Anti-implantation effects of indomethacin and celecoxib in rats
Nongluck Sookvanichsilp*, Pawitra Pulbutr
Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, ThailandAbstract
Pregnant Wistar rats were used to investigate the anti-implantation effect of cyclooxygenase (COX) inhibitors, indomethacin (nonse-
lective COX-1/COX-2 inhibitor) and celecoxib (specific COX-2 inhibitor). Indomethacin at doses of 2.5 and 5 mg/kg/day and celecoxib atdoses of 40, 80, and 160 mg/kg/day were orally administered once daily to each group (n ϭ 8) on Days 3–5 of pregnancy (Day 1 ϭ spermdetection). Indomethacin and celecoxib at anti-implantation dosages were further investigated for the effects on changes in endometrialvascular permeability in pregnant rats and uterine decidualization in pseudopregnant rats. The results demonstrated that indomethacin at adose of 5 mg/kg/day as well as celecoxib at doses of 80 and 160 mg/kg/day could significantly reduce the proportion of pregnant rats. Atthe anti-implantation dosages, they exhibited no significant effect on proportion of rats with blue dye sites in the endometrial vascularpermeability study, but they could significantly reduce the uterine decidualization. From these findings, the anti-implantation effect of thetwo COX inhibitors may principally be from decidualization defects, and COX inhibitors should, therefore, be used with caution inchildbearing age women. On the other hand, specific COX-2 inhibitors with their good gastric safety profile may have a potential role innonhormonal postcoital contraception. 2002 Elsevier Science Inc. All rights reserved. Keywords: Anti-implantation; Celecoxib; COX inhibitors; Indomethacin; Postcoital contraception
[4 –10]. Cyclooxygenase (COX) inhibitors, nonsteroidal an-tiinflammatory drugs (NSAIDs) used worldwide, inhibit
Synchronized development of the embryo to the blasto-
prostaglandin synthesis. COX exists in two isoforms,
cyst stage by the time of arrival in the uterine cavity and
COX-1 and COX-2. COX-1 is a constitutive enzyme
differentiation of the uterus to the receptive state are essen-
present in many tissues, including the stomach, kidneys, and
tial to the implantation process . The endometrial re-
platelets. This isoform is responsible for the production of
sponse to the embryo implantation varies in different spe-
prostaglandins involved in general “housekeeping” activi-
cies; however, one phenomenon appears to be constant: the
ties, for example, maintenance of gastric mucosal integrity,
implantation of the blastocyst is preceded by an increase in
vascular hemostasis, and regulation of renal blood flow.
uterine vascular permeability leading to stromal edema .
COX-2 is an inducible enzyme and mainly produced at the
The stromal cells, under the influence of progesterone, are
sites of inflammation [11–13]. Indomethacin, a nonselective
transformed into a complex tissue known as decidua (de-
COX-1/COX-2 inhibitor, and celecoxib, a specific COX-2
cidualization) . In rats, the induction of decidualization
inhibitor with a good gastric safety profile, are used for
by nontraumatic stimuli, such as intrauterine oil injection,
anti-inflammatory and analgesic effects to treat various
can occur on Day 5 of pseudopregnancy or after exposure of
rheumatologic disorders. In addition, celecoxib is used to
the uterus to the appropriate combination and concentrationof progesterone and estrogen .
reduce the number of polyps in patients with familial ad-
Considerable evidence exists indicating that prostaglan-
enomatous polyposis [13–15]. The adverse effect of the two
dins are important in blastocyst implantation, endometrial
COX inhibitors on blastocyst implantation was investigated
vascular permeability, and uterine decidualization process
in the present study. In addition, because both endometrialvascular permeability and uterine decidualization are crucialevents for implantation, the effects of the two COX inhib-itors on these changes were also the aims of the present
* Corresponding author. Tel.: ϩ662-644-8677; fax: ϩ662-247-4696. E-mail address: [email protected] (N. Sookvanichsilp).
0010-7824/02/$ – see front matter 2002 Elsevier Science Inc. All rights reserved. PII: S 0 0 1 0 - 7 8 2 4 ( 0 1 ) 0 0 3 2 2 - 5
N. Sookvanichsilp, P. Pulbutr / Contraception 65 (2002) 373–378
Table 1Effect of indomethacin and celecoxib on implantation in rats
a Day 1 ϭ the day of finding sperm in the vagina. b % Implantation sites compared with the control group, calculated from the mean values. * p Ͻ 0.05, ** p Ͻ 0.01, *** p Ͻ 0.001 compared with the control group. 2. Materials and methods 2.2. Effect of indomethacin and celecoxib on endometrialvascular permeability2.1. Effect of indomethacin and celecoxib on implantation
For the second experiment, vaginal smears were taken
Female Wistar rats, weighing 160 –200 g, were obtained
and examined daily in the same manner as mentioned
from the National Animal Center, Mahidol University, Sa-
above. The pregnant rats were divided into four groups,
laya. They were housed in an air-conditioned room with free
consisting of eight rats per group, as indicated in Table 2.
access to a commercial pellet diet and tap water. All rats
Indomethacin at an oral dose of 5 mg/kg/day as well as
were allowed to acclimatize for one week before any ex-
celecoxib at oral doses of 80 and 160 mg/kg/day, doses that
periments were started. The experiment protocol was ap-
caused a significant reduction in the proportion of pregnant
proved by the Animal Ethics Committee, Faculty of Phar-
rats in the first experiment, were given to rats once daily on
Days 3–5 of pregnancy. To determine endometrial vascular
Vaginal smears were taken daily and examined micro-
permeability, these rats were given an intravenous injection
scopically. Female rats were caged individually with proven
of 0.5 mL of 0.5% Evans blue dye in 0.9% sodium chloride
fertile Wistar males in the afternoon of the proestrous stage.
solution via a tail vein  in the morning of Day 6 of
Mating was confirmed by the presence of spermatozoa in
pregnancy. Fifteen minutes after the Evans blue dye injec-
the vaginal smear on the next morning (Day 1 of pregnan-
tion, the rats were killed. The uteri were examined for the
cy). The pregnant rats were divided into six groups, con-
presence of blue dye sites, which is indicative of increased
sisting of eight rats per group, as indicated in Table 1.
endometrial vascular permeability. The number of blue dye
Indomethacin (Indocid 25 mg capsule, Merck Sharp &
Dohme) at doses of 2.5 and 5 mg/kg/day and celecoxib(Celebrex 200 mg capsule, Searle) at doses of 40, 80, and
2.3. Effect of indomethacin and celecoxib on uterine
160 mg/kg/day were administered by oral intubation once
daily to each group on Days 3–5 of pregnancy. The ratswere sacrificed on Day 8 of pregnancy, and the number of
For this third experiment, pseudopregnant rats were
used. Induction of decidualization was performed in a sim-
Table 2Effect of indomethacin and celecoxib on Evans blue dye reaction in rats
a Day 1 ϭ the day of finding sperm in the vagina. b No significant differences in number of rats with blue dye sites between groups. c % Blue dye sites compared with the control group, calculated from the mean values. * p Ͻ 0.05 compared with the control group. N. Sookvanichsilp, P. Pulbutr / Contraception 65 (2002) 373–378
Table 3Effect of indomethacin and celecoxib on uterine decidualization in rats
Uterine wet weight (mg)/100 g body weight, mean Ϯ SEM n ϭ 8
a % Uterine weight compared with the control group, calculated from the mean values. b No significant differences in mean weights of noninjected horns between groups. * p Ͻ 0.01, ** p Ͻ 0.001 compared with the control group.
ϩ p Ͻ 0.05 compared with 160 mg/kg/day celecoxib-treated group.
ilar manner to those previously described [17,18]. Female
of pregnant rats as well as the number of normal implanta-
rats were ovariectomized and allowed one week to recover
tion sites, when compared with controls (Table 1). Cele-
from the operation. To obtain the state of pseudopregnancy,
coxib at doses of 80 and 160 mg/kg/day, given on Days 3–5
the ovariectomized rats were treated by subcutaneous (sc)
of pregnancy, also exhibited significant effect on implanta-
injections with the hormone regimen of estradiol-17␤ (E )
tion. A complete inhibition of normal implantation, how-
and progesterone (P ) at varying doses and duration. The
ever, was seen only in 160 mg/kg/day celecoxib-treated rats.
regimen consisted of 0.2 g E in the morning for three
Both COX inhibitors at any dosages mentioned produced no
days (Days Ϫ2, Ϫ1, and 0 of pseudopregnancy), 0.2 g E
gastrointestinal bleeding as evaluated by stool observation.
and 1 mg P in the afternoon of the equivalent of Day 0 of
Indomethacin at a dose of 10 mg/kg/day, given once daily
pseudopregnancy, 4 mg P in the afternoon of Days 2 and 3,
on Days 3–5 of pregnancy, caused a severe gastrointestinal
0.3 g E and 4 mg P in the afternoon of Day 4, and 0.1 g
E and 4 mg P in the morning of five following days (Days
5–9 of pseudopregnancy). Decidualization was induced on
3.2. Effect of indomethacin and celecoxib on endometrial
Day 5 of pseudopregnancy by artificial deciduogenic stim-
ulus, which was a unilateral intrauterine injection of 50 Lof sesame oil at the ovarian end of the uterus. A tight
At anti-implantation dosages (i.e., indomethacin at a
ligature was tied just caudal to the site of injection to
dose of 5 mg/kg/day and celecoxib at doses of 80 and 160
prevent leakage of oil from the uterus. The contralateral
mg/kg/day, given on Days 3–5 of pregnancy), the two COX
noninjected horn served as a non-pseudopregnant control.
inhibitors produced only a 25% reduction in the proportion
On Days 3–5 of pseudopregnancy, the rats were admin-
of rats with blue dye sites (Table 2). A slightly significant
istered orally once daily indomethacin or celecoxib at anti-
difference from controls (p ϭ 0.04) in the mean number of
implantation doses as indicated in Table 3. The rats were
blue dye sites found in the higher dose celecoxib-treated rats
killed on Day 10 of pseudopregnancy, and uteri were then
removed and blotted dry before weighing. 3.3. Effect of indomethacin and celecoxib on uterine
Quantitative data were expressed as mean Ϯ SEM and
Decidualization of the hormone-pretreated uterine horn
analyzed by Student’s two-tailed, unpaired t-test by using
induced by intrauterine oil injection exhibited about four
the Microsoft Excel 97. Fisher’s exact test was used for
times greater wet weight than the noninjected uterine horn.
analysis of qualitative data. Statistical significance was set
Mean weight of oil-injected (pseudopregnant) horns ob-
tained from rats treated with indomethacin and celecoxib atanti-implantation doses (Table 3) given on Days 3–5 ofpseudopregnancy were very significantly lower than con-
trols (p Ͻ 0.01 - Ͻ 0.001). Moreover, the weight of pseu-dopregnant horns from 160 mg/kg/day celecoxib group was
3.1. Effect of indomethacin and celecoxib on implantation
significantly lower than that from 5 mg/kg/day indometha-cin group. No significant difference was found in the mean
Indomethacin at a dose of 5 but not 2.5 mg/kg/day, given
weight of the pseudopregnant horns when comparing the
on Days 3–5 of pregnancy, significantly reduced the number
N. Sookvanichsilp, P. Pulbutr / Contraception 65 (2002) 373–3784. Discussion
Prostaglandins and COX-2 appeared to play pivotal role
in decidualization [7–9,20,21]. Interestingly, in the present
COX-derived prostaglandins are critical in female repro-
study, indomethacin and celecoxib at anti-implantation
duction. COX inhibitors have been reported to interfere with
doses administered on Days 3–5 of pseudopregnancy ex-
implantation [19 –21]. Significant reduction in the propor-
hibited a highly significant decrease in uterine decidualiza-
tion of pregnant rats treated with 5 mg/kg/day indometha-
tion as assessed by uterine weight, when compared with
cin, a nonselective COX-1/COX-2 inhibitor, on Days 3–5 of
controls. Moreover, the highest degree of reduction of de-
pregnancy in the present study was similar to the results
cidualization was found with 160 mg/kg/day celecoxib, the
reported by Phillips and Poyser  and Poyser . In
dose that exhibited a complete inhibition of blastocyst im-
their studies, treatment of rats with sc indomethacin injec-
plantation. Therefore, from these findings, the anti-implan-
tion at a dose of 3 mg/kg twice daily on Days 3– 4 of
tation effect of the two COX inhibitors may principally be
pregnancy significantly reduced the number of implantation
sites. However, there was no significant effect of indometh-
Did the anti-implantation effect of indomethacin and
acin on the proportion of rats with implantation or the mean
celecoxib result from COX-2 inhibition or from COX-1/
number of implantation sites when indomethacin was given
COX-2 inhibition? Many studies have indicated the role of
sc at a dose of 1 mg/rat twice on Day 5 of pregnancy (the
COX-2 in blastocyst implantation [20,30,31]. The role of
day of blastocyst implantation); only the mean weight of
COX-2 in implantation could also be indicated by the in-
implantation sites was significantly less than in controls
hibitory effect of DuP697  and celecoxib (the present
. This could be due to too late an initiation of drug
study). However, both COX-1 and COX-2 are expressed in
the uterine epithelium at different times in early pregnancy.
Lim et al.  reported that treatment with DuP697, a
COX-1 is expressed preferentially in uterine epithelium
selective COX-2 inhibitor, on Days 3– 4 of pregnancy in
prior to implantation. It is then down-regulated after embryo
mice resulted in a dose-dependent inhibition of implanta-
attachment, whereas COX-2 is expressed in the luminal
tion. The interfering effect of celecoxib, which is a specific
epithelium and subepithelial stromal cells at the time since
COX-2 inhibitor, on implantation at doses of 80 and 160
attachment [12,32,33]. Overlapping pathways of the COX
mg/kg/day on Days 3–5 of pregnancy in rats was also
systems in female reproduction may exist so that COX-2
compensation occurs in the absence of COX-1  and
Administration of indomethacin and celecoxib at anti-
COX-2 inhibition in COX-1(Ϫ/Ϫ) mice induced severe
implantation dosages (5 mg/kg/day indomethacin and 80
reproductive failure , suggesting a lack of alternative
and 160 mg/kg/day celecoxib on Days 3–5 of pregnancy) in
sources of prostaglandin synthesis . Whether celecoxib
the present study produced only a 25% reduction in the
at doses used in the present study (up to 160 mg/kg) could
proportion of rats with blue dye sites (indicative of in-
inhibit COX-1 was a question. Celecoxib demonstrated
creased endometrial vascular permeability) when the inves-
375-fold selectivity for COX-2 over COX-1 . In rats,
tigation was performed in the morning of Day 6 of preg-
celecoxib treatment decreased the stomach PGE
nancy. Previous studies also revealed no significant effect of
(COX-1) by approximately 40% at 10 mg/kg, but the de-
indomethacin at a dose of 1 mg/rat twice on Day 5 of
cline was not dose-related, and no gastrointestinal lesions
pregnancy  or 3 mg/kg twice daily on Days 3– 4 of
were observed at any doses (up to 200 mg/kg) [36,37],
pregnancy  on the proportion of rats with uterine dye
whereas indomethacin completely inhibited PGE synthesis
sites or the mean number of dye sites when the investigation
in the stomach at a dose of 3 mg/kg . Therefore, at
was done in the morning of Day 6 of pregnancy. Even
anti-implantation doses in the present study, celecoxib
though many authors reported the role of prostaglandins and
COX-2 in endometrial vascular permeability [22–24], lack
Although COX-1 expression is very low or undetectable
of significant effect on endometrial vascular permeability of
during the time of implantation , recently, Reese et al.
the two COX inhibitors in the present study together with
 showed that simultaneous inhibition of COX-1 and
the results from those other two studies [16,19] may indicate
COX-2 produced more effects on early pregnancy events
that prostaglandins are not the only critical mediators in-
than inhibition of either isoform alone. In the present study,
volved in this event. This observation coincides with the
indomethacin demonstrated a significant reduction in the
previous findings that demonstrated that other mediators
proportion of pregnant rats at a dose of 5 mg/kg, which was
such as histamine [25,26] and platelet-activating factor [27–
about 2–3 times higher than the anti-inflammatory doses
29] were able to produce increased endometrial vascular
(approximately 2 mg/kg) , whereas a similar degree of
permeability. Because the increased endometrial vascular
reduction in the proportion of pregnant rats was found with
permeability that leads to extravasation, uterine edema, and
celecoxib at a dose of 80 mg/kg, which was about eight
brings about blastocyst apposition appeared to be nonsig-
times higher than doses used for anti-inflammation (approx-
nificantly affected by COX inhibitor treatment in the present
imately 10 mg/kg) [35,36]. Based on anti-inflammatory
study, the critical mechanism(s) of the two COX inhibitors
potency (COX-2 inhibition), a celecoxib dose required to
should involve some of the other following events.
produce a significant effect on blastocyst implantation was
N. Sookvanichsilp, P. Pulbutr / Contraception 65 (2002) 373–378
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