A COMPARISON OF THE LUTEOLYTIC EFFECT OF PGF2a

AND CORTISOL IN THE PREGNANT RABBIT

M. Abel, (1) J. Taurog(2) and P. W. Nathanielsz” (1)

(1) Physiological Laboratory, Cambridge.

(2) University of Texas, Southwestern Medical
School, Dallas, Texas.

Abstract

Intra-aortic infusion of cortisol and PGF2a into

the 21 day pregnant rabbit will initiate parturition.
PGF2cl is able to depress plasma progesterone concentration
more rapidly than cortisol. The possibility that
cortisol acts by stimulating PGF2a synthesis as reported
in other species is discussed.

Acknowledgements

Our thanks are due to Mr Clarke and Mr Bancroft

for their expert care of the experimental animals. This
work received support from the Medical Research Council.
We thank Dr John Pike of the UpJohn Company, Kalamazoo
for supplying us with PGF2a.

* Requests for reprints should be addressed to

Dr P.W. Nathanielsz.

Accepted July 9, 1973

SEPTEMBER 1973 VOL. 4 NO. 3 431

PROSTAGLANDINS

INTRODUCTION

Prostaglandin F2a (PGF2a) has been shown to be

luteolytic in the rabbit (Duncan & Pharris, 1970). It
has also been demonstrated that relatively small doses of
PGF2a given by intravascular infusion into the mother will
depress plasma progesteroneconcentration towards the end
of gestation in the sheep (Liggins, Grieves, Kendall &
Knox 1972), goat Thorburn, Nicol, Bassett, Shutt & Cox,
1972), and rabbit t Abel, Smith & Nathanielsz, 1973). In
the sheep, glucocorticoid administration to foetus or mother
will also produce a fall in plasma progesterone(Liggins
et al, 1972; Fylling, 1971) and it has been shown in the
sheep that foetal administration of dexamethasone results
in an increase in placental prostaglandin concentrations
(Liggins & Grieves, 1971).

In the rabbit, experiments using continuous intra-

aortic infusions of PGF2a combined with recording of
uterine pressure at day 21 of pregnancy have demonstrated
that the oxytocic action of PGF2a is absent for several
hours after the commencement of PGF2a administration. It
has been suggested that in this species the PGF2a infusion
must first decrease circulatory plasma progesterone before
contractions are induced (Nathanielsz, Abel 8,Smith, 1972).

With increasing dose rates of maternal infusion of

cortisol the minimum latency between the commencement of
infusion on day 21 and delivery in the pregnant rabbit is
72 h. With the highest doses of PGF2a used (75 pg/h) the
latency was shorter - 35 h (Nathanielsz et al, 1972). In
this paper the effect of infusion of saline, cortisol or
PGF2a on peripheral plasma progesterone concentrations in
the 21 day pregnant rabbit are compared.

MATERIALS AND METHODS

The care of animals and surgical procedures for

insertion of intra-aortic and inferior vena caval catheters
were as described previously (Nathanielsz 8.Abel, 1973).

Sampling procedure
Blood samples were withdrawn from either catheter as
required over a period of 30 set to 2 min, centrifuged
immediately and stored at - 20" C until assayed.

432 SEPTEMBER 1973 VOL. 4 NO. 3

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Assay of plasma progesterone

Progesterone was assayed using an antiserum kindly

orovided by Dr G.Abraham (Abraham, Swerdloff, Tulchinsky
!,Odell, 1971).+ In our hands, recovery of added progest-
erone was 4.86 - 0.38 for 5 ng/ml, 10.22 - 0.31 for
10 ng/ml (Mean f S.E.M., n = 7 for each amount).

RESULTS
Plasma progesterone concentrations on different intra-
aortic infusion regimes begun on DZl of pregnancy

I. Effect of continuous infusion of saline

Fig. 1A demonstrates the fall in plasma progesterone

from 021 to D31 in four saline infused rabbits. A similar
fall was observed in four other animals. All saline control
animals exhibited a marked fall in plasma progesterone
concentration on the day after surgery. After a period
of recovery, plasma progesterone concentrations showed day
to day fluctuations similar to those reported by Kendall
& Liggins (1972). This data is included in Figs.2 and 3
for comparison with the effects of various other infusion
regimes.

II. Effect of continuous infusion of cortisol until the

time of delivery.

Cortisol at different dose rates, 1200 kg/h (lB),

300 /q/h (1C) and 75 kg/h (1D) induced delivery as previously
described. Delivery was preceded by a fall in plasma
progesterone to less than 5 ng/ml in all but one animal
(Fig.1). The overall rate of fall in progesterone
concentration from commencement of infusion to delivery
was fastest at the highest dose.

III.Effect of infusions of 1200 pg cortisol/h for short

periods of time

From Fig.2 it may be seen that the rate of fall of

plasma progesterone was as rapid in animals infused with
cortisol for 12h or 24h as it was in those which received
cortisol at the same dose rate continuously until the time
of delivery. In one of the animals infused for 6h and both
animals infused for only 3h, plasma progesterone fell more
slowly and delivery occurred after a considerably longer
time interval.

SEPTEMBER 1973 VOL. 4 NO. 3 433

 PROSTAGLANDINS

3' '2' '4' '6' ‘8’

18
C
14

DAYS POST-OP .
FIG.1 The effect of continuous intra-aortic infusion of
cortlsol into the 21 day pregnant rabbit until deliver
compared with saline in.fusionin four animals (A). (BY rrcl";o';ed
clgcortisol/h, (D) - 75 ,ugcortisol/h. Arrows show time of
delivery. Ordinate, plasma progesterone, &ml; Abscissa,
days post operation.

434 SEPTEMBER 1973 VOL. 4 NO. 3

 PROSTAGLANDINS

307 f
- I

1
26- ;
A - I B,
22- '
- I
18 18' :
- I
14- 1
- I
10; ;

; 0’ ‘2’ ‘4’ ‘6’ ‘8’

Y C
i2
a 22-

18- 18-

14 14-

10 lo-

6-

2-
III
I
I

0' '2' '4' 'G 0 2' '4' 'G'

DAYS POST-OP
FIG 2. The effect of short term intro-aortic infusion of
cortisol on plasma progesterone concentrations compared with
saline controls (A). 1200 pg cortisol/h for 24 h, ------, 12 h
(B), for 6 h (C), for 3 h (D). All infusions were
begun imhediately after surgery for implantation of the catheters
on D21. Coordinates as in Fig.1. Slowest fall in plasma
progesterone concentration occurred in the two animals which
were infused for only 3 h. In these two animals delivery
occurred after 84 and 118 h. The mean latency to delivery
following continuous infusion at this dose was 72.92 6.3 h.

SEPTEMBER 1973 VOL. 4 NO. 3 435

PROSTAGLANDINS

18 1

'0' '2' '4' '0' '2' ‘4’

DAYS POST-OP
FIG.3 The effect of continuous intro-aortic infusion of PGFPat
Into the 21 day pregnant rabbit until deliver occurred
compared with saline infusion in 4 animals,(Afi- PGF2a -..._sion
infu
rates,(B) - 2.25 PGF2a/h, (C) - 0.45 PGFPu/h a;d (D) ~~~__ _.__
11.25 PGF2a
/h. (Co-ordinates as in Fig. 1).

436 SEPTEMBER 1973 VOL. 4 NO. 3

IV. Effect of continuous PGF2a infusion at varying doses

Fig. 3 demonstrates that high doses of PGF2a (2.25pg/h)

resulted in a more rapid decrease in plasma progesterone
concentrationthan low doses (11.25ng PGF2a/h).

DISCUSSION

In previous experiments it was demonstratedthat

cortisol and PGF2a, when administered to the 21 Day pregnant
rabbit, would induce parturition (Nathanielst& Abel, 1973;
Nathanielsz et al., 1972). The time interval to delivery
was affected by the rate of infusion. Animals could be
subdivided into three groups according to the rate of
infusion. In the case of both PGF2a and cortisol there
was a threshold infusion rate below which parturitiondid
not occur significantlyearlier than when animals were
infused with saline. For cortisol the threshold infusion
rate was about 80 pg cortisollh, and for PGF2a it was
somewhat less than 1.125 rig/h.. Above these rates of
infusion, there was a significantdecrease in the latency
to delivery as the rate of infusion of PGF2a was increased
to 2.25 pg/h and as cortisol was increased to 0.3 mg/h.
Increasing infusion rates above these levels did not
decrease the time interval to delivery. The route of
infusion of PGF2a is also of importance, the intra-aortic
route being more effective than the intravenousone.

The results presented here confirm that intravascular

glucocorticoids,when administeredto the pregnant rabbit
in the later stages of gestation, will lower plasma
progesteroneconcentration Nendall & Liggins, 1972). It
is also apparent that the operative procedures followed
by saline infusion caused a fall in plasma progesterone.
In the saline infused animals plasma progesteroneconcent-
rations recovered and gestation continued to term.
Infusion of cortisol caused a further fall in plasma
progesterone,the rate of which was influenced by both the
rate and duration of the infusion. The rate of fall of
plasma progesteroneduring continuous cortisol infusion
was faster at the highest rate (1200-500 pg cortisol/h)
than at the two lower dose rates. As previouslydescribed,
increasing the rate of infusion above 300 &h did not
further reduce the latency to delivery. It is thus
possible to relate the previouslydescribed dose-response
effects of cortisol infusions on delivery to the ability
of cortisol to depress plasma progesteroneconcentrations.
Similarly, termination of infusion of the cortisol after
SEPTEMBER 1973 VOL. 4 NO. 3 437
PROSTAGLANDINS

3h (Fig.2D) resulted in a slower fall in plasma pro esterone

than when the infusion was continued for 12 or 24h 9Fig.2B).
These findings are consistent with those reported previously
for the effect on delivery alone.

PGF2a also caused a fall in plasma progesterone which

appeared to be determined by the rate of infusion. It has
been demonstrated in the sheep that glucocorticoid
administration to mother and foetus will raise placental
and myometrial PGF2a concentrations (Liggins & Grieves,
1971). Intravascular exogenous PGF2a administered to the
mother will cause a fall in circulating rogesterone in
the pregnant sheep (Liggins et al., 1972 7 , goat (Thorburn
et al., 1972), and rabbit (Abel, et al., 1973). It is also
possible that progesterone may inhibit the release of
PGF2cc from the placenta and myometrium (G.D. Thorburn,
personal communication). If this is so, any mechanism
which enhances PGF2a production and release might initiate
a positive feedback system resulting in progressively
greater PGF2a release as the progesterone block fails.
The results presented here demonstrate that the rate of
fall of plasma progesterone in the PGF2a treated animals
is faster than in the cortisol treated animals, a necessary
prerequisite for accepting the possibility that cortisol
acts through the production of PGF2a in the pregnant rabbit.
Arachidonic acid will induce premature delivery in the
rabbit (Nathanielsz, Abel & Smith, 1973). This observation
suggests that endogenously produced prostaglandin may play
a role in parturition in this species.

As reported previously in the rabbit when intra-

aortic infusions of PGF2a are commenced on D21, myometrial
contractions recorded using a radio-telemetry system do
not appear in under 15-18h even on the highest dosages
(Nathanielsz et al., 1972). The latency to the onset of
myometrial activity is even longer with cortisol (Abel
& Nathanielsz, unpublished observation). It will be noted
that plasma progesterone has fallen to less than half the
pre-operative level by the end of 24 h in 4 out of 5
PGF2a treated rabbits. Data regarding sequential analysis
of peripheral plasma progesterone in the same pregnant
doe is very limited. The results reported here are in
agreement with those of Kendall 8,Liggins (1972) in
showing that there is considerable variation in absolute
levels between animals and a reasonable degree of day to
day variation in individual animals. Both these observations
and the finding that surgery affects progesteronsconcent-
ration demonstrate the naed for sequential results on the
same animal rather than pooled individual data. It is
also possible that litter size ma affect the plasma
438 SJ PTEMBER 1973 VOL. 4 NO. 3
 PROSTAGLANDINS

progesterone concentration. Although on approximate

threshold for delivery has been discerned it is not yet
possible to state whether there is on absolute plasma
progesteronethreshold above which uterine contractions
are inhibited; again this may be related to litter size.

Parturition in our cortisol infused animals was

accompanied by marked nesting behaviour involving the
plucking of copious amounts of fur. Nesting activity was
almost absent on the PGF2a regimes. Delivery of foetuses
was a sporadic affair with PGF2a but in the cortisol
infused animals most of the foetuses were delivered within
a short time interval. At post mortem, mammary development
and milk engorgement was much more marked in the cortisol
treated animals. It would therefore appear that in the
cortisol-inducedanimals, delivery more closely resembles
normal parturition than in the PGF2a treated animals.

The fall in peripheral plasma progesteroneconcen-

tration in the cortisol infused animals is more gradual
than that in the PGF2a treated rabbits. It is possible
that the cortisol infusion activates processes other
than the productionof PGF2a which occur during normal
labour and which are by-passed by the PGF2a regime. One
mechanism that requires investigationis the possible
linkage between cortisol, oestrogen and PGF2a. There is
need .fordata regarding the role of oestrogen in part-
urition in the rabbit.

SEPTEMBER 1973 VOL. 4 NO. 3 439

PROSTAGLANDINS

REFERENCES

Abel, M., Smith, G.W. d Nathanielsz, P.W. (1973). Prosta-

glandin induced parturition in the rabbit; quantitative
aspects of the route and duration of administration.
J. Endocr. In press.

Ab~;$;r.G.~.~.Swerdloff, R., Tulchinsky, D. d Odell, W.D.

a ioimmunoassay of plasma progesterone.
J. clin. Endocr. Metab. 32, 619-624.

Duncan, G.W. & Pharriss, B.B. (1970). Effect of non-steroidal

compounds on fertility Fedn Proc. Fedn Am. Sots. exp. Biol
29, 1232-1239.

Fylling, P. (1971). Premature parturition following dexa-

methasone administration to pregnant ewes. Acta endocr.,
Copenh. 66, 289.

Kendall, J.Z. & Liggins, G.C. (1972). The effect of dexa-

methasone on pregnancy in the rabbit, J. Reprod. Fert.
29, 409-413.

Liggins, G.C. & Grieves, S.A. (1971). Possible role for

prostaglandin F2a in parturition in sheep. Nature, Lond.
232, 629-631.

Li gins G.C., Grieves, S.A., Kendall, J.Z. & Knox, B.S.

1972) . The physiological roles of progesterone,
i!
oestradiol-17P and prostaglandin F2a in the control of
ovine parturition. J. Reprod. Fert Suppl. 16, 85-103.

Nathanielsz, P.W., Abel, M. & Smith, G.W. (1972). Initiation

of parturition in the rabbit by intraaortic infusion of
prostaglandin F2a. J. Endocr. 55, 617-618.

Nathanielsz, P.W. & Abel, M. (1973). Initiation of parturi-

tion in the rabbit by maternal and foetal administration of
cortisol: Effect of rate and duration of administration:
Suppression of delivery by progesterone. J. Endocr. x,
47-54.

Nathanielsr, P.W., Abel,-M 8 Smith, G.W. (1973). Foetal and

Neonatal Physiology: Proceedings of the Sir Joseph Barcroft
Centenary Symposium. Pub. Cambridge University Press. Ed.
pmgli;e&.S., Cross K.W., Dawes, G.D. 8,Nathanielsz, P.W.
. - .

Thorburn, G.D., Nicol, D.H., Bassett, J.M., Shutt, D.A. h Cox,

R.I.(1972). Parturition in the goat ond sheep: change in
corticosteroids, progesterone, oestrogens and prostaglandin
F2a. J. Reprod. Fert. Suppl. l-6, 61-84.

44G SEPTEMBER 1973 VOL. 4 NO. 3