Ovulation may constitute a cyclic, inflammatory-like process, wherein the increased expression of interleukin (IL)-1 and the biosynthesis of prostaglandins may be established corollaries. In this communication we hypothesize that glucocorticoids, potent anti-inflammatory principles, may exert an antiovulatory effect by interfering with ovarian IL-1-driven prostaglandin biosynthesis. To test this hypothesis, we examined the effect of treatment with dexamethasone on the activity of ovarian phospholipase A₂ (PLA₂), the event-limiting enzyme in prostaglandin biosynthesis, and on the gene expression pattern of secretory and cytosolic PLA₂ (sPLA₂ and cPLA₂, respectively). Whole ovarian dispersates from immature rats were cultured under serum-free conditions for 48 h in the absence or presence of dexamethasone. At the conclusion of this culture period, PLA₂ activity was determined in cell sonicates and conditioned media. Parallel probing for sPLA₂ and cPLA₂ transcripts was also undertaken using a solution hybridization/RNAse protection assay. Treatment of whole ovarian dispersates with dexamethasone produced a significant (P<0.005) decrease in basal cellular and extracellular PLA₂ activity to 27 and 40% of controls, respectively. A 5-fold decrease in the basal steady state levels of sPLA₂ (but not cPLA₂) transcripts was also noted. Co-treatment with dexamethasone produced complete inhibition of IL-1-stimulated cPLA₂ transcripts but not of IL-1-supported cellular and extracellular PLA₂ activity or sPLA₂ transcripts. A glucocorticoid receptor antagonist (RU486), blocked the ability of dexamethasone to inhibit basal sPLA₂ transcripts and extracellular PLA₂ activity. The inhibitory effect of dexamethasone proved glucocorticoid-specific in that aldosterone and 17β-estradiol were without effect. Taken together, these observations suggest that dexamethasone is capable of inhibiting basal (but not IL-1-supported) ovarian PLA₂ activity, a glucocorticoid receptor-mediated effect due, in part, to a decrease in sPLA₂ gene expression. Our findings further suggest that sPLA₂ and cPLA₂ are differentially regulated and that they may well differ in their relative contribution to ovarian prostaglandin biosynthesis in general and to PLA₂ activity in particular. To the extent that IL-1 plays a central role in the ovulatory process, these findings argue against the view that the chronic anovulatory state induced by glucocorticoid excess is due, if only in part, to suppression of ovarian IL-1-dependent PLA₂ activity.