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Effect of prostaglandin F2 alpha at different stages of guinea-pig pregnancy
PROSTAGLANDINS
EFFECT OF PROSTAGLANDIN F2 ALPHA AT DIFFERENT STAGES OF GUINEA-PIG PREGNANCY Iris L Sin and John J Evans University Department of Obstetrics and Gynaecology, Christchurch Clinical School of Medicine, Christchurch Women's Hospital, Christchurch, New Zealand ABSTRACT It is believed that suppression of the processes by which prostaglandin F2 alpha is released from the uterus during the estrous cycle is vital to maintenance of pregnancies in guinea-pigs. Prostaglandin F2 alpha was injected into pregnant guinea-pigs at four different stages of gestation to investigate the effect increased prostaglandin might have, The study revealed an alteration in the sensitivity of the pregnancy to prostaglandin F2 alpha as pregnancy progressed. Recovery from the prostaglandin insult was more likely if the injection was given after Day 24 than before In some animals the serum progesterone levels fell followDay 18. ing the injection and then subsequently recovered. It appears that effects which are potentially hazardous to the pregnancy are countered in a variety of ways, INTRODUCTION There is much evidence to support the hypothesis that prostaglandin F2 alpha (PGF2a) is the luteolytic agent in guinea-pigs (1,2), As in humans, the progesterone, which is required to support pregnancy, comes during early gestation from maintained corpora lutea and later from placentae. Therefore for a successful pregnancy to occur it is essential that corpora lutea of pregnancy are maintained. As a corollary, the process by which PGF2a induces luteolysis must be inhibited. This study investigated the effect on pregnancy, of PGF2a administered to pregnant guinea-pigs at various times during gestation, METHODS Vaginal membranes of female guinea-pigs were observed dailytomonitor estrus and the animals mated during the cycle or post partum. The day on which a vaginal plug was observed was taken as the day of Pregnancy was subsequently confirmed when possible mating (Day 1). by continued closure of the membrane and high serum progesterone concentrations, It was sometimes not possible to verify pregnancies at early gestations, and experimental abortion rates were calculated after adjusting for occasions when term pregnancies did not Pregnant animals were result from matings in the control animals. injected, twice daily, intraperitoneallywith PGF2a (0.125 mg,
OCTOBER 1984 VOL. 28 NO. 4
517
PROSTAGLANDINS
Prostin F2 alpha as the trimethamine salt; Upjohn Ltd, Sussex, UK). The animals were divided into four groups, Those in Group I were injected on Days 10 and 11, those in Group II on Days 17 and 18, those in Group III on Days 25 and 26, those in Group IV on Days 30 and 31. Controls were injected with vehicle at corresponding times and bled with the same protocol as used for experimental animals, The animals were bled under light halothane anesthesia by heart puncture. Serum was collected and progesterone concentrations were measured by radioimmunoassay (3). Tissue for histology was fixed in 10% formalin or Bouin's fluid and embedded in paraffin wax. Sections were stained with haematoxylin and eosin. Maximum luteal cell size was estimated by assuming that the cells were ovoid with two diameters being two-thirds of the maximum observed diameter. RESULTS The first group of 14 animals was injected with PGF2a on Days 10 and 11 of pregnancy (seven are illustrated in Fig. 1). Most of these aborted their pregnancies between Days 17 and 25; only three carried their pregnancies to term. All guinea-pigs which carried their pregnancies to term had levels of progesterone that remained within the normal range from the time of injection until parturition. On the other hand the guinea-pigs which aborted had progesterone levels below the normal range for pregnancy from Day 14. In one of those animals which continued its pregnancy after PGF2a administration a temporary drop in progesterone levels, although not to below the normal range, was observed. The corpora lutea were examined in animals killed on Day 14. The histological appearance of corpora lutea from injected animals was no !?a13 although the luteal cells were smaller (1.52 + 0.26 x 10 urn ; mean32 SSM) than those in control pregnant gu&ea-pigs (2.17 2 0.13 x 10 urn ) (P < 0.001, t-test). The second group, of 14 pregnant guinea-pigs, was injected on Days 17 and 18 (five are illustrated in Fig. 2). Most aborted by Day 30 after having had progesterone concentrations which were never above 40 ng/ml. One guinea-pig aborted its pregnancy at Day 34 after normal progesterone levels up to the last sample, before Another animal in the group had low abortion, taken on Day 29. progesterone levels (27 ng/ml at Day 27; 52 ng/ml at Day 36) but carried its pregnancy to term, Two continued their pregnancies with normal progesterone levels from Day 22. Histology was performed on the ovaries on Day 21, of animals treated on3Dayg 17 and 18. The luteal cells were smaller (1.63 t 0.43 x 10 urn ) in the treated animaJs tgan those from pregnant control guinea-pigs (3.31 + 0.39 x 10 urn ) (P < 0.02, t-test) and also showed extensive vacuolisation. There were 6 animals in the third group injected with prostaglandin Two aborted by Day 30, and 4 continon Days 25 and 26 (Fig. 3). ued until term with progesterone levels in the normal range,
518
OCTOBER
1984 VOL. 28 NO. 4
PROSTAGLANDINS
I
I
I
I
5
I
10
15
20
25
DAY
OF PREGNANCY
Progesterone concentratipns in 7 guinea-pigs which were Figure 1 The dashed injected with PGF2a on Days 10 and 11 of pregnancy. line is the normal range for pregnancy, the solid line is the H, pregnancy was aborted; normal range for the estrous cycle. o-o. pregnancy was carried to term.
OCTOBER -1984VOL. 28 NO. 4
51’9
PROSTAGLANDINS
200
100
50
20
10
5
2
5 DAY
10
15
20
25
OF PREGNANCY
Progesterone concentrations in 5 guinea-pigs which were Figure 2 The dashed injected with PGF2a on Days 17 and 18 of pregnancy. line is the normal range for pregnancy, the solid line is the M, pregnancy was aborted; normal range for the estrous cycle. M, pregnancy was carried to term.
520
OCTOBER
1984 VOL. 28 NO. 4
PROSTAGLANDINS
800
1
1
800
.1: 5
3 i
0
400
6 6 s 0
200
%
20 DAY
40 OF
80
80
PREGNANCY
Progesterone concentrations in 6 guinea-pigs which were Figure 3 The dashed injected with PGF2a on Days 25 and 26 of pregnancy. u, pregnancy was line is the normal range for pregnancy. M, pregnancy was carried to term. aborted; In the fourth group there were 5 animals injected on Days 30 and Of the 2 which aborted their pregnancies, 1 aborted 31 (Fig. 4). having had normal progat Day 33, and the other at Day 42 after In the latter guinea-pig there was a esterone levels at Day 38. clear drop in progesterone between Days 30 and 32 and the level subsequently rose before the animal aborted, In the 3 animals which continued their pregnancies to term frequent blood sampling revealed that they all showed a dip in progesterone concentration after the injection, followed by a rise. The corpora lutea of ovaries examined histologically on Day 343con5ained luteal cells that were the same size (4312 3 0.30 x 10 urn ) as those from controls (4.00 + 0.32 x 10 urn ), but there seemed to be an increased mito& activity in the cells from treated animals. The outcome of the pregnancies as affected tabulated (Table 1). After injection of
OCTOBER
1984 VOL. 28 NO. 4
by PGF2a injections was prostaglandin, at all
521
PROSTAGLANDINS
800
T L
-
800-
a 3 i 0
400-
z ii 8 g
200-
\
\ \ \
\40
80
OF CREGNAUC~
’
20 DAY
I \ . 80
Figure 4 Progesterone.concentrations in 5 guinea-pigs which were injected with PGF2a on Days 30 and 31 of pregnancy. The dashed line is the normal range for pregnancy, e-e, pregnancy was aborted; -, pregnancy was carried to term, ,, Table 1 The effect ou tcoqe of pregnancy Group
Days injected
I II III IV
10, 17, 25, 30,
522
11 18 26 31
of
prostaglandin
F2 alpha
injections
Number injected
Number aborted
Number continued
14 14 6 5
11 11 2 2
3 3 4 3
OCTOBER
on the
1984 VOL; 28 NO. 4
PROSTAGLANDINS
times there were some animals which continued their pregnancies. The chance of continuing was greater if the injections were given after Day 25 (64%, 7/11) than if the injections were given before Day 18 (22%, 6/28) (P (0.01, Chi squared test). DISCUSSION This study revealed that at early stages guinea-pig pregnancies The importance of a mechanism which were sensitive to PGF2a. countered prostaglandin acivity was thereby demonstrated. Late in gestation (Day 43) high doses of PGF2a (10 mg/day s.c.) are able to induce abortions apparently by direct action on the An effect on corpora lutea by lower doses (1 mg/day s.c;-) uterus. at the same stage has been briefly suggested (4). The present study investigated the effect of PGF2a in small doses (0.25 mg/day i.p.) at early and mid-gestation. Injection of PGF2a on Days 10 and 11 caused a different histological outcome from injections on Days 17 and 18, the latter inducing more The reason for this is uncertain but it regressive changes. appears that there is a decrease in the forces suppressing PGF2a production between Days 15 and 25 of pregnancy (5). There might therefore have been a bigger contribution from endogenous PGF2a at Nevertheless pregnancies of 25 and Days 17 and 18 in our study. 26 days old were less sensitive to PGF2a injection. The decreased sensitivity of more mature pregnancies to administered PGF2a is consistent with tolerance of the higher endogenous levels which are reflected by increased urinary excretion of prostaglandin metabolAlthough the increased proportion of ites from near Day 24 (6). progesterone derived from the placenta at later times (7) might contribute to the decreased sensitivity of the older pregnancies to PGF2a, other factors (eg recep,tor activity in the corpus luteum) will possibly have effects. However the revealing that pregnancies are sensitive to PGF2a, especially at earlier times of gestation vigorously reinforces the hypothesis that an antiluteolysin, which suppresses endogenous prostaglandin release (5,8) at early stages, is important for maintenance of pregnancy. Recently gonadotrophic activity was demonstrated to be ,present in placenta and subplacenta from Day 10 of pregnancy, maximum concentrations being present about Day 17 and 18 (9). It is possible that it was this activity which rescued some progesterone-' synthesizing systems after PGF2a had caused a reduction in circulThe route such activity might take in order to ating levels. affect the ovary has not been resolved, and it has been suggested that a placental luteotrophin begins to be active only after Day 14In vitro PGF2a specifically inhibited the stimulation of (10). progesterone by gonadotrophin (11) without affecting basal product-
.OCTOBER
.1984 VOL. 28 WO. 4
,523
PROSTAGLANDMS
ion and therefore some of the results obtained might have revealed an effect on a luteotrophic stimulus. Such an activity could be modified in vivo by the presence of an antiluteolysin at times of reduced luteotrophic potency. The relationship between antiluteolytic mechanisms, which suppress PGF2a activity, and luteotrophic processes, which counter PGF2a by positively stimulating luteal functions, is one of the most intriguing issues raised by this study. Questions unanswered by this study are whether the PGF2a acts primarily on the corpora lutea or on the conceptus, and whether the mode of action of the prostaglandin is the same at each stage of gestation. A change in sensitivity of pregnancy to PGF2a was observed in the investigation, For a successful pregnancy it appears that a variety of maintenance mechanisms operate. ACKNOWLEDGEMENTS We thank the staffs of the Departments of Animal Research and Histology for assistance and Professor J T France for a gift of progesterone antiserum. The investigationwas supported by grants from Foundation for the Newborn and The N 2 Medical Research Council REFERENCES Blatchley, F.R., B.T. Donovan, E.W. Horton and N.L. Poyser. The release of prostaglandins and progestin into the uteroovarian venous blood of guinea-pigs during the oestrous cycle and following oestrogen treatment. J Physiol 223: 69, 1972. Poyser, N.L. and E.W. Horton. Plasma progesterone levels in guinea-pigs actively immunized against prostagalndin F2a, hysterectomized or treated with intra-uterine indomethacine. J Endocr 67: 81, 1975. Evans, J.J., I.L. Sin, A.Y. Merrick and P.R. Kelleher. Effect of oestrogen on pregnancy of guinea-pigs, J Reprod Fert 62: 205, 1981. Studies on Elger, W., B. Kosub, W. Skuballa and R. Korte. prostaglandin-inducedabortion in guinea-pigs. Adv Prost Thromboxane Res (B. Samuelsson and R. Paoletti eds) 2: 673, 1976. Maule Walker, F.M. and N.L. Poyser, Production of prostaglandins by the early pregnant guinea-pig uterus in vitro. J Endocr 61: 265, 1974. Granstrom, E. and H. Kindahl. Radioimmunoassay for urinary metabolites of prostaglandin F2a. Prostaglandins 12: 759, 1976.
OCTOBER
1984 VOL. 28 NO. 4
PROSTAGLANDINS
7
Progesterone in systemic blood Heap, R.B. and R. Deanesly. and placentae of intact and ovariectomized pregnant guineaJ Endocr 34: 417, 1966. pigs.
8
Control of luteal function Bland, K.P. and B.T. Donovan. during early pregnancy in the guinea-pig, J Reprod Fert 20: 491, 1969.
9
Humphreys, E.M., B.M. Hobson and L. Wide. Gonadotropic activity of the guinea-pig placenta during pregnancy. J Reprod Fert 65: 231, 1982.
10
The secretory Heap, R.B., D.V. Illingworth and J.S. Perry. activity of the corpus luteum in the guinea-pig and its role in the establishment and maintenance of pregnancy. Le Corps Jaune (R. Denamur ed) 69, 1973,
11
Richardson, M.C. and M.J. Peddie. Inhibiting effect of PGF2a on hCG-stimulated progesterone production in vitro by luteal cells from guinea-pigs at different stages of the J Reprod Fert 66: 117, 1982. oestrous cycle.
Editor: Marc Bygdeman
OCTOBER
Received: 7-16-84
1984 VOL. 28 NO. 4
Accepted: 8-24-84
525
EFFECT OF PROSTAGLANDIN F2 ALPHA AT DIFFERENT STAGES OF GUINEA-PIG PREGNANCY Iris L Sin and John J Evans University Department of Obstetrics and Gynaecology, Christchurch Clinical School of Medicine, Christchurch Women's Hospital, Christchurch, New Zealand ABSTRACT It is believed that suppression of the processes by which prostaglandin F2 alpha is released from the uterus during the estrous cycle is vital to maintenance of pregnancies in guinea-pigs. Prostaglandin F2 alpha was injected into pregnant guinea-pigs at four different stages of gestation to investigate the effect increased prostaglandin might have, The study revealed an alteration in the sensitivity of the pregnancy to prostaglandin F2 alpha as pregnancy progressed. Recovery from the prostaglandin insult was more likely if the injection was given after Day 24 than before In some animals the serum progesterone levels fell followDay 18. ing the injection and then subsequently recovered. It appears that effects which are potentially hazardous to the pregnancy are countered in a variety of ways, INTRODUCTION There is much evidence to support the hypothesis that prostaglandin F2 alpha (PGF2a) is the luteolytic agent in guinea-pigs (1,2), As in humans, the progesterone, which is required to support pregnancy, comes during early gestation from maintained corpora lutea and later from placentae. Therefore for a successful pregnancy to occur it is essential that corpora lutea of pregnancy are maintained. As a corollary, the process by which PGF2a induces luteolysis must be inhibited. This study investigated the effect on pregnancy, of PGF2a administered to pregnant guinea-pigs at various times during gestation, METHODS Vaginal membranes of female guinea-pigs were observed dailytomonitor estrus and the animals mated during the cycle or post partum. The day on which a vaginal plug was observed was taken as the day of Pregnancy was subsequently confirmed when possible mating (Day 1). by continued closure of the membrane and high serum progesterone concentrations, It was sometimes not possible to verify pregnancies at early gestations, and experimental abortion rates were calculated after adjusting for occasions when term pregnancies did not Pregnant animals were result from matings in the control animals. injected, twice daily, intraperitoneallywith PGF2a (0.125 mg,
OCTOBER 1984 VOL. 28 NO. 4
517
PROSTAGLANDINS
Prostin F2 alpha as the trimethamine salt; Upjohn Ltd, Sussex, UK). The animals were divided into four groups, Those in Group I were injected on Days 10 and 11, those in Group II on Days 17 and 18, those in Group III on Days 25 and 26, those in Group IV on Days 30 and 31. Controls were injected with vehicle at corresponding times and bled with the same protocol as used for experimental animals, The animals were bled under light halothane anesthesia by heart puncture. Serum was collected and progesterone concentrations were measured by radioimmunoassay (3). Tissue for histology was fixed in 10% formalin or Bouin's fluid and embedded in paraffin wax. Sections were stained with haematoxylin and eosin. Maximum luteal cell size was estimated by assuming that the cells were ovoid with two diameters being two-thirds of the maximum observed diameter. RESULTS The first group of 14 animals was injected with PGF2a on Days 10 and 11 of pregnancy (seven are illustrated in Fig. 1). Most of these aborted their pregnancies between Days 17 and 25; only three carried their pregnancies to term. All guinea-pigs which carried their pregnancies to term had levels of progesterone that remained within the normal range from the time of injection until parturition. On the other hand the guinea-pigs which aborted had progesterone levels below the normal range for pregnancy from Day 14. In one of those animals which continued its pregnancy after PGF2a administration a temporary drop in progesterone levels, although not to below the normal range, was observed. The corpora lutea were examined in animals killed on Day 14. The histological appearance of corpora lutea from injected animals was no !?a13 although the luteal cells were smaller (1.52 + 0.26 x 10 urn ; mean32 SSM) than those in control pregnant gu&ea-pigs (2.17 2 0.13 x 10 urn ) (P < 0.001, t-test). The second group, of 14 pregnant guinea-pigs, was injected on Days 17 and 18 (five are illustrated in Fig. 2). Most aborted by Day 30 after having had progesterone concentrations which were never above 40 ng/ml. One guinea-pig aborted its pregnancy at Day 34 after normal progesterone levels up to the last sample, before Another animal in the group had low abortion, taken on Day 29. progesterone levels (27 ng/ml at Day 27; 52 ng/ml at Day 36) but carried its pregnancy to term, Two continued their pregnancies with normal progesterone levels from Day 22. Histology was performed on the ovaries on Day 21, of animals treated on3Dayg 17 and 18. The luteal cells were smaller (1.63 t 0.43 x 10 urn ) in the treated animaJs tgan those from pregnant control guinea-pigs (3.31 + 0.39 x 10 urn ) (P < 0.02, t-test) and also showed extensive vacuolisation. There were 6 animals in the third group injected with prostaglandin Two aborted by Day 30, and 4 continon Days 25 and 26 (Fig. 3). ued until term with progesterone levels in the normal range,
518
OCTOBER
1984 VOL. 28 NO. 4
PROSTAGLANDINS
I
I
I
I
5
I
10
15
20
25
DAY
OF PREGNANCY
Progesterone concentratipns in 7 guinea-pigs which were Figure 1 The dashed injected with PGF2a on Days 10 and 11 of pregnancy. line is the normal range for pregnancy, the solid line is the H, pregnancy was aborted; normal range for the estrous cycle. o-o. pregnancy was carried to term.
OCTOBER -1984VOL. 28 NO. 4
51’9
PROSTAGLANDINS
200
100
50
20
10
5
2
5 DAY
10
15
20
25
OF PREGNANCY
Progesterone concentrations in 5 guinea-pigs which were Figure 2 The dashed injected with PGF2a on Days 17 and 18 of pregnancy. line is the normal range for pregnancy, the solid line is the M, pregnancy was aborted; normal range for the estrous cycle. M, pregnancy was carried to term.
520
OCTOBER
1984 VOL. 28 NO. 4
PROSTAGLANDINS
800
1
1
800
.1: 5
3 i
0
400
6 6 s 0
200
%
20 DAY
40 OF
80
80
PREGNANCY
Progesterone concentrations in 6 guinea-pigs which were Figure 3 The dashed injected with PGF2a on Days 25 and 26 of pregnancy. u, pregnancy was line is the normal range for pregnancy. M, pregnancy was carried to term. aborted; In the fourth group there were 5 animals injected on Days 30 and Of the 2 which aborted their pregnancies, 1 aborted 31 (Fig. 4). having had normal progat Day 33, and the other at Day 42 after In the latter guinea-pig there was a esterone levels at Day 38. clear drop in progesterone between Days 30 and 32 and the level subsequently rose before the animal aborted, In the 3 animals which continued their pregnancies to term frequent blood sampling revealed that they all showed a dip in progesterone concentration after the injection, followed by a rise. The corpora lutea of ovaries examined histologically on Day 343con5ained luteal cells that were the same size (4312 3 0.30 x 10 urn ) as those from controls (4.00 + 0.32 x 10 urn ), but there seemed to be an increased mito& activity in the cells from treated animals. The outcome of the pregnancies as affected tabulated (Table 1). After injection of
OCTOBER
1984 VOL. 28 NO. 4
by PGF2a injections was prostaglandin, at all
521
PROSTAGLANDINS
800
T L
-
800-
a 3 i 0
400-
z ii 8 g
200-
\
\ \ \
\40
80
OF CREGNAUC~
’
20 DAY
I \ . 80
Figure 4 Progesterone.concentrations in 5 guinea-pigs which were injected with PGF2a on Days 30 and 31 of pregnancy. The dashed line is the normal range for pregnancy, e-e, pregnancy was aborted; -, pregnancy was carried to term, ,, Table 1 The effect ou tcoqe of pregnancy Group
Days injected
I II III IV
10, 17, 25, 30,
522
11 18 26 31
of
prostaglandin
F2 alpha
injections
Number injected
Number aborted
Number continued
14 14 6 5
11 11 2 2
3 3 4 3
OCTOBER
on the
1984 VOL; 28 NO. 4
PROSTAGLANDINS
times there were some animals which continued their pregnancies. The chance of continuing was greater if the injections were given after Day 25 (64%, 7/11) than if the injections were given before Day 18 (22%, 6/28) (P (0.01, Chi squared test). DISCUSSION This study revealed that at early stages guinea-pig pregnancies The importance of a mechanism which were sensitive to PGF2a. countered prostaglandin acivity was thereby demonstrated. Late in gestation (Day 43) high doses of PGF2a (10 mg/day s.c.) are able to induce abortions apparently by direct action on the An effect on corpora lutea by lower doses (1 mg/day s.c;-) uterus. at the same stage has been briefly suggested (4). The present study investigated the effect of PGF2a in small doses (0.25 mg/day i.p.) at early and mid-gestation. Injection of PGF2a on Days 10 and 11 caused a different histological outcome from injections on Days 17 and 18, the latter inducing more The reason for this is uncertain but it regressive changes. appears that there is a decrease in the forces suppressing PGF2a production between Days 15 and 25 of pregnancy (5). There might therefore have been a bigger contribution from endogenous PGF2a at Nevertheless pregnancies of 25 and Days 17 and 18 in our study. 26 days old were less sensitive to PGF2a injection. The decreased sensitivity of more mature pregnancies to administered PGF2a is consistent with tolerance of the higher endogenous levels which are reflected by increased urinary excretion of prostaglandin metabolAlthough the increased proportion of ites from near Day 24 (6). progesterone derived from the placenta at later times (7) might contribute to the decreased sensitivity of the older pregnancies to PGF2a, other factors (eg recep,tor activity in the corpus luteum) will possibly have effects. However the revealing that pregnancies are sensitive to PGF2a, especially at earlier times of gestation vigorously reinforces the hypothesis that an antiluteolysin, which suppresses endogenous prostaglandin release (5,8) at early stages, is important for maintenance of pregnancy. Recently gonadotrophic activity was demonstrated to be ,present in placenta and subplacenta from Day 10 of pregnancy, maximum concentrations being present about Day 17 and 18 (9). It is possible that it was this activity which rescued some progesterone-' synthesizing systems after PGF2a had caused a reduction in circulThe route such activity might take in order to ating levels. affect the ovary has not been resolved, and it has been suggested that a placental luteotrophin begins to be active only after Day 14In vitro PGF2a specifically inhibited the stimulation of (10). progesterone by gonadotrophin (11) without affecting basal product-
.OCTOBER
.1984 VOL. 28 WO. 4
,523
PROSTAGLANDMS
ion and therefore some of the results obtained might have revealed an effect on a luteotrophic stimulus. Such an activity could be modified in vivo by the presence of an antiluteolysin at times of reduced luteotrophic potency. The relationship between antiluteolytic mechanisms, which suppress PGF2a activity, and luteotrophic processes, which counter PGF2a by positively stimulating luteal functions, is one of the most intriguing issues raised by this study. Questions unanswered by this study are whether the PGF2a acts primarily on the corpora lutea or on the conceptus, and whether the mode of action of the prostaglandin is the same at each stage of gestation. A change in sensitivity of pregnancy to PGF2a was observed in the investigation, For a successful pregnancy it appears that a variety of maintenance mechanisms operate. ACKNOWLEDGEMENTS We thank the staffs of the Departments of Animal Research and Histology for assistance and Professor J T France for a gift of progesterone antiserum. The investigationwas supported by grants from Foundation for the Newborn and The N 2 Medical Research Council REFERENCES Blatchley, F.R., B.T. Donovan, E.W. Horton and N.L. Poyser. The release of prostaglandins and progestin into the uteroovarian venous blood of guinea-pigs during the oestrous cycle and following oestrogen treatment. J Physiol 223: 69, 1972. Poyser, N.L. and E.W. Horton. Plasma progesterone levels in guinea-pigs actively immunized against prostagalndin F2a, hysterectomized or treated with intra-uterine indomethacine. J Endocr 67: 81, 1975. Evans, J.J., I.L. Sin, A.Y. Merrick and P.R. Kelleher. Effect of oestrogen on pregnancy of guinea-pigs, J Reprod Fert 62: 205, 1981. Studies on Elger, W., B. Kosub, W. Skuballa and R. Korte. prostaglandin-inducedabortion in guinea-pigs. Adv Prost Thromboxane Res (B. Samuelsson and R. Paoletti eds) 2: 673, 1976. Maule Walker, F.M. and N.L. Poyser, Production of prostaglandins by the early pregnant guinea-pig uterus in vitro. J Endocr 61: 265, 1974. Granstrom, E. and H. Kindahl. Radioimmunoassay for urinary metabolites of prostaglandin F2a. Prostaglandins 12: 759, 1976.
OCTOBER
1984 VOL. 28 NO. 4
PROSTAGLANDINS
7
Progesterone in systemic blood Heap, R.B. and R. Deanesly. and placentae of intact and ovariectomized pregnant guineaJ Endocr 34: 417, 1966. pigs.
8
Control of luteal function Bland, K.P. and B.T. Donovan. during early pregnancy in the guinea-pig, J Reprod Fert 20: 491, 1969.
9
Humphreys, E.M., B.M. Hobson and L. Wide. Gonadotropic activity of the guinea-pig placenta during pregnancy. J Reprod Fert 65: 231, 1982.
10
The secretory Heap, R.B., D.V. Illingworth and J.S. Perry. activity of the corpus luteum in the guinea-pig and its role in the establishment and maintenance of pregnancy. Le Corps Jaune (R. Denamur ed) 69, 1973,
11
Richardson, M.C. and M.J. Peddie. Inhibiting effect of PGF2a on hCG-stimulated progesterone production in vitro by luteal cells from guinea-pigs at different stages of the J Reprod Fert 66: 117, 1982. oestrous cycle.
Editor: Marc Bygdeman
OCTOBER
Received: 7-16-84
1984 VOL. 28 NO. 4
Accepted: 8-24-84
525