Oxytocin and Contractility of the Pregnant Human Utekus*

OXYTOCIN AND CONTRACTILITY OF THE PREGNANT HUMAN UTEKUS*

By Roberto Caldeyro-Barcia and Juan J. Poseiro Seccicin Fisiologta Obstdtrica, hacultad de Medicina, Montmideo, lirzigiray

~~ETHODSFOR RECORDIKGUTERIKE CONTRACTILITY Quaizlitafice Study The contractility of the pregnant human uterus is measured through the recording of the amniotic fluid pressure'. by means of a thin polyethylene catheter introduced into the amniotic sac through the anterior abdominal wall and connected with a Sanborn electromanometer, model 121C, which is plugged to a Sanborn Poly-Viso recorder, model 1.50.t The intensity (amplitude) of each contraction is measured by the rise in pressure (mm. Hg) it produces in the amniotic fluid. The frequency is expressed by the number of contractions per 10 min. The product (intensity x frequency) of the contractions is called uterine activity and is expressed in Montevideo Units (LIont. U.) A detailed description of the methods for the quantitative analysis of the records of amniotic fluid pressure has been pub- lished recently.3 The tonus (lower pressure between the contractions) is also measured.

Methodsfor Sludyiq the Coordination of lhe Contractions The intramyometrial pressure is recorded simultaneously in 4 different parts of the uterus by means of 4 microballoons (volume: 0.02 ml.) inserted in the thickness of the uterine wall, each one connected to a recording electromanometer. This method enables us to study the origin of the contractile wave, its propagation through the uterus, and its force and duration in the different areas of the organ. Through these data, we may gather considerable informa- tion on the coordination of uterine action.', THESPONTAXEOUS UTERIXE CONTRACTILITY DURIKG NORMAL PKEGNAKCYAKD LABOR For a better understanding of the effects of oxytocin, it. is necessary to know the spontaneous behavior of the uterus during the normal pregnancy cycle. Pregnancy. The results obtained in more than 500 pregnant women studied are shown diagrammatically in FIGURE 1. During the first 30 weeks of pregnancy, uterine activity (striped area) is lower than 20 Jlont. U. Tracing A illustrates the characteristics of uterine contractility at this time of pregnancy; very small contractions (which remain localized to a small area of the * The work reported in this paper, aided by a grant from the Josiah Macy, Jr. Foundation and from The Rockefeller Foundation, New E'ork, N. Y., was performed in association with Hermbgenes Alvarez, Seraffn V. Pose, Charles H. IIendricks, Yamandd Sica-Blanco, Miguel A. Carballo, V. H. Gonzblez-Panizza, Carlos M6ndez-Bauer, Carlos Fielitz, and Luis A. Cihils. t Sanborn Company, Waltham, Mass. 813 814 Annals New York Academy of Sciences I-] I-]

'""I In- In- 6 hours after [Advanced First Stage)- : - delivery 0

1 12 hours after deliverv zw OI 50 24 hours after t- delivery =m

'15' 20' ' ' '25' I 40 ' ' ' ' ' ' 30' ' ' ' ' 35' ' ' ' 1'2' WEEKS OF PREGNANCY PUERPERIUM Ficrrm 1. The evolution of spontaneous uterine activity throughuut the pregnancy cycle-illustrated by the striped area and measured on the lell-side scale. Typical (schemat i- cal) tracings of uterine contractility at diflerent stages of the cycle are skiown. uterus) are produced every minute. From time to time a larger (Braxton Hicks) contraction is recorded. Prelabor. After the thirtieth week, uterine activity increases slowly aid gradually due to the increase of the intensity and frequency of the Braxton Hicks contractions (tracings B and C), which also improve their coordination, spreading through the uterus. This period of increasing uterinc activity, lasting for several weeks, is called prclabor. During this period the uterine cervix is progressively ripened. Beginning of labor. Uterine activity increases rapidly. Clinical labor usually starts when uterine activity reaches values between 80 and 120 llont. c'. (average I00 Rlont. IT.) There is no clear-cut division between prelabor and labor, only a gradual and progressive transition. The small localized and incoordinated contract ions, typical of pregnancy, tend to disappear ;is prelabor advancer arid are absent from the tracings recorded in normal labor. Labor. During labor, uterine activity continues to increase until the fetuc is delivered. The contractions increase their intensity and frequency as Caldeyro-Barcia & Poseiro : Contractility of the Uterus 815 shown by tracing D (early first stage), E (advanced first stage), and F (second stage of labor). In tracing F the intensity of the contractions is 50 mm. Ilg, and their frequency is 5 contractions per 10 min.; uterine activity is equal to SO x 5 = 2.50 Mont. U. In normal labor uterine activity usually ranges between 100 and 250 Mont. U. Early puerperium. After delivery of the fetus, uterine activity diminishes rapidly.* The frequency of the contractions usually decreases first, being reduced to 1 contraction per 10 min. (tracing I) 12 hours after the delivery. The inlensity of the contractions diminishes afterward (tracing J).

THEUTERINE RESPONSE TO OXYTOCIN Methodology Oxytocin infusion. Natural pure oxytocin and synthetic oxytocin, supplied by du Vigneaud,' were used as standards of comparison. The majority of the experiments were carried on with synthetic oxytocin (Syntocinon).t Yo significant differences were observed between these preparations.8 Oxytocin was administered by continuous intravenous infusion, as advised by Theobald et UZ.,~ Hellman,lo and Page." The infusions were made with a Continuous Slow Injector1 provided with 6 speeds. The infusions were started at the rate of 1 milli Unit (mu.) of oxytocin per minute (1 rnU./min.)? which was maintained for 30 to 60 min.; the infusion rate was then increased to 2 mU./min. and maintained for a similar period of time. In this way thc infusion rate was successively duplicated (4, 8, 16, 32 mU./min.) until uterine contractility reached values similar to t.hose recorded in spontaneously beginning normal labor. Clinical material. These infusions were carried on in 40 pregnant women from the seventeenth week of pregnancy onward. In 8 cases the uterine rcsponse to oxytocin was studied several times, in the same subject, at different stages of pregnancy. The subjects were not in labor when the infusion started, although in some cases labor began during the study period as a consequence of the infusion (see below). We shall consider only the results attained before the onset of labor because, when labor starts, the stable conditions required for a pharmacological study no longer obtain.

Characterislics of lhe Oxylocin-Produced Conlraclians If oxytocin is infused in the proper doses, it causes an increase of the intensity and frequency of uterine contractions without significantly raising the tonus (FIGURE 2);3,l2. l3 it also accelerates the spreading of the contractile waves

* The third stage of labor (tracing G) is accomplished by the first 2 or 3 contractions performed by the uterus after the delivery of the fetus.6 t Supplied by Sandoz Pharmaccuticals, Hanover, N. J. 1Manufactured by Palmer Ltd., London, England. A similar infusion pump can be obtained in the United States from The Harvdrd Annaratus Comnanv Inc.. Dover. Mass. S16 lilnnals ?Jew Yo& Academy of Sciences through the organ arid improves thc coordination of thc contractions, which acquire the so-called Triple L)escendcnt Gradient5 characteristic of normal labor. In the tracings of amniotic fluid pressure and of intramyometrial prcs- sure, the contractions produced by oxytocin infusion are indistinguishable from

WEEKS OF PREGNANCY-~~ I 30 I 40 rnmng SPONTI\NEOUS-~~ - ___ 0 A-~~ hl 1 5 15 Freq 5 2 29 U.A 5 10 43

1 22 39 - 83 40 ~___ W 4- 20--- o-- o-- ~- .-$2 I"t 1 E Freq 89 UA 9 L- W a 60- - - 40- - v1 20- ~-__ eL n- c In1 2 25 45 3 .- Frrq 79 43 39 A. .- UA 16 106. 178 E- 40 w 20--- __ ~~ ~ 0- 0- - ~ ZE In1 5 43 45 Freq 58 46 49 z UA 29 199 221 0 0- 3 mlnlle5 zLL z 16 0 4 3 cant perm min 0c- 235 MOnlw Units

32 0 ~~~ In1 38 mm.Hg Freq 5.7 con1 per 10min. U A 217. Moniw. Units

- I.. .., .:-u mmuias FIGUEJL2. Uterine responses to ox) tocin infusion obtained at the twentieth, thirtieth, and fortieth weeks of normal pregnancy. Typical segments of the original records of uterine contractility are shown. Each vertical column has been built with segments of the same record. Caldeyro-Barcia & Poseiro : Contractility of the Uterus 8 17 those recorded during spontaneously beginning, normal labor.* The physiological pattern of the contractions produced by the continuous intravenous infusion of oxytocin was recorded for the first time by Hellman et aE.14 By increasing progressively the infusion rate of oxytocin, it is possible to reproduce at will all types of uterine activity spontaneously performed by the uterus at the different stages of prelabor and labor (compare FIGURES 1 and 2).

Induction of Labor If the infusion of oxytocin is continued for the necessary length of time, labor will start and proceed normally. To start labor, it is necessary to produce a given amount of strong (40 mm. Hg) uterine contractions; this amount is large (between 200 and 300 contractions) when the uterine cervix is unripe, and it is small (less than 100 contractions) when the cervix is ripe.I2 In cases where it is not advisable to induce labor, the oxytocin infusion nevertheless can be performed, the only precaution being to keep its duration below a cer- tain limit in order not to produce the amount of contractions needed for starting labor.

INFLUENCEOF THE GESTATIONALAGE Uterine Responses to Oxytocin Infusion at the T-wentieth, Thirtieth, and Fortieth Weeks FIGURE2 shows tracings of uterine contractility obtained in the same subject at the twentieth, thirtieth and fortieth weeks of pregnancy (respectively, in the vertical columns on the left side, in the middle, and on the right side). The upper row shows the spontaneous activity of the uterus at the three stages of pregnancy. The underlying rows show the effects of the infusion of oxytocin; each row corresponds to a given infusion rate (indicated on the scale at the left side). The black frames indicate (for each gestational age) the row where uterine activity has reached labor ranges (over 100 hlont. U.) At the fortieth week, 2 mU./min. are enough to raise uterine activity over 100 Mont. U,; at the thirtieth week, 4 mU./min. are required and, at the twentieth week, 16 mu./ min. At the twentieth week the spontaneous activity is very low and infusion rates under 8 mU./min. are almost without effect on the uterus; however, when the infusion rate is increased more than 8 mU./min., uterine activity is raised to the labor range of values. With 32 mU./min., uterine activity becomes similar to that recorded in advanced stages of labor. Roughly, it can be stated that, in order to obtain similar uterine responses, the infusion rate must be 8 times higher at the twentieth week than at term pregnancies. * The smaii, localized and incoordinated Contractions recorded during pregnancy and during abnormal lahor are seldom seen in the records obtained during oxytocin infusions, which usually show only the strong, rhj thmic, and well-coordinated contractions characteristic of normal lahor. a18 Annals New York Academy of Sciences

At the thirtieth week the spontaneous activity is slightly higher than at the twentieth week, but the response to oxytocin has increased greatly: 1 and 2 mU./min. producing definite effects and 4 mU./min. sufficing to raise uterine contractility to labor values. At the fortieth week the spontaneous activity is much higher than at the thirtieth week and uterine response to oxytocin has also increased, but in a smaller degree than between the twentieth and thirtieth weeks. Evolution Throughout Pregnancy of Uterine Response to Oxytocin Infusion FIGURE3 shows the results obtained from 6 records made at different stages of pregnancy. Three of these 6 records are those shown in FIGURE 2. The 6 records were selected from a total of 62 because they were considered typical for their respective gestational ages.

3.5

30 .-tu) C 3 251 'p 0 c c RANGE OF 5 201 UTERINE * ACTIVITY -I- RECORDED -> IN NORMAL AND c t~ 15C SPONTANEOUSLY a BEGINNING zw LABOR IY w 100 I- 3

20 30 40 WEEKS OF PREGNANCY FIGURE3. Evolution of the uterine response to oxytocin infusion during the second half 01 pregnancy. Each vertical column corresponds to one record. The thick line that joins the rhomhus indicates thc evolution of uterine response to 4 mU /inin. The other lines correslwntl to the other infusion rates. Caldeyro-Barcia & Poseiro : Contractility of the Uterus 819

The spontaneous uterine activity (striped area) follows the same general course as indicated in FIGURE 1, the only difference being that, in term pregnancies, and as the subjects considered in FIGURE 3 were not in labor, the spontaneous activity remains well below the labor range of values, not surpass- ing 60 Mont. U. The uterine response to low infusion rates (1 and 2 mU./min.) increases slowly between the twentieth and thirtieth weeks; it increases rapidly after the thirtieth week, and again continues to increase very slowly during the last weeks of pregnancy. The response to high infusion rates (8 and 16 mU./min.) increases sharply between the twentieth and thirtieth weeks, and then increases very little until term. The response to medium infusion rates (4 mU./min.) follows an evolution halfway between the other two and is considered as the most representative for illustrating the changes of uterine response to oxytocin infusion during pregnancy. Uterine response to oxytocin infusion increases with the age of pregnancy, reaching almost its maximum values at the thirty-sixth week, and showing little changes between the thirty-sixth and the fortieth weeks and during labor. Theobald et uZ.,’~ Aburel et aZ.,16 and Smyth” state that “uterine irri- tability” increases greatly during the days preceding labor, a concept currently accepted among obstetricians and physiologists. However, these authors fail to fulfill one or more of the following requirements : (1) accurate recording of uterine contractions; (2) quantitative evaluation of the spontaneous uterine activity; and (3) administration of oxytocin by continuous intravenous infusion. In prolonged pregnancies (that is, after the fortieth week) the spontaneous uterine activity and the response to low infusion rates are similar to those recorded at the fortieth week; high infusion rates produce uterine responses smaller than those obtained at the fortieth week. At each one of the different stages of pregnancy considered in this paper, the uterine activity produced by very high infusion rates (32 mU./min.) is very close to the maximum activity that can be performed by the uterus. Already at the twentieth week the infusion of 32 mU./min. produces a strong activity (comparable to that of advanced labor) ; the maximum uterine response increases until some time after the thirtieth week, and then decreases slightly during the last week? of pregnancy. UiJerences Between the Rabbd and the Woman in the Uterine Response to Oxytocin Throughout Pregnancy In the rabbit (according to Schofield18), from the second to the twenty- ninth days of pregnancy, the uterus does not respond at all to oxytocin (FIGURE 4), even if administered at very large doses (I.V. injection of 5,000 mu.). In the last 2 or 3 days of pregnancy the uterus reacquires its reactivity to oxytocin, the average threshold dose being 24 mu. of oxytocin. Thus, a very great increase occurs in the uterine response to oxytocin during the stages of pregnancy just preceding labor. S20 Annals New Pork Academy of Scicnccs

~‘IGCRE4. Differences between rabbit and woman in the evolution of uterine response lo 0x1 tocin throughout pregnancy (highly schematic).

In contrast, the pregnant human uterus always responds to oxytocin;* the important increase of that response occurs before the thirty-sixth week. No significant changes are observed during the last 4 weeks of pregnancy or during labor.

TtIE ~OSR-EFFECTRELATrONsIrrP Ticfluerice oj” the Gestafionul Age on /he Dose-Elect Curves FIGURE5 shows, for the same three records of FIGURE 2, the uterine activity plotted against the infusion rate of oxytocin (dose-effect curves). Each curvc starts (on the ordinate axis) from the value of the spontaneous uterine activity (black circles), which increases with the gest.ationa1 age. The influence of gestational age can be appreciated easily. At the twentieth week the dose-effect curve is very flat, indicating the small uterine response to low and medium infusion rates; the curvc rises when high infusion rates are reached. At the thirtieth week the curvc is much steeper, showing the increase in uterine response to low infusion rates. The increase in slope of the curve is still more evident at the fortieth week.

Shape oj the Dose-Eject Curite Every dose-effect curve rises asymptotically to a maximum value of uterine activity, which ranges between 2.50 and 350 Mont. U. The curves corresponding to the twentieth and thirtieth weeks are S shaped, as should be expected for a curve relating the concentration of a drug and its effects.? * Our earliest studies have been performed at the sevcntecnth wcck of pregnancy, 1x11 l\Ioirlg has tested the uterus at the ninth week of pregnancy and fount1 it responsive to ox) tocin. t We assumc that the concentration of exogenous oaytocin in the blood is proportional-~ for :I given experiment- to thc rate of infusion of the drug-. Caldeyro-Barcia & Poseiro : Contractility of the Uterus 821

I OXYTOCIN INFUSION RATE (rn~rnin) SPONrANEWS UTERINE ACTIVITY FIGURE5. Dose-effect curves at the twentieth, thirtieth, and fortieth weeks of normal pregnancy. Each curve corresponds to one of the records shown in FIGURE 2. The spontaneous uterine activity of each record is indicated by black circles. The uterine activities recorded during the different inlusion rates of oxytocin are indicated with the same symbols as in FIGURE 3.

The curve corresponding to term pregnancy also can be considered as S shaped, if we assume that the lower part of the S is placed at the left of the axis of the ordinates (due to the increase of the spontaneous activity and of the slope of the curve). Dose-Effect Mathematical Relationship During Late Pregnancy FIGURE6 shows the mean dose-effect curve of 20 cases studied between the thirty-sixth and the fortieth weeks of normal pregnancy. During these 4 weeks, uterine response to oxytocin is very consistent and shows little varia- tion, as illustrated by the Standard Deviation of the Mean curve of FIGURE 6. The function of this mean curve? is UA4 = UA,,,,,t + AUA,,,,,(l - ePR.lnf) where UA is the uterine activity recorded during the oxytocin infusion; inf is the rate of the infusion; UASpontis the spontaneous uterine activity existing before the infusion is started; AUAmi,xis the maximum increase of uterine activity (over UAsPont)that will be produced when inf increases infinitely; and R measures the reactivity of the pregnant woman to oxytocin infusion and depends upon (1) the sensitiveness of the myometrium to oxytocin, and (2) the “clearance” of oxytocin. These two factors will be discussed below.

ABNORMALRESPONSE TO OXYTOCIN Response higher thapz normal. In toxemia of pregnancy,’2 the spontaneous uterine contractility and the response to oxytocin infusion are much higher 522 Annals New Yo& Academy of Sciences

012 4 8 16 OXYTOCIN INFUSION RATE (mvmin.) @

FIGURE6. Mean dose-effect curvc at late normal pregnancy (between the thirty-sixth and fortieth weeks). Average of 20 cascs. Thc striped area indicates f2Standard Deviations.

than normal, as illustrated in FIGURE 7 by the dose-effect curve corresponding to a case of eclampsia. These findings confirm previous reports.2't2' Responses lower than .rzormal. These have been found in polyhydramnios,2s myxedema,2' and elderly prirnigravida'* (FIGURE Ol, and in 2 cascs that were clinically considered as normal pregnancies. Tn 7 cases with fetal death,1Y the response was normal in 6 cases and lower than normal in 1 case.

PC)STINFUSIOK DISAPPEARANCE OF OXYTOCIh' EFFECTS

After the interruption of oxytocin infusion (EI~~UKE8), uterine activity diminishes progressively. If labor has not si arted, uterine activity returns to the original preinfusion level of spontaneous activity. If labor has already started, uterine activity decreases after interrupting the infusion, but remains stabilized at a higher level of spontaneous activity;'2 this level increases as labor advances. In mid-pregnancy the decline in uterine activity is very rapid, being com- pleted in 1.5 to 2.5 min. The decline becomes progressively slower until the thirty-sixth week, when approximately 1 hour is required in order to return io the spontaneous activity level. No changes are observed in the rate of decline between the thirty-sixth and fortieth weeks.26 - ECLAMPSIA

SPONTANEOUS UTERINE ACTIVITY

FIGURE7. Dose-effect curves in abnormal cases, where the uterine response to oxytocin infusion and the spontaneous activity are much higher-as in eclampsia-or significantly lower-as in a case of an elderly primigravida-than in normal term pregnancies.

-1 -1 20th week of Pregnancy

5 o 6 10 is 20 25 30 rninules

INFUSION RATE 8 mwmin. 40th week OF Pregnancy s24 :\nnals New York Academy of Sciences

These rerults are in disagreement with those of I?tge,l1 who claims that in late pregnancies the uterine effects of oxytocin disippear 3 min. after the infusion is dircontinued. DIscussIoN The Incrense of Uteritae Response to Oxytyfncin Infusion Occurring as Pregnancy Advances Two mechanisms can explain this increase (FIGURE 9) : (1) A ugmenfation qf the sensitiveness of the myometrium. The response of the uterus to a given concentration uf uxytocjn in the internal en\‘7irotiment increases throughout pregnancy.zb (2) Reducfioiz of the fotal ability of the body to iftactinat? arzd excrete oxytorin (“clearance” of o.rytocin). The lower the clearance, the greater the hlood level of oxytocin (and consequently the uterine reqponse) produced by a given infusion rate of oxytocin. The rate of decline of uterine activity (after the interruption of the oxytocin infusion) can be used as an indirect measure of the clearance of oxytocin in the body (FIGURE 8). If this assumption is correct, the clearance of oxytocin would be high in the twentieth week and would diminish until the thirty- sixth week, then remaining unchanged (FIGURE 10).I5 These changes of the clearance could be partially responsible for the opposite simultaneous changes occurring in the uterine response to oxytocin infusion (FIGUKIS 3).

Representing (Inacttvation

FICXJRE9. Hydraulic rnoclel illustrating trio lactors conditioning the response of the uterus io the infusion of ovytocin (highlv schematic). ’I’hese factors are. (1) thc scnsitivcness of thc myometrium (llarey tambour) tb the oxytocin of thc hlood (hydrostatic pressure of water in the container); (2) the “clearance” of oxytocin, that is, the total ability of the pregnant woman to inactivate and excrete oxytocin, indicated by the area of the hole in the bottom 01 the container. Caldeyro-Barcia & Poseiro : Contractility of the Uterus 825

100%

WEEKS OF PREGNANCY FIGURE10. Comparison between the evolution throughout pregnancy of the ilt vivo “clearance” of oxytocin and of the plasma oxytocinase (highly schematic). The values found at term pregnancy have been adopted as 100 per cent.

The Mechanisms of Ihe Clewance of Oxytocin Throughout Pregnancy In thewoman, the ability of plasma to inactivateoxytocin*increases markedly as pregnancy advance^,^^-^^ reaching almost maximum values at the thirty- sixth week32and showing little change until the end of pregnancy (FIGURE lo).? This increase is due to an enzyme, the oxyt~cinase,~~which seems to be produced by the Oxytocinase appears in the blood only during pregnancy, and only in those species with placenta hemochorialis (human and monkey). During the last 4 weeks of pregnancy the blood plasma incubated at 38” C. with oxytocin requires 7 to 9 min. to inactivate SO per cent of the added oxy- to~in.~~These in zdro results are in close agreement with those obtained in vioo by Sica-Blanco and Gonz&leL-Paniua,26who have estimated that 9 min. are required for the disappearance of 50 per cent of the oxytocin existing in * In the inactivation by plasma oaytocinase, no significant difference has been observedx between synthetic oxytocin (Syntocinon) and natural oxytocin (Pitocin), as has been claimed by Semni.31 t Dicker and TylerW are the only authors who claim that the ability of the plasma to inactivate oxytocin decreases as labor approaches and is abolished in the plasma obtained during normal labor. 826 Annals New York Academy of Sciences the body of the pregnant woman at the moment of the interruption of the oxytocin infusion.* It follows that, during the last 4 weeks of pregnancy, plasma oxytocinase may account (as the only acting mechanism) for the in oioo clearance of oxytocin (FIGURE10). In mid-pregnancy, on the contrary, plasma oxytocinase, which is much lower than during late cannot explain by itself the high in ziizo clearance of oxytocin existing at that time.25 This discordance suggests that other mechanisms of clearance (inactivation or excretion) of oxytocin must be active in mid-pregnancy (FIGURE10). A great diminution of these unknown mechanisms (such as, renal excretion and hepatic inactivation) must be postulated in order to explain the lowering of the ia view clearance of oxytocin that occurs as pregnancy advances,25 in spite of the simultaneous increase of plasma oxytocinase (FIGUKE It should be emphasized that the iiz vion estimation of oxytocin clearancez5 and the in vitro determination of the plasma oxyto~inase~~have been carried on in the same group of pregnant women.

Estimation of the Rate of Secretiota of Oxytocin that Would be Necessary for Producing Labor Assuming that, in the pregnant woman, endogenous oxytocin is the principal factor that increases uterine activity during prelabor and labor (see below), there are two possible mechanisms that could explain this action (1) an increase of the uterine response to a constant secretion rate of oxytocin and (2) an augmentation of the rate of secretion of oxytocin. We have seen (FIGURE3) that in the pregnant woman there are no important changes in the uterine response to oxytocin infusion, neither between the thirty-sixth and the fortieth weeks of pregnancy nor during labor. Therefore it is necessary to postulate an augmentation of the rate of secretion of oxytocin in order to explain the great increase of uterine activity that occurs during spontaneous prelabor and labor. At the beginning of labor (uterine xtivity : 100 Llont. U.) the secretion rate? should be in the neighborhood of 2 mTJ./min. (FIGURE 11); and it should increase up to 8 mU./’min. in order to raise uterine activity to the over-200 Mont. U. usually recorded during advanced labor. The progrewive distension of the uterine cervix and of the vagina that ocwr as labor advances could be one of the causes that reflexly increase the secretion of oxytocin during labor.37 After delivery of the fetus, as the distension of the birth canal ceases, the oxytocin secretion and the uterine activity diminish very rapidly (FIGURE1). Is Oxyfocin the Hormone that Produces Sponlaneous Labor in the Womaiio A complete discussion of the subject is not possible here; for this purpose, the reader is referred to Cross,38 Harris,3‘’ Fit~patrick,~~and Theobald ef a1 l5

* Thcse estimates are in disagreement with those of Page, who states that only 502’ or 90” sec are needed for the inactivation in vivo of 50 per cent of the oxytocin by the action of “pitocindse” (ox) tocinase) t Assuming that the secretion of cndogennus ouytocin ha5 thc samc utcrinc cticcc ts as the infusion of exogcnous oxytoLin made at a similar rate. Caldeyro-Barcia & Poseiro: Contractility of the Uterus 827

I 20 30 Weeks of Pregnancy FIGURE11. Comparison between the recorded values of spontaneous uterine activity during pregnancy, prelahor, and labor (striped area) taken from FIGURE 1 and the estimated uterine responses to several rates of secretion of endogenous oxytocin (highly schematic).

We shall present only some facts taken from our own research in the pregnant woman which speak in favor of the oxytocin hypothesis of labor. (1) All the characteristics (shape, coordination, intensity, frequency, duration, and tonus) of the contractions produced by the infusion of oxytocin on the pregnant human uterus are indistinguishable from those of the contractions recorded in spontaneous labor. (2) The doses of oxytocin necessary to inject per minute per kilogram of body weight, in late pregnancy, in order to raise uterine activity to labor values, are of the same general range as the doses of ADH (the twin sister of oxytocin) required for the inhibition of water diuresi~.~~.41 This fact was first noticed by Theobald el uL9 (3) The infusion of oxytocin, lasting for from 5 to 10 hours, causes a significant increase of plasma oxytocinase.32 The similar increase that occurs spontaneously during pregnancy can be accepted as indirect evidence of an augmented secretion of endogenous oxytocin. * (4) We have recorded significant increases of the contractility of the pregnant human uterus as a consequence of the action of the following agents [which are known to cause the release of oxytocin and antidiuretic hormone

(ADH)] :197 37, 39, 42-44 (a) intravenous injection of hypertonic NaC1, morphinep6 * Samuels,48 speaking about ADH, says that “the rate of destruction of the hormone indicates its importance in relation to immediate adjustments of the environment.” Applying this view to oxytocin, we can consider that the augmentation of the ability of the plasma to inactivate the hormone, which occurs as pregnancy advances, suggests that oxytocin has an important role in parturition. s2s Annals New York .lcademq- of Sciences and pyrogenic agents (with production of chills) ; atid (b) stimulatioll of the nipples or distension of the uterine cervix or vagina. (5) It has been estimated in our laboratory26that, during labor induced by oxytocin infusion, the concentralion of exogenous oxytocin in blood is between 20 and 40 mU. per liter of plasma.* These figures are in good agreement wit.h tliosc presenled by Theobald el u!.!'. l5 ;ind by I;itzpatrick,'" ~vvhicl.1have been obtained by different mcthotls. If the blood concentration of endogenous oxytocin during spontaneous labor were of the same range, it would be difficult to make its determination with the methods available at prese1it.t The surprisingly high concentration of endogenous oxytocin found hy Bisset et nZ.47 in the blood of humans could be due to the anesthetic employed during the determination.

SUMMARE. ,4 quantitative study ol the contractility of the pregnant human uterus is made by the recording of the amniotic fluid pressure. The uterine response to the continuous intravenous infusion of oxytocin increases with the age of pregnancy, reaches almost its maximum values at the thirty-sixth week, and shows no significant changes between the thirty-sixth and fortieth weeks and during labor. In term pregnancies, infusion rates between 2 and 8 mu. of oxytocin per minute are sufficient to raise uterine activity to the lowest and highest values, respectively, recorded during spontaneous normal labor. At the twentieth week, infusion rates 8 times higher are necessary for the same purpose. For each stage of normal pregnancy there is a consistent quantitative relationship between the response of the uterus and the infusion rate of oxyiocin. In toxemia of pregnancy, uterine response is higher than normal. The mechanisms conditioning the ut.erine response to the infusion of oxytocin, and the in viao "clearance" of the injected oxytocin are discussed. The role of endogenous oxytocin in spontaneous normal labor is discussed also, and its hypothetical secretion rate is estimated. References 1. ALVAREZ,H. & K. CALDEYRO~HARCIA.1950. Contractility oi the human uterus recorded hy new methods. Surg. Gynecol. Obstet. 91: 1-13. 2. CAT,I)EYXO-HAR(U,K., S. V. POSE& H. ALVAREZ.1957. Uterine contractility in polyhydramnios and the effects of the withdrawal of the cxccss of amniotic fluid. .1111. J. Obsiet. Gynecol. 7: 1238-1254. 3. CALDEYRO-BARCIA,R., Y. SICA-BLANCO,J. J. POSEIRO,V. GONZALEZ-PANIZZA,C. MEN- DEZ-BAUER, c. E'IELITZ, H. ALVAREZ, s. v. POSE & c'. H. HENDRICKS.1957. .\ quantitative study of the action of synthetic oxytocin 011 the pregnant human uterus. J. Pharmacol. Rxpll. 'Therap. 121: 18-31,

* These estimations were based on the assumption that all the oxytocin was contained in the intravascular compartment; if oxytocin diffuses to the interstitial fluid, its concentration should he much lower. Heller4Ghas shown that synthetic oxytocin binds with plasma pro- teins. 7 The same conclusion has been reached by Heller16 in relation to the concentration of entlogenou~AI)H in peripheral hlood of man and rat. Caldeyro-Barcia & Poseiro: Contractility of the Uterus 829

4. CALDEYRO-BARCIA,I<. & H. f1LVAKE:Z. 1952. ..2btiorrnal uterine actixi in labor. J. Obstet. Gynaecol. Brit. Empire. 69: 646-656. 5. ALVAREZ,H. & K. CALDEYRO-BARCIA.1954. The normal and ahnormal contractilc waves of the uterus during labor. Gynaecologia. 138: 190-212. 6. ALVAREZ,H., R. CALDB~RO-BARCIA,A. GUEVARA, S. D'ALBENAS& G. Ruocco. 19.54. Ergonovine and the third stage oi labor. Obstet. & Gynecol. 4: 105-116. 7. DU V~GNEAUD,V., C. RESSLER,J. M. SWAK.C. W. ROBERTS& P. KATSOYANNIS.1954. The synthesis of oxytocin. J. Am. Chem. SOC.76: 3115-3121. 8. BOISSONAS,R. A,, S. T. GUTTYANN,P. A. J.AQI~ENOCJLI& J. P. WALLER. 19.56. Synthesis and biological activity of a ncw potcnt analogue of oxytocin. Nature. 178: 260-271. 9. THEOBALD,G. W., A. GRAHAM,J. CAMPBELL,P. D. GAUGE& W. J. DKISCOLL.1948. The use of pcst-pituitary cstract in physiological amounts in obstetrics. Brit. Med. J. 2: 123--134. 10. HELLMAN,L. M. 1949. Factors influencing successful posterior pituitary treatment ol functional uterine dystocia with particular consideration of intravenous administration. Am. J. Cbstet. Gynecol. 67: 3a-372. 11. PAGE, E. W. 1954. The usefulness ol intravenous Pitocin infusions in obstetrics. Western J. Surg. Ohstet. Gynecol. 62: 125-135. 12. CALDEYRO-BARCIA,R., H. ALVAREZ, J. J. POSEIRO,C. H. HENDRICRS,Y. SK.4-BLANC0, S. V. POSE,L. 4. CIBILS,M. A. CARBALLO,V. H. GONZALEZ-PANIZZA,C. FIELIIZ, C. MENDEZ-BAUER& E. A. DE TELIAS.1957. Induction of labor with synthetic oxytocin. Proc. 2nd Uruguayan Congr. Obstet. Gynecol. Montevideo. 1: 6-88. 13. C'ALDEYRO-B4RCIA, R. 1957. Oxytocin and pregnant human uterus. Proc. 4th Pan-American Conpr. Endocrinol. Rucnos Aircs. 9-21. 14. HELLMAN,L. M., J. S. HARRIS& S. R. M. REYNOLDS.19.50. Intravenous pituitary extract in labor with data on patterns of uterine contractility. Am. J. Obstet. Gynecol. 69: 4148. 15. THEOBALD,G. W.,H. A. KELSEY& J. M. B. MUIRHEAD. 1956. The Pitocin drip. J. Obstet. Gynaecol. Brit. Empire. 63: 64-662. 16. ABUREL,E., V. PETRESCU& E. RADULESCU.1957. hlisurazidne tlell'escilabiliti uterina nella donna durlnte la gravidanza, il travhglio ed il post-partum. Un nubvo mstodo d'investigazihe clinica. Minerva med. 48: 1365-1369. 17. SMYTH,C. N. 1958. Uterine irritahility. The conce t and its clinical applications exemplified by the oxytocin-sensitivity text. Lancet. f: 237-239. 18. SCHOFIELI),B. M. 19.57. The hormonal control of myometrial function during pregnancy. J. Physiol. 138: 1-10. 19. MOIR, C. 1944. The effect of postcrior lobc pituitary gland fractions on the intact human uterus. J. Obstet. Gynaecol. Brit. Empire. 61: 181-197. 20. BRKJNS,P. D., E. S. TAYLOR,R. M. ANKER& V. E. DROSE. 1957. Uterine contractility, circulation and urinary steroids in premature delivery. Am. J. Obstet. Gynecol. 73: 5 79-588. 21. WOODBURY,R. A., K. P. AHLQUIST,B. ABREU,R. TORPIN& W. G. WATSON. 1946. The inactivation of Pitocin and Pitressin by human pregnancy blood. J. Pharmacol. Exptl. Therapy. 86: 359-365. 22. ALVAREZ,H. & R. CALDEYRO-BARCIA.1954. Physiopathology of uterine contractility and its clinical applications. Proc. 2nd Latin Am. Congr. Obstet. Gynecol. SHo Paulo. Maternidade e infancia. 18: 11-132. 23. POSE,S. V. 1957. Induction of labor in polyhydramnios. Proc. 2nd Uruguayan Congr. Obstet. & Gynecol. 2: In press. 24. ALVAREZ,H., R. CALDEYRO-BARCIA,J. XI. CERVINO,J. C. MLISSIO-FOURNIER.1957. Influence of thyroid treatment on thc responsc to oxytocin of the pregnant human uterus in a case of myxedema. Proc. 4th Panamcrican Congr. Endocrinol. Buenos Aires. (Abstr.) 191. 25. SICA-BLANCO,1'. & v. &NZALEZ-P.ANIZ%A. 1957. Diminution of utcrinc activity after interruption 01 oxytocin infusion in pregnant women. Proc. 2nd Uruguayan Congr. Obstet. Gynecol. 2: In press. 26. GONZALEZ-PANIZZA,V. & Y. SICA-HLAXO. 19.57. Estimation of oxytocin blood level during labor induced with oxytocin infusion. Proc. 2nd Uruguayan Congr. Obstet. Gvnecol. 2: Tn nress.. ~~ ~~~ 27. PAGE,E. W. 1946_The value of plasma pitocinase determinations in obstetrics. Am. J. Obstet. Gynecol. 62: 1014-1022. 28. CRoxA'rro, H., K. CROXATTC)& &I.REYES. 1948. The effect of hypertension on the inactivation of osytocin by the serum of pregnant women. Science. 108: 658. 830 Annals New York Academy of Sciences

29. KANAZAWA,7‘. 1954. Supplementary studics on hlood pitociuase. J. Jal~an.0l)stet. Gynecol. SOC.1: 42-72. 30. SEMM, K. 1955. Die klinische Bedeutung dcr O?iytocinasehesti~iirnur~g.Kiin.

Wochschr. 33(441:\--,- 81 7418 31. SEMM,K. 1957. Uer Abbau voii synthetischem Oxytocin. Naturwisscnsch. 4411.5) : 424428. 32. CARBALLO,1LI. A. & C. MEKDEZ-BAUER.1957. Inactivation of oxytocin by the plasma of prcgnant women. Proc. 2nd Uruguayan Congr. Obstet. Gynecol. 2: In press. 33. DICKER,S. E. & C. TYLER. 1955. Inactivation of oxytocin and vasopressin by blood plasma of pregnant women. J. Obstet. Gynaecol. Brit. Empire. 63: 690-694. 34. WEKLE., E. & K. SEMX. 1955. Cber die Oxytocinase ries Schwang~ren1,lutes. Arch. Gynakol. 187: 449453. 35. IIAWKER, R. W. 1056. Inactivation of antidiuretic hormone and oxytocin tlurin,rr pregnancy. Quart. J. Exptl. Physiol. 41: 301-308. 36. CARRALLO,M. A. & C. MENDEZ-BATTER.1957. The placental origin of osytocinase. Proc. 2nd Uruguayan Congr. Obstet. Gynecol. 2: In press. 37. FERGUSON,J. K. W. 1941. 4 study of thc motility of the intact uterus at term. Surg. Gynecol. Ohstet. 73: 359-366. 38. CROSS,B. A. 1955 The posterior pituitary gland in relation to reproduction and lactation. Brit. Med. Bull. 11: 151-155. 39. HARRIS, G. W. 1935. The Neural Control of the Pituitary Gland. Arnold. London, England. 40. FITZPATKICL,R. J. 1054. On oxytocin and uterine function. In ‘The Neuroliypohysis : 203-220. Rutterworth. London, England. 41. DICKER.S. F,. 1954. The fate of the antidiuretic activity of I’itrcssin in rats. J. Physiol. 124: 464475. 42. ,$BRAHAMS. V. C. & M. PICKFORD.19.54. Simultaneous ohscrvations on thc ratc of urine flow and spontaneous utcrinc movements in the dog, and their relationship to posterior lohc activity. J. Physiol. 126: 329-346. 43. Bouo, R. C. DE. 1944. The antidiuretic action of morphine and its mechanism. J. Pharmacol. Exptl. Therap. 82: 74;82. 44. LORAND,S. & J. ASBOT. 1952. Uber die durch Reizung der Brustwarze angeregtcn reflektorischen Uteruskontraktionen. Zentr. Gyniikol. 74: 345-357. 45. CALDEYRO-BARCIA,R., H. .~LVAREZ & J. J. POSEIRO. 1955. iZction of morphine on the contractility of the human uterus. Arch. intern. pharmacodynamie. 101: 171-188. 46. HELLER,H. 1957. The state and concentration of the neurohypophysial hormones in blood. Ciba Foundation Colloquia on Endocrinology. Hormones in Blood. 11: 3-19. Little, Brown. Boston, Mass. 47. BISSET,G. W., J. LEE & A. F. HROMWICH. 1056. Oxytocin and antidiurctic activity in blood from the internal jugular vein in man. Lancet. 2: 1129-1132. 18. SAMUELS,L. T. 1957. Ciba Foundation Colloquia on Endocrinology. Hormones in Blood. 11: 17. Little, Brown. Boston, Mass.