We have been engaged in a systematic study of the conditions of somatomedin generation in the rat correlating the dose and duration of GH administered to hypophysectomized rats, with the changes in serum somatomedin concentration and the uptake of S35-Sulfate by cartilage segments from the treated animals. We have found that the rise in serum somatomedin requires higher doses of GH than change in S35-Sulfate uptake by cartilage. These observations suggest that somatomedin may be removed from the serum rapidly on formation. The effects of cortisol and estrogens on somatomedin generation has been studied. In certain experiments that somatomedin rise induced by GH is inhibited by cortisol and estrogens. We have begun a study of somatomedin generation by liver. First of all, we have examined the GH receptors in liver membrane. Growth hormone receptors in pregnant rabbit liver membranes provide a good assay for receptor bindable GH. We are studying the effects of estrogens and GH in modifying receptor density in rat livers. We have perfected the conditions for rat liver perfusion and have shown that somatomedin like activity appears in the perfusate after the addition of GH to the medium. We are anxious to investigate whether a relationship exists between GH receptor density and the formation of somatomedin by isolated rat livers after exposure to GH. We also will investigate the effects of hormone synergism with GH in promoting somatomedin synthesis.