Abstract
This study investigated cortisol inactivation by 11beta-hydroxysteroid dehydrogenase (11beta HSD) enzymes in porcine granulosa cells from antral follicles at different developmental stages and in ovarian cysts. In granulosa cells, cortisol oxidation increased threefold with antral follicle diameter (P < 0.001). This trend was paralleled by a threefold increase in NADP(+)-dependent 11beta-dehydrogenase activity in granulosa cell homogenates with follicle diameter. Intact granulosa cells from ovarian cysts exhibited significantly lower enzyme activities than cells from large antral follicles. Neither intact cells norcell homogenates displayed net 11-ketosteroid reductase activities. Since porcine follicular fluid (FF) from large antral follicles and ovarian cysts contains hydrophobic inhibitors of glucocorticoid metabolism by type 1 11beta HSD, this studyalso investigated whether levels of 11beta HSD inhibitors changed during follicle growth and could affect cortisol metabolism in granulosa cells. The extent of inhibition of 11beta HSD1 activity in rat kidney homogenates decreased progressively from 50 +/- 8% inhibition by FF from small antral follicles (P < 0.001) to 23 +/- 6% by large antral FF (P < 0.05). Cyst fluid inhibited 11beta HSD1 activity by 59 +/- 4% (P < 0.001). Likewise, net cortisol oxidation in granulosa cells was significantly decreased by large antral FF (35-48% inhibition, P < 0.05) and cyst fluid (45-75% inhibition, P < 0.01). We conclude that inactivation of cortisol by 11beta HSD enzymes in porcine granulosa cells increases with follicle development but is significantly decreased in ovarian cysts. Moreover, changes in ovarian cortisol metabolism are accompanied by corresponding changes in the levels of paracrine inhibitors of 11beta HSD1 within growing ovarian follicles and cysts, implicating cortisol in follicle growth and cyst development.
Highlights
Inter-conversion of the physiological glucocorticoid, cortisol and its inert 11-ketosteroid metabolite, cortisone, is catalysed by 11b-hydroxysteroid dehydrogenase (11bHSD) enzymes
Net 11b-dehydrogenase activities increased in granulosa cells during antral follicle growth but low levels of cortisol oxidation were observed in granulosa cells from ovarian cysts
The inhibitory effects of FF and cyst fluid on cortisol oxidation in porcine granulosa cells could be attributed to hydrophobic components eluted at high concentrations of methanol, consistent with our previous findings regarding suppression of NADP(H)-dependent cortisol metabolism in rat kidney homogenates by hydrophobic components of porcine follicular fluid (FF; Thurston et al 2003a)
Summary
Inter-conversion of the physiological glucocorticoid, cortisol and its inert 11-ketosteroid metabolite, cortisone, is catalysed by 11b-hydroxysteroid dehydrogenase (11bHSD) enzymes. 11bHSD1, first isolated from the liver (Lakshmi & Monder 1988), can catalyse both cortisol oxidation and cortisone reduction, albeit with a relatively low substrate affinity (Agarwal et al 1989, Monder & Lakshmi 1990, Tannin et al 1991). This NADP(H)-dependent enzyme is bidirectional, the current view is that in most tissues q 2007 Society for Reproduction and Fertility ISSN 1470–1626 (paper) 1741–7899 (online). This has been attributed to preferential usage of NADPH for gonadal steroid synthesis (Michael et al 2003, Ge et al 2005).
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