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Glucocorticoids play important roles in organ development and 'fetal programming'. Fetal exposure to excess glucocorticoids reduces birth weight and causes later hypertension. To investigate these processes further we have determined the detailed ontogeny in the mouse of the glucocorticoid receptor (GR) and 11beta-hydroxysteroid dehydrogenase type-1 (11beta-HSD1), which amplifies glucocorticoid levels locally; the ontogeny was determined using in situ hybridisation from embryonic day 9.5 (E9.5, term=E19) until after birth. At E9.5 fetal GR mRNA levels are very low, except in fetal placenta. GR gene expression rises during gestation with striking tissue-specific differences in timing and extent. Before E13.5, an increase is clear in gastrointestinal (GI) and upper respiratory tracts, discrete central nervous system (CNS) regions, precartilage and especially in the liver (E10.5-E12). Later, further increases occur in lung, GI and upper respiratory tracts, muscle, pituitary and thymus. In a few tissues such increases are temporary, e.g. ureteric ducts (E13.5-E16.5) and pancreas (E14.5-E16.5, expression later falling sharply). Fetal 11beta-HSD1 mRNA expression is first clearly observed at E14.5-E15, initially in the fetal placenta then in the umbilical cord. Later, 11beta-HSD1 expression is seen as follows: (i) from E15 in lung and liver, rising strongly; (ii) thymus, from E15 (lower level); (iii) at low levels in a few brain regions, including the hippocampus (E16.5+); and (iv) in muscle group fascial planes and tendon insertions. This is the first detailed study of the ontogeny of these two genes and, in combination with previous work on the ontogeny of 11beta-HSD2 and the mineralocorticoid receptor, suggests potential critical periods of glucocorticoid sensitivity during development for several organ systems.

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1), a regulator of intrahepatocellular glucocorticoid activity, is bidirectional in homogenates but catalyses 11 beta-reduction (regenerating glucocorticoid) in intact primary hepatocytes in culture. To examine this discrepancy at the whole-organ level, we examined 11 beta-HSD-1 activity in the intact bivascularly perfused rat liver. On a single pass through male rat liver, 44+/-5% of 11-dehydrocorticosterone (11-DHC) recovered was 11 beta-reduced to corticosterone, whereas 10+/-1% of corticosterone was 11 beta-dehydrogenated to 11-DHC. 11 beta-Reduction was less in female liver (21+/-2%, P<0.01) and was significantly greater with perfusion of all substrate via the portal vein (50+/-3%) than via the hepatic artery (30+/-2%, P<0.05). 11 beta-Reductase activity was not saturated by 11-DHC (10(-)(9)-10(-)(6) M). Perfusion with carbenoxolone (CBX, 10(-)(6)-10(-)(3 )M) did not alter 11 beta-reduction of 11-DHC. In contrast, pretreatment with CBX in vivo (10 mg/day) for 7 days inhibited 11 beta-reductase (19+/-4% conversion, P<0.01). Concentrations of 11-DHC in male rat plasma were 44+/-6 nM. Thus 11 beta-HSD-1 is predominantly an 11 beta-reductase in the intact rat liver and is only inhibited by chronic administration of CBX. The substantial concentrations of plasma 11-DHC as substrate suggest that 11 beta-HSD-1 activity and its potential selective inhibition could modify glucocorticoid action in vivo.

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the reversible metabolism of corticosterone to inert 11-dehydrocorticosterone. At least two isoforms exist. 11 beta-HSD-1, the first to be characterised and the only isoform for which a cDNA has been isolated, is highly expressed in liver, kidney and hippocampus. The activity of 11 beta-HSD 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 patterns of GH release (continuous in females, pulsatile in males). We have now investigated whether this applies to 11 beta-HSD, using dwarf rats (congenitally deficient in GH) and hypophysectomised animals. 11 beta-HSD activity and 11 beta-HSD-1 mRNA expression in liver was significantly lower in control female than male rats (50% and 72% of male levels respectively). These sex differences in the liver were attenuated in dwarf rats, with both males and females showing similar levels of 11 beta-HSD activity to control males. Administration of continuous (female pattern) GH to dwarf male rats decreased hepatic 11 beta-HSD activity (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 attenuated hepatic 11 beta-HSD activity (25% fall) and 11 beta-HSD-1 mRNA expression (82% fall) in hypophysectomised animals.(ABSTRACT TRUNCATED AT 250 WORDS)

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) catalyses the reversible conversion of corticosterone to inactive 11-dehydrocorticosterone, thus regulating glucocorticoid access to mineralocorticoid and perhaps glucocorticoid receptors in vivo. 11 beta-OHSD has been purified from rat liver and an encoding cDNA isolated from a liver library. However, several lines of indirect evidence suggest the existence of at least two isoforms of 11 beta-OHSD, one found predominantly in glucocorticoid receptor-rich tissues and the other restricted to aldosterone-selective mineralocorticoid target tissues and placenta. Here we have examined the effects of chronic (10 day) manipulations of sex-steroid levels on 11 beta-OHSD enzyme activity and mRNA expression in liver, kidney and hippocampus and present further evidence for the existence of a second 11 beta-OHSD isoform in kidney. Gonadectomized male and female rats were given testosterone, oestradiol or blank silicone elastomer capsules, controls were sham-operated. In male liver, gonadectomy+oestradiol treatment led to a dramatic decrease in both 11 beta-OHSD activity (69 +/- 8% decrease) and mRNA expression (97 +/- 1% decrease). Gonadectomy and testosterone replacement had no effect on male liver 11 beta-OHSD. However, in female liver, where 11 beta-OHSD activity is approximately 50% of that in male liver, gonadectomy resulted in a marked increase in 11 beta-OHSD activity (120 +/- 37% rise), which was reversed by oestradiol replacement but not testosterone treatment. In male kidney, gonadectomy+oestradiol treatment resulted in a marked increase in 11 beta-OHSD activity (103 +/- 4% rise). By contrast, 11 beta-OHSD mRNA expression was almost completely repressed (99 +/- 0.1% decrease) by oestradiol treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Steroid-metabolizing enzymes modulate the effects of androgens on brain differentiation and function, but no similar enzymatic system has been demonstrated for adrenocorticosteroids which exert feedback control on the hypothalamus. 11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) rapidly metabolizes physiological glucocorticoids (corticosterone, cortisol) to inactive products, thereby regulating glucocorticoid access to peripheral mineralocorticoid and glucocorticoid receptors in a site-specific manner. Using in-situ hybridization, we found expression of 11 beta-OHSD mRNA in neurones of the hypothalamic paraventricular nucleus (PVN) where corticotrophin-releasing factor-41 (CRF-41) is synthesized and from where it is released into hypophysial portal blood. Administration of glycyrrhetinic acid (GE), a potent 11 beta-OHSD inhibitor, decreased CRF-41 release into hypophysial portal blood in the presence of unchanged circulating glucocorticoid levels, suggesting that 11 beta-OHSD regulates the effective corticosterone feedback signal to CRF-41 neurones. These effects of GE were not observed in adrenalectomized animals, demonstrating dependence on adrenal products. In contrast, GE led to two- to threefold increases in arginine vasopressin and oxytocin release into portal blood, effects also dependent upon intact adrenal glands. These results suggest that 11 beta-OHSD in the PVN, and possibly other sites, may represent a novel and important control point of corticosteroid feedback on CRF-41 release in vivo.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the conversion of physiological glucocorticoids to inactive products, thus modifying the access of glucocorticoids to glucocorticoid and mineralocorticoid receptors. Glucocorticoids may affect ovarian function both indirectly and via binding to ovarian receptors. We have demonstrated 11 beta-HSD bioactivity and mRNA expression in rat ovary in vitro. The enzyme was localized to oocytes and luteal bodies immunohistochemically using two antibodies raised against purified rat liver 11 beta-HSD. These data are supported by in-situ hybridization studies, which also localized 11 beta-HSD mRNA expression to oocytes and luteal bodies. The results suggest that 11 beta-HSD may modulate the effects of glucocorticoid on ovarian function.