Anovulation in cyclooxygenase-2-deficient mice is restored by prostaglandin E-2 and interleukin-1 beta

Mice carrying a null mutation for either of the two cyclooxygenase (COX) is oenzymes, necessary for prostanoid production, exhibit several isotype-spec ific reproductive abnormalities. Mice deficient in COX-1 are fertile but ha ve decreased pup viability, whereas mice deficient in COX-2 fail to ovulate and have abnormal implantation and decidualization responses. The present study identifies the specific contribution of each COX isoenzyme in hypotha lamic, pituitary, and ovarian function and establishes the pathology and re scue of the anovulatory syndrome in the COX-3-deficient mouse. In both COX- 1-and COX-2-deficient mice, pituitary gonadotropins were selectively increa sed, whereas hypothalamic LHRH and serum gonadotropin levels were similar t o those in wild-type animals (+/+). No significant differences in serum est rogen or progesterone were noted among the three genotypes. Exogenous gonad otropin stimulation with PMSG and hCG produced a comparable 4-fold increase in ovarian PGE(2) levels in wild-type and COX-1(-/-) mice. COX-2(-/-) mice had no increase in PGE(2) over PMSG-stimulated levels. Wild-type and COX1( -/-) mice ovulated in response to PMSG/hCG; very few COX-2(-/-) animals res ponded to this regimen. The defect in ovulation in COX-2 mutants was attrib uted to both an abnormal cumulus oophorum expansion and subsequent stigmata formation. Gonadotropin stimulation and concurrent treatment with PGE(2) o r interleukin-1 beta resulted in ovulation of COX-2(-/-) mice comparable to that in COX-2(+/+) whereas treatment with PGF(2 alpha) was less effective. Collectively, these data demonstrate that COX-2, but not COX-1, is require d for the gonadotropin induction of ovarian PG levels; that COX-2-related p rostanoids are required for stabilization of the cumulus oophorum during ov ulation; and that ovulation can be restored in the COX-2(-/-) animals by si multaneous treatment with gonadotropins and PGE(2) or interleukin-1 beta.