Postgrad. med. J. (January 1969) 45, 57-64.

The luteo-placental shift, the guardian of pre-natal life

ARPAD CSAPOM.D.

The Department of Obstetrics and Gynecology, Washington University School of Medicine,St Louis, Missouri

IntroductionThe 'Iuteo-placental shift' is defined here as a

shift in progesterone synthesis during pregnancyfrom the corpus luteum to the placenta. Distinctchanges in the regulation of uterine function follow.It is predicted that this shift in the anatomical siteofhormone support, from an extra- to an intra-uterinelocation, changes the distribution of progesterone,the character of the myometrial block and, therefore,uterine activity and reactivity. In different speciesthe shift seems to occur at different times in gestationand to different degrees. It is these variations in thetiming and the degree of the shift which best explainthe noted 'species differences' in uterine activity. Ifso, 'species differences' are superimposed modifica-tions, rather than fundamental alterations, of thebasic regulatory mechanism of uterine function.The purpose of the shift is thought to be the pro-

tection of pregnancy beyond the life span of thecorpus luteum, thus allowing continued pre-nataldevelopment. However, by weakening the proges-terone block, the shift often permits a gradual early'evolution' of uterine activity and reactivity longbefore term. If this 'evolution process' overstepsphysiological limits a 'hostile' contractile environ-ment develops, exposing the foetus to considerablehazards and, in extreme conditions, to prematurityand pre-natal defects. The experiments to be re-ported examine the merits of these concepts in thehuman, the rat and the rabbit.A critical survey of the current literature (Csapo

& Wood, 1968) revealed that several maternal andfoetal factors are implicated in the complex regu-latory mechanism in control of uterine functionduring gestation and at labour. However, the con-tributions of these factors appear to differ insignificance. The 'luteo-placental unit' dominatesuterine function, for when its influence is completeit cannot be overruled by the others. Experienceswith foetal death in utero and with the surgicalseparation of the 'foeto-placental unit', reveal that itis the placental, rather than the foetal component,which affects the myometrium directly. Foetal deathhas no acute, but only a chronic, influence on the

continuation of pregnancy. The duration of gesta-tion with a dead foetus seems to depend on therelationship between residual placental function anduterine volume. Within the 'luteo-placental unit' theplacental component appears to be dominant, for itis indispensable in all species, while the luteal com-ponent is not. Even the rabbit, the champion ofluteal dominance, requires placental support for thesustenance of the corpus luteum, an effect readilysubstituted for by estrogen therapy (Porter, Becker& Csapo, 1968).

It is proposed to describe results obtained bymulti-disciplinary teamwork in a series of experi-ments undertaken in the human female, the rat andrabbit in collaboration with a number ofinvestigatorsin my laboratory: Drs Abe, Kerenyi, Ogata, Pinto-Dantas, Porter and Takeda, and in the steroid-chemical laboratory of Dr Wiest.

1. Clinical trialsExtensive and carefully controlled observations

were carried out in twenty-six non-pregnant patientswith normal menstrual cycles. Intra-uterine pressurechanges were recorded by means of small balloonsattached to catheters and inserted into the uterinecavity through the vagina (Csapo et al., 1966).Spontaneous activity and the response to intra-venous oxytocin were recorded sequentially throughthe menstrual cycle. During the menstrual flowregular pressure cycles of high amplitude and lowfrequency were recorded. After the cessation of themenstrual flow the pressure decreased while thefrequency increased. On day 16 the pressure cycleswere of minimum amplitude and high frequency-features characteristic of a 'blocked' uterus. Thiscondition of suppressed activity prevailed until aboutday 26 when the pressure cycles increased somewhat.A marked increase in pressure occurred during thelast day of the cycle. The quantitative differencebetween the recorded pressure at day 2 and at otherstages of the cycle was statistically significant* at the

* For biostatistical analysis the authors are grateful to Dr.J. A. Hagans, Dr. C. A. Schlagel and Dr. J. A. Soda of TheUpjohn Company, Kalamazoo, Michigan.

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58 Arpad Csapo

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Z.. .OEPA.OPS... 3Y:A:::3FIG. 1 (A). The spontaneous activity and oxytocinresponse of the human uterus at day 16 of the normalmenstrual cycle. Intra-uterine pressure is measured bythe 'demobilized microballoon' method.

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FIG. 1 (B). The spontaneous activity and oxytocinresponse of the human uterus during the 7th week ofnormal pregnancy. Intra-uterine pressure is measuredby the 'demobilized microballoon' method. Note thatas during the normal mid-cycle there is no response tooxytocin in doses up to 128 mU/min.

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FIG. I (C). The spontaneous activity and oxytocinresponse of the human uterus during the 14th week ofnormal pregnancy. Intra-uterine pressure is measuredby the 'transabdominal method'. Note the distinct, butlimited, response to oxytocin.

level of P<0 01, but not between days 16-17 and26. The changes were paralleled by the oxytocinresponse, which was distinct during the menstrualflow and subsequently gradually disappeared.Characteristically, there was no oxytocin responseduring the secretory phase, irrespective of the doseand the method of administration (Fig. 1). Occasion-ally a slight increase in resting pressure was recorded.By day 26 an abortive response could again beobtained which increased at the end of the cycle.These observations are in harmony with the

findings (Van der Molen & Groen, 1965; Runne-baum & Zander, 1967; Johansson, Neill & Knobil,1968) that a rise in plasma progesterone precedesovulation by several days and declines sharply atthe end of the cycle. Furthermore, progesteronetreatment reduces the peak pressure of spontaneousactivity found at the beginning of the cycle anddelays its evolution at the end (Csapo et al., 1966).Thus in the non-pregnant human female the be-haviour of the myometrium near and after the mid-cycle is in accordance with the ovarian support ofthe progesterone block, characterized in the pregnantrabbit.

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The luteo-placental shift

During the 7th week of pregnancy five obstetric-ally normal patients were studied in collaborationwith Pinto-Dantas by the same method used innon-pregnant patients. No oxytocin response couldbe obtained, even with infusion rates of 128 mU/min(Fig. 1). However, when intra-uterine pressure wasrecorded transabdominally in patients more than14 weeks pregnant (Bengtsson & Csapo, 1962), itwas found that a response to oxytocin could alwaysbe obtained, though massive doses (128 mU/min)were required in the second trimester to induce18 mmHg pressure (Fig. 1). In the 36th week, thespontaneous pressure cycles reached 18 mmHg and8 mU/min oxytocin induced an average 37 mmHgpressure. At 40 weeks spontaneous and oxytocin-induced pressure cycles were 32 and 65 mmHg,respectively (Csapo & Sauvage, 1968).

Wilson (1937) demonstrated by clinical observa-tions in eleven patients that at the 7th week ofgestation the ovaries are 'indispensable' to the main-tenance of pregnancy as a rule. This indicates that acertain degree of placental 'maturity' is a pre-requisite of the luteo-placental shift and that at the7th week this maturity is not reached invariably.Thus the described observations of oxytocin responsefall into place. They reveal that so long as the ovariesare the source of progesterone, the response of themyometrium to oxytocin may be completely sup-pressed. After the luteo-placental shift, however,this no longer holds and there is always a response,though very high doses of oxytocin may be requiredfor a partial response.

2. Experiments in pregnant ratsA report, describing physiological, electro-physio-

logical and some of the steroid chemical observationshas been presented (Csapo, 1967). A brief summaryof these results will be sufficient here in providingbackground for the description of electrophysiolo-gical experiments.Holtzman-bred Sprague-Dawley rats, 80-90 days

old and 200-230 g weight were used. The time ofmating was determined with ± 3 hr accuracy. Theseries consisted of 647 rats and the data relating totheir pregnancies were carefully documented. Theaverage litter size was ten, 94% of the litters con-sisting of six to fourteen foetuses. In over 80% ofthe mothers the foetuses were unequally distributedbetween the two horns. Between the 13th and 22nddays of pregnancy, the foetal and placental weightat a given time in gestation was closely similar inthe different animals with an average standarddeviation of less than 30%. Thirty-two controlanimals were allowed to go to term and, of these,thirty delivered on the morning of the 22nd daywhile two, which had more than twelve foetuses,

delivered the previous night. Delivery was com-pleted in about 30 min.Ovariectomy before day 14 (5-6 days after im-

plantation) resulted in rapid death and resorptionof the litter. This was not surprising (in view ofWilson's clinical study, 1937) in that at day 13 therat placenta is 0 11 g, only 200% of the 'mature'value (0 55 ± 0-01 g at day 20). After the 13th daythe placental weight increases rapidly, as does thesuccess of the ovariectomized animal in maintainingpregnancy. Thus ovariectomy at 16-17 days resultedin over 60% foetal survival at day 21. This observa-tion provides evidence that, in the rat, the ovary isdispensable towards the end of pregnancy to aconsiderable degree, at least under the conditions ofour experiments, conducted between September andApril.The success of the ovariectomized animal in

maintaining pregnancy was distinctly dependent onplacental hypertrophy. If placental hypertrophy didnot occur, premature delivery started on the 19thto 20th day. A group of twenty-four ovariectomizedanimals with intact pregnancy had an averageplacental weight of 0 65 ± 0 02 g, while thirty-threeanimals in premature delivery 0,56 + 0 01 g. Thisdifference, documented by examining 495 placentae,is highly significant (P <0 001).The character of this premature delivery appeared

to be of considerable theoretic interest, in that:(1) It started from the uterine horn of greater

volume, as a rule.(2) Only a limited number of foetuses were dis-

charged at long intervals and their placentaewere retained.

(3) Delivery was interrupted and prolonged forhours or days, allowing a fraction of the litterto reach term.

Thus by discharging a number of foetuses andretaining the placentae, the animal apparently'turned off' myometrial activity and still remainedpregnant. As the uterine volume increased with thecontinued growth of the remaining foetuses, how-ever, it became optimal again for 'turning on'activity and another foetus was delivered. In thisway a protracted delivery was achieved. However,neither placental hypertrophy, nor placental reten-tion (and the lowering of the foetal/placental ratio)provided complete protection of the foetuses whichwent to term, for the incidence of foetal defects wasmarked. Deformities, haemorrhage, oedema, missingextremities and hydramnios were frequent, especiallyin the two foetuses located at the cervical end of thehorn. Those foetuses which did reach term withoutmarked defects were unusually mature.The development of a 'hostile' uterine environ-

ment after ovariectomy was readily prevented by'sustained' progesterone replacement therapy. The

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Arpad Csapo

effective dose was high, relative to that required byovariectomized rabbits, for a daily dose of less than2 mg did not always offer 100% protection. How-ever, at 2 mg/day and higher dose levels, pregnancywas maintained even if ovariectomy was performedbefore the 15th day. It was found that if ovariectomywas carried out on days 14-15 of pregnancy,'decremental' progesterone therapy (sequential dailydoses of 4, 3, 2, 1.5, 1 0 and 0 5 mg) was also effectivein maintaining pregnancy to term, despite the factthat the treatment was discontinued 3 days beforeterm. Both forms of progesterone replacementtherapy promoted marked placental hypertrophyand increased the weight of the newborn. Anindependent study showed that gestagens, other thanprogesterone, are also effective (Van der Vies &Feenstra, 1967). It was found unnecessary to addoestrogen to the progesterone therapy in order toachieve viable young, for the foetuses, delivered atterm by hysterectomy, developed normally in thecare of foster mothers. However, if 2 mg or more ofoestradiol were added to the daily doses of proges-terone, then the placental hypertrophy was sup-pressed, while 10 mg/day oestradiol suppressed evennormal placental growth, resulting in prematuredelivery. In contrast, continued progesterone therapy,without oestrogen, prolonged gestation and deliverycould not be induced with oxytocin at term.

Additional experiments (in fifty-one rats) werecarried out on the 17th day of pregnancy. Bothovaries were removed and in one horn all theplacentae were dislocated by gentle pressure be-tween finger and thumb to move the whole con-ceptus sac sideways. After recovery, the animalswere housed on a grating which allowed deliveredfoetuses and placentae to pass through onto thetray below. Twenty-three rats received 4 mg/dayprogesterone, the remainder were left untreated. Allwere kept under close observation and killed 12-48hr after the operation. The distribution of concep-tuses in the uterine horns was carefully recordedboth at the time of operation and at the time ofautopsy. In the untreated rats, 75% of the dislocatedconceptuses were aborted but only 4% of the intactfoetuses. On the other hand, in those animals whichwere receiving progesterone treatment, only 8% ofthe dislocated conceptuses were aborted. Thus theseexperiments show that the complete removal of the'systemic' luteal progesterone component, togetherwith the unilateral removal of the 'local' placentalcomponent, creates a functional 'asymmetry' be-tween the two uterine horns and the majority offoetuses are delivered from one horn but retainedin the other. However, when the status quo of the'systemic' progesterone is restored by daily injectionsof progesterone, the majority of foetuses are retainedin both horns.

The precise electrophysiological conditions associ-ated with this functional asymmetry of the myo-metrium was investigated in collaboration withDr H. Takeda. The study was carried out in eightrats 48 hr after ovariectomy and unilateral disloca-tion of the placentae. Under ether anaesthesia theabdomen was opened by midline incision and thecervical ends of the two uterine horns were exposed.Through a longitudinal slit in the vagina, a micro-balloon (0.8 ml capacity), was inserted into eachuterine horn and connected to a Statham pressuretransducer by a polyethylene tube. The balloonswere filled with water, and the vaginal wound closed.Two 'suction' electrodes (Hoffman et al., 1959)were subsequently used for the recording of theelectric activity of the two uterine horns. Theseelectrodes consisted of a polyethylene tube (0 5 mmbore) surrounding an Ag-AgCl wire (01 mmdiameter). These electrodes were placed over theserosal surface of the various uterine regions andapplied by vacuum suction so that the electrode tipwas in close contact with the myometrium duringsuction and was kept in place by it. When suctionwas discontinued the electrode was readily detached.A spiral shaped 'reference' electrode was placed inthe vagina. The electrodes were connected to an A.C.amplifier with a 2-sec time constant and the signalswere recorded simultaneously with the intra-uterinepressure (by a Grass Polygraph). The exposeduterine regions were kept moist by covering themwith sterile gauze soaked in warm saline andrecordings were made in different regions of bothhorns.The action potentials recorded by suction elec-

trodes result from the potential difference createdbetween the transiently ischaemic (depolarized)'suction region' and the nearby uterine portions.Since these electrodes record the activity of groupsof cells, rather than of one cell, the amplitude of theaction potentials depends on the number of cellswhich fire synchronously. The shape of the potentialsalso depend on the electrical synchrony betweencells (Hoffman et al., 1959).The electrophysiological findings in the various

areas of the uterus are illustrated by the originaltracings of Fig. 2. In the experimental (placenta-dislocated) horn, from which most of the foetuseshad already been delivered, marked electricalactivity was recorded in all areas and the train dis-charges of the different myometrial regions weresynchronous. Furthermore, electrical activity wasregular and occurred synchronously with the intra-uterine pressure of that horn. Such activity indicatesthat the myometrium has already escaped from theprogesterone block (Csapo & Takeda, 1965). Incontrast to this horn in which the placentae hadbeen dislocated 48 hr previously, the control horn

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The luteo-placental shift

(a) (b) 20mu

I

FIG. 2. The influence of the placenta on spontaneousand oxytocin-induced electrical and mechanical activityof the myometrium. On the 16th day of pregnancy in therat, both ovaries were removed and, in one horn, theplacentae were dislocated. The latter horn aborted itscontents on day 17 and recordings were made on day 18.(a) Diagram of the recording positions of the suctionelectrodes on the two horns of the uterus. X, Experi-mental horn which had aborted its contents; Y, intacthorn. (b) Tracings of spontaneous pressure changes inthe two horns and of electrical activity recorded fromsites 1-8. The effect is shown of an intravenous injectionof 20 mU oxytocin on pressure and on sites 1, 4, 7 and 8.Note the synchronous electrical activity in the activeaborted horn (1, 2 and 3) and the high, regular wavesof intra-uterine pressure associated with it (X). Theinterplacental region of the intact horn (4) displaysdistinct but irregular electrical activity and as the elec-trodes are moved closer to the cervix away from thelowermost placenta, electrical activity improves (5 and6). In contrast, as the electrodes approach the placentalbed, the train discharges gradually diminish (7 and 8).This asynchronous electrical activity is characteristic ofthe progesterone block and only permits irregularpressure cycles of limited magnitude. The effect ofoxytocin is to improve both mechanical and electricalactivity in the empty horn (X and 1). However, in theintact horn, although electrical activity is improved inthe interplacental region (4), no distinct train dischargesare triggered in the placental region (8) and, as a result,there is little improvement in the pressure cyclesrecorded in this horn (Y).

showed much less activity. There were, however,differences in electrical activity according to thedistance of the recording site from the placenta.Thus when the electrodes were applied to themyometrium in an interplacental region, distinctbut irregular electrical activity was recorded. As theelectrodes were moved closer to the cervix and awayfrom the lowermost placenta, electrical activityimproved. When, on the other hand, electrodesapproached the placental bed, the train dischargesgradually diminished and became minimal over theplacental bed. This mixture of restricted asynchro-nous electrical activity, which is characteristic of theprogesterone block (Csapo & Takeda, 1965), allowedonly small and irregular intra-uterine pressurecycles, as illustrated in Fig. 2. The effect of oxytocin,also shown in Fig. 2, was to improve the electricalactivity, both in the horn which had already de-livered and at the interplacental sites of the intacthorn, while having little effect upon the activityrecorded from the placental sites. Oxytocin in theexperimental horn generated increased intra-uterinepressure at high frequency whereas its inconsistenteffect on different areas of the intact horn did notimprove the pressure in that horn.

These results demonstrate a functional asymmetrybetween the intact pregnant and placenta-dislocateduterine horns of the bicornuate rat uterus as well asbetween the anti-placental and placental regions ofthe intact pregnant horn itself. The functionalasymmetry of the intact horn apparently dependson the topographical relationship of the uterinearea to functional placentae. The question is whetherthis asymmetry is directly related to progesterone, orwhether the placental effect is mediated by otherfactors, for example, structural differences betweenuterine regions. Our contention that this placenta-dependent functional asymmetry is causally relatedto the direct effect of progesterone, is based on thefollowing observations.

It has been shown (Takeda, personal communica-tion) that when the rat uterus is excised at the endof pregnancy and strips are suspended in an isolatedorgan bath, the electrophysiological difference be-tween placental and non-placental sites graduallydisappears. This in vitro evolution of activity in theplacental regions cannot be accounted for by struc-tural changes but rather by the metabolism ofprogesterone in the endocrinologically unsupporteduterus (Wiest, 1963). Such a rapid in vitro deteriora-tion of the myometrial block has also been demon-strated in the rat uterus on the 10th day of pregnancyby a quick evolution of the train discharge and ashift in the 'strength-duration' curve (threshold) as afunction of the duration of in vitro exposure (seeFig. 2, Csapo, 1968).

x

y

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Experiments are in progress in collaboration withDr W. Wiest to measure the progesterone contentof uterus, placenta and peripheral plasma in rats.The estimations are being carried out with thesensitive and specific 'double isotope derivativedilution' method of Wiest (1967). At present thenumber of results is insufficient for completestatistical analysis but various pointers are becomingapparent. In one series, rats were ovariectomized onthe 17th day of pregnancy and the placentae in onehorn were dislocated. Abortion from the placenta-dislocated horn began about 10 hr later and theanimals were killed 18 hr after the operation forprogesterone analysis. Results indicated not only ageneral progesterone withdrawal, but a differencebetween the intact and experimental horn. Thus theprogesterone concentration was apparently greaterin the intact horn than in the active horn which hadaborted its foetuses. Progesterone therapy startedat the time ofovariectomy prevented delivery from theplacenta-dislocated hornand diminished the differencebetween the two horns in the concentration of proges-terone. Additional results are needed, however, toestablish the statistical significance of these findings.

It might be argued that the findings referred toearlier of synchronous electrical activity and highintra-uterine pressure cycles in the horn with dis-located placentae, were due to structural changes,i.e. to an increase in wall thickness and in thenumber of cells near the electrode, resulting fromthe shortening of this horn during the process ofabortion. This seems unlikely, however, since it wasshown (Csapo, Takeda & Wood, 1963) that it islengthening of myometrial fibres (up to an optimalvalue) induced by volume increase in the parturientrabbit uterus which increases the synchrony of traindischarges and intra-uterine pressure.

Thus, in general, structural differences fail toaccount for the observed functional asymmetry ofthe uterus, whereas differences in progesterone con-centration apparently do.

It is important to note here that there were signi-ficant exceptions to a consistent relationship be-tween plasma and uterine progesterone concentra-tions. For example, in control rats the concentrationsin the two tissues were similar and both decreasedat the end of pregnancy. However, when rats wereovariectomized on day 16 and pregnancy wasmaintained until day 21 as a result of placentalhypertrophy, the 'pre-partum' concentration ofprogesterone in the uterus was similar to that ofcontrols, whereas the concentration in the plasmawas about one-third of that in controls, the differencebeing significant with P < 0-001. Hence it is notalways possible to predict uterine from plasmaconcentrations and it would seem wiser always tomake direct measurements in the relevant tissues.

Experiments in pregnant rabbitsWe also examined the 'dispensibility' of the corpus

luteum in pregnant rabbits and the potential of thisanimal to perform the 'luteo-placental shift' success-fully. A total of fifty-two New Zealand Whiterabbits, with precisely dated pregnancies, werestudied under experimental conditions previouslydescribed (Csapo & Lloyd-Jacob, 1962). In thecontrol animals (thirty-two in number), delivery wasinduced with a single i.v. dose of 100mU oxytocin,starting on day 30 of gestation. In case of inductionfailure, this treatment was repeated at intervals of12 hr until the animal delivered. Induced, ratherthan spontaneous, delivery was preferred in orderto recover the majority of foetuses and placentae forimmediate measurements.The twenty experimental animals (with litters of

less than eight; Fig. 3, numbers in double circles)were ovariectomized on the 18th or 19th day ofgestation, i.e. 11-12 days after implantation. Thisprocedure terminates pregnancy within 48 hr unlessprotection is guaranteed by progesterone therapy.In order to test for the placental compensatorypotential of these ovariectomised rabbits, a 'tran-sient decremental' progesterone therapy was given(Fig. 3) in order to sustain pregnancy during theinitial period of predicted placental compensatoryeffort. Treatment began at the time of ovariectomyat the 4 mg/day level. The hormone was given in oil,intramuscularly, in two divided daily doses. It wasdecreased by 1 mg every 2nd day and tapered off tothe level of 0-5 mg!day on days 26-27.

Ovariectomy) ()i4) No. of toetuses in eoch horn

(iQ(9 ,J(.23 Induced by lOOmU oxytocin i.v.Q2X23 j5QQ Unilateral placental dislocation(dg 123) Hysterectomy Term

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c Minimum sustained progesterone level

8 20 22 24 26 28 30 32Days of gestation

FIG. 3. Showing the times of ovariectomy, decrementalprogesterone therapy and subsequent delivery of foetusesin twenty rabbits. Litter size is shown by the numbersin circles. Delivery was spontaneous unless otherwiseindicated. The broken horizontal line shows theminimum level of continued progesterone administra-tion necessary for the maintenance of pregnancy.

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The luteo-placental shift

TABLE 1. The effect in pregnant rabbits of ovariectomy + transient, decremental progesteronetreatment on foetal and placental weights at delivery, as compared with normal controls

Control Experimental

Foetus (g) Placenta (g) Foetus (g) Placenta (g)

Day 30 40 ± 10 45 4 0-2 (9) 53 ± 19 10-1 ± 05(5)Day 31 47 ± 0-8 5-1 ± 0-1 (17) 60 ± 1-2 7-7 ± 0 5(6)Day 32 50 ± 1-5 5-1 ± 0-7 (6) 75 ± 2-2 9 0 ± 0 4 (4)Total average 46 ± 0-6 5 0 ± 0 1 (32) 68 ± 1-2 9 1 ± 0-3 (15)

The figures in parentheses represent the number of pregnant rabbits studied.The difference in both foetal and placental weights between control and experimental groups, at

30, 31 and 32 days, as well as the total average difference is highly significant (P<0 001).The four experimental animals, delivered prematurely between days 28 and 30, had an

average placental value of 5-4 ± 0 3 g. This value is similar to that of the controls, but signi-ficantly different (P<0 001) from that of the fifteen experimental animals.

In fifteen out of twenty ovariectomized rabbits,pregnancy was maintained until days 30-32, that is,several days after the cessation of progesteronetreatment. When delivery occurred in these fifteen,either spontaneously or induced by oxytocin (Fig. 3,see arrows), oversized foetuses and placentae weredischarged (Table 1). In three animals pregnancy hadto be terminated by hysterectomy (Fig. 3, black dotson circles) because oxytocin failed to induce completedelivery. Thus the combined effect of ovariectomy +transient decremental progesterone therapy (sodesigned as to imitate the gradual luteal proges-terone withdrawal of human pregnancy) created, inthe majority of animals, a regulatory condition inwhich the ovaries became dispensible for themaintenance of pregnancy.

Table 1 shows the average foetal and placentalweights (in g-SD) of the thirty-two control andnineteen experimental rabbits as a function of theday of delivery. On days 30, 31 and 32 the averagefoetal and placental weights of the control andexperimental animals are significantly different withP < 0 001 and the averages for the 3 days combinedare also significantly different with P< 0001. Theaverage placental weight of those four experimentalrabbits which delivered on days 28 and 29 is similarto that of the controls but significantly lower(P < 0 001) than that of the remaining fifteenexperimental rabbits which maintained pregnancyfor a longer period. The rabbit which delivered onday 26 likewise had placentae of comparable weightto controls.

It is evident, therefore, that the maintenance ofpregnancy in ovariectomized rabbits (transientlysupported during initial placental compensatoryeffort by decremental progesterone therapy) coin-cided with marked placental hypertrophy andaccelerated pre-natal development of the foetus.

This and the additional observation that those fiverabbits which failed in placental hypertrophydelivered prematurely, suggest that placental hyper-trophy and the mainitenance ofpregnancy are causallyrelated. Thus effective luteo-placental shift in rabbitsand rats, aiming at the maintenance of pregnancyin the absence of luteal function, apparently dependson the success of placental compensatory effort.

In three of the rabbits in the experimental group,in addition to the ovariectomy and decrementalprogesterone therapy, the placentae were dislocatedin one horn on day 24. While all three animalscarried pregnancy until days 30-31 in the intactcontrol horn (Fig. 3), they all aborted, completelyor partially, within 48 hr from the horn in which theplacentae had been dislocated. This simultaneousoccurrence in the rabbit (as in the rat) of unilateralabortion from one uterine horn and intact pregnancyin the other, is evidence of a local, unilateral,placenta-dependent controlling factor. Whether thisfactor in the rabbit is progesterone (as it appears tobe in the rat) is now under investigation.

ConclusionsThe experiments presented show that in pregnant

rabbits and rats, as in human patients, the corporalutea are dispensible provided that the animal caneffectively accomplish compensatory placental hyper-trophy. This change, the luteo-placental shift,results in such modifications in myometrial regula-tion as to allow arcuate or bicornuate uterine hornsto function independently from one another anddeliver their contents at different times. ThusNature's puzzle, the delivery of human twins severalweeks apart, which led to the concept of the 'local'effect of placental progesterone (Csapo, 1956, 1961),has been reproduced experimentally. This concepthas gained considerable support from the findings

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64 Arpad Csapo

that both the electrophysiological and mecanicalhfunctional asymmetry of the uterus may be inducedby unilateral placental dislocation, that this pro-cedure results in a reduction in uterine progesteroneconcentration and that this fall in uterine proges-terone can be balanced by progesterone substitutiontherapy preventing the discharge of the dislocatedconceptuses. The premises stated in the Introductionare supported, therefore, by experimental evidence.The significance of placental hypertrophy in an

effective luteo-placental shift is also demonstrated.That the placental dominated human pregnancy, asopposed to the luteal dominated rat and rabbitpregnancy, involves marked placental hypertrophyis indicated by the low foetal/placental ratio: 7.3 incontrast to 9 8 and 11 7, respectively. Prematuredelivery in ovariectomized rats focused upon thesignificance of this ratio by revealing that whenplacental hypertrophy fails, placental retention andthe lowering of the foetal/placental ratio becomesthe ultimum refugiens in the maintenance of preg-nancy. When all the experiments described are con-sidered, the control over placental growth emergesas the outstanding problem of obstetrics and itssupporting disciplines. This regulatory mechanismmust be understood before any claims are justifiedfor a predictable control over the function of thepregnant uterus and the protection of pre-natal life.

AcknowledgmentsThe author is grateful to Dr Martti Pulkkinen and Elise

Csapo for assistance during the experiments, for the process-ing of the data and for statistical analysis and to Dr BrendaM. Schofield and Dr David Porter for the benefit of discus-sions.

This work was supported by Grants HDO 1478 and5-K6-HD 20,169 from the National Institute of Health,United States Public Health Service and the SunnenFoundation.

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