EVIDENCE FROM DWARF RATS THAT GROWTH-HORMONE MAY NOT REGULATE THE SEXUAL-DIFFERENTIATION OF LIVER CYTOCHROME-P450 ENZYMES AND STEROID 5-ALPHA-REDUCTASE

Differences in the pattern of growth hormone (GH) secretion in mature rats (i.e., "continuous" secretion in females versus "pulsatile" secretion in males) are thought to be the underlying cause of sex-dependent differences in a subpopulation of liver microsomal P450 enzymes and steroid 5-alpha-reductase. A new strain of dwarf rats (NIMR/AS) has recently been shown to have low or undetectable levels of circulating GH due to a selective defect in pituitary GH synthesis. We have measured the levels and/or activity of IIA1 (P450a), IIA2 (P450m), IIC11 (P450h), IIC12 (P450i), IIIA2 (a P450p isozyme), and steroid 5-alpha-reductase in liver microsomes from male and female dwarf rats, to test the hypothesis that the expression of these sexually dimorphic enzymes is regulated by GH. In mature rats, the levels of liver microsomal IIA2, IIC11, and IIIA2 were higher in male than in female dwarf rats, whereas the levels of activity of IIA1, IIC12, and steroid 5-alpha-reductase were greater in female than in male dwarf rats. These sex differences resulted from age-related changes in either male dwarf rats (i.e., an increase in IIC11 and IIA2 and a decrease in IIA1) or female dwarf rats (i.e., an increase in IIC12 and 5-alpha-reductase and a decrease in IIIA2). The magnitudes of these sex-dependent, age-related changes were essentially indistinguishable from those observed in normal rats. These unexpected results suggest that GH is not the pituitary factor responsible for regulating the levels of sexually dimorphic, steroid-metabolizing enzymes in rat liver. Alternatively, it is possible that these enzymes are regulated by extremely low levels of GH. In either case, the current model of how steroid-metabolizing enzymes are regulated in rats must be revised to account for the normal sexual differentiation of these enzymes in dwarf rats.