experimental protocols. To elucidate specific long-term effects of nat ural estrogens on hepatocytes, small pieces of ovarian tissue were transpla nted via the portal vein into the livers of ovariectomized female rats. One week, 3 weeks, and 3 months after transplantation the transplants were fou nd to proliferate and to secrete estradiol, Three weeks after transplantati on the hepatocytes of the liver acini downstream of the stimulated transpla nts already showed a remarkable loss of glycogen, distinct cytoplasmic amph ophilia, enlargement of their nuclei, a strong increase in the number and s ize of peroxisomes, an increase in proliferative activity and apoptotic eli mination, and changes in the activity of certain key enzymes of energy meta bolism. All hepatocellular alterations could be inhibited by the estrogen r eceptor antagonist toremifene and are, therefore, attributed to specific ef fects of estradiol produced by the transplants. The observed alterations re semble in some respects amphophilic preneoplastic liver foci, which particu larly occur after long-term administration of nongenotoxic hepatocarcinogen s, including the adrenal steroid hormone dehydroepiandrosterone. In a preli minary experiment three of six animals exhibited a hepatocellular carcinoma , and another animal developed a hepatocellular adenoma 18 months after int rahepatic ovarian tissue transplantation.