11-BETA-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 parturitio n. Recent studies show that luteal regression in the rat can be blocke d by the administration of synthetic glucocorticoids, yet endogenous g lucocorticoids are maximal at the time of normal luteal regression in pregnancy. This suggests that endogenous glucocorticoid may be inactiv ated locally within the CL, presumably via the enzyme 11 beta-hydroxys teroid dehydrogenase type 2 (11 beta-HSD-2), which is known to regulat e glucocorticoid access to receptors in other target tissues. This pos sibility was examined in the present study by measurement of 11 beta-H SD-2 messenger RNA (mRNA) expression and bioactivity in rat CL over th e second half of pregnancy, pregnancy, thus covering periods of maxima l and minimal progesterone secretion. 11 beta-HSD-2 bioactivity was me asured in luteal homogenates obtained from rats on days 11, 16, 19, an d 22 of pregnancy (term=day 23). Bioactivity was measurable in CL at e ach stage of pregnancy, with an apparent K-m for corticosterone of app roximately 100 nM. Enzyme activity was lowest on day 11 (maximum veloc ity, 1.0+/-0.6 pmol/min . mg protein), increased more than 5-fold by d ay 16 (6.2+/-0.5), then increased by an additional 4-fold by day 19 (2 4.3+/-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 bioactivi ty in CL, mRNA for 11 beta-HSD-2 was not detectable in CL by Northern analysis on either day 11 or day 16, but was clearly evident on days 1 9 and 22. In situ hybridization also revealed a substantial up-regulat ion of 11 beta-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 expressi on in CL for either 11 beta-HSD-1 or the mineralocorticoid receptor at any stage. These data show that a marked induction of 11 beta-HSD-2 m RNA expression and bioactivity occurs within the CL late in rat pregna ncy and thus suggest that local inactivation of endogenous glucocortic oids facilitates luteal regression.