**4. 11-hydroxysteroid dehydrogenase – biological role in the regulation of glucocorticoid metabolisms and cortisol levels**

The glucocorticosteroids exert diverse actions throughout the body and many of them have important implications in the reproduction and metabolite syndrome. It was recognized that within potential target cells, the actions of glucocorticoids are modulated by 11 hydroxysteroid dehydrogenases (11β-HSD) which catalyse the reversible inactivation of cortisol and corticosterone to their inert 11-ketosteroid metabolites, cortisone and 11 dehydrocorticosterone, respectively [101]. The actions of physiological glucocorticoids (cortisol and corticosterone) are modulated by isoforms of the enzyme 11β-HSD (Figure 5, [108]). To date, two isoforms of 11β-HSD have been identified: 1) 11β-HSD1 acts predominantly as an NADP(H)-dependent reductase that converts inactive circulating 11 ketosteroids, into active glucocorticoids generating active cortisol or corticosterone; 2) 11β-HSD2 is a high affinity NAD+-dependent enzyme that catalyses the inactivation of glucocorticoids [102-107]. Although the biochemistry of 11β-HSD is well established, the physiological significance of glucocorticoid metabolism by these enzymes is still not fully

**Figure 5.** 11-hydroxysteroid dehydrogenase (11-HSD) (Adopted by Seckl et al., 2004 [108])

understood. The enzymatic inactivation of cortisol and corticosterone by 11β-HSD enzymes appears to be of central importance for protection of gonadal steroidogenesis, prevention of intra-uterine growth retardation and metabolite syndrome.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 129

histochemical demonstration of 11-HSD in the rat LCs on 35 pnd. The developmental pathway of ALCs population is accompanied with an increase in the 11-HSD activity and thus the enzyme can be used as a marker for steroidogenic differentiation of LCs [112,124,126,127]. Examination of 11-HSD in the LCs revealed that both oxidative and reductive activities were barely detectable in the progenitors (PLCs), intermediate in immature type (ILCs), and highest in ALCs. The ratio of the two activities favored reduction in PLCs and ILCs and oxidation in ALCs [109]. Clear recognizable oxidative activity of 11- HSD is present from 31 pnd onward, first in single ALCs and later in majority of these cells [127]. ALCs population expresses high levels of 11-HSD oxidative activity [109,125] and enzymatic behavior of 11-HDS in LCs is not consistent with the presence of type 1 alone [127,128]. Developmental analysis of 11-HSD in rat LCs revealed that 11-HSD reductive activity predominated in LCs precursors, whereas in adult LCs, the enzyme was primarily oxidative [118]. This switch, observed in the predominant direction of catalysis of 11-HSD from reduction to oxidation in adult LCs, may protect this cell type from glucocorticoidmediated inhibition of steroidogenesis. It was demonstrated that the adult LCs expressed not only 11-HSD type 1, an oxidoreductase, but also type 2, an unidirectional oxidase [129, 130]. Due to its high affinity for glucocorticoid substrates and exclusively oxidative activity, 11-HSD type 2 may also play a protective role in blunting the suppressive effects of glucocorticoids on LCs steroidogenesis. The inhibition of 11-HSD1 predominantly lowered reductase activity whereas by inhibition of 11-HSD2 alone, the oxidase activity was more prominently suppressed [131]. Recently, it has been reported that products such 7αhydroxytestosterone significantly switched 11β-HSD1 oxidoreductase activities toward reductase in developing rat testis and thus regulates the direction of 11β-HSD1 activity in LCs [132]. It seems that the switch of 11-HDS activity from reduction to oxidation during the transition from PLCs to ALCs [109] can be associated with the presence of 11-HSD2.

As mentioned above the main function of glucocorticoids in adult LCs is inhibition of T biosynthesis [111]. Glucocorticoids directly regulate T production in LCs through glucocorticoid receptor (GR)-mediated repression of the genes that encode T biosynthetic enzymes [143,109]. The response of LCs to glucocorticoids depends not only on the number of GR and the circulating concentration of glucocorticoids, but also on the ratio of 11-HSD oxidative and reductive activities [144]. When oxidation predominates over reduction, 11- HSD decreases the intracellular availability to active glucocorticoid, attenuating GRmediated responses [118]. In this way, T production is maintained in the presence of normal serum concentrations of corticosterone and it is inhibited only if 11-HSD oxidative capacity

By using experimental model for treatment with ethane-dimethnesulphonate (EDS) of mature rats our studies provided new data about expression pattern of 11-HSD during renewal of LCs population [133]. The quantitative immunohistochemical analysis of 11 HSD2 pattern after EDS treatment revealed progressive increases in the reaction intensity during postnatal development (on d 21after EDS) and reached a maximum on d35 and that is a turning point in the development from immature to mature LCs [133]. These changes in 11-HSD2 expression are consistent with previous data about structural and functional

in LCs is reduced.

This review focuses on the importance of 11β-HSD isoenzymes in the developing and aging testis, ovary, adrenal gland, placenta and adipose tissue. The current work aims to provide recent understanding of the biological roles played by 11β-HSD in different processes and diseases including reproduction, adrenal gland function, cystic ovarian disease, and the metabolite syndrome. In addition, this review summarizes recent knowledge based on human data and genetic models on the clinical importance of 11β-HSD in relation to metabolite syndrome.
