Rescue of Female Infertility from the Loss of Cyclooxygenase-2 by Compensatory Up-regulation of Cyclooxygenase-1 Is a Function of Genetic Makeup

Cyclooxygenase-2 (COX-2), an inducible rate-limiting enzyme in prostaglandin biosynthesis, is implicated in various physiological and pathological processes including female fertility, renal function, angiogenesis, inflammation, and tumorigenesis. We showed previously that targeted deletion of Ptgs2 encoding COX-2, but not Ptgs1 encoding COX-1, in C57BL/6J/129 mice produces complete female infertility resulting from multiple reproductive failures spanning ovulation, fertilization, and implantation. Here we show that Ptgs2 null mice on a CD1 background have dramatically improved female fertility including ovulation, fertilization, and implantation, giving rise to live births. We provide evidence that this improved fertility in CD1 Ptgs2 null mice is the result of a compensatory up-regulation of Ptgs1 which does not occur in C57BL/6J/129 mice missing Ptgs2. These results clearly demonstrate for the first time that COX-1 can replace specific functions of COX-2 in vivo in the context of genetic disparity. In light of this finding, the therapeutic use and efficacy of COX-2-specific inhibitors among human populations without regard for genetic and ethnic diversities should be revisited. Cyclooxygenase-2 (COX-2), an inducible rate-limiting enzyme in prostaglandin biosynthesis, is implicated in various physiological and pathological processes including female fertility, renal function, angiogenesis, inflammation, and tumorigenesis. We showed previously that targeted deletion of Ptgs2 encoding COX-2, but not Ptgs1 encoding COX-1, in C57BL/6J/129 mice produces complete female infertility resulting from multiple reproductive failures spanning ovulation, fertilization, and implantation. Here we show that Ptgs2 null mice on a CD1 background have dramatically improved female fertility including ovulation, fertilization, and implantation, giving rise to live births. We provide evidence that this improved fertility in CD1 Ptgs2 null mice is the result of a compensatory up-regulation of Ptgs1 which does not occur in C57BL/6J/129 mice missing Ptgs2. These results clearly demonstrate for the first time that COX-1 can replace specific functions of COX-2 in vivo in the context of genetic disparity. In light of this finding, the therapeutic use and efficacy of COX-2-specific inhibitors among human populations without regard for genetic and ethnic diversities should be revisited. Cyclooxygenases, COX 1The abbreviations used are: COX, cyclooxygenase(s); eCG, equine chorionic gonadotropin; hCG, human chorionic gonadotropin; PG, prostaglandin; PLA2, phospholipase A2; sPLA2, secretory PLA2.-1 and COX-2, mediate the conversion of arachidonic acid into prostaglandin (PG)H2, which is then converted to various PGs by specific synthases (1Smith W.L. DeWitt D.L. Garavito R.M. Annu. Rev. Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2521) Google Scholar). Although both COX-1 and COX-2 isoforms are encoded by separate genes, Ptgs1 and Ptgs2, respectively, they share similar structural and kinetic properties and show distinct cell-specific expression and regulation (1Smith W.L. DeWitt D.L. Garavito R.M. Annu. Rev. Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2521) Google Scholar). COX-1 is thought to serve “housekeeping” functions as a constitutive enzyme. COX-2, however, is highly inducible by diverse stimuli including cytokines, growth factors, mitogens, and tumor promoters and regulates inflammation, differentiation, mitogenesis, and angiogenesis (1Smith W.L. DeWitt D.L. Garavito R.M. Annu. Rev. Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2521) Google Scholar). PGs are implicated in various physiological and pathological functions because of their vasoactive, mitogenic, and differentiating properties (2Dubois R.N. Abramson S.B. Crofford L. Gupta R.A. Simon L.S. Van De Putte L.B. Lipsky P.E. FASEB J. 1998; 12: 1063-1073Crossref PubMed Scopus (2250) Google Scholar). Ovulation and implantation are considered analogous to “proinflammatory” responses, and thus participation of PGs in these processes has long been speculated. For example, gonadotropin-mediated Ptgs2 expression in ovarian follicles preceding ovulation is consistent with the presumed role of PGs in follicular rupture during ovulation (3Sirois J. Simmons D.L. Richards J.S. J. Biol. Chem. 1992; 267: 11586-11592Abstract Full Text PDF PubMed Google Scholar, 4Joyce I.M. Pendola F.L. O'Brien M. Eppig J.J. Endocrinology. 2001; 142: 3187-3197Crossref PubMed Scopus (97) Google Scholar). PGs are also implicated as important mediators of increased localized endometrial vascular permeability at the site of the blastocyst during implantation, a prerequisite condition for this process. Distinct expression patterns of COX isoforms in the peri-implantation mouse uterus suggest their roles in uterine biology and implantation (5Chakraborty I. Das S.K. Wang J. Dey S.K. J. Mol. Endocrinol. 1996; 16: 107-122Crossref PubMed Scopus (320) Google Scholar). The relative importance of COX isoforms in female fertility has been characterized by gene targeting studies in mice. The loss of the Ptgs2 gene leads to multiple reproductive failures that include ovulation, fertilization, implantation, and decidualization (6Dinchuk J.E. Car B.D. Focht R.J. Johnston J.J. Jaffee B.D. Covington M.B. Contel N.R. Eng V.M. Collins R.J. Czerniak P.M. Gorry S.A. Trzaskos J.M. Nature. 1995; 378: 406-409Crossref PubMed Scopus (903) Google Scholar, 7Lim H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar), whereas Ptgs1-deficient mice have normal fertility except for parturition defects (8Langenbach R. Morham S.G. Tiano H.F. Loftin C.D. Ghanayem B.I. Chulada P.C. Mahler J.F. Lee C.A. Goulding E.H. Kluckman K.D. Kim H.S. Smithies O. Cell. 1995; 83: 483-492Abstract Full Text PDF PubMed Scopus (1053) Google Scholar, 9Reese J. Paria B.C. Brown N. Zhao X. Morrow J.D. Dey S.K. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 9759-9764Crossref PubMed Scopus (124) Google Scholar). There is now increasing evidence that mutation of a gene often results in substantially altered phenotypes depending on the genetic background of mice in which the mutation is maintained (10Dietrich W.F. Lander E.S. Smith J.S. Moser A.R. Gould K.A. Luongo C. Borenstein N. Dove W. Cell. 1993; 75: 631-639Abstract Full Text PDF PubMed Scopus (616) Google Scholar, 11Threadgill D.W. Dlugosz A.A. Hansen L.A. Tennenbaum T. Lichti U. Yee D. LaMantia C. Mourton T. Herrup K. Harris R.C. Barnard J.A. Yuspa S.H. Coffey R.J. Magnuson T. Science. 1995; 269: 230-234Crossref PubMed Scopus (1277) Google Scholar, 12Bonyadi M. Rusholme S.A. Cousins F.M. Su C.A. M. R.J. 1997; PubMed Scopus Google Scholar, A. K. J. Endocrinology. PubMed Scopus Google Scholar, L.A. 2000; Google Scholar). For example, the targeting of the growth showed that growth on a background results in peri-implantation by the of the this on a background to defects giving rise to In mutation on a CD1 background with functions of the and D.W. Dlugosz A.A. Hansen L.A. Tennenbaum T. Lichti U. Yee D. LaMantia C. Mourton T. Herrup K. Harris R.C. Barnard J.A. Yuspa S.H. Coffey R.J. Magnuson T. Science. 1995; 269: 230-234Crossref PubMed Scopus (1277) Google Scholar). by studies phenotypes in mice with genetic for in growth M. Rusholme S.A. Cousins F.M. Su C.A. M. R.J. 1997; PubMed Scopus Google Scholar), A. K. J. Endocrinology. PubMed Scopus Google and L.A. 2000; Google Scholar). These to (10Dietrich W.F. Lander E.S. Smith J.S. Moser A.R. Gould K.A. Luongo C. Borenstein N. Dove W. Cell. 1993; 75: 631-639Abstract Full Text PDF PubMed Scopus (616) Google Scholar, 12Bonyadi M. Rusholme S.A. Cousins F.M. Su C.A. M. R.J. 1997; PubMed Scopus Google Scholar), of the We now show for the first time that a compensatory up-regulation of Ptgs1 female fertility Ptgs2 in a genetic COX-1, which is considered as a constitutive and functions as an inducible similar to the COX-2 a of phenotypes on genetic have as and inhibitors are used for the of without regard for genetic diversities among human populations R.J. Rev. PubMed Scopus Google Scholar). of the Ptgs2 gene in by as previously (6Dinchuk J.E. Car B.D. Focht R.J. Johnston J.J. Jaffee B.D. Covington M.B. Contel N.R. Eng V.M. Collins R.J. Czerniak P.M. Gorry S.A. Trzaskos J.M. Nature. 1995; 378: 406-409Crossref PubMed Scopus (903) Google Scholar). of and the (6Dinchuk J.E. Car B.D. Focht R.J. Johnston J.J. Jaffee B.D. Covington M.B. Contel N.R. Eng V.M. Collins R.J. Czerniak P.M. Gorry S.A. Trzaskos J.M. Nature. 1995; 378: 406-409Crossref PubMed Scopus (903) Google Scholar, 7Lim H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar). is evidence that the genetic background of mice to phenotypes (10Dietrich W.F. Lander E.S. Smith J.S. Moser A.R. Gould K.A. Luongo C. Borenstein N. Dove W. Cell. 1993; 75: 631-639Abstract Full Text PDF PubMed Scopus (616) Google Scholar, 11Threadgill D.W. Dlugosz A.A. Hansen L.A. Tennenbaum T. Lichti U. Yee D. LaMantia C. Mourton T. Herrup K. Harris R.C. Barnard J.A. Yuspa S.H. Coffey R.J. Magnuson T. Science. 1995; 269: 230-234Crossref PubMed Scopus (1277) Google Scholar, 12Bonyadi M. Rusholme S.A. Cousins F.M. Su C.A. M. R.J. 1997; PubMed Scopus Google Scholar, A. K. J. Endocrinology. PubMed Scopus Google Scholar, L.A. 2000; Google Scholar), to Ptgs2 null female mice on genetic reproductive we Ptgs2 in CD1 mice by with C57BL/6J/129 mice In C57BL/6J/129 to CD1 an then to CD1 and the for with of the genetic background and Ptgs2 null mice for The of of secretory phospholipase as in CD1 and mice Wang and S. K. in to the of by null mutation in C57BL/6J/129 mice evidence that this of the CD1 genetic of the mice used in the to of and for Ovulation and ovulation and fertilization, mice with with the background and on and of and with to and an mice an of of equine chorionic by a of of human H. W. Trzaskos J. R.M. Dey S.K. Biol. 2001; PubMed Scopus Google Scholar). with and for the and on of by an of B.C. Dey S.K. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar). on and without implantation with to mice an of of in uterine on and of the and and the in uterine used as an of decidualization H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. 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PubMed Google Scholar). of COX-1 and COX-2 in uterine on of by as previously R.A. Das S.K. Morrow J.D. Dey S.K. R.N. Google Scholar). Ovulation and in CD1 Ptgs2 null female mice on genetic reproductive we Ptgs2 in CD1 mice by with C57BL/6J/129 Ptgs2 mice. female fertility with the of in CD1 mice with complete in C57BL/6J/129 null mice as previously H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar). the of this improved fertility in CD1 female we in their reproductive phenotypes during in CD1 mice CD1 and mice with with the mice for of at and Although in CD1 the with of of mice with in a the ovulation and the of and on of a in ovulation in CD1 mice as to of ovulation in C57BL/6J/129 mice H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar, H. W. Trzaskos J. R.M. Dey S.K. Biol. 2001; PubMed Scopus Google Scholar). in of the CD1 mice with of with of In an in the in CD1 mice at a of in of CD1 mice. Although this is the in is the in C57BL/6J/129 mice previously H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar, H. W. Trzaskos J. R.M. Dey S.K. Biol. 2001; PubMed Scopus Google Scholar). similar of ovulation and in these null mice the of this of We that of the result of in CD1 Ptgs2 null because of of the we the of on of in CD1 with the of results on of the Ptgs2 null mice and of the as by and female a of Ptgs2 null showed of These results that of to because of their to and during In of and in CD1 mice Ptgs2 null are we that of of to a is and a for normal and during K. S. T. T. J. N. S. A. 2000; PubMed Scopus Google Scholar). We normal of in Ptgs2 null the as the of Ptgs2 to be a for the an of the with of and altered in CD1 Ptgs2 null mice results show that ovulation and to are improved with the of CD1 genetic background in Ptgs2 null of Ptgs1 and Ptgs2 with Ovulation and in C57BL/6J/129 and CD1 the of improved ovulation in CD1 C57BL/6J/129 we in the ovarian expression of Ptgs1 and Ptgs2 during ovulation in mice and Ptgs1 expression in Ptgs2 mice on CD1 and C57BL/6J/129 a of and to follicular growth and ovulation at a time H. W. Trzaskos J. R.M. Dey S.K. Biol. 2001; PubMed Scopus Google Scholar). this ovulation and for in of Ptgs1 and Ptgs2 at time Ptgs1 and Ptgs2 expression in C57BL/6J/129 and CD1 Although Ptgs1 Ptgs2 at with the of the Ptgs2 expression at in the follicles in both of mice. this expression in C57BL/6J/129 mouse by a at whereas in CD1 mouse the expression dramatically at and at Ptgs2 expression but at a with Ptgs2 expression in C57BL/6J/129 and ovulation Ptgs2 expression in CD1 of that for C57BL/6J/129 mice and the in Ptgs2 expression these of mice during ovulation, expression localized to and of Ptgs1 expression in C57BL/6J/129 mice first at at by a up-regulation at with at In CD1 the at with up-regulation at by expression In to Ptgs2 the expression of Ptgs1 to with in In the of Ptgs2, Ptgs1 expression at these time in both of mice similar to in The of ovulation and with the expression studies in and that the relative of PGs in ovulation and the genetic background of mice. The results also provide evidence that expression of COX-1 COX-2 in and ovulation is for of this whereas expression of COX-2 is a for normal and is consistent with of ovulation and in C57BL/6J/129 Ptgs2 as to normal ovulation with in CD1 Although the is that cell-specific expression of Ptgs2 in follicles is to ovulation (3Sirois J. Simmons D.L. Richards J.S. J. Biol. Chem. 1992; 267: 11586-11592Abstract Full Text PDF PubMed Google Scholar, 4Joyce I.M. Pendola F.L. O'Brien M. Eppig J.J. Endocrinology. 2001; 142: 3187-3197Crossref PubMed Scopus (97) Google Scholar), evidence that COX-1 is important in this in the at the We that the of ovulation in CD1 COX-2 null mice as to of ovulation in C57BL/6J/129 mice is the result of and ovarian expression of COX-1 in CD1 in C57BL/6J/129 in which COX-1 expression is and CD1 in the of of implantation is as the time during which the blastocyst a with the uterus B.C. Dey S.K. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar, H. Das S.K. Paria B.C. Dey S.K. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). In the uterus on of with the of the of the S.K. Wang Paria B.C. D. J.A. M. Dey S.K. PubMed Google Scholar). In to normal ovulation and improved fertilization, in of the CD1 Ptgs2 null mice with is in to and of complete of in C57BL/6J/129 H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar). failures in CD1 mice that uterine defects from the time of to parturition We thus of this implantation decidualization in these mice. vascular permeability at the site of as an of normal implantation, on and of the by the B.C. Dey S.K. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar). We that a of in CD1 Ptgs2 null but the of implantation of of of an of implantation in whereas implantation in of the CD1 mice. The of implantation not the result of the of because the of null mice which to on The of these normal with of in the of We that in CD1 on the normal of implantation. as in of CD1 mice showed distinct implantation on of evidence that implantation the normal these results demonstrate that a of at the normal of the normal time of implantation in CD1 mice. an of implantation on of in CD1 Ptgs2 null the at that that during the normal to whereas the of to have been in null mice in which implantation of occur the normal H. H. Paria B.C. H. Morrow J. Dey S.K. PubMed Google Scholar). of in CD1 Ptgs2 null mice at the normal time that of improved implantation the of COX-2 by PGs not be for implantation. this we the Ptgs1 expression in CD1 Ptgs2 null at the of blastocyst Ptgs1 for the of Ptgs2 during in CD1 COX-1 can the of COX-2, we first the expression of Ptgs1 in both CD1 and null mice during implantation by in Ptgs2, not is in the uterus at the site of blastocyst during implantation. in with the of implantation Ptgs1 is in the and implantation on in CD1 mice in a the expression of Ptgs2 in mice as previously (5Chakraborty I. Das S.K. Wang J. Dey S.K. J. Mol. Endocrinol. 1996; 16: 107-122Crossref PubMed Scopus (320) Google Scholar). the expression of Ptgs1 in CD1 Ptgs2 null mice to the and of the implantation in a with Ptgs2 expression in The results of and of COX-1 are consistent with in results of considered important for implantation H. Gupta R.A. Paria B.C. Morrow J.D. R.N. Trzaskos J.M. Dey S.K. PubMed Scopus Google Scholar), in CD1 mice missing the Ptgs2 gene also by compensatory up-regulation of COX-1 and the results suggest that compensatory up-regulation of Ptgs1 in a similar to Ptgs2 the loss of Ptgs2 in the in CD1 Ptgs2 null mice. In this compensatory not in C57BL/6J/129 Ptgs2 null mice and for the in these mice. C57BL/6J/129 mice because of mutation as to CD1 mice that of H. H. Paria B.C. H. Morrow J. Dey S.K. PubMed Google Scholar, J. W. M. C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). is also that in to to increased arachidonic acid for COX-1 in of uterine PGs in CD1 mice during of PGs in CD1 mice. of PGs in of CD1 and mice on and of are as in uterine CD1 and mice CD1 and C57BL/6J/129 the of the the blastocyst and uterine the blastocyst and into decidualization can also be in by of H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar). Although implantation for a of in CD1 the of decidualization in the of COX-2 is not we the decidualization in mice by on of The results show that of the C57BL/6J/129 mice showed of of CD1 mice similar to that in CD1 mice with to increased uterine the results suggest that the is often in CD1 the of the uterine to to decidualization we compensatory expression of Ptgs1 in CD1 mice missing Ptgs2 at the time of implantation, we that Ptgs1 also for Ptgs2 during decidualization in this of mice. we that Ptgs1 in the in CD1 Ptgs2 null mice in a that the Ptgs2 expression in similar uterine expression of Ptgs1 in C57BL/6J/129 Ptgs2 null complete of decidualization The of COX-1 by is consistent with the results of in provide evidence for COX-1 of COX-2 for decidualization in CD1 we used a J. A. J.J. K. P.C. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, J. Zhao X. Brown N. Dey S.K. Endocrinology. 2001; 142: PubMed Scopus Google Scholar), to COX-1 and on with dramatically decidualization in CD1 mice These results that PGs can for the of COX-2 during implantation and decidualization in CD1 mice. These are and that the genetic background is important in of reproductive phenotypes in Ptgs2 null mice. into CD1 of the uterine on the of implantation, into Ptgs2 null and implantation on and by the B.C. Dey S.K. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar). In CD1 of the in on of the showed of implantation in of CD1 of from these null blastocyst but of the we the of the showed implantation in CD1 mice as in the of the implantation and of in Ptgs2 null of implantation of the with on the of blastocyst and on the implantation in CD1 Ptgs2 null mice on of showed of implantation. These results provide evidence that COX-1 can the loss of COX-2 in CD1 mice. a of implantation often in CD1 Ptgs2 null we this altered of implantation the of the implantation in showed of of the implantation showed of in CD1 on and of these implantation in and with from these is to be that similar growth also CD1 mice on in similar occur in C57BL/6J/129 we blastocyst in C57BL/6J/129 mice and implantation and as previously H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar). We that of the in of the on of the showed of implantation in of C57BL/6J/129 not evidence for on of the showed in of C57BL/6J/129 In mice on of the showed of implantation that in of and site a These results of of in C57BL/6J/129 Ptgs2 null mice H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar). provide evidence that COX-2 has an role in implantation and decidualization in C57BL/6J/129 mice H. Paria B.C. Das S.K. Dinchuk J.E. Langenbach R. Trzaskos J.M. Dey S.K. Cell. 1997; 91: 197-208Abstract Full Text Full Text PDF PubMed Scopus (1287) Google Scholar, H. Gupta R.A. Paria B.C. Morrow J.D. R.N. Trzaskos J.M. Dey S.K. PubMed Scopus Google Scholar). can be improved by compensatory up-regulation of Ptgs1 depending on the genetic of inhibitors and their use for the of with efficacy the to genetic role in COX-2 of normal ovulation with improved and implantation in CD1 mice in the of COX-2 suggest that the efficacy of inhibitors and be a of genetic also in human populations with ethnic and Although specific gene phenotypes in the context of genetic background in mice D.W. Dlugosz A.A. Hansen L.A. Tennenbaum T. Lichti U. Yee D. LaMantia C. Mourton T. Herrup K. Harris R.C. Barnard J.A. Yuspa S.H. Coffey R.J. Magnuson T. Science. 1995; 269: 230-234Crossref PubMed Scopus (1277) Google Scholar, 12Bonyadi M. Rusholme S.A. Cousins F.M. Su C.A. M. R.J. 1997; PubMed Scopus Google Scholar, A. K. J. Endocrinology. PubMed Scopus Google Scholar, L.A. 2000; Google Scholar), the is often that altered phenotypes are the result of participation of a studies have the of in phenotypes (10Dietrich W.F. Lander E.S. Smith J.S. Moser A.R. Gould K.A. Luongo C. Borenstein N. Dove W. Cell. 1993; 75: 631-639Abstract Full Text PDF PubMed Scopus (616) Google Scholar, 12Bonyadi M. Rusholme S.A. Cousins F.M. Su C.A. M. R.J. 1997; PubMed Scopus Google Scholar). We that a compensatory gene is an by which is in the context of genetic disparity. is consistent with that the altered phenotypes are the result of expression of COX isoforms in the and of COX-2 by COX-1, which functions as an inducible in a similar to results also demonstrate for the first time the role of ovarian cell-specific COX isoforms in ovulation and The has been that COX-2, but not COX-1, is to ovulation (3Sirois J. Simmons D.L. Richards J.S. J. Biol. Chem. 1992; 267: 11586-11592Abstract Full Text PDF PubMed Google Scholar, 4Joyce I.M. Pendola F.L. O'Brien M. Eppig J.J. Endocrinology. 2001; 142: 3187-3197Crossref PubMed Scopus (97) Google Scholar). of of ovulation in but normal ovulation in CD1 in the of COX-2 with ovarian expression of Ptgs1 and Ptgs2 in these of mice and of Ptgs1 in the of Ptgs2. evidence that COX-1 COX-2 in can replace in the of ovulation, In of expression of COX-2, but not COX-1, is consistent with the that COX-2 is important for I.M. Pendola F.L. O'Brien M. Eppig J.J. Endocrinology. 2001; 142: 3187-3197Crossref PubMed Scopus (97) Google Scholar, J.M. M.B. 1995; Full Text PDF PubMed Scopus Google Scholar). The complete of in C57BL/6J/129 mice and in CD1 mice in the of COX-2 that COX-2 of is an important in and to fertilization, expression of COX-1 to ovulation can as in CD1 Ptgs2 is consistent with the that are important for the of Eppig J.J. Science. PubMed Scopus Google Scholar). results of genetic and expression studies demonstrate for the first time the relative of and COX isoforms in ovulation and Although the of COX regulation in C57BL/6J/129 and CD1 is not is now evidence that multiple in the ovulation M. Biol. PubMed Scopus Google Scholar). is that the reproductive are C57BL/6J/129 and CD1 mice. we demonstrate a genetic role of COX-1 in ovulation in vivo in the of expression of COX-1 and COX-2 in the peri-implantation mouse uterus that PGs in uterine and implantation (5Chakraborty I. Das S.K. Wang J. Dey S.K. J. Mol. Endocrinol. 1996; 16: 107-122Crossref PubMed Scopus (320) Google Scholar). Ptgs1 is in the the uterus on and but is by the of to the of implantation. In Ptgs2 is in the and the blastocyst at the time of with the on (5Chakraborty I. Das S.K. Wang J. Dey S.K. J. Mol. Endocrinol. 1996; 16: 107-122Crossref PubMed Scopus (320) Google Scholar). expression is to both C57BL/6J/129 and CD1 mice. Although uterine COX-2 is for implantation in C57BL/6J/129 a compensatory up-regulation of COX-1 in the uterus at the site of the blastocyst in CD1 mice COX-2 evidence that COX-1 is also inducible in a similar to that of COX-2 a specific genetic and to improved implantation in CD1 mice with complete of implantation in C57BL/6J/129 mice missing Ptgs2. Although COX-2 can be by COX-1, COX-2 is an important for the of female reproductive is by the of the normal of implantation for in CD1 mice missing the Ptgs2 to and is similar to in mice H. H. Paria B.C. H. Morrow J. Dey S.K. PubMed Google Scholar). These studies a that a in the during the of is important as implantation the normal of uterine leads to increased in J. PubMed Scopus Google Scholar). In in vivo evidence that a compensatory COX-1 up-regulation substantially female infertility in a genetic the use of including COX-2 inhibitors and genetic to R.J. Rev. PubMed Scopus Google Scholar, J.A. J. PubMed Scopus Google Scholar), a therapeutic use and efficacy of COX-2 inhibitors in among human populations without regard for genetic and ethnic There is now evidence for the of and genetic J.A. J. PubMed Scopus Google Scholar). the use of these should be on genetic with to their efficacy and including their during H. L. J. 2001; PubMed Scopus Google Scholar, L. R. J. PubMed Google Scholar).