Experimental data were collected to test whether the effect of estrogens required a direct action of the steroid on their target cells for induction of (i) cell multiplication and (ii) cell-type-specific protein synthesis. Ovariectomized quails were perfused for 24 hr with several doses of estradiol-17beta (E(2)) (0.05-6.8 ng/min) through either the jugular vein or the portal vein. E(2) plasma concentrations increased progressively when the perfusion rate through the jugular vein was 0.5 ng/min and higher. With the portal vein, by contrast, E(2) plasma concentrations increased over the concentration in unperfused ovariectomized animals only when the perfusion rate was above 2 ng/min. An increase in DNA concentration per oviduct was observed regardless of the route of administration and the rate of perfusion, starting at 0.5 ng/min. Nuclear estrophilins increased when E(2) was perfused through the jugular vein at rates of 0.5 ng/min or greater. This same parameter was not increased in oviducts of quail perfused through the portal vein even at a perfusion rate of 2.0 ng/min. Progestophilins were induced in the oviducts of quail perfused through the jugular vein at rates of 2 ng/min and above; on the other hand, progestophilins were induced in birds perfused through the portal vein at rates above 2 ng/min. Ovalbumin was not induced in quail oviducts at any rate and route of perfusion. The induction of the synthesis of cell-type-specific protein (progestophilins, in this case) seems to require, however, the direct action of E(2). The E(2) concentrations effecting the induction of progestophilins were higher than those necessary to effect the proliferation of oviduct cells. These results suggest that the E(2) effect on cell proliferation is indirect, it involves an intermediary step at the liver, and it does not require increased concentration of nuclear estrophilins.