Growth Stimulation and Tumor Promotion in Rat Liver by Ethynyl Estradiol and Other Estrogens

Abstract

During the mid 1970s, a series of case reports were published that described a strong association in women between prolonged oral contraceptive (OC) use and the appearance of liver neoplasms (1,2). Based on clinical observations, which included a few examples of regression of the liver neoplasms following cessation of OC use, and the experimental demonstrations that synthetic estrogens were not mutagenic, we hypothesized that the synthetic steroidal estrogens would be promoters of hepatocarcinogenesis (3). Subsequently, we (3) and others (2,4) demonstrated that mestranol (17-α ethynyl estradiol 3-methyl ether) and ethynyl estradiol (EE) are promoters of the appearance of preneoplastic foci and hepatocellular carcinomas in several strains of female rats. The strength of the promoting ability of these estrogens compared to several other promoters in the rat model of hepatocarcinogenesis is indicated by calculation of their promotion indices (PI), which are a function of the volume fraction of treated liver occupied by altered hepatic foci (AHF), divided by the volume fraction of control liver occupied by AHF, times the dose of promoting agent administered per week (5). The PI of phenobarbital, a classic liver promoter, was calculated to be 140, whereas the PIs for mestranol, EE, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were calculated to be 54,000, 93,000, and 28,000,000, respectively. Thus, while the synthetic steroidal estrogens are considerably less potent than TCDD, they are approximately 400–700 times more potent than phenobarbital. In addition, both mestranol and EE treatment results in the appearance of AHF in the livers of noninitiated rats. However, studies on these two estrogens conducted in two laboratories failed to demonstrate significant genotoxic effects or ability to initiate hepatocarcinogenesis.