effect of prostaglandin f 2α (pgf 2α), indomethacin, tamoxifen or estradiol-17β on prostaglandin...

Effect of prostaglandin F2a (PGF2a), indomethacin,tamoxifen or estradiol-17b on prostaglandin E (PGE),

PGF2a and estradiol-17b secretion in 88 to 90-daypregnant sheep<

P.J. Bridges, Y.S. Weems, L.M. Kim, B.R. LeaMaster, D.L. Vincent,C.W. Weems*

Dept. of Animal Sciences, University of Hawaii, 1800 East-West Road, Honolulu, HI 96822, USA

Received 17 April 1999; received in revised form 15 May 1999; accepted 12 July 1999

Abstract

Treatment with PGF2a plus estradiol-17b aborts 90-day pregnant ewes, whereas PGF2a orestradiol-17b alone does not abort ewes. The objective of this experiment was to evaluate whethertamoxifen, an estrogen receptor antagonist, estradiol-17b, prostaglandin F2a (PGF2a),indomethacin, or some of their interactions affected ovine uterine/placental secretion of PGF2a,estradiol-17b or prostaglandins E (PGE), because a single treatment with PGF2a and estradiol-17bgiven every 6 h aborts 90-day pregnant ewes. Concentrations of PGF2a in uterine venous bloodwere increased (P # 0.05) by estradiol-17b, PGF2a 1 estradiol-17b, and PGF2a 1 tamoxifen,and decreased (P # 0.05) by indomethacin or PGF2a 1 indomethacin at 72 h when compared tothe 0 h samples. Concentrations of PGE in uterine venous blood were decreased (P # 0.05) byindomethacin and PGF2a 1 indomethacin and increased (P # 0.05) by PGF2a 1 estradiol-17b at72 h when compared to the 0 h samples. Concentrations of PGF2a in inferior vena cava blood at6 h were increased (P # 0.05) by PGF2a either alone or in combination with indomethacin,tamoxifen, or estradiol-17b, which is due to the PGF2a injected. Concentrations of PGF2a ininferior vena cava blood in PGF2a 1 estradiol-17b-treated 88- to 90-day pregnant ewes increased

* Corresponding author. Tel.:11-808-956-8337; fax:11-808-956-4883.E-mail address:[email protected] (C.W. Weems)< This research was supported in part by United States Department of Agriculture Cooperative State Research,

Education and Extension Services (USDA CSREES) Special Grant No. 95-34135-1776 to C.W. Weems andmanaged by the Pacific Basin Advisory Group and Hawaii Hatch Project 259 as its contribution to USDA W–112Regional Research Project.

Prostaglandins & other Lipid Mediators 58 (1999) 167–178

0090-6980/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved.PII: S0090-6980(99)00036-2

(P # 0.05) linearly over the 72-h sampling period and averaged 4.01 0.4 ng/ml. Concentrationsof PGF2a in inferior vena cava blood of control, PGF2a, tamoxifen, PGF2a 1 indomethacin,PGF2a 1 tamoxifen, and estradiol-17b-treated ewes did not differ (P $ 0.05) and averaged 0.410.04 ng/ml. Profiles of PGE in inferior vena cava blood of 88- to 90-day pregnant ewes treatedwith vehicle, PGF2a, estradiol-17b, tamoxifen, tamoxifen1 PGF2a, or estradiol-17b 1 PGF2adid not differ (P $ 0.05). Concentrations of PGE in inferior vena cava blood of 88- to 90-daypregnant ewes treated with indomethacin or PGF2a 1 indomethacin were lower (P # 0.05) thanin control ewes. Concentrations of estradiol-17b in jugular venous plasma of PGF2a 1estradiol-17b-treated 88- to 90-day pregnant ewes increased linearly and differed (P # 0.05) fromcontrols. Profiles of estradiol-17b in jugular venous plasma of PGF2a, indomethacin, tamoxifen,and PGF2a 1 tamoxifen and PGF2a 1 indomethacin, estradiol-17b, and controls did not differ(P $ 0.05). It is concluded that treatment with a single injection of PGF2a and estradiol-17bgiven every 6 h causes a linear increase in PGF2a and estradiol-17b. © 1999 Elsevier Science Inc.All rights reserved.

Keywords:PGF2a; PGE; Estradiol-17b; Tamoxifen; Indomethacin; Pregnancy; Sheep

1. Introduction

Half of the plasma progesterone in the general circulation at 90 to 100 days of pregnancyin sheep is from the placenta and half is from the corpus luteum [1]. Eighty percent of thecirculating plasma estradiol-17b at 90 to 100 days of pregnancy in sheep is from the placenta[2]. In addition, PGF2a increases estradiol-17b secretion [2] and causes luteolysis, but doesnot abort intact or ovariectomized 90- to 100-day pregnant ewes [1] or 70-day pregnant ewes[3]. Data from the same ewes in the experiment reported herein and reported previouslyindicates that treatment of 88- to 90-day pregnant ewes with a single injection of PGF2a andestradiol-17b every 6 h causes abortion [4].

Concentrations of PGE in uterine venous plasma averages 6 ng/ml, whereas uterinesecretion of PGF2a is inhibited and in uterine venous blood averages 200 pg/ml over the 72-hsampling period [5]. Both the corpus luteum [6] and placenta [5] secrete much PGE but littlePGF2a at 90 days of pregnancy in sheep. Placental secretion of estradiol-17b increases earlyafter treatment with PGF2a in 90- to 100-day pregnant ewes [2] and is followed 64 h laterby a concomitant increase in PGE [5,7], PGF2a [5,7], and pregnancy-specific protein B(PSPB; [8]), which is followed by a quadratic increase in progesterone in uterine venousblood [1]. It is thought that PGE prevents PGF2a inhibition of placental progesteronesecretion [7]. Estradiol-17b seems to regulate placental secretion of PSPB [4]. Also, PSPBregulates placental secretion of PGE, PGE regulates placental secretion of progesterone, andPGE protects placental secretion of progesterone from PGF2a, because PGF2a does notaffect placental secretion of progesterone in vivo or in vitro, nor cause abortion, but doesregress the corpus luteum [1,7]. Estradiol-17b is luteolytic when given at midcycle bycausing a premature increase in uterine secretion of PGF2a and shortens the estrous cycle ofewes [1,9]. Although a single injection of PGF2a increases placental secretion of estradiol-17b in 90- to 100-day intact or ovariectomized ewes does not cause abortion [2], a single

168 P.J. Bridges et al. / Prostaglandins & other Lipid Mediators 58 (1999) 167–178

injection of PGF2a plus estradiol-17b given every 6 h for 72 h aborts 90-day pregnant ewes,whereas tamoxifen or estradiol-17b given alone every 6 h increases PSPB secretion but doesnot cause abortion [4]. Therefore, the objective of this experiment was to determine theeffects of PGF2a, indomethacin, estradiol-17b, tamoxifen, PGF2a 1 indomethacin, PGF2a1 tamoxifen, and PGF2a 1 estradiol-17b on secretion of PGF2a, PGE, and estradiol-17bby 88- to 90-day pregnant ewes.

2. Materials and methods

Three-year-old Merino crossbred ewes were checked twice daily (8:00 a.m. and 5:00 p.m.)for estrus with brisket-painted vasectomized rams during the normal breeding season.Paint-marked ewes were removed from the flock and mated twice with two different intactrams of proven fertility. Estrus was designated as Day 0 of pregnancy. Ewes were returnedto the flock on Day 4 postbreeding to monitor return to estrus.

Ewes were fasted for 12 h before surgery and received 1 cc (0.54 mg) atropine sulfate(Phoenix Pharmaceutical Co., Inc., St. Joseph, MO, USA) intramuscularly as a preanesthetic30 min before induction of anesthesia. At 88 to 90 days of pregnancy, ewes were laparoto-mized under pentobarbital sodium (Anthony Products Co., Arcadia, CA, USA) anesthesiagiven i.v. A polyvinyl catheter ([1,5]; Cole Parmer, Chicago, IL, USA) was installed in thejugular vein and in the inferior vena cava via the saphenous vein [4,10]. The vena cavacatheter was positioned 5 cm anterior to the juncture of the ovarian vein with the vena cava,which was confirmed by a mid-ventral laparotomy at 0 and 72 h.

Ewes (n 5 5 ewes/treatment) were randomized to receive treatments of vehicle, PGF2a(8 mg/58 kg/BW; UpJohn Co. Inc., Kalamazoo, MI, USA), estradiol-17b (500 mg; SigmaChemical Co. Inc., St. Louis, MO, USA), indomethacin (100 mg; Sigma), which is aninhibitor of prostaglandin synthesis; tamoxifen (40 mg; Sigma), which is an estrogenreceptor antagonist [11] PGF2a 1 indomethacin; PGF2a 1 tamoxifen, and PGF2a 1estradiol-17b given intramuscularly. Treatment with PGF2a was given at 0 h only and allother treatments were given every 6 h through 66 h. Vehicle for PGF2a was tromethamine(THAM) buffer (Sigma); for tamoxifen and estradiol-17b, safflower oil; and for indometh-acin, ethanol.

Samples of uterine venous blood were collected at 0 and 72 h for analysis for PGE andPGF2a by radioimmunoassay [5]. Jugular venous plasma was collected at 0 h and every 6 hfor the remainder of the 72-h sampling period and every 20 min from 62 to 66 h for analysisfor estradiol-17b by radioimmunoassay [2]. Inferior vena cava plasma was collected at 0 hand every 6 h for the remainder of the 72-h sampling period and every 20 min from 62 to66 h for analysis for PGE and PGF2a by radioimmunoassay [5]. Blood samples werecollected via heparinized needles and syringes for analysis for PGE and PGF2a receivedimmediately 0.1 ml of 0.1 N HCl after collection to prevent synthesis of prostaglandins afterblood collection [5]. Plasma was separated by centrifugation and stored at220°C until assay[5]. Intra and interassay coefficients of variation for PGF2a, PGE, and estradiol-17b,respectively, were 4 and 6, 7 and 9, and 3 and 8.

All data sets were analyzed for homogeneity of variance by Bartlett’s boxF-test [12]. Data

169P.J. Bridges et al. / Prostaglandins & other Lipid Mediators 58 (1999) 167–178

for PGE were transformed by log 10 (=) 1 10 and for PGF2a and estradiol-17b by squareroot prior to analysis [10]. Data for PGF2a or PGE in uterine venous blood at 0 and 72 h wereanalyzed by a factorial ANOVA [12]. Profiles of estradiol-17b in jugular venous blood andPGE and PGF2a in vena cava blood were analyzed by a split-plot design for ANOVA forrepeated measures [13]. When significance was detected (P # 0.05), means were comparedby a least-significant difference test [12]. This experiment was approved by the Universityof Hawaii IACUC committee.

3. Results

Concentrations of PGF2a in uterine venous blood at 0 h did not differ (P $ 0.05) amongtreatment groups (Table 1). Concentrations of PGF2a in uterine venous blood were increased(P # 0.05) by estradiol-17b, PGF2a 1 estradiol-17b, and PGF2a 1 tamoxifen and weredecreased (P # 0.05) by indomethacin and PGF2a 1 indomethacin at 72 h (Table 1).Concentrations of PGE in uterine venous plasma at 0 h did not differ (P $ 0.05) amongtreatment groups (Table 1). Concentrations of PGE in uterine venous plasma were decreased(P # 0.05) by indomethacin or PGF2a 1 indomethacin and increased (P # 0.05) by PGF2a1 estradiol-17b at 72 h (Table 1).

There was a treatment3 time effect (P # 0.05) on concentrations of estradiol-17b injugular venous plasma over the 72 h sampling period (Figs. 1–3). Profiles of estradiol-17bin jugular venous plasma of PGF2a 1 estradiol-17b-treated 88- to 90-day pregnant ewesincreased linearly (P # 0.05) and differed from control ewes (P # 0.05; Fig. 3). Profiles ofestradiol-17b in jugular venous plasma of control (Fig. 1), PGF2a- (Fig. 1), tamoxifen- (Fig.1), PGF2a 1 indomethacin- (Fig. 2), PGF2a 1 tamoxifen- (Fig. 3), and estradiol-17b-treated (Fig. 1) 88- to 90-day pregnant ewes did not differ (P $ 0.05) from controls.

There was a treatment3 time interaction (P # 0.05) on concentration of PGF2a in

Table 1Uterine venous plasma PGF2a and PGE from 88 to 90-day pregnant ewes

Treatment1 Uterine venous2

PGF2a

(ng/ml)

Uterine venous2

PGE(ng/ml)

0 h 72 h 0 h 72 h

Control 0.646 0.11a 0.586 0.09a 2.896 0.11a 2.986 0.28a

PGF2a 0.696 0.08a 0.696 0.10a 2.946 0.23a 3.116 0.33a

Indomethacin 0.636 0.08a 0.116 0.02c 2.716 0.18a 1.186 0.12c

Tamoxifen 0.596 0.07a 0.616 0.10a 2.626 0.29a 2.896 0.42a

Estradiol-17b 0.586 0.08a 2.986 1.08b 2.766 0.14a 2.966 0.48a

PGF2a 1 tamoxifen 0.596 0.10a 5.716 2.08b 2.416 0.31a 2.866 0.31a

PGF2a 1 estradiol 17-b 0.786 0.28a 4.996 1.48b,g 2.496 0.17a 4.676 0.39e

PGF2a 1 indomethacin 0.586 0.11a 0.176 0.04c 2.816 0.27a 1.046 0.19c

1 Five ewes per treatment group.2 Mean1 S.E.M. with different superscripts within rows or columns within variable are significant atP # 0.05.


inferior vena cava plasma (Figs. 4–6). Concentrations of PGF2a in inferior vena cava plasmaincreased (P # 0.05) at 6 h post-treatment in all ewes receiving PGF2a, either alone or incombination with tamoxifen or estradiol-17b (Figs. 4–6). Concentrations of PGF2a ininferior vena cava plasma in PGF2a 1 estradiol-17b-treated 88- to 90-day pregnant ewesincreased linearly (P # 0.05) and averaged 4.01 0.4 ng/ml over the 72-h sampling.

There was a treatment3 time effect (P # 0.05) on PGE in inferior vena cava plasma of88- to 90-day pregnant ewes (Figs. 7–9). Profiles of PGE in inferior vena cava plasma didnot differ (P $ 0.05) among control, PGF2a-, PGF2a 1 tamoxifen-, tamoxifen- andestradiol-17b-treated 88- to 90-day pregnant ewes (Figs. 7 and 9). Profiles of PGE in inferiorvena cava plasma of 88- to 90-day pregnant ewes treated with indomethacin or PGF2a 1indomethacin (Fig. 8) differed from control-treated ewes. There was an increase (P # 0.05)in PGE in inferior vena cava plasma of PGF2a 1 estradiol-17b-treated ewes from 65: 40 hthrough 72 h post treatment (Fig. 9).

4. Discussion

Although a single challenge with PGF2a does not cause abortion in intact or ovariecto-mized 90- to 100-day pregnant ewes [1], in a previously reported study that used the same

Fig. 1. Profiles of estradiol-17b in jugular venous plasma of 88- to 90-day pregnant ewes treated with controlvehicles, PGF2a, tamoxifen, or estradiol-17b. Profiles did not differ (P $ 0.05).


ewes as this study, a single challenge with PGF2a and estradiol-17b given every 6 h for 72 hterminated pregnancy in 40% of the ewes [4]. Concentrations of PGF2a in uterine venousplasma of intact or ovariectomized 90- to 100-day pregnant ewes are less than 200 pg/mlover a 72-h period and endogenous PGF2a in uterine venous blood increases for a shortduration at 64 h after treatment with PGF2a [5]. In the present study, a single treatment withPGF2a increased PGF2a in vena cava plasma at 6 h, which was due to treatment withPGF2a. However, 88- to 90-day pregnant ewes challenged with a single dose of PGF2a plusestradiol-17b every 6 h showed a linear increase in estradiol-17b in jugular venous plasmaand a linear increase in PGF2a in inferior vena cava plasma, leading to abortion by 40% ofthe ewes [4]. Treatment with PGF2a or estradiol-17b alone does not abort 88- or 90-daypregnant ewes [4]. Moreover, treatment with PGF2a or estradiol-17b alone does not affectthe profiles of PGF2a in vena cava blood. However, chronic treatment with estradiol-17balone or tamoxifen1 a single injection of PGF2a increased PGF2a at 72 h in uterine venousand vena cava blood. Thus, chronic estradiol-17b treatment plus a single injection withPGF2a overcomes the inhibition during pregnancy on uterine secretion of PGF2a [14–17].Although tamoxifen is an estrogen receptor antagonist [18], it is suggested that tamoxifengiven with PGF2a can increase PGF2a because the estrogenb receptor mediates an agonisticeffect of the estrogen receptor antagonists such as tamoxifen or raloxifene [11]. An alter-native explanation for a single injection of PGF2a plus tamoxifen given chronically to induceincreases in endogenous uterine venous or vena cava PGF2a at 72 h may be the nonsignif-icant increase in estradiol-17b seen at 60 to 62 h in this treatment group. Thus, to terminate

Fig. 2. Profiles of estradiol-17b in jugular venous plasma of 88- to 90-day pregnant ewes treated with controlvehicles, indomethacin, or PGF2a 1 indomethacin. Profiles did not differ (P $ 0.05).


Fig. 4. Profiles of PGF2a in inferior vena cava plasma of 88- to 90-day pregnant ewes treated with controlvehicles, PGF2a, tamoxifen or estradiol-17b. There was a treatment3 time effect (P # 0.05).

Fig. 3. Profiles of estradiol-17b in jugular venous blood of 88- to 90-day pregnant ewes treated with controlvehicles, PGF2a 1 tamoxifen, or PGF2a 1 estradiol-17b. Profiles differed (P # 0.05).


Fig. 5. Profiles of PGF2a in inferior vena cava plasma of 88- to 90-day pregnant ewes treated with controlvehicles, indomethacin or PGF2a 1 indomethacin. There was a treatment3 time effect (P # 0.05).

Fig. 6. Profiles of PGF2a in inferior vena cava plasma of 88- to 90-day pregnant ewes treated with controlvehicles, PGF2a 1 tamoxifen, of estradiol-17b. Profiles differed atP # 0.05.


pregnancy at this stage of gestation with PGF2a, chronic treatment with estradiol-17b isrequired.

Estradiol-17b given alone to 88- to 90-day pregnant ewes did not affect profiles ofestradiol-17b in jugular venous blood, except in one ewe. This would suggest that theestradiol-17b given alone was probably quickly converted to the inactive estrogen, estronesulfate [19–21]. However, when a single injection of PGF2a plus estradiol-17b is given to88- to 90-day pregnant ewes, estradiol-17b in jugular venous blood increases linearly overthe 72-h treatment period, resulting in abortions [4]. Estrogen is necessary for pregnancymaintenance in baboons [23–27]. This could explain the necessity for the inhibition ofuterine PGF2a secretion [14–16] during gestation where concentrations of PGF2a are lessthan 200 pg/ml, and PGE averages 6 ng/ml [5,7], because the placenta secretes 80% of theestrogen at this stage of gestation [2]. During the last 15 days of pregnancy, this inhibitionis lost and estrogen given to sheep increases uterine secretion of PGF2a, and PGF2a givenalone increases estradiol-17b secretion [14,15].

At 90 to 100 days of gestation in sheep, PGF2a causes a sustained increase in estradiol-17b for 72 h. This was followed 64 h after treatment with PGF2a by a concomitant increasein endogenous PGF2a [5,6], PGE [5,7], and PSPB [7,8], which was followed by a quadraticincrease in uterine venous progesterone [1,7]. Estradiol-17b appears to regulate placentalsecretion of PSPB in sheep [4] and PSPB seems to regulate placental secretion of PGE insheep [28]. Although exogenous estradiol-17b given to the ewes in this experiment in a study

Fig. 7. Profiles of PGE in inferior vena cava plasma of 88- to 90-day pregnant ewes treated with control vehicles,PGF2a, tamoxifen, or estradiol-17b. Profiles did not differ (P $ 0.05).


Fig. 8. Profiles of PGE in inferior vena cava plasma of 88- to 90-day pregnant ewes treated with control vehicles,indomethacin, or PGF2a 1 indomethacin. Profiles differed atP # 0.05.

Fig. 9. Profiles of PGE in inferior vena cava plasma of 88- to 90-day pregnant ewes treated with control vehicles,PGF2a 1 tamoxifen, or PGF2a 1 estradiol-17b. There was a treatment3 time effect (P # 0.05).


reported previously increased PSPB [4], increases in PGE secretion were seen only in thePGF2a 1 estradiol-17b toward the end of the sampling period, whereas indomethacindecreased PGE but no abortions were seen within the experimental period.

In summary, it is concluded that abortions occur in pregnant ewes with a sustainedendogenous secretion of PGF2a and estradiol-17b and not when endogenous estradiol-17bor PGF2a alone are increased at midgestation [2,7]. This suggests that the progesterone:estradiol-17b ratio may influence the inhibition on PGF2a secretion by the placentomes[25–30].

Acknowledgments

The authors thank Ms Sharleen Fujimoto and Trudie Kaleiheana for typing the manuscriptand Mr Wayne Toma for computer graphics. This paper is Journal Series No. 4425 of theUniversity of Hawaii College of Tropical Agriculture and Human Resources. The authors arealso indebted to Mr Bruce Robinson, Niihau Ranch and Mr Eric Johnson of Hawaii MegaCor for support.

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