SEXUAL DIMORPHISM OF HEPATIC 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN THE RAT - THE ROLE OF GROWTH-HORMONE PATTERNS

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the rever sible metabolism of corticosterone to inert 11-dehydrocorticosterone. At least two isoforms exist. 11 beta-HSD-1, the first to be characteri sed and the only isoform for which a cDNA has been isolated, is highly expressed in liver, kidney and hippocampus. The activity of 11 beta-H SD in rat liver is higher in males, due to oestrogen repression of 11 beta-HSD-1 gene transcription in females. Sexual dimorphism in rodent liver proteins is frequently mediated indirectly via sex-specific patt erns of GH release (continuous in females, pulsatile in males). We hav e now investigated whether this applies to 11 beta-HSD, using dwarf ra ts (congenitally deficient in GH) and hypophysectomised animals. 11 be ta-HSD activity and 11 beta-HSD-1 mRNA expression in liver was signifi cantly lower in control female than male rats (50% and 72% of male lev els respectively). These sex differences in the liver were attenuated in dwarf rats, with both males and females showing similar levels of 1 1 beta-HSD activity to control males. Administration of continuous (fe male pattern) GH to dwarf male rats decreased hepatic 11 beta-HSD acti vity (30% fall) and mRNA expression (77% fall), whereas the same total daily dose of GH given in the male (pulsatile) pattern had no effect on hepatic 11 beta-HSD in female dwarf rats. Continuous GH also attenu ated hepatic 11 beta-HSD activity (25% fall) and 11 beta-HSD-1 mRNA ex pression (82% fall) in hypophysectomised animals. However, oestradiol itself suppressed hepatic 11 beta-HSD activity (25% fall) and 11 beta- HSD-1 mRNA expression (60% fall) in hypophysectomised rats. Renal 11 b eta-HSD activity showed no sexual dimorphism in control or dwarf rats, although overall activity was lower in dwarf animals. By contrast, 11 beta-HSD-1 mRNA expression was higher in male than female kidney in b oth control and dwarf strains. Neither GH pattern had any effect on 11 beta-HSD activity or 11 beta-HSD-1 mRNA levels in the kidney of dwarf rats, although continuous GH attenuated 11 beta-HSD activity (28% fal l) and 11 beta-HSD-1 mRNA expression in kidney (47% decrease) in hypop hysectomised animals. Oestradiol attenuated renal 11 beta-HSD-1 mRNA e xpression (74% fall) in hypophysectomised rats, but increased enzyme a ctivity (62% rise) in the kidney. None of the manipulations had any ef fect on hippocampal 11 beta-HSD activity or gene expression. These dat a demonstrate the following. (i) Sexual dimorphism of hepatic 11 beta- HSD is mediated, in part, via sex-specific patterns of GH secretion ac ting on 11 beta-HSD-1 gene expression. (ii) There is an additional dir ect repressive effect of oestrogen on hepatic 11 beta-HSD-1. (iii) Oth er tissue-specific factors are involved in regulating 11 beta-HSD-1, a s neither peripheral GH nor oestrogen have effects upon hippocampal 11 beta-HSD-1. (iv) The regulation of 11 beta-HSD-1 mRNA expression in t he kidney broadly parallels the Liver. The lack of correlation between changes in expression of the 11 beta-HSD-1 gene and renal 11 beta-HSD activity reflects the presence of an additional gene product(s) in th e kidney, the expression of which is largely independent of GH.