11β-Hydroxysteroid dehydrogenase type 2 in the rat corpus luteum: Induction of messenger ribonucleic acid expression and bioactivity coincident with luteal regression

The corpus luteum (CL) is the major source of progesterone during rat pregnancy, and its regression precedes and is essential for parturition. Recent studies show that luteal regression in the rat can be blocked by the administration of synthetic glucocorticoids, yet endogenous glucocorticoids are maximal at the time of normal luteal regression in pregnancy. This suggests that endogenous glucocorticoid may be inactivated locally within the CL, presumably via the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β- HSD-2), which is known to regulate glucocorticoid access to receptors in other target tissues. This possibility was examined in the present study by measurement of 11β-HSD-2 messenger RNA (mRNA) expression and bioactivity in rat CL over the second half of pregnancy, thus covering periods of maximal and minimal progesterone secretion. 11β-HSD-2 bioactivity was measured in luteal homogenates obtained from rats on days 11, 16, 19, and 22 of pregnancy (term = day 23). Bioactivity was measurable in CL at each stage of pregnancy, with an apparent K(m) for corticosterone of approximately 100 nM. Enzyme activity was lowest on day 11 (maximum velocity, 1.0 ± 0.6 pmol/min · mg protein), increased more than 5-fold by day 16 (6.2 ± 0.5), then increased by an additional 4-fold by day 19 (24.3 ± 4.3), and this high level of activity was maintained to day 22 (26.5 ± 5.2). In kidney, the apparent K(m), for corticosterone was lower than that in CL, but remained unchanged throughout pregnancy [overall mean, 28.9 ± 1.9 nM) as did the maximum velocity (overall mean, 25.4 ± 1.3 pmol/min · mg protein). Consistent with the pattern of bioactivity in CL, mRNA for 11β-HSD-2 was not detectable in CL by Northern analysis on either day 11 or day 16, but was clearly evident on days 19 and 22. In situ hybridization also revealed a substantial up- regulation of 11β-HSD-2 expression specifically within the CL on days 19 and 22, whereas glucocorticoid receptor mRNA expression was consistent across all stages. In contrast, there was no detectable mRNA expression in CL for either 11β-HSD-1 or the mineralocorticoid receptor at any stage. These data show that a marked induction of 11β-HSD-2 mRNA expression and bioactivity occurs within the CL late in rat pregnancy and thus suggest that local inactivation of endogenous glucocorticoids facilitates luteal regression.