Expression of 11β-Hydroxysteroid Dehydrogenase, Glucocorticoid Receptor, and Mineralocorticoid Receptor Genes in Rat Ovary1

Abstract

A new concept in reproductive endocrinology is that the status of the ovary as a glucocorticoid target organ alters with follicular development. Evidence for a physiological role of glucocorticoids in the regulation of ovarian folliculogenesis has been strengthened by the discovery that 11beta-hydroxysteroid dehydrogenase (11betaHSD) mRNA expression in human granulosa cells is developmentally regulated. In this study, we quantified the pattern of expression and investigated the cellular location of 11betaHSD type 1 (11betaHSD1), 11betaHSD type 2 (11betaHSD2), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) mRNAs during follicular maturation in rat ovary. Immature female rats received treatment with eCG to induce preovulatory follicular development or eCG followed by hCG to induce luteinization. 11betaHSD1, 11betaHSD2, GR, and MR mRNAs were all detectable by ribonuclease protection assay in ovarian total RNA. Treatment with eCG alone caused an approximately 8-fold increase in the ovarian level of 11betaHSD1 mRNA, which rose to approximately 30-fold after additional treatment with hCG. Equine CG alone did not measurably affect the ovarian 11betaHSD2 mRNA level, but additional treatment with hCG reduced it to 34% of the control level. Expression of GR mRNA was unchanged by any gonadotropin treatment, while MR mRNA was down-regulated. A similar pattern of 11betaHSD1, 11betaHSD2, GR, and MR mRNA expression was observed in isolated granulosa cells. These results provide direct experimental evidence that 11betaHSD genes are gonadotropically regulated in the rat ovary, including granulosa cells, and are consistent with a shift in glucocorticoid metabolism from inactivation (due to oxidation by 11betaHSD2) to activation (reduction by 11betaHSD1) during hCG-induced granulosa cell luteinization.

Local Amplification of Glucocorticoids by 11β-Hydroxysteroid Dehydrogenase Type 1 Promotes Macrophage Phagocytosis of Apoptotic Leukocytes

“…Our data support this role and, in addition, illustrate the particular importance of 11␤ reduction of 11-keto glucocorticoids early in the inflammatory response in vivo. A similar anti-inflammatory role for 11␤-HSD1 in tissue repair of the ovary following ovulation has been proposed (28,29) where 11␤-HSD1 expression is induced in granulosa cells by the actions of luteinizing hormone and IL-1␤ (30) and in surface epithelial cells by IL-1␣ and TNF-␣ (31). Induction of sterile inflammation within the peritoneum resulted in a rapid and dramatic increase in 11␤-HSD1 activity in peritoneal cells, which declined to normal (resident) levels 4 days later.…”

Immunohistochemical Demonstration of the Mineralocorticoid Receptor, 11β-Hydroxysteroid Dehydrogenase-1 and −2, and Hexose-6-phosphate Dehydrogenase in Rat Ovary

“…Ovaries of animals such as the rat, in which many ova mature at once and the estrus cycle is relatively short, comprise many corpora from several cycles in various stages of degeneration. Tetsuka et al (1999) found that gonadotropin treatment of immature non-cycling rats increased ovarian mRNA for 11b-HSD1, decreased that for 11b-HSD2 and MR, and left GR mRNA levels unchanged . We did not find consistent cyclical changes in message for MR, 11b-HSD1, or 11b-HSD2, probably because our animals were postpubertal rats whose ovaries comprised corpora from several previous cycles in various stages of involution; nor was there a measurable difference in protein by Western blot for the 11b-HSD enzymes, although this is not a very quantitative method.…”

“…Cyclical changes in adrenal steroid receptors, 11b-HSD1, and/or 11b-HSD2 message in total RNA isolated from a variety of species have been reported, but the results are not consistent, probably due to differences in species and conditions of study (Tetsuka et al 1999(Tetsuka et al ,2003Thurston et al 2003a,b;Fru et al 2006;Jonas et al 2006). Ovaries of animals such as the rat, in which many ova mature at once and the estrus cycle is relatively short, comprise many corpora from several cycles in various stages of degeneration.…”

“…mRNA for the MR, as well as 11b-HSD1, 11b-HSD2, and GR, have been detected in rat ovaries (Tetsuka et al 1999). However, the dearth of specific antibodies that consistently recognize the MR protein in both Western blots and IHC has hindered its study until recently (Gomez-Sanchez et al 2006), and little is known about MR protein expression or function of the MR in the ovary.…”

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response

“…Prior to ovulation 11β-HSD2 but not 11β-HSD1 is expressed, rendering granulosa cells glucocorticoid insensitive. Following ovulation, only 11β-HSD1 is switched on in luteinised granulosa cells, being further increased by IL-1β (Tetsuka et al, 1999;Tetsuka et al, 1997). In addition, prostaglandins may increase 11β-HSD1 activity in luteinised granulosa cells (Jonas et al, 2006) (as well as in chorion trophoblast cells (Alfaidy et al, 2001)), although the prostaglandin induction of activity appeared to be mediated post-translationally.…”