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Laboratory of Experimental Pathology (B.J.D., D.E.L.) and Laboratory of Environmental Carcinogenesis/Mutagenesis (C.A.L., H.F.T., R.L.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; Myriad Genetics, Inc. (S.G.M.), Salt Lake City, Utah 84108; and the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center (W.C.W.), Durham, North Carolina 27710
Address all correspondence and requests for reprints to: Dr. Barbara J. Davis, Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Box 12233, Research Triangle Park, North Carolina 27709. E-mail: davis1{at}niehs.nih.gov
Mice carrying a null mutation for either of the two cyclooxygenase
(COX) isoenzymes, necessary for prostanoid production, exhibit several
isotype-specific reproductive abnormalities. Mice deficient in COX-1
are fertile but have 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 hypothalamic, pituitary, and
ovarian function and establishes the pathology and rescue of the
anovulatory syndrome in the COX-2-deficient mouse. In both COX-1- and
COX-2-deficient mice, pituitary gonadotropins were selectively
increased, whereas hypothalamic LHRH and serum gonadotropin levels were
similar to those in wild-type animals (+/+). No significant differences
in serum estrogen or progesterone were noted among the three genotypes.
Exogenous gonadotropin stimulation with PMSG and hCG produced a
comparable 4-fold increase in ovarian PGE2 levels in
wild-type and COX-1-/- mice. COX-2-/- mice
had no increase in PGE2 over PMSG-stimulated levels.
Wild-type and COX-1-/- mice ovulated in response to
PMSG/hCG; very few COX-2-/- animals responded to this
regimen. The defect in ovulation in COX-2 mutants was attributed to
both an abnormal cumulus oophorum expansion and subsequent stigmata
formation. Gonadotropin stimulation and concurrent treatment with
PGE2 or interleukin-1ß resulted in ovulation of
COX-2-/- mice comparable to that in COX-2+/+,
whereas treatment with PGF2
was less effective.
Collectively, these data demonstrate that COX-2, but not COX-1, is
required for the gonadotropin induction of ovarian PG levels; that
COX-2-related prostanoids are required for stabilization of the
cumulus oophorum during ovulation; and that ovulation can be restored
in the COX-2-/- animals by simultaneous treatment with
gonadotropins and PGE2 or interleukin-1ß.
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