Dose-related opposite effects of hydrocortisone on hepatocyte proliferation in the rat

To evaluate the role of glucocorticoids in the regulation of hepatocyte proliferation, high doses (6.25 mg/kg or more) and low doses (1.25 mg/kg or less) of hydrocortisone were injected into various categories of rats which had very different levels of proliferation. We used: (a) suckling rats whose stable unsynchronized proliferation can be stimulated and synchronized by acute inflammation or cyproterone feeding; (b) adult rats with a low level of proliferation, and (c) 2/3 hepatectomized rats during the first period of synchronized proliferation or during the second period of lower and unsynchronized proliferation. The kinetics of the labelling index and mitotic index were observed after hydrocortisone injection. High doses inhibited proliferation, as already found by many investigators. This effect was observed in suckling and hepatectomized rats and during acute inflammation in suckling or adult rats. Low doses had no inhibitory activities and, on the contrary, stimulated proliferation in some situations. The highest stimulations were observed during the early period after 2/3 hepatectomy or in combination with acute inflammation either in suckling rats or in 2/3 hepatectomized rats during the late period of regeneration. In all these situations hydrocortisone was a cofactor active during the early G1-phase. In contrast, in normal suckling rats a slight stimulation was observed due to an action at the G0-G1 transition. No such effect was found in adult rats. Our data show that doses of hydrocortisone in the therapeutic range or close to physiological values do not inhibit and, on the contrary, can stimulate hepatocyte proliferation.