Serum Testosterone:estradiol Ratio and the Development of Hepatocellular Carcinoma Among Male Cirrhotic Patients

The reason for the large male predominance in the occurrence of hepatocellular carcinoma (HCC) remains unknown, and sex hormones may contribute to this phenomenon. We examined possible associations of serum levels of testosterone, free testosterone, estradiol, sex hormone binding globulin, and testosterone:estradiol ratio (T:E2 ratio) with HCC development in a follow-up study of 46 Japanese male patients with liver cirrhosis predominantly of hepatitis C virus origin (76%). Serum samples were collected between December 1985 and December 1987, and the patients were completely followed until the end of 1995 for an average of 5.1 years. During the follow-up period, 20 patients (43%) developed HCC. Univariate analysis demonstrated that serum T:E2 ratio and testosterone were significant predictors of HCC; the hazard ratios (and 95% confidence intervals) in the middle and upper tertiles relative to the lower tertile were 2.0 (0.5-7.6) and 4.0 (1.1-14.6; P trend = 0.03) for T:E2 ratio and 0.8 (0.2-3.1) and 2.9 (1.0-8.5; P trend = 0.05) for testosterone. Adjustment for age, serum albumin, hepatitis virus markers, and other clinicobiological variables substantially increased the corresponding hazard ratios. In multivariate analysis, serum free testosterone appeared to be associated with increased risk, yet independent associations with estradiol and sex hormone binding globulin were not evident. These results indicate that elevated serum testosterone, together with decreased serum estrogens, may promote the development of HCC in cirrhosis.