The hypothesis that the plasma pattern of growth hormone (GH) regulates hepatic steroid metabolism in the rat was studied in two different animal models: 1) different plasma patterns of GH were achieved by the administration of human GH at different frequencies or by infusing the hormone continuously by means of Alzet osmotic minipumps to hypophysectomized female rats and 2) the plasma pattern of GH in animals with an intact pituitary gland was investigated under conditions which lead to feminization of hepatic steroid metabolism. The pattern of GH was determined by studying minimum and maximum plasma GH levels in blood samples taken from the tip of the tail at various times. After continuous administration of human GH to hypophysectomized female rats, the liver microsomal metabolism of 4-[4-14C]androstene-3,17-dione was feminized, e.g. the ratio between 5α-reductase and 16α-hydroxylase activities (5α/16α ratio) increased from 2.45 ± 0.21 to 31.2 ± 1.76. Similar results were observed when the animals were given the same total dose of hGH in sc injections every 3 h or every 6 h, whereas less frequent injections (every 12 h) were without feminizing effect. Orchidectomy or estrogen treatment of male rats resulted in the expected increase in the liver 5α/16α ratio. Concomitantly, increased minimum plasma GH levels were observed, i.e. the plasma pattern of GH became similar to that found in intact female rats. Replacement therapy with testosterone reversed the effect of orchidectomy on both the 5α/16α ratio and the plasma pattern of GH. These results demonstrate that the plasma pattern of GH influences hepatic steroid metabolism. Increased trough plasma GH values or absence of time periods with undetectable plasma levels of GH appears to be a major determinant for feminization of hepatic steroid metabolism. Since sex steroids were found to influence the plasma pattern of GH, it appears that differences in the plasma pattern of GH between male and female rats explain the sex-differentiated hepatic steroid metabolism.
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