OXYTOCIN AND CONTRACTILITY OF THE PREGNANT HUMAN UTEKUS
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OXYTOCIN AND CONTRACTILITY OF THE PREGNANT
HUMAN UTEKUS*
By Roberto Caldeyro-Barcia and Juan J. Poseiro
Seccicin Fisiologta Obstdtrica, hacultad de Medicina, Montmideo, lirzigiray
RECORDIKG
~ ~ E T H O DFOR
S UTERIKE 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 ex-
pressed 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 S l u d y i q 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 electromanom-
eter. 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 UTERIXECONTRACTILITY DURIKGNORMAL
PKEGNAKCY AKD 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 preg-
nancy, uterine activity (striped area) is lower than 20 Jlont. U. Tracing A
illustrates the characteristics of uterine contractility a t this time of preg-
nancy; 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.
813814 Annals New York Academy of Sciences
]-I
[Advanced First Stage)-
'""I
-
n
I
: -
0
6 hours after
delivery
1 12 hours after
deliverv
w
z
OI
50 24 hours after
t-
delivery
= m
0
'15' ' ' 20' ' ' ' '25' ' ' ' 30' ' ' ' ' 35' ' ' ' I 40 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 a i d
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 i s progressively ripened.
Beginning of labor. Uterine activity increases rapidly. Clinical labor
usually starts when uterine activity reaches values between 80 and 120 l l o n t .
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 asCaldeyro-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).
THEUTERINERESPONSE
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 U Z . , ~ 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. I n 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 be-
ginning normal labor.
Clinical material. These infusions were carried on in 40 pregnant women
from the seventeenth week of pregnancy onward. I n 8 cases the uterine
rcsponse to oxytocin was studied several times, in the same subject, at differ-
ent 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 intens-
ity 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 per-
formed 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. I n 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
- 40 ~ _ _ _
83
W -
0
2
4-
o- ~-
.-$ 2 I"t 1
E Freq 89
UA 9
L-
W 60- -
a 40-
-
-
v1 20- ~-__
e L n
-
c In1 2 25 45
.-3
A.
Frrq 79 43 3 9
.- UA 16 106. 178
E-
40
w
Z E ---02
-0
In1
Freq
5
58
- ~
43
4 6
__ ~~
45
4 9
~
z UA 29 199 221
0
0- mlnlle5
3
LL
z
z 16
0 4 3 cant perm min
0
c-
235 MOnlw Units
32 0 ~~~
In1 mm.Hg
38
Freq 5.7 con1 per 10min.
U A 217. Moniw. Units
- I . . .., .:-u
mmuias
FIGUEJL 2. Uterine responses to ox) tocin infusion obtained a t 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 physio-
logical 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 a t will all types of uterine activity spontaneously performed by the
uterus a t 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 pro-
duce 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.
OF THE GESTATIONAL
INFLUENCE AGE
Uterine Responses to Oxytocin Infusion at the T-wentieth, Thirtieth, and
Fortieth Weeks
FIGURE2 shows tracings of uterine contractility obtained in the same sub-
ject 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,; a t 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 a t term pregnancies.
* The smaii, localized and incoordinated Contractions recorded during pregnancy and dur-
ing 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 a t 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 a t 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
FIGURE 3 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.
35.
30
.-
t
u)
C
3
251
'p
0
c
c
RANGE OF
5 201 UTERINE
*I- ACTIVITY
-> RECORDED
-c IN NORMAL AND
SPONTANEOUSLY
t~ 15C
a BEGINNING
w LABOR
z
IY
w 100
I-
3
50
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 m U /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 preg-
nancies, 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 thir-
tieth 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 a t 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 in-
fusion.
I n prolonged pregnancies (that is, after the fortieth week) the spontaneous
uterine activity and the response to low infusion rates are similar to those re-
corded 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 a t the twentieth week the infusion of 32 mU./min. produces a strong
activity (comparable to that of advanced labor) ; the maximum uterine re-
sponse 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 i n 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 oxyto-
cin, the average threshold dose being 24 m u . of oxytocin. Thus, a very great
increase occurs in the uterine response to oxytocin during the stages of preg-
nancy just preceding labor.S20 Annals New Pork Academy of Scicnccs
~ ‘ I G C R E4. Differences between rabbit and woman in the evolution of uterine response lo
0x1 tocin throughout pregnancy (highly schematic).
I n 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 ~ O S R - E F F ERCE LTA T r O N s I r r P
Ticfluerice oj” the Gestafionul A g e on /he Dose-Elect Curves
5 shows, for the same three records of FIGURE 2, the uterine activity
FIGURE
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. A t the thirtieth week the curvc is much steeper, showing the in-
crease in uterine response to low infusion rates. The increase in slope of the
curve is still more evident a t 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 th e sevcntecnth wcck of pregnancy, 1x11
l\Ioirlg has tested the uterus a t th e ninth week of pregnancy and fount1 it responsive to ox) to-
cin.
t We assumc t h a t 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
SPONrANEWS
UTERINE
OXYTOCIN INFUSION RATE (rn~rnin)
ACTIVITY
FIGURE 5. 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 spon-
taneous 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
FIGURE 6 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 U A 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 activ-
ity (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.
ABNORMAL RESPONSE TO OXYTOCIN
Response higher thapz normal. In toxemia of pregnancy,’2 the spontaneous
uterine contractility and the response to oxytocin infusion are much higher522 Annals New Yo& Academy of Sciences
0 1 2 4 8 16
OXYTOCIN INFUSION RATE (mvmin.) @
FIGURE 6. Mean dose-effect curvc at late normal pregnancy (between the thirty-sixth and
fortieth weeks). Average of 20 cascs. Thc striped area indicates f 2 Standard 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 O F OXYTOCIh' EFFECTS
After the interruption of oxytocin infusion ( E I ~ ~ U K 8),
E uterine activity
diminishes progressively. If labor has not s i arted, uterine activity returns
to the original preinfusion level of spontaneous activity. If labor has al-
ready started, uterine activity decreases after interrupting the infusion, but
remains stabilized at a higher level of spontaneous activity;'2 this level in-
creases 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 i o
the spontaneous activity level. No changes are observed in the rate of de-
cline between the thirty-sixth and fortieth weeks.26- ECLAMPSIA
SPONTANEOUS
UTERINE
ACTIVITY
FIGURE 7. 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- 20th week of Pregnancy
5 o 6 10 is 20 25 30 rninules
INFUSION RATE
8 mwmin. 40th week OF Pregnancys24 :\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 in-
fusion is dircontinued.
DIscussIoN
The Incrense of Uteritae Response to OxytyfncinInfusion 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 in-
fusion 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
i o 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 a t the thirty-
sixth week32and showing little change until the end of pregnancy (FIGURE lo).?
, ~ ~ seems to be produced
This increase is due to an enzyme, the o x y t ~ c i n a s ewhich
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-
~ ~ in zdro results are in close agreement with those obtained in
t o ~ i n . These
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
* I n 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 in-
activate 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 a t the moment of the interruption of the oxy-
tocin infusion.* I t follows that, during the last 4 weeks of pregnancy, plasma
oxytocinase may account (as the only acting mechanism) for the in oioo clear-
ance of oxytocin (FIGURE10).
I n 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,25in
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 o x y t o ~ i n a s ehave
~ ~ 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 aug-
mentation of the rate of secretion of oxytocin.
We have seen (FIGURE3 ) that in the pregnant woman there are no impor-
tant 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 x t i v i t y :
100 Llont. U.) the secretion rate? should be i n 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 secre-
tion 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 dimin-
ish very rapidly (FIGURE1).
I s Oxyfocin the Hormone that Produces Sponlaneous Labor i n the W o m a i i o
A complete discussion of the subject is not possible here; for this purpose,
, ~ ~ Theobald ef a1 l 5
the reader is referred to Cross,38 Harris,3‘’ F i t ~ p a t r i c k and
* 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 t s 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 preg-
nant woman which speak in favor of the oxytocin hypothesis of labor.
(1) All the characteristics (shape, coordination, intensity, frequency, dura-
tion, 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 d i u r e s i ~ .41~ ~This
. fact was first noticed
by Theobald el uL9
(3) The infusion of oxytocin, lasting for from 5 to 10 hours, causes a signifi-
cant 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 preg-
nant 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)] 37, 39, 42-44 (a) intravenous injection of hypertonic NaC1, morphinep6
:197
* Samuels,48 speaking about ADH, says that “the rate of destruction of the hormone indi-
cates 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!.!'. l 5 ;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.47in 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 in-
creases 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.
I n term pregnancies, infusion rates between 2 and 8 m u . 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 rela-
tionship 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 oxyto-
cin, and the in viao "clearance" of the injected oxytocin are discussed. The
role of endogenous oxytocin in spontaneous normal labor i s discussed also,
and its hypothetical secretion rate is estimated.
References
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