Anovulation in Cyclooxygenase-2-Deficient Mice Is Restored by Prostaglandin E2 and Interleukin-1β*

Abstract

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-1beta resulted in ovulation of COX-2(-/-) mice comparable to that in COX-2(+/+), whereas treatment with PGF2alpha 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-1beta.

Disrupted hyaluronan binding protein 1 (HABP1) expression: one of the key mediator for ovarian dysfunction in polycystic ovary rat

“…Besides we studied COC expansion; another crucial process for oocyte development, ovulation, and fertilization [38][39][40]; and observed that cultured COCs, with LH?FSH and along with RU486, both setups showed normal COC expansion (Fig. 4b, c) as also revealed by previous studies [41][42][43][44]. Since cumulus cells do not express progesterone receptor (PR), COC expansion seems to be unaffected by RU486 (a PR antagonist).…”

Extracellular matrix in ovarian follicular development and disease

“…Both mural granulosa and cumulus cells express high levels of COX-2 mRNA 4 h post-hCG in the mouse, with a second peak of COX-2 expression by cumulus cells at 12 h. LH is the principal determinant of COX-2 mRNA levels in mural granulosa cells (but not the COC) during the first peak of expression in ovulatory follicles. COX-2 mRNA levels in cumulus cells 12 h after hCG treatment are likely to be a function of factors derived from both the oocyte and the follicle wall, other than interleukin-1β (IL-1β) (Joyce et al 2001), which has previously been shown to restore ovulation in COX-2-deficient mice (Davis et al 1999). IL-1β stimulation also results in extensive leucocyte perifollicular infiltration in both COX-2 wild-type and null mice; however, in COX-2-deficient mice, this infiltration extends into the follicular antrum (Davis et al 1999), suggesting other COX-2-mediated roles in the follicle.…”

Expression of cytokine‐induced neutrophil chemoattractant suppresses tumor necrosis factor alpha expression and thereby prevents the follicles from undergoing atresia and apoptosis

“…The ovulation rate is reduced by COX‐2 suppression and this phenomenon can be inhibited by supplying prostaglandin E 2 or IL‐1 beta 13. However, it was unknown whether CINC/gro or COX‐2 took precedence in this process.…”

“…In contrast, COX‐2 is an inducible isoform that is responsive to many growth factors and to cytokine stimulation, especially to the factors that are produced during ovulation 11, 12. The ovulation rate is reduced by COX‐2 suppression13, 14 and this suppression can be inhibited by supplying prostaglandin E 2 or IL‐1 beta 13, 15…”