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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
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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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. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Two distinct isoforms, COX-1 and COX-2, have been identified on different chromosomes (6, 7) with distinct tissue distribution and expression patterns (8, 9, 10, 11), providing evidence that these enzymes have unique biological actions despite having similar catalytic activities (5). COX-1 is a constitutively active isoenzyme in many cells (12); it is the only isoform present in platelets (13) and is an important intermediary in cellular homeostasis (8). By comparison, COX-2 is an inducible isoform responsive to many growth factors and cytokine stimuli.
Both the preovulatory LH surge and ovulation have been reported to be blocked by the COX inhibitor, indomethacin (4, 14, 15). This blockade appears to occur at the levels of the hypothalamus and ovary, but not at the pituitary level (4, 16, 17). In the hypothalamus, PGs have been shown to stimulate the secretion of LHRH (18), which leads to the release of the gonadotropins (17). Recent evidence indicates that immortalized LHRH neurons contain transcripts for both COX-1 and COX-2, they biosynthesize PGE2, and that this prostanoid stimulates the secretion of LHRH (19). Although additional studies have shown that PGE2 may affect maturation of the LHRH neuronal system during puberty and pulsatile secretion of LHRH (20), the selective contributions of COX-1 or COX-2 to neuroendocrine reproductive function remain to be investigated.
PGs also exert potent effects on ovarian function in all species. Low levels of COX are found in stromal/thecal cells, and it is most likely responsible for maintaining basal levels of ovarian PGs (1, 21, 22). COX-2 is induced in granulosa cells specifically in response to the gonadotropin-induced ovulatory surge, and the temporal correlation of COX-2 message and protein induction in cumulus granulosa cells of mature follicles with this surge provides compelling evidence that COX-2 is important in mediating ovulation (2, 22, 23, 24, 25). Inhibition of COX by nonsteroidal antiinflammatory drugs, such as indomethacin, partially or completely blocks the release of the ovum in all species (including human) studied to date under a variety of experimental conditions (4, 15, 26). However, both COX isoforms are inhibited by nonsteroidal antiinflammatory drugs, and thus, it has been difficult to distinguish whether COX-2 is essential for or associated with ovulation, or whether COX-1 is required for or ancillary to COX-2 during follicular maturation and ovulation. As mice carrying a null mutation for COX-2 fail to ovulate and have abnormal implantation and decidualization responses (27), whereas mice deficient in COX-1 are fertile (28), it appears that COX-2, but not COX-1, is required for ovulation.
COX-2 also appears central to the interaction of PGs and cytokines during ovulation. Specifically, interleukin-1ß (IL-1ß) activity has been linked to the regulation of COX-2 in numerous tissues and inflammatory responses (29), and it appears to be involved in ovulation (30, 31, 32). Most evidence suggests that the ovulatory action of IL-1ß is mediated through the induction of COX-2 and PG production (29, 31, 33, 34). However, in the perfused rat ovary, IL-1ß stimulated ovulation when COX enzyme activity was inhibited with indomethacin (32), providing some evidence that IL-1ß may act independently of PGs. IL-1ß appears to be a contributor to ovarian function and ovulation itself, as an intact functional IL-1ß system is present in the ovary of the mouse, rat, and human (30, 33, 34). In the mouse, IL-1ß is produced in thecal-interstitial cells and to a lesser extent in granulosa cells, whereas the IL-1 receptor is located in all oocytes and granulosa cells of mature antral follicles (33). In addition, IL-1ß is produced in the preovulatory follicle in response to the LH surge, and treatment with IL-1ß receptor antagonists can block ovulation in the mouse (35). However, IL-1ß receptor-deficient mice are fertile (36), suggesting that IL-1ß may not be critical to ovulation.
To assess the interactions of COX-2 and IL-1ß during ovulation and to further delineate the roles of COX-1 and COX-2 in reproductive function, we have examined levels of LHRH, gonadotropin, and sex steroids in mice that have the COX-1 or COX-2 genes functionally deleted. The results indicate that pituitary gonadotropin levels are affected by the COX mutations and establish that COX-2 is essential for the structural maintenance of the cumulus oophorum and for the formation of the stigmata to release the ovum. Furthermore, ovulation can be restored in COX-2-/- mice by treatment with PGs or IL-1ß.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, PGE2, IL-1ß,
10% hydrogen peroxide, 3,3'-diaminobenzidine tetrahydrochloride,
chloramine-T, and phenylmethylsulfonylfluoride were purchased from
Sigma Chemical Co. (St. Louis, MO). The 10% neutral
buffered formalin, hematoxylin, eosin, toluidine blue O (TB) and
periodic acid-Schiff were purchased from Fisher Scientific
(Pittsburgh, PA). The COX-2 polyclonal antiserum was obtained from
Cayman Chemical Co. (Ann Arbor, MI), and the donkey antirabbit IgG
biotin antiserum and the peroxidase-conjugated streptavidin were
purchased from Jackson ImmunoResearch Laboratories, Inc.
(West Grove, PA). RIA kits for estradiol and progesterone were
purchased from Diagnostic Products (Los Angeles, CA), the
PGE2 kit was purchased from Amersham
(Arlington Heights, IL), and the mouse (m) LH and rat (r) FSH RIAs were
developed and provided by Dr. A. Parlow at Harbor-University of
California-Los Angeles. The A772 antiserum for the LHRH RIA was
obtained from Dr. A. Arimura at Tulane University (New Orleans, LA).
Sephadex G-100 resin was purchased from Pharmacia Biotech
(Piscataway, NJ), and synthetic LHRH was obtained from Phoenix Pharmaceuticals, Inc. (Mountain View, CA).
Animals
COX-1- or COX-2-deficient mice were obtained as previously
described (28, 37). Genotype analyses were performed by PCR. The
forward primer for identification of COX-1-/-
mice was 5'-GCAGCCTCTGTTCCACATACAC-3', the forward primer for the COX-1
wild-type mice was 5'-AGGAGATGGCTGCTGAGTTGG-3', and the reverse primer
for both reactions was 5'-AATCTGACTTTCTGAGTTGCC-3'. The forward primer
for the COX-2-/- mice was
5'-ACGCGTCACCTTAATATGCG-3', the forward primer for the COX-2 wild-type
mice was 5'-ACACACTCTATCACTGGCACC-3', and the reverse primer for both
reactions was 5'-ATCCCTTCACTAAATGCCCTC-3'. The PCR reaction was run in
the presence of 10% dimethylsulfoxide, where a cycle at 94 C for 1 min
was followed by 30 cycles at 94 C for 30 sec, 55 C for 30 sec, and 72 C
for 30 sec. The size of the PCR product for the COX-1+/+
was 601 bp, that for the COX-1-/- was 646 bp,
that for the COX-2+/+ was 760 bp, and that for the
COX-2-/- was 905 bp.
Mice were housed one to three animals per cage on a 12-h light, 12-h dark cycle. Food and water were provided ad libitum. Estrous cyclicity was determined by daily vaginal cytology in mice without knowledge of genotypes beginning 2 weeks after vaginal opening, which occurred when mice were 32–34 days old. Breeding experiments were instituted when the mice were 8–16 weeks of age, and stimulation studies were conducted when the mice were 4–12 weeks old. Mice were killed by carbon dioxide, except for mice used in the hypothalamic and pituitary studies, which were killed by cervical dislocation. For serum hormone analyses, blood was collected under CO2 asphyxiation by cardiac puncture. Serum was separated from red blood cells by centrifugation and stored at -70 C until RIA. All experiments were conducted in accordance with the Guidelines for the Care of Experimental Animals and under an approved protocol from the NIEHS animal care and use committee.
Induction of ovulation
Mice were administered 15 IU PMSG, sc, in sterile water followed
42–48 h later with a single injection of 15 IU hCG, ip, in sterile
water. Mice were killed under CO2 gas 24 h after hCG
treatment. Parenthetically, it should be noted that in our preliminary
studies and in a previous report (27), superovulation attempted in the
COX-2-/- mice with a regimen of 5 IU PMSG and 5
IU hCG was unsuccessful. For this reason, we selected a 15-IU
protocol.
PGF2 and PGE2 were first dissolved in
ethanol and then diluted in saline to a final concentration of 3%
ethanol and were given at a dose of 40 µg/mouse, sc, concurrent with
the hCG administration and followed by a second injection 4 h
later. The IL-1ß was dissolved in sterile water, and mice received a
100-ng dose (38) concurrent with treatment by hCG. A second dose of
IL-1ß was given 4 h later.
For breeding studies, females were housed overnight with proven fertile males after the hCG treatment. Mating was assessed by the presence of a vaginal plug.
Ovarian histology
Ovarian morphology and ovulation were assessed in
COX-2+/+, COX-2+/-,
COX-2-/-, and COX-1-/-
mice by examining histological step-sections of one or both ovaries and
oviducts. Ovaries and oviducts were fixed for 24 h in 10% neutral
buffered formalin and processed for histopathology. Ovarian morphology
and ovulation were assessed by examining step-sections taken every 25
µm through the entire tissue from one or both ovaries and oviducts.
Every fifth section was saved unstained for immunohistochemistry or
staining with TB (at pH 4.5) or periodic acid-Schiff. The
immunohistochemistry for COX-2 was performed on deparaffinized sections
that were trypsinized for 20 min at 37 C and blocked with a 3%
hydrogen peroxide solution. Murine COX-2 antiserum (1:750) was applied
for 60 min, sections were then incubated with donkey antirabbit IgG
biotin-conjugated antibody (1:100) for 30 min, followed by
peroxidase-conjugated streptavidin (1:400) for 30 min. Positive
staining was visualized with 3,3'-diaminobenzidine tetrahydrochloride
using hematoxylin as a counterstain. All incubations were performed at
room temperature. Corresponding sections from each tissue were treated
as described above, except for the deletion of the primary antiserum to
serve as a negative control. Additionally, sections from
COX-2-/- mice were used as controls. For
illustrations, photomicrographs were taken using a Zeiss Axiophot
photomicroscope (Carl Zeiss, New York, NY), and selected
color slides were imported into Adobe Photoshop version 5.0 (Adobe, San
Jose, CA) on a Macintosh 7600/132 PowerPC via a Polaroid SprintScan 35
(Cambridge, MA) and stored on an Iomgea 2GB JAZ drive (Roy, UT). The
images were collected at a resolution of 675 pixels/in. Images were
then processed into black and white figures using Photoshop, and
letters, arrows, arrowheads, boxes, and scale bars were added. Once the
images were finalized, they were printed using a Kodak DS 8650 dye
sublimation printer (Eastman Kodak Co., Rochester,
NY).
Ovulation was quantitated in wild-type and COX-2-/- mice by flushing oviducts separated from the ovaries and counting oocytes under a dissecting scope as previously described (39) in two to five mice per time point in at least two separate experiments. Ovaries were fixed in formalin or frozen at -70 C for further morphological or biochemical studies.
RIAs
The 17ß-estradiol and progesterone levels were determined
using commercially available RIA kits. The minimal detectable doses
were 1.4 pg/ml for estradiol and 0.03 ng/ml for progesterone; the
intraassay variabilities were approximately 6% and 5%, respectively.
The mouse LH and rat FSH RIA kits were obtained from Dr. A. Parlow
(Harbor-University of California-Los Angeles). The mLH and rFSH were
iodinated by chloramine-T and purified over Sephadex G-100 columns, and
the RIAs were run as previously described (40). The minimal detectable
doses were 2.6 pg and 3.4 ng, whereas the intraassay variabilities were
approximately 6% and 7% for mLH and rFSH, respectively. Synthetic
LHRH was iodinated by chloramine-T, purified, and used in the LHRH RIA
as previously described (41). The A772 antiserum for LHRH
recognizes the C-terminal region of the molecule (42). The minimal
detectable dose was 0.8 pg, whereas the intraassay variability was
approximately 6%.
Extraction of LHRH from the hypothalamus was performed as outlined previously (41). The LH and FSH were extracted from mouse anterior pituitaries with 1.0 N acetic acid and 200 µM phenylmethylsulfonylfluoride. Pituitary samples were sonicated in ice-cold buffer and centrifuged at 15,000 rpm for 15 min at 4 C, and the supernatant was removed. Samples were lyophilized and stored at -80 C until RIA. The pellet was reserved for later protein determination (43).
Basal and stimulated PGE2 levels in the wild-type and COX-deficient mice were measured and considered to be representative of total PG production (28, 37). Consequently, for the present studies PGE2 levels were also used to represent total PG production, and ovarian PGE2 was measured by RIA (Amersham). Briefly, one ovary per mouse was removed and homogenized, and the centrifuged supernatant was submitted to methyl oximation following the manufacturer’s instructions. The minimal detectable dose was 0.8 pg/tube, and the inter- and intraassay coefficients of variation were less than 12% and 10%, respectively.
Statistics
The data are presented as the mean and SEM. The
number of observations and replications are noted in the figure
legends. All statistics were run using the SAS Institute, Inc. (Cary, NC), package of programs (JMP). Main effects of
group (treatment) and time were assessed using two-way ANOVA. Due to
the heterogeneity of variance for the serum estradiol and progesterone
measurements, these values were log transformed and submitted to ANOVA.
Serum and pituitary LH and FSH levels as well as hypothalamic LHRH
contents were analyzed by one-way ANOVA. When statistical significance
(P < 0.05) was achieved, Fisher’s least significant
difference or Newman-Keuls test was used for the post-hoc
comparisons. Oocyte numbers and treatment effects were compared using
Wilcoxon/Kruskal-Wallis nonparametric rank sum test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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When sexually mature littermate pairs of COX-2-/- and COX-2+/- females were cohoused with proven fertile wild-type males (n = 3 pairs), all females copulated, as evidenced by vaginal plugs within 2 days after cohabitation. However, none of the COX-2-/- females demonstrated gestational weight gain or delivered pups, whereas COX-2+/- females delivered viable litters. COX-2-/- mice (n = 4) were also treated with PMSG (5 IU), then with hCG (5 IU) 48 h later, and were housed overnight with proven fertile males. Female mice copulated, as evidenced by vaginal plugs the following day, but did not impregnate.
Concentrations of hormones in hypothalamus, pituitary, and
serum
Hypothalamic tissue levels of LHRH were not significantly
different among the wild-type (564 ± 67.8 pg/mg protein; n =
9), COX-1-/- (635.2 ± 49.3 pg/mg
protein; n = 6), and COX-2-/-
(565.7 ± 58.4 pg/mg protein; n = 6) mice. However, pituitary
FSH contents in COX-1-/- and
COX-2-/- mice were significantly enhanced
relative to those in wild-type animals (Fig. 1A
). Additionally, there was a tendency
for COX-2-/- mice to exhibit increased
pituitary LH levels (Fig. 1B). Although FSH and LH levels were variable
in sera from all three genotypes (Fig. 1, C and D), there was a
tendency for serum FSH values to be higher in the COX-1- and
COX-2-deficient mice.
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). However, 8 h
after hCG treatment, COX-2+/+ and
COX-1-/- mice ovaries showed a significant
4-fold increase in PGE2 contents, whereas PGE2
values were unchanged in COX-2-/- mice ovaries.
Twenty-four hours after hCG treatment, ovarian PGE2
concentrations were reduced in the COX-2+/+ and
COX-1-/- ovaries, although they were still
elevated over the level after PMSG stimulation alone.
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, A and B). However, about 10% of the
mature follicles in COX-2+/+ mice failed to
undergo cumulus expansion and were minimally immunopositive for COX-2
protein (Fig. 3, A and C). In contrast,
COX-2-/- mice had limited and unorganized
cumulus expansion in their preovulatory follicles 8 h after hCG
treatment (Fig. 3, D and E). Moreover, the granulosa cells of the
corona radiata typically failed to enlarge and elongate. Immunostaining
for COX-2 protein was negative in COX-2-/-
ovaries (Fig. 3F).
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). Corpora
hemorrhagica exhibited focal exophytic protrusions adjacent to the
stigmata (Fig. 4C). In contrast, corpora hemorrhagica of
COX-2-/- mice were characterized by a large
antral cavity circumferentially surrounded by multiple layers of luteal
cells (Fig. 4B). The oocyte was detached from the cumulus mass and
retained within the antral cavity. There was no evidence of cellular
reorganization around the apex to form the stigmata. By 36–40 h after
hCG administration, luteal cells were morphologically comparable among
all genotypes; however, the oocyte could be identified within corpora
lutea of the COX-2-/- mice (as in Fig. 4D).
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Restoration of ovulation
When ova were flushed from oviducts 24–32 h after superovulation,
19 ± 4 ova contained within the cumulus mass were recovered from
COX-2+/+ mice (Fig. 5). In marked contrast, only one of the
five superovulated COX-2-/- mice released any
ova, i.e. two, and there was no evidence of associated
cumulus mass. However, treatment of COX-2-/-
mice (n = 4) with PGE2 or IL-1ß restored the number
of ova comparable to that in COX-2+/+ (Fig. 5).
Fewer ova were released after PGF2 treatment, in part
because two of the five mice failed to release any ova, although the
ova that were released in the other three mice were contained within
the cumulus mass.
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or IL-1ß) resulted in the structural maintenance of the
oocyte-cumulus mass complex within the oviducts 24–32 h after
treatment (Fig. 6). Eight hours after
superovulation and PGE2, PGF2, or IL-1ß
treatments, cumulus expansion was organized. There was reduced
metachromatic staining for proteoglycans as determined by TB staining
(44) in the cumulus oophorus of COX-2-/- mice
compared with that in COX-2+/+ animals (Fig. 7, A–C). Treatment with PG or IL-1ß
restored TB metachromasia in the COX-2-/- mouse
ovary (Fig. 7D). PGE2 or IL-1ß also restored formation of
the stigmata in COX-2-/- mice (not shown).
However, IL-1ß also stimulated an extensive infiltrate of neutrophils
into the perifollicular vessels and in the antral spaces. Additionally,
neutrophils were found adherent to the oocyte and among the cumulus
oophorum. IL-1ß treatment in COX-2+/+ mice
similarly stimulated a marked perifollicular, intravascular
accumulation of neutrophils, but without accumulation into the
preovulatory follicles (not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Neuroendocrine alterations in COX-1- and COX-2- deficient
mice
PGs act to modulate the secretion of LH and, to some extent, FSH
(17), primarily through modulation of hypothalamic LHRH, as
PGE2 stimulates the release of LHRH in vivo
(16), but does not directly influence the release of LH from the
pituitary (16, 17). Moreover, PGE2 may be involved in the
regulation of the LHRH pulse generator (17, 18, 20). As immortalized
LHRH neurons contain transcripts for both COX-1 and COX-2 (18), it was
expected that enzyme-deficient mice would exhibit perturbations in LHRH
that would ultimately affect reproductive cycles and ovulation.
However, analysis of hypothalamic LHRH demonstrated comparable levels
among wild-type, COX-1-deficient, and COX-2-deficient mice. These
results suggest that the absence of COX-1 or COX-2 enzyme is not rate
limiting for LHRH synthesis, that prostanoid production by either
enzyme is sufficient to maintain basal levels of LHRH in the
hypothalamus, or that one isoform is able to compensate for the other.
Given that the present studies measured LHRH content, it is still
possible that pulsatile secretion of LHRH during the cycle could be
altered, and this is currently under investigation.
Content analysis revealed that pituitary gonadotropin levels were slightly increased in COX-deficient mice. These results suggest that the lack of either COX isoenzyme may affect gonadotropin synthesis or release. Indomethacin was shown to potentiate LH secretion stimulated by arachidonic acid in vitro (23), and as deletion of either COX-1 or COX-2 isoenzyme should bear some similarity to inhibition by indomethacin, pituitary contents of the gonadotropins might be expected to be enhanced in these mice. However, serum gonadotropins and sex steroids had been comparable among the wild-type, COX-1-/-, and COX-2-/- mice. Further, the enzyme-deficient mice exhibit estrous cycles and mate upon introduction of the male. Thus, overall, the neuroendocrine axis appears to be intact in COX-1- and COX-2-deficient mice, although there may be subtle changes that affect the efficiency of its function.
COX-1 and COX-2 in ovarian function
The control of COX-2 in response to the gonadotropin surge and its
relation to the timing of ovulation have been eloquently described by
Richards (2, 25) and others (22). It has been unclear, however, what
are the contributing roles of either COX-1 or COX-2 in ovarian
follicular development, ovulation, and luteal function. By comparing
ovarian responses in COX-1 and COX-2 mutant mice, the present studies
show that the COX-2 isoform alone, and independently of COX-1, is
necessary for ovulation because COX-2-/- mice
fail to produce ovarian PGs in response to exogenous gonadotropins and
are anovulatory compared with COX-1-/- mice.
Although COX-2 induction has been implicated as an important factor in
granulosa cell differentiation factor (2), it appears that neither
isoform is essential for granulosa cell differentiation and luteal
formation, as ovarian morphology and steroid hormone production in the
various genotypes were comparable by 24–30 h after a gonadotropin
surge or in the naturally cycling mouse. Indeed, there was only a
slight temporal delay in the formation of the corpus luteum (CL) in the
COX-2-deficient mouse. However, ovarian PGE2 levels were
slightly suppressed in COX-1 and COX-2 mutant mice compared with those
in wild-type mice 24 h after hCG, suggesting that both isoenzymes
contribute to PG production during CL formation. Additionally, higher
levels of PGE2 in COX-2-/- mice
(which have an intact COX-1 enzyme) compared with those in
COX-1-/- mice (which have an intact COX-2
enzyme) suggest that COX-1 PGs may have a greater role in CL function
than COX-2.
COX-2 required for maintenance of cumulus oophorum
expansion
The major ovarian pathology attributed to the absence of COX-2 is
a failed coordinated release of ova in response to gonadotropin
stimulation. The release of the ovum requires both the activation and
expansion of the cumulus oophorum and initiation of proteolytic
cascades to lyse the follicle wall (3). Activation of the cumulus
oophorum is characterized by polarization and separation (expansion) of
the granulosa cells surrounding the oocyte with the production of
proteoglycans enriched in hyaluronic acid (45, 46). This process is
critical to successful ovulation and fertilization, as inhibition of
hyaluronic acid synthesis both suppresses cumulus expansion in the
mouse cumulus oocyte complex in vitro and decreases
fertilization rates (47). Cumulus expansion is also temporally
correlated with COX-2 induction and PG production in response to the
ovulatory gonadotropin surge (1, 2, 48, 49).
The COX-2-deficient mice exhibited attenuated expansion of the cumulus oophorus in response to exogenous gonadotropins, although the oocyte itself was activated and exhibited germinal vesicle breakdown and resumption of meiosis. A few preovulatory follicles from gonadotropin-stimulated COX-2+/+ mice were also observed to be negative for COX-2 protein in cumulus cells that failed to completely polarize and expand. None of the COX-2-deficient mice could maintain the structural organization of the cumulus oophorum expansion over time. Further, the occasional ovum that was released in superovulated COX-2-/- mice in these studies and that reported by others (27) was devoid of the accompanying cumulus mass. Thus, COX-2-induced PGs appear necessary to both fully expand and then stabilize the cumulus oophorum complex. The failed cumulus stabilization may be in part attributed to altered hyaluronic acid production, as staining for hyaluronic acid was greatly reduced in the COX-2-/- mice, but was restored by PG treatment. Alternatively, COX-2 PGs may be necessary to stabilize the cumulus complex by recruiting other factors involved in cumulus stabilization as described by others (47, 50).
The fact that single ova without the cumulus are released from COX-2-deficient mice at least suggests that follicle lysis can occur without COX-2 PGs. However, gonadotropin-stimulated COX-2-deficient mice consistently fail to complete the typical cellular reorganization around the apex of a stimulated follicle. The stigmata is formed by localized cellular structural alterations and changes in both collagen and proteoglycan production (3, 51, 52). PGE2 specifically stimulates the incorporation of glucosamine into the apical wall of human follicles to facilitate follicle rupture (52). Thus, PGs appear to be important in initiating changes in proteoglycan content in the follicle wall as well as in the cumulus oophorum. It is reasonable, then, to propose that both cumulus expansion and follicle rupture may be altered in the COX-2-deficient mouse because of attenuated proteoglycan synthesis. Further studies are planned to measure proteoglycan synthesis in COX-2-deficient mice.
Roles of PGs and IL-1ß in ovulation
In the COX-2-/- mouse, cumulus activation,
stigmata formation, and ovulation were restored by treatment with
PGE2 or IL-1ß. PGF2 was only partially
effective in this regard. These data suggest that the PGE
receptor-mediated pathways are the primary prostanoid signaling
pathways in cumulus expansion and ovulation, and that IL-1ß can
trigger ovulation independently of COX-2, at least in the mouse. Based
on our results, the PGF2 receptor-mediated pathways
appear to play a minor role in ovulation, and their success may be due
to the ability of PGF2 to bind to PGE2
receptors (53). Additionally, the PGF2
receptor-deficient mouse ovulates but has a parturition defect (54),
providing further evidence that although PGF2 plays only
a minor role in ovulation, it has a dominant role during
luteolysis.
These data are consistent with other data that demonstrate the role of COX and particularly PGE2 in ovulation (3, 15, 32, 48). However, other studies have suggested that COX-mediated PGs are not critical to the process of ovulation (55, 56). Although such differences are usually difficult to explain, studies with COX-deficient mice provide a few possible explanations. First, our studies comparing COX-1- and COX-2-deficient mice demonstrate that it is critical that COX-2 is inhibited. The use of low doses of indomethacin to inhibit COX and PG production (55) may differentially inhibit COX-1, but not COX-2. Thus, ovulation could occur as it does in the COX-1-/- mouse. As the indomethacin dose may affect the response, so may differences in the dose and source of PGs. COX-2 is expressed in a specific population of cells within the follicle during ovulation. If COX-2 induction is not completely blocked in these cells, ovulation may still proceed. Finally, there appears to be a redundancy in the signaling systems that may stimulate or inhibit ovulation when initiated at different times. Redundancies may explain why other signals, such as IL-1ß, override the COX-2 deficiency.
Previous studies (31, 57) have shown an interaction between IL-1ß and COX-2 in ovarian tissue. The restoration of ovulation in the COX-2-deficient mouse by IL-1ß suggests that either IL-1ß is downstream of COX-2 or that the COX-2 and IL-1ß pathways are partially redundant during ovulation. Although the specific nature of the interaction of COX-2 and IL-1ß and its receptors in COX-2-/- mice will require further study at the molecular level, we suggest that COX-2 and IL-1ß and their respective receptors are the interdependent, intercellular factors necessary for mucification of the cumulus oocyte complex as proposed by Camaioni et al. (50).
Overall, our studies with the COX-deficient mice demonstrate that each isoenzyme has a predetermined, specified role in reproduction even though COX-1 and COX-2 participate in identical enzymatic reactions. Assessment of the hypothalamic and pituitary functions suggest that the anovulatory syndrome is primarily ovarian dependent, but alterations occur in pituitary hormone levels in both COX-1- and COX-2-deficient mice that may further contribute to the anovulation and infertility. In the ovary, regulation of COX-2 by the gonadotropins and the cell-specific expression of this enzyme play an indispensable role in ovulation and, thus, fertility. The described interaction among COX-2, PGE2, and IL-1ß in ovulation provides an important model to understand the cell signaling processes and mechanics of tissue remodeling in the ovary.
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Acknowledgments |
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Footnotes |
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Received August 17, 1998.
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References |
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receptor
expression by interleukin-1ß in cultured human granulosa-luteal
cells. Endocrinology 138:3638–3644 and IL-1ß and altered
brain cytokine mRNA and serum cytokine levels, in IL-1ß-deficient
mice. Proc Natl Acad Sci USA 94:2681–2686 in human
pre-ovulatory follicular fluid. Hum Reprod 9:9–12This article has been cited by other articles:
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  Z. Liu, D. G. de Matos, H.-Y. Fan, M. Shimada, S. Palmer, and J. S. Richards Interleukin-6: An Autocrine Regulator of the Mouse Cumulus Cell-Oocyte Complex Expansion Process Endocrinology, July 1, 2009; 150(7): 3360 - 3368. [Abstract] [Full Text] [PDF]
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J. Liu, E.-S. Park, and M. Jo Runt-Related Transcription Factor 1 Regulates Luteinized Hormone-Induced Prostaglandin-Endoperoxide Synthase 2 Expression in Rat Periovulatory Granulosa Cells Endocrinology, July 1, 2009; 150(7): 3291 - 3300. [Abstract] [Full Text] [PDF]
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 M. E Matzkin, S. I Gonzalez-Calvar, A. Mayerhofer, R. S Calandra, and M. B Frungieri Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F2{alpha} production in hamster Leydig cells Reproduction, July 1, 2009; 138(1): 163 - 175. [Abstract] [Full Text] [PDF]
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 Y. Ren, R. G. Cowan, R. M. Harman, and S. M. Quirk Dominant Activation of the Hedgehog Signaling Pathway in the Ovary Alters Theca Development and Prevents Ovulation Mol. Endocrinol., May 1, 2009; 23(5): 711 - 723. [Abstract] [Full Text] [PDF]
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Q. Li, F. Jimenez-Krassel, J. J Ireland, and G. W Smith Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process Reproduction, February 1, 2009; 137(2): 297 - 307. [Abstract] [Full Text] [PDF]
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S. Kurusu, M. Jinno, H. Ehara, T. Yonezawa, and M. Kawaminami Inhibition of ovulation by a lipoxygenase inhibitor involves reduced cyclooxygenase-2 expression and prostaglandin E2 production in gonadotropin-primed immature rats Reproduction, January 1, 2009; 137(1): 59 - 66. [Abstract] [Full Text] [PDF]
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N. Markosyan and D. M. Duffy Prostaglandin E2 Acts via Multiple Receptors to Regulate Plasminogen-Dependent Proteolysis in the Primate Periovulatory Follicle Endocrinology, January 1, 2009; 150(1): 435 - 444. [Abstract] [Full Text] [PDF]
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K. Sayasith, N. Bouchard, M. Dore, and J. Sirois Regulation of Bovine Tumor Necrosis Factor-{alpha}-Induced Protein 6 in Ovarian Follicles during the Ovulatory Process and Promoter Activation in Granulosa Cells Endocrinology, December 1, 2008; 149(12): 6213 - 6225. [Abstract] [Full Text] [PDF]
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 S. D. Fiedler, M. Z. Carletti, X. Hong, and L. K. Christenson Hormonal Regulation of MicroRNA Expression in Periovulatory Mouse Mural Granulosa Cells Biol Reprod, December 1, 2008; 79(6): 1030 - 1037. [Abstract] [Full Text] [PDF]
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V. M. Portela, P. B. D. Goncalves, A. M. Veiga, E. Nicola, J. Buratini Jr., and C. A. Price Regulation of Angiotensin Type 2 Receptor in Bovine Granulosa Cells Endocrinology, October 1, 2008; 149(10): 5004 - 5011. [Abstract] [Full Text] [PDF]
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 T. da Silva Faria, F. de Bittencourt Brasil, F. J B Sampaio, and C. da Fonte Ramos Maternal malnutrition during lactation alters the folliculogenesis and gonadotropins and estrogen isoforms ovarian receptors in the offspring at puberty J. Endocrinol., September 1, 2008; 198(3): 625 - 634. [Abstract] [Full Text] [PDF]
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F. Nuttinck, B. M.-L. Guienne, L. Clement, P. Reinaud, G. Charpigny, and B. Grimard Expression of genes involved in prostaglandin E2 and progesterone production in bovine cumulus-oocyte complexes during in vitro maturation and fertilization Reproduction, May 1, 2008; 135(5): 593 - 603. [Abstract] [Full Text] [PDF]
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 J. Kim, M. Sato, Q. Li, J. P. Lydon, F. J. DeMayo, I. C. Bagchi, and M. K. Bagchi Peroxisome Proliferator-Activated Receptor {gamma} Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice Mol. Cell. Biol., March 1, 2008; 28(5): 1770 - 1782. [Abstract] [Full Text] [PDF]
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 R. B. Gilchrist, M. Lane, and J. G. Thompson Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality Hum. Reprod. Update, March 1, 2008; 14(2): 159 - 177. [Abstract] [Full Text] [PDF]
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 P. Feuerstein, V. Cadoret, R. Dalbies-Tran, F. Guerif, R. Bidault, and D. Royere Gene expression in human cumulus cells: one approach to oocyte competence Hum. Reprod., December 1, 2007; 22(12): 3069 - 3077. [Abstract] [Full Text] [PDF]
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M. Shimada, Y. Yanai, T. Okazaki, Y. Yamashita, V. Sriraman, M. C. Wilson, and J. S. Richards Synaptosomal-Associated Protein 25 Gene Expression Is Hormonally Regulated during Ovulation and Is Involved in Cytokine/Chemokine Exocytosis from Granulosa Cells Mol. Endocrinol., October 1, 2007; 21(10): 2487 - 2502. [Abstract] [Full Text] [PDF]
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 B. Samuelsson, R. Morgenstern, and P.-J. Jakobsson Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target Pharmacol. Rev., September 1, 2007; 59(3): 207 - 224. [Abstract] [Full Text] [PDF]
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 E. Gershon, A. Hourvitz, S. Reikhav, E. Maman, and N. Dekel Low expression of COX-2, reduced cumulus expansion, and impaired ovulation in SULT1E1-deficient mice FASEB J, June 1, 2007; 21(8): 1893 - 1901. [Abstract] [Full Text] [PDF]
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D. L. Russell and R. L. Robker Molecular mechanisms of ovulation: co-ordination through the cumulus complex Hum. Reprod. Update, May 1, 2007; 13(3): 289 - 312. [Abstract] [Full Text] [PDF]
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R. A. Dragovic, L. J. Ritter, S. J. Schulz, F. Amato, J. G. Thompson, D. T. Armstrong, and R. B. Gilchrist Oocyte-Secreted Factor Activation of SMAD 2/3 Signaling Enables Initiation of Mouse Cumulus Cell Expansion Biol Reprod, May 1, 2007; 76(5): 848 - 857. [Abstract] [Full Text] [PDF]
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 W.-L. Yang, K. Q. Cai, J. L. Smedberg, E. R. Smith, A. Klein-Szanto, T. C. Hamilton, and X.-X. Xu A Reduction of Cyclooxygenase 2 Gene Dosage Counters the Ovarian Morphological Aging and Tumor Phenotype in Wv Mice Am. J. Pathol., April 1, 2007; 170(4): 1325 - 1336. [Abstract] [Full Text] [PDF]
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M. Hsieh, D. Lee, S. Panigone, K. Horner, R. Chen, A. Theologis, D. C. Lee, D. W. Threadgill, and M. Conti Luteinizing Hormone-Dependent Activation of the Epidermal Growth Factor Network Is Essential for Ovulation Mol. Cell. Biol., March 1, 2007; 27(5): 1914 - 1924. [Abstract] [Full Text] [PDF]
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K. Sayasith, N. Bouchard, M. Dore, and J. Sirois Cloning of equine prostaglandin dehydrogenase and its gonadotropin-dependent regulation in theca and mural granulosa cells of equine preovulatory follicles during the ovulatory process Reproduction, February 1, 2007; 133(2): 455 - 466. [Abstract] [Full Text] [PDF]
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 J. Inzunza, A. Morani, G. Cheng, M. Warner, J. Hreinsson, J.-A. Gustafsson, and O. Hovatta Ovarian wedge resection restores fertility in estrogen receptor beta knockout (ERbeta-/-) mice PNAS, January 9, 2007; 104(2): 600 - 605. [Abstract] [Full Text] [PDF]
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K. Sayasith, M. Dore, and J. Sirois Molecular characterization of tumor necrosis {alpha}-induced protein 6 and its human chorionic gonadotropin-dependent induction in theca and mural granulosa cells of equine preovulatory follicles Reproduction, January 1, 2007; 133(1): 135 - 145. [Abstract] [Full Text] [PDF]
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Y. L. Pon and A. S. T. Wong Gonadotropin-Induced Apoptosis in Human Ovarian Surface Epithelial Cells Is Associated with Cyclooxygenase-2 Up-Regulation via the {beta}-Catenin/T-Cell Factor Signaling Pathway Mol. Endocrinol., December 1, 2006; 20(12): 3336 - 3350. [Abstract] [Full Text] [PDF]
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 T. Takahashi, J. D. Morrow, H. Wang, and S. K. Dey Cyclooxygenase-2-derived Prostaglandin E2 Directs Oocyte Maturation by Differentially Influencing Multiple Signaling Pathways J. Biol. Chem., December 1, 2006; 281(48): 37117 - 37129. [Abstract] [Full Text] [PDF]
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N. Markosyan, B. L. Dozier, F. A. Lattanzio, and D. M. Duffy Primate Granulosa Cell Response via Prostaglandin E2 Receptors Increases Late in the Periovulatory Interval Biol Reprod, December 1, 2006; 75(6): 868 - 876. [Abstract] [Full Text] [PDF]
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M Gaytan, C Bellido, C Morales, J E Sanchez-Criado, and F Gaytan Effects of selective inhibition of cyclooxygenase and lipooxygenase pathways in follicle rupture and ovulation in the rat. Reproduction, October 1, 2006; 132(4): 571 - 577. [Abstract] [Full Text] [PDF]
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 I. Ben-Ami, S. Freimann, L. Armon, A. Dantes, D. Strassburger, S. Friedler, A. Raziel, R. Seger, R. Ron-El, and A. Amsterdam PGE2 up-regulates EGF-like growth factor biosynthesis in human granulosa cells: new insights into the coordination between PGE2 and LH in ovulation Mol. Hum. Reprod., October 1, 2006; 12(10): 593 - 599. [Abstract] [Full Text] [PDF]
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M. B. Frungieri, S. I. Gonzalez-Calvar, F. Parborell, M. Albrecht, A. Mayerhofer, and R. S. Calandra Cyclooxygenase-2 and Prostaglandin F2{alpha} in Syrian Hamster Leydig Cells: Inhibitory Role on Luteinizing Hormone/Human Chorionic Gonadotropin-Stimulated Testosterone Production Endocrinology, September 1, 2006; 147(9): 4476 - 4485. [Abstract] [Full Text] [PDF]
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 H. Wang, S. K. Dey, and M. Maccarrone Jekyll and Hyde: Two Faces of Cannabinoid Signaling in Male and Female Fertility Endocr. Rev., August 1, 2006; 27(5): 427 - 448. [Abstract] [Full Text] [PDF]
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O. Yoshino, H. E. McMahon, S. Sharma, and S. Shimasaki A unique preovulatory expression pattern plays a key role in the physiological functions of BMP-15 in the mouse PNAS, July 11, 2006; 103(28): 10678 - 10683. [Abstract] [Full Text] [PDF]
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S. Assou, T. Anahory, V. Pantesco, T. Le Carrour, F. Pellestor, B. Klein, L. Reyftmann, H. Dechaud, J. De Vos, and S. Hamamah The human cumulus-oocyte complex gene-expression profile Hum. Reprod., July 1, 2006; 21(7): 1705 - 1719. [Abstract] [Full Text] [PDF]
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I. Hernandez-Gonzalez, I. Gonzalez-Robayna, M. Shimada, C. M. Wayne, S. A. Ochsner, L. White, and J. S. Richards Gene Expression Profiles of Cumulus Cell Oocyte Complexes during Ovulation Reveal Cumulus Cells Express Neuronal and Immune-Related Genes: Does this Expand Their Role in the Ovulation Process? Mol. Endocrinol., June 1, 2006; 20(6): 1300 - 1321. [Abstract] [Full Text] [PDF]
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M. Shimada, I. Hernandez-Gonzalez, I. Gonzalez-Robayna, and J. S. Richards Paracrine and Autocrine Regulation of Epidermal Growth Factor-Like Factors in Cumulus Oocyte Complexes and Granulosa Cells: Key Roles for Prostaglandin Synthase 2 and Progesterone Receptor Mol. Endocrinol., June 1, 2006; 20(6): 1352 - 1365. [Abstract] [Full Text] [PDF]
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T. Sun, W.-B. Deng, H.-L. Diao, H. Ni, Y.-Y. Bai, X.-H. Ma, L.-B. Xu, and Z.-M. Yang Differential expression and regulation of prostaglandin E synthases in the mouse ovary during sexual maturation and luteal development. J. Endocrinol., April 1, 2006; 189(1): 89 - 101. [Abstract] [Full Text] [PDF]
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M. Conti, M. Hsieh, J.-Y. Park, and Y.-Q. Su Role of the Epidermal Growth Factor Network in Ovarian Follicles Mol. Endocrinol., April 1, 2006; 20(4): 715 - 723. [Abstract] [Full Text] [PDF]
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C. Ko, M. C. Gieske, L. Al-Alem, Y. Hahn, W. Su, M. C. Gong, M. Iglarz, and Y. Koo Endothelin-2 in Ovarian Follicle Rupture Endocrinology, April 1, 2006; 147(4): 1770 - 1779. [Abstract] [Full Text] [PDF]
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A Hourvitz, E Gershon, J D Hennebold, S Elizur, E Maman, C Brendle, E Y Adashi, and N Dekel Ovulation-selective genes: the generation and characterization of an ovulatory-selective cDNA library. J. Endocrinol., March 1, 2006; 188(3): 531 - 548. [Abstract] [Full Text] [PDF]
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Q. Li, F. Jimenez-Krassel, Y. Kobayashi, J. J Ireland, and G. W Smith Effect of intrafollicular indomethacin injection on gonadotropin surge-induced expression of select extracellular matrix degrading enzymes and their inhibitors in bovine preovulatory follicles. Reproduction, March 1, 2006; 131(3): 533 - 543. [Abstract] [Full Text] [PDF]
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 B Lohrke, T Viergutz, and B Kruger Polar phospholipids from bovine endogenously oxidized low density lipoprotein interfere with follicular thecal function J. Mol. Endocrinol., December 1, 2005; 35(3): 531 - 545. [Abstract] [Full Text] [PDF]
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M Shozu, N Minami, H Yokoyama, M Inoue, H Kurihara, K Matsushima, and K Kuno ADAMTS-1 is involved in normal follicular development, ovulatory process and organization of the medullary vascular network in the ovary J. Mol. Endocrinol., October 1, 2005; 35(2): 343 - 355. [Abstract] [Full Text] [PDF]
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T. Pakarainen, F.-P. Zhang, L. Nurmi, M. Poutanen, and I. Huhtaniemi Knockout of Luteinizing Hormone Receptor Abolishes the Effects of Follicle-Stimulating Hormone on Preovulatory Maturation and Ovulation of Mouse Graafian Follicles Mol. Endocrinol., October 1, 2005; 19(10): 2591 - 2602. [Abstract] [Full Text] [PDF]
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S. A. Pangas and M. M. Matzuk The Art and Artifact of GDF9 Activity: Cumulus Expansion and the Cumulus Expansion-Enabling Factor Biol Reprod, October 1, 2005; 73(4): 582 - 585. [Abstract] [Full Text] [PDF]
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J. M. A. Tullet, V. Pocock, J. H. Steel, R. White, S. Milligan, and M. G. Parker Multiple Signaling Defects in the Absence of RIP140 Impair Both Cumulus Expansion and Follicle Rupture Endocrinology, September 1, 2005; 146(9): 4127 - 4137. [Abstract] [Full Text] [PDF]
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K. Sayasith, J. G. Lussier, and J. Sirois Role of Upstream Stimulatory Factor Phosphorylation in the Regulation of the Prostaglandin G/H Synthase-2 Promoter in Granulosa Cells J. Biol. Chem., August 12, 2005; 280(32): 28885 - 28893. [Abstract] [Full Text] [PDF]
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J. F. Couse, M. M. Yates, B. J. Deroo, and K. S. Korach Estrogen Receptor-{beta} Is Critical to Granulosa Cell Differentiation and the Ovulatory Response to Gonadotropins Endocrinology, August 1, 2005; 146(8): 3247 - 3262. [Abstract] [Full Text] [PDF]
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J. M. A. Emmen, J. F. Couse, S. A. Elmore, M. M. Yates, G. E. Kissling, and K. S. Korach In Vitro Growth and Ovulation of Follicles from Ovaries of Estrogen Receptor (ER){alpha} and ER{beta} Null Mice Indicate a Role for ER{beta} in Follicular Maturation Endocrinology, June 1, 2005; 146(6): 2817 - 2826. [Abstract] [Full Text] [PDF]
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 N. El-Nefiawy, K. Abdel-Hakim, and N. Kanayama The selective prostaglandin EP4 agonist, APS-999 Na, induces follicular growth and maturation in the rat ovary Eur. J. Endocrinol., February 1, 2005; 152(2): 315 - 323. [Abstract] [Full Text] [PDF]
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H. Ashkenazi, X. Cao, S. Motola, M. Popliker, M. Conti, and A. Tsafriri Epidermal Growth Factor Family Members: Endogenous Mediators of the Ovulatory Response Endocrinology, January 1, 2005; 146(1): 77 - 84. [Abstract] [Full Text] [PDF]
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L.-M. Gui and I. M. Joyce RNA Interference Evidence That Growth Differentiation Factor-9 Mediates Oocyte Regulation of Cumulus Expansion in Mice Biol Reprod, January 1, 2005; 72(1): 195 - 199. [Abstract] [Full Text] [PDF]
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L.J. McKenzie, S.A. Pangas, S.A. Carson, E. Kovanci, P. Cisneros, J.E. Buster, P. Amato, and M.M. Matzuk Human cumulus granulosa cell gene expression: a predictor of fertilization and embryo selection in women undergoing IVF Hum. Reprod., December 1, 2004; 19(12): 2869 - 2874. [Abstract] [Full Text] [PDF]
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J. W. Newman, J. E. Stok, J. D. Vidal, C. J. Corbin, Q. Huang, B. D. Hammock, and A. J. Conley Cytochrome P450-Dependent Lipid Metabolism in Preovulatory Follicles Endocrinology, November 1, 2004; 145(11): 5097 - 5105. [Abstract] [Full Text] [PDF]
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D. L. Simmons, R. M. Botting, and T. Hla Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition Pharmacol. Rev., September 1, 2004; 56(3): 387 - 437. [Abstract] [Full Text] [PDF]
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J. Sirois, K. Sayasith, K. A. Brown, A. E. Stock, N. Bouchard, and M. Dore Cyclooxygenase-2 and its role in ovulation: a 2004 account Hum. Reprod. Update, September 1, 2004; 10(5): 373 - 385. [Abstract] [Full Text] [PDF]
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 J. L. Goulet, A. J. Pace, M. L. Key, R. S. Byrum, M. Nguyen, S. L. Tilley, S. G. Morham, R. Langenbach, J. L. Stock, J. D. McNeish, et al. E-Prostanoid-3 Receptors Mediate the Proinflammatory Actions of Prostaglandin E2 in Acute Cutaneous Inflammation J. Immunol., July 15, 2004; 173(2): 1321 - 1326. [Abstract] [Full Text] [PDF]
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 A. Salustri, C. Garlanda, E. Hirsch, M. De Acetis, A. Maccagno, B. Bottazzi, A. Doni, A. Bastone, G. Mantovani, P. B. Peccoz, et al. PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization Development, April 1, 2004; 131(7): 1577 - 1586. [Abstract] [Full Text] [PDF]
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L. Mittaz, D.L. Russell, T. Wilson, M. Brasted, J. Tkalcevic, L.A. Salamonsen, P.J. Hertzog, and M.A. Pritchard Adamts-1 Is Essential for the Development and Function of the Urogenital System Biol Reprod, April 1, 2004; 70(4): 1096 - 1105. [Abstract] [Full Text] [PDF]
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K. Sayasith, N. Bouchard, M. Sawadogo, J. G. Lussier, and J. Sirois Molecular Characterization and Role of Bovine Upstream Stimulatory Factor 1 and 2 in the Regulation of the Prostaglandin G/H Synthase-2 Promoter in Granulosa Cells J. Biol. Chem., February 20, 2004; 279(8): 6327 - 6336. [Abstract] [Full Text] [PDF]
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T. KUWANO, S. NAKAO, H. YAMAMOTO, M. TSUNEYOSHI, T. YAMAMOTO, M. KUWANO, and M. ONO Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis FASEB J, February 1, 2004; 18(2): 300 - 310. [Abstract] [Full Text] [PDF]
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D. L. Russell, K. M. H. Doyle, S. A. Ochsner, J. D. Sandy, and J. S. Richards Processing and Localization of ADAMTS-1 and Proteolytic Cleavage of Versican during Cumulus Matrix Expansion and Ovulation J. Biol. Chem., October 24, 2003; 278(43): 42330 - 42339. [Abstract] [Full Text] [PDF]
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S. A. Ochsner, A. J. Day, M. S. Rugg, R. M. Breyer, R. H. Gomer, and J. S. Richards Disrupted Function of Tumor Necrosis Factor-{alpha}-Stimulated Gene 6 Blocks Cumulus Cell-Oocyte Complex Expansion Endocrinology, October 1, 2003; 144(10): 4376 - 4384. [Abstract] [Full Text] [PDF]
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T. Sakurai, K. Tamura, S. Okamoto, T. Hara, and H. Kogo Possible Role of Cyclooxygenase II in the Acquisition of Ovarian Luteal Function in Rodents Biol Reprod, September 1, 2003; 69(3): 835 - 842. [Abstract] [Full Text] [PDF]
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T. E. Curry Jr. and K. G. Osteen The Matrix Metalloproteinase System: Changes, Regulation, and Impact throughout the Ovarian and Uterine Reproductive Cycle Endocr. Rev., August 1, 2003; 24(4): 428 - 465. [Abstract] [Full Text] [PDF]
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F. Gaytan, C. Bellido, M. Gaytan, C. Morales, and J. E. Sanchez-Criado Differential Effects of RU486 and Indomethacin on Follicle Rupture During the Ovulatory Process in the Rat Biol Reprod, July 1, 2003; 69(1): 99 - 105. [Abstract] [Full Text] [PDF]
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J.-Y. Park, F. Richard, S.-Y. Chun, J.-H. Park, E. Law, K. Horner, S-L C. Jin, and M. Conti Phosphodiesterase Regulation Is Critical for the Differentiation and Pattern of Gene Expression in Granulosa Cells of the Ovarian Follicle Mol. Endocrinol., June 1, 2003; 17(6): 1117 - 1130. [Abstract] [Full Text] [PDF]
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 J Martel-Pelletier, D Lajeunesse, P Reboul, and J-P Pelletier Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs Ann Rheum Dis, June 1, 2003; 62(6): 501 - 509. [Abstract] [Full Text] [PDF]
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 C. M. Milner and A. J. Day TSG-6: a multifunctional protein associated with inflammation J. Cell Sci., May 15, 2003; 116(10): 1863 - 1873. [Abstract] [Full Text] [PDF]
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S. A. Ochsner, D. L. Russell, A. J. Day, R. M. Breyer, and J. S. Richards Decreased Expression of Tumor Necrosis Factor-{alpha}-Stimulated Gene 6 in Cumulus Cells of the Cyclooxygenase-2 and EP2 Null Mice Endocrinology, March 1, 2003; 144(3): 1008 - 1019. [Abstract] [Full Text] [PDF]
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D. L. Russell, S. A. Ochsner, M. Hsieh, S. Mulders, and J. S. Richards Hormone-Regulated Expression and Localization of Versican in the Rodent Ovary Endocrinology, March 1, 2003; 144(3): 1020 - 1031. [Abstract] [Full Text] [PDF]
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E. Segi, K. Haraguchi, Y. Sugimoto, M. Tsuji, H. Tsunekawa, S. Tamba, K. Tsuboi, S. Tanaka, and A. Ichikawa Expression of Messenger RNA for Prostaglandin E Receptor Subtypes EP4/EP2 and Cyclooxygenase Isozymes in Mouse Periovulatory Follicles and Oviducts During Superovulation Biol Reprod, March 1, 2003; 68(3): 804 - 811. [Abstract] [Full Text] [PDF]
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J.-G. Cheng and C. L. Stewart Loss of Cyclooxygenase-2 Retards Decidual Growth but Does Not Inhibit Embryo Implantation or Development to Term Biol Reprod, February 1, 2003; 68(2): 401 - 404. [Abstract] [Full Text] [PDF]
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L. L. Espey and J. S. Richards Temporal and Spatial Patterns of Ovarian Gene Transcription Following an Ovulatory Dose of Gonadotropin in the Rat Biol Reprod, December 1, 2002; 67(6): 1662 - 1670. [Abstract] [Full Text] [PDF]
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D. M. Duffy and R. L. Stouffer Follicular administration of a cyclooxygenase inhibitor can prevent oocyte release without alteration of normal luteal function in rhesus monkeys Hum. Reprod., November 1, 2002; 17(11): 2825 - 2831. [Abstract] [Full Text] [PDF]
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F. Gaytan, E. Tarradas, C. Bellido, C. Morales, and J. E. Sanchez-Criado Prostaglandin E1 Inhibits Abnormal Follicle Rupture and Restores Ovulation in Indomethacin-Treated Rats Biol Reprod, October 1, 2002; 67(4): 1140 - 1147. [Abstract] [Full Text] [PDF]
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 L. Koumas and R. P. Phipps Differential COX localization and PG release in Thy-1+ and Thy-1- human female reproductive tract fibroblasts Am J Physiol Cell Physiol, August 1, 2002; 283(2): C599 - C608. [Abstract] [Full Text] [PDF]
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S. Varani, J. A. Elvin, C. Yan, J. DeMayo, F. J. DeMayo, H. F. Horton, M. C. Byrne, and M. M. Matzuk Knockout of Pentraxin 3, a Downstream Target of Growth Differentiation Factor-9, Causes Female Subfertility Mol. Endocrinol., June 1, 2002; 16(6): 1154 - 1167. [Abstract] [Full Text] [PDF]
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Y.-L. Wu and M. C. Wiltbank Transcriptional Regulation of the Cyclooxygenase-2 Gene Changes from Protein Kinase (PK) A- to PKC-Dependence after Luteinization of Granulosa Cells Biol Reprod, May 1, 2002; 66(5): 1505 - 1514. [Abstract] [Full Text]
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 C. G Egan, J. C Lockhart, W. R Ferrell, S. M Day, and J. S McLean Pathophysiological basis of acute inflammatory hyperaemia in the rat knee: roles of cyclo-oxygenase-1 and -2 J. Physiol., March 1, 2002; 539(2): 579 - 587. [Abstract] [Full Text] [PDF]
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 B. Hinz and K. Brune Cyclooxygenase-2---10 Years Later J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 367 - 375. [Abstract] [Full Text] [PDF]
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 J. S. Richards, D. L. Russell, S. Ochsner, M. Hsieh, K. H. Doyle, A. E. Falender, Y. K. Lo, and S. C. Sharma Novel Signaling Pathways That Control Ovarian Follicular Development, Ovulation, and Luteinization Recent Prog. Horm. Res., January 1, 2002; 57(1): 195 - 220. [Abstract] [Full Text] [PDF]
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D. M. Duffy and R. L. Stouffer The ovulatory gonadotrophin surge stimulates cyclooxygenase expression and prostaglandin production by the monkey follicle Mol. Hum. Reprod., August 1, 2001; 7(8): 731 - 739. [Abstract] [Full Text] [PDF]
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I. M. Joyce, F. L. Pendola, M. O'Brien, and J. J. Eppig Regulation of Prostaglandin-Endoperoxide Synthase 2 Messenger Ribonucleic Acid Expression in Mouse Granulosa Cells during Ovulation Endocrinology, July 1, 2001; 142(7): 3187 - 3197. [Abstract] [Full Text] [PDF]
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J. Reese, X. Zhao, W.-G. Ma, N. Brown, T. J. Maziasz, and S. K. Dey Comparative Analysis of Pharmacologic and/or Genetic Disruption of Cyclooxygenase-1 and Cyclooxygenase-2 Function in Female Reproduction in Mice Endocrinology, July 1, 2001; 142(7): 3198 - 3206. [Abstract] [Full Text] [PDF]
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M. D. Calder, A. N. Caveney, M. E. Westhusin, and A. J. Watson Cyclooxygenase-2 and Prostaglandin E2(PGE2) Receptor Messenger RNAs Are Affected by Bovine Oocyte Maturation Time and Cumulus-Oocyte Complex Quality, and PGE2 Induces Moderate Expansion of the Bovine Cumulus In Vitro Biol Reprod, July 1, 2001; 65(1): 135 - 140. [Abstract] [Full Text] [PDF]
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J. S. Richards Perspective: The Ovarian Follicle--A Perspective in 2001 Endocrinology, June 1, 2001; 142(6): 2184 - 2193. [Full Text] [PDF]
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H. Matsumoto, W.-g. Ma, W. Smalley, J. Trzaskos, R. M. Breyer, and S. K. Dey Diversification of Cyclooxygenase-2-Derived Prostaglandins in Ovulation and Implantation Biol Reprod, May 1, 2001; 64(5): 1557 - 1565. [Abstract] [Full Text]
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C. D. Loftin, D. B. Trivedi, H. F. Tiano, J. A. Clark, C. A. Lee, J. A. Epstein, S. G. Morham, M. D. Breyer, M. Nguyen, B. M. Hawkins, et al. Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2 PNAS, January 23, 2001; (2001) 31573498. [Abstract] [Full Text]
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G. A. Dissen, J. A. Parrott, M. K. Skinner, D. F. Hill, M. E. Costa, and S. R. Ojeda Direct Effects of Nerve Growth Factor on Thecal Cells from Antral Ovarian Follicles Endocrinology, December 1, 2000; 141(12): 4736 - 4750. [Abstract] [Full Text] [PDF]
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 A. Kirschenbaum, D. R. Liotta, S. Yao, X.-H. Liu, A. P. Klausner, P. Unger, E. Shapiro, I. Leav, and A. C. Levine Immunohistochemical Localization of Cyclooxygenase-1 and Cyclooxygenase-2 in the Human Fetal and Adult Male Reproductive Tracts J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3436 - 3441. [Abstract] [Full Text]
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T.-L. Erkinheimo, K. Saukkonen, K. Narko, J. Jalkanen, O. Ylikorkala, and A. Ristimäki Expression of Cyclooxygenase-2 and Prostanoid Receptors by Human Myometrium J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3468 - 3475. [Abstract] [Full Text]
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F. Filion, N. Bouchard, A. K. Goff, J. G. Lussier, and J. Sirois Molecular Cloning and Induction of Bovine Prostaglandin E Synthase by Gonadotropins in Ovarian Follicles Prior to Ovulation in Vivo J. Biol. Chem., August 31, 2001; 276(36): 34323 - 34330. [Abstract] [Full Text] [PDF]
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C. D. Loftin, D. B. Trivedi, H. F. Tiano, J. A. Clark, C. A. Lee, J. A. Epstein, S. G. Morham, M. D. Breyer, M. Nguyen, B. M. Hawkins, et al. Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2 PNAS, January 30, 2001; 98(3): 1059 - 1064. [Abstract] [Full Text] [PDF]
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J. A. Elvin, C. Yan, and M. M. Matzuk Growth differentiation factor-9 stimulates progesterone synthesis in granulosa cells via a prostaglandin E2/EP2 receptor pathway PNAS, August 29, 2000; 97(18): 10288 - 10293. [Abstract] [Full Text] [PDF]
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C. G. Egan, J. C. Lockhart, W. R. Ferrell, S. M. Day, and J. S. McLean Pathophysiological basis of acute inflammatory hyperaemia in the rat knee: roles of cyclo-oxygenase-1 and -2 J. Physiol., January 25, 2002; (2002) 200101347. [Abstract] [PDF]
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