Corticosterone inhibits proliferation of rat liver cells, but it can be inactivated by blocking its cytoplasmic receptors in liver cells with other steroids (progesterone). High levels of progesterones in animals lead to stimulated proliferation in the liver. Abnormally high proliferation in the liver may promote malignant transformation or may make it possible for smaller amounts of hepatocarcinogenic substances to induce tumors in a shorter time than normal.There now appears to be a good correlation between long-term steroid treatment and the incidence of liver tumors. Certain changes in the liver cells after steroid treatment have been observed and are of the same nature as changes in livers with cirrhosis or viral hepatitis. These 2 diseases are known to have a high liver tumor incidence rate. Some steroids are known to be active as cocarcinogenic substances during the growth of liver tumors induced by different carcinogens. Many indices indicate that steroid hormones induce or promote tumors, but the mechanism of action remains unknown. Goldfarb (1976) proposed that these steroids may be lowgrade carcinogens or that they may be converted into carcinogenic compounds through partial degradation by intestinal bacteria or by drug metabolizing systems in hepatocytes. A different model is proposed to clarify the mechanism of steroid action and its relation to the induction of liver tumors. The physiological rate of cell renewal in the lives of adult rats is constant. At any time 1% of the liver cells are in the DNA synthesis phase and 0.001% are in mitosis. During pregnancy or after removal or destruction of liver cells, the rate of cell proliferation increases greatly. The intensity of cell proliferation in the liver of rats depends on the concentration of biologically active corticosterone in the blood. After total adrenalectomy of adult male rats, the corticosterone level in the serum declines in the 1st and 2nd postoperative days from 5 mcg/100 ml of serum to an undetectable amount. The inhibitory effect of the corticosteroids on DNA synthesis in liver cells "in vitro" is well known. It is assumed that corticosterone is an inhibitor of cell proliferation in the liver and that reduction or elimination of corticosterone results in cell proliferation in the liver. Elimination of corticosterone cannot be effected by adrenalectomy in male rats. Theoretically it is shown that the stimulation by progesterone results in inactivation of corticosterone. No significant differences are observed between the corticosterone concentrations in control and pregnant rats, but there is a significant increase of progesterone. The injection of progesterone stimulates mitoses in the liver with the number of mitoses being dependent on the amount and the number of injections of this hormone.
