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Immunologic and biologic activity of oxytocin in midtrimester pregnancy
Immunologic and biologic activity of oxytocin in midtrimester pregnancy A LOIS V ASICKA, M.D., F.A.C.O.G. P. KIJMARESAN, D.V.M., PH.D.
C. LI. M.D.
J.
SCHEFFS, M.D .. F.A.C.O.G.
BrookZ;n, New York
Immunologic and biologic activity of oxytocin (OT) were studied by simultaneous monitoring of plasma OT measured by radioimmunoassay (RIA) and uterine contractility measured by recording of intrauterine pressures during the step-up rate of infusion of synthetic OT. The results in 11 patients with midtrimester pregnancy and step-up increase of OT infusion by 20 mU. showed a positive correlation of the increase of plasma OT and utet·ine contractility only at the plasma OT levels of 20 to 60 p.U. per milliliter and only with hypertonic contractility but no correlation at plasma levels below and above this range. The lack of correlation of "dose and response" either prior to OT infusion or during low or very high rate of infusion suggests that other factors than merely the quantity of plasma OT are involved in determining the degree of uterine response. (AM. j. 0BSTET. GYNECOL. 127: 171, 1977.)
ity of OT, 3 • 4 but resulting 1,2-acyclic OT behaved immunologically as native or synthetic OT. 5 With the use of :radioimmunoassay, 6 plasma OTis measurable more than in 50 per cent of early pregnancies and practically in all of third-trimester pregnancies. The quantity of plasma OT, however, shows considerable variation among individual patients and also among gestational weeks. Moreover, the concentrations of plasma OT during prenatal period frequently reach high levels whereas uterine contractility fails to sho·w proportional increase. The question of OT content and uterine re· sponse has been studied extensively in the past. 7 The results had been frustrated, though, by the lack of an adequate method of measuring OT. Consequently, the up-to-date view of the subject is divided into two groups: (l) some workers believe that the quantity of OTis the primary factor which determines the uterine response and (2) others believe that the uterine sensitivity to oxytocin is the primary factor which determines the degree of uterine contractility. It was felt that the question of uterine response to knmvn plasma OT concentration should now be studied further since RIA is available. In this preliminary report the data are presented concerning plasma OT concentrations and corresponding uterine contractility after step-up OT infusion in midtrimester patients undergoing abortion.
OT is composed of only eight amino acids, it has been shown to possess a potential for biologic and immunologic dissociation just like many other peptide hormones. Significant dissociation of immunologic and biologic activity has been demonstrated in vitro for several analogues of OT and vaso pressin. 1 Two known inactivators of OT have been studied, namely, sodium thioglycollate and plasma oxytocinase. The former cleaves the molecule at S-S bond, 2 and the latter acts on the hemicystinyl-tyrosyl bond forming I ,2-acyclic OT. 3 Incubation with thioglycollate destroyed the biologic activity of OT but left the immunologic activity intact. 4 Incubation with plasma oxytocinase almost destroyed the biologic activALTHOUGH
From thr Department of Obstetrics and Gynecology at the Coney Island Hospital affiliated with the Maimonides Medical Center. State University of New York, School oj Medicine, Doumstate Medu·al Center. Supported by Grants from the National Institutes of Child Health and Human Development, United States Public
Health Seruice, No. HD04 984-03 and The Population Council of New York. Rerrivedfor puhlication October 14, 1975.
Revised March 22, 1976. Accepted April 9, 1976. Reprint requests: Dr. P. Kumaresan, Coney Island
Hospital, Brooklyn, New York 11235. 171
172 Vasicka et al. :\m.
J
January 15. I Y77 Obstet. Gmeml.
01
J:
E E
...::J
0
(D
fh fh
... c. ~
c: ·;:;:
-...
0
N
::J 1'0
-
20
c:
time in
minutes
Fig. I. Uterine contractility curve + C. U. was defined as mm. Hg x minute. The sum of C.l'. under the area of intramerine pressure curve of 5 minutes was used for comparison (see text).
Table I. Oxytocin measurement in plasma J.tL. per milliliter After infusiun stopped (minute.~)
Oxytocin infusion/or 20 minu/1'S (rnU.Imin.) Patimt l. 2. 3. 4.
5. 6
...,
'·
8.
9. 10. II.
Mean
V.L B. B.
c ()
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s. s.
0
P.D.
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R. R. C. G.
0
T.v. P.]. C. M. S. V. P. :\i.
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28 5 0 3 17 20 7
20
25 8 0 18 10
5 !5
5 15 10
20 12
I
40
33 23 28 75 23 15 43 50 18 17 28 32
I
60
88 35 40 120 25 15 120
50 35 15 23 51
j
80
65 50 50 35 110 98 50 70 30 23 55 58
Materials and methods
Patients in this study group were admitted to the hospital the day before the instillation of saline and consent was obtained from each patient for continuous monitoring of intrauterine pressure and obtaining blood samples for RIA measurements of plasma OT. Eleven selected healthy primigravidas at 19 to 21 weeks of pregnancy were monitored continuously for intrauterine pressure changes prior to and during stepup rate of infusion of synthetic OT. The first blood samples for plasma OT were collected from the forearm vein by means of an indwelling needle with a heparin lock after 30 minutes of monitoring the intrauterine pressure. Oxytocin was infused in another antecubital vein, starting with an initial dose of 20 mU. per minute, and increasing the dose level to 40, 60, 80. and 100 mU. per minute for every 20 minutes. Blood samples were collected just before the next dose level was increased. During the postinfusion period. the samples were collected at I, 2, 5. 10, 20, and 30 minute
I
I
100
70 65 65 171
100 45 80 98 88
80
65 120 120 .'i5 50 100 87
120 80 133 45 35 100 84
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100 65 75 60 55 78 78 100
65 65
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88
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20
23
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49
35
12
16
13
65 43
intervals, while monitoring of the uterine contractility was continued. Uterine response to OT infusion was expressed in contractility units (C.U.). The unit was defined as mm. Hg x minute. The sum of C.U. under the area of intrauterine pressure cure of the last 5 minutes of each 20 minute period was used for comparison of biologiL activity of OT (Fig. 1). The radioimmunoassay procedure for human plasma OT without extracting has been described elsewhere. 6 Results
Oxytocin measurement in plasma during ste.p-up rate of oxytocin infusion. The results are shown in Table I and Fig. 2. Prior to OT infusion plasma OT \'>·as measurable in five out of II patients with the mean of 7 ttU. per milliliter (range, 0 to 28 ttl!. per milliliter): six patients showed no radioimmunoassayable OT. At the end of the first 20 minutes of OT infusion at the rate of 20 mU. per minute, all patients except
Oxytocin activity in midtrimester pregnancy
Volume 127 Number 2
173
c:
E
:
e
0
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u 0
,..
0 "'
"0 0 "'E o "' "' "' Q. 0 "'
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20
40
60
80
time in minutes
100
I
4
8
12
16
20
24
28
32
minutes alter oxytocin infusion has been stopped
Fig. 2. Plasma OT during step-up rate of OT infusion and during the 30 minutes after OT was stopped.
one showed measurable OT in their blood with a mean of 12 J.L U. per milliliter (range, 0 to 25 J.L U. per milliliter). At the end of 40 mU. per minute infusion rate of OT, all patients showed measurable plasma OT with a mean of 32 J.LU. per milliliter (range, 15 to 75 J.LU. per milliliter). Gradual increase of plasma OT was observed in subsequent periods with the mean of 51, 58, and 87 J.LV. per milliliter during the end of OT infusion of 60, 80, and 100 mU. per minute, respectively. Considering the average of plasma OT it appears that there has been an increment of plasma OT in each 20 minute period which gradually increased with time and stepped-up OT infusion. Close view on individual patients and individual samples, however, shows that: (I) there is marked individual variation in plasma OT levels and (2) that pulsating pattern of plasma OT prevails (Table I). After OT was stopped, an exponential decrease of OT could be seen within a 20 minute period of OT withdrawal (Fig. 2), although spurts of plasma OT were observed in four patients at the 20 to 30 minute periods (Table I). Plasma OT level and corresponding uterine activity. Fig. 3 shows mean uterine contractility which is expressed as C. U. on the vertical line and plasma OT
levels are expressed in microunits per milliliter and plotted on the horizontal. The curve of the relationship of plasma OT and corresponding uterine activity shows a linear relationship only in the range of 20 to 60 J.LU. per milliliter of plasma OT concentration. The uterine contractility relative to this range of plasma concentration showed a maximum response in all components, that is an increase in tonus, intensity, and frequency of contractions. Uterine contractility under this range of OT was closely similar to mild or moderate tetanicity and grossly dissimilar to physiologic labor; however, distinct relaxation between contractions as first evidence of physiologic labor began to appear during this range of OT concentration. Exceptions were noted in the range of plasma OT level below 20 and above 60 J.LV. per milliliter. Regular uterine contractility was observed with the levels of OT 20 J.LU. per milliliter in plasma, or variable hypertonicity superimposed on previous physiologic contractility was encountered. Within the plasma OT levels above 60 J.L U. per milliliter essentially three types of uterine responses were noted: (I) continuation of physiologic type of contractility with good relaxations, (2) tetanicity superimposed on previous physiologic labor, and (3)
174 Vasicka et al. Am.
0
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· - - • after oxytocin infusion 0
"'
0
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20
40
60
80
plasma oxytoc•n concentration
100
120
,uu 1 ml
Fig. 3. Plasma OT and uterine activity. Note linear correlation of plasma OT and uterine activity after OT was discontinued (lower curve). During OT infusion (upper curve) linear correlation is observed only during 20 to 60 ~-tU. per milliliter, but not with higher or lower OT levels.
desultory contractility-failure of the uterus to produce good contractions (tachyphylaxis). The lower curve in Fig. 3 shows the comparison of uterine contractility and plasma OT concentration after OT infusion of 100 m U. per minute had been stopped, and Fig. 4 shows both these parameters in relation to time. Mean uterine contractility (mm. Hg X min.) and plasma OT levels expressed in microunits per milliliter are plotted on vertical lines and time in minutes on horizontal lines. It could be seen that plasma OT concentration exponentially decreased with OT half-life (t\12) of 71!2 minutes, whereas contra<:tility showed a similar curve but distinctly more flat with half-life contractility of 22 minutes.
Comment It has been common clinical experience that oxytocin causes the uterus to contract and, depending on the dose and duration of infusion, it induces labor at term. At the same time it is difficult to conceive that relatively
January 15, 1977 Obstet. GynN·ol.
J.
high concentrations of OT have been found in the blood of pregnant patients 6 without evidence ol proportional uterine a<:tivitv. Quantitative relationship of plasma OT and uterine response is an important clinical issue which had been studied extensively, e~pe <:ially since the introduction of measurements of intrauterine pressures by Caldeyro-Barcia and assmiarcs 7 abroad and bv Hendricks in this country. Conviming evidence has been produced that the induction of labor with the use of OT has to be done in a controlled manner. As far as the mechanism of labor is concerned, the results of these studies led to a belief that uterine
Oxytocin activity in midtrimester pregnancy
Volume 127 Number 2
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AFTU Ol't7!XIfl/ INFfiSION HAS IIIN t1'fllli*l>
Fig. 4. Plasma OT and uterine contractility decline after the OT infusion was stopped at the end period of the rate of 100 mU. per minute. The curve for plasma OT level is indicated by dotted circles and uterine contractility by plus signs.
ship between plasma OT concentration and uterine response, plus the evidence that immunologically competent OT has been measured, leads us to consider that
individual myometrial sensitivity to OT exists and serves as the determining factor of uterine work, and possibly the labor itself.
REFERENCES I. Glick, S. M., Kumaresan, P., Kagan, A., et a!.: Radioim-
munoassay of oxytocin. Protein and polypeptide hormones, Excerpta Medica International Congress Series 161: 81, 1968. 2. Van Dyke, H. P., Chow, B. F., Greep, R. 0., et a!.: 'T'he isolation of protein from the neurohypophysis of ox pituitary with content of oxytocic, pressor and diuretic inhibiting activity, J. Pharmacal. Exp. Ther. 74: 190, 1942. 3. Ferrier, B. M., Hendrie,]. M., and Branda, L. A.: Plasma oxytocinase: The synthesis and biological properties of the first product of the degradation of oxytocin by this enzyme, Can.]. Biocbem. 52: 60, 1974. 4. Kumaresan, P., Kagan, A., and Glick, S. M.: Oxytocin:
5. 6.
7.
8.
Effects of degradation on radioimmunologic and biologic activity, Science 166: 1160, 1969. Kumaresan, P.: Immunological properties of 1,2-acyclic oxytocin, (Manuscript in Preparation, 1976.) Kumaresan, P .. Anandarangam, P. B., Dianzon, W., et al.: Plasma oxytocin levels during human pregnancy and labor as determined by radioimmunoassay, AM. J. 0BSTET. GYNECOL. 119: 215, 1974. Caldeyro-Barcia, R., Sica-Blanco, Y., Poseiro,]. ]., eta!.: A guantiative study of the action of synthetic oxytocin on the pregnant human uterus, J. Pharmacal. Exp. Ther. 121 (1): 18, 1957. Caldeyro-Barcia. R., and Heller, H., editors: Oxytocin, Oxford, 1961, Pergamon Press, Inc., 137.
C. LI. M.D.
J.
SCHEFFS, M.D .. F.A.C.O.G.
BrookZ;n, New York
Immunologic and biologic activity of oxytocin (OT) were studied by simultaneous monitoring of plasma OT measured by radioimmunoassay (RIA) and uterine contractility measured by recording of intrauterine pressures during the step-up rate of infusion of synthetic OT. The results in 11 patients with midtrimester pregnancy and step-up increase of OT infusion by 20 mU. showed a positive correlation of the increase of plasma OT and utet·ine contractility only at the plasma OT levels of 20 to 60 p.U. per milliliter and only with hypertonic contractility but no correlation at plasma levels below and above this range. The lack of correlation of "dose and response" either prior to OT infusion or during low or very high rate of infusion suggests that other factors than merely the quantity of plasma OT are involved in determining the degree of uterine response. (AM. j. 0BSTET. GYNECOL. 127: 171, 1977.)
ity of OT, 3 • 4 but resulting 1,2-acyclic OT behaved immunologically as native or synthetic OT. 5 With the use of :radioimmunoassay, 6 plasma OTis measurable more than in 50 per cent of early pregnancies and practically in all of third-trimester pregnancies. The quantity of plasma OT, however, shows considerable variation among individual patients and also among gestational weeks. Moreover, the concentrations of plasma OT during prenatal period frequently reach high levels whereas uterine contractility fails to sho·w proportional increase. The question of OT content and uterine re· sponse has been studied extensively in the past. 7 The results had been frustrated, though, by the lack of an adequate method of measuring OT. Consequently, the up-to-date view of the subject is divided into two groups: (l) some workers believe that the quantity of OTis the primary factor which determines the uterine response and (2) others believe that the uterine sensitivity to oxytocin is the primary factor which determines the degree of uterine contractility. It was felt that the question of uterine response to knmvn plasma OT concentration should now be studied further since RIA is available. In this preliminary report the data are presented concerning plasma OT concentrations and corresponding uterine contractility after step-up OT infusion in midtrimester patients undergoing abortion.
OT is composed of only eight amino acids, it has been shown to possess a potential for biologic and immunologic dissociation just like many other peptide hormones. Significant dissociation of immunologic and biologic activity has been demonstrated in vitro for several analogues of OT and vaso pressin. 1 Two known inactivators of OT have been studied, namely, sodium thioglycollate and plasma oxytocinase. The former cleaves the molecule at S-S bond, 2 and the latter acts on the hemicystinyl-tyrosyl bond forming I ,2-acyclic OT. 3 Incubation with thioglycollate destroyed the biologic activity of OT but left the immunologic activity intact. 4 Incubation with plasma oxytocinase almost destroyed the biologic activALTHOUGH
From thr Department of Obstetrics and Gynecology at the Coney Island Hospital affiliated with the Maimonides Medical Center. State University of New York, School oj Medicine, Doumstate Medu·al Center. Supported by Grants from the National Institutes of Child Health and Human Development, United States Public
Health Seruice, No. HD04 984-03 and The Population Council of New York. Rerrivedfor puhlication October 14, 1975.
Revised March 22, 1976. Accepted April 9, 1976. Reprint requests: Dr. P. Kumaresan, Coney Island
Hospital, Brooklyn, New York 11235. 171
172 Vasicka et al. :\m.
J
January 15. I Y77 Obstet. Gmeml.
01
J:
E E
...::J
0
(D
fh fh
... c. ~
c: ·;:;:
-...
0
N
::J 1'0
-
20
c:
time in
minutes
Fig. I. Uterine contractility curve + C. U. was defined as mm. Hg x minute. The sum of C.l'. under the area of intramerine pressure curve of 5 minutes was used for comparison (see text).
Table I. Oxytocin measurement in plasma J.tL. per milliliter After infusiun stopped (minute.~)
Oxytocin infusion/or 20 minu/1'S (rnU.Imin.) Patimt l. 2. 3. 4.
5. 6
...,
'·
8.
9. 10. II.
Mean
V.L B. B.
c ()
()
s. s.
0
P.D.
()
R. R. C. G.
0
T.v. P.]. C. M. S. V. P. :\i.
I
28 5 0 3 17 20 7
20
25 8 0 18 10
5 !5
5 15 10
20 12
I
40
33 23 28 75 23 15 43 50 18 17 28 32
I
60
88 35 40 120 25 15 120
50 35 15 23 51
j
80
65 50 50 35 110 98 50 70 30 23 55 58
Materials and methods
Patients in this study group were admitted to the hospital the day before the instillation of saline and consent was obtained from each patient for continuous monitoring of intrauterine pressure and obtaining blood samples for RIA measurements of plasma OT. Eleven selected healthy primigravidas at 19 to 21 weeks of pregnancy were monitored continuously for intrauterine pressure changes prior to and during stepup rate of infusion of synthetic OT. The first blood samples for plasma OT were collected from the forearm vein by means of an indwelling needle with a heparin lock after 30 minutes of monitoring the intrauterine pressure. Oxytocin was infused in another antecubital vein, starting with an initial dose of 20 mU. per minute, and increasing the dose level to 40, 60, 80. and 100 mU. per minute for every 20 minutes. Blood samples were collected just before the next dose level was increased. During the postinfusion period. the samples were collected at I, 2, 5. 10, 20, and 30 minute
I
I
100
70 65 65 171
100 45 80 98 88
80
65 120 120 .'i5 50 100 87
120 80 133 45 35 100 84
2
I
5
100 65 75 60 55 78 78 100
65 65
30
25
28 70
88
75 28
I
10
35 50 78 50
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8
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1,')
lO
5
]()
20
23
25 35 25 23
23
]5 20
49
35
12
16
13
65 43
intervals, while monitoring of the uterine contractility was continued. Uterine response to OT infusion was expressed in contractility units (C.U.). The unit was defined as mm. Hg x minute. The sum of C.U. under the area of intrauterine pressure cure of the last 5 minutes of each 20 minute period was used for comparison of biologiL activity of OT (Fig. 1). The radioimmunoassay procedure for human plasma OT without extracting has been described elsewhere. 6 Results
Oxytocin measurement in plasma during ste.p-up rate of oxytocin infusion. The results are shown in Table I and Fig. 2. Prior to OT infusion plasma OT \'>·as measurable in five out of II patients with the mean of 7 ttU. per milliliter (range, 0 to 28 ttl!. per milliliter): six patients showed no radioimmunoassayable OT. At the end of the first 20 minutes of OT infusion at the rate of 20 mU. per minute, all patients except
Oxytocin activity in midtrimester pregnancy
Volume 127 Number 2
173
c:
E
:
e
0
"'
u 0
,..
0 "'
"0 0 "'E o "' "' "' Q. 0 "'
'Q
" 2
"'"'
Q,)
E o ~-r--~--~--~--r-~~~---r--~--~--~--T---r-~ 0
20
40
60
80
time in minutes
100
I
4
8
12
16
20
24
28
32
minutes alter oxytocin infusion has been stopped
Fig. 2. Plasma OT during step-up rate of OT infusion and during the 30 minutes after OT was stopped.
one showed measurable OT in their blood with a mean of 12 J.L U. per milliliter (range, 0 to 25 J.L U. per milliliter). At the end of 40 mU. per minute infusion rate of OT, all patients showed measurable plasma OT with a mean of 32 J.LU. per milliliter (range, 15 to 75 J.LU. per milliliter). Gradual increase of plasma OT was observed in subsequent periods with the mean of 51, 58, and 87 J.LV. per milliliter during the end of OT infusion of 60, 80, and 100 mU. per minute, respectively. Considering the average of plasma OT it appears that there has been an increment of plasma OT in each 20 minute period which gradually increased with time and stepped-up OT infusion. Close view on individual patients and individual samples, however, shows that: (I) there is marked individual variation in plasma OT levels and (2) that pulsating pattern of plasma OT prevails (Table I). After OT was stopped, an exponential decrease of OT could be seen within a 20 minute period of OT withdrawal (Fig. 2), although spurts of plasma OT were observed in four patients at the 20 to 30 minute periods (Table I). Plasma OT level and corresponding uterine activity. Fig. 3 shows mean uterine contractility which is expressed as C. U. on the vertical line and plasma OT
levels are expressed in microunits per milliliter and plotted on the horizontal. The curve of the relationship of plasma OT and corresponding uterine activity shows a linear relationship only in the range of 20 to 60 J.LU. per milliliter of plasma OT concentration. The uterine contractility relative to this range of plasma concentration showed a maximum response in all components, that is an increase in tonus, intensity, and frequency of contractions. Uterine contractility under this range of OT was closely similar to mild or moderate tetanicity and grossly dissimilar to physiologic labor; however, distinct relaxation between contractions as first evidence of physiologic labor began to appear during this range of OT concentration. Exceptions were noted in the range of plasma OT level below 20 and above 60 J.LV. per milliliter. Regular uterine contractility was observed with the levels of OT 20 J.LU. per milliliter in plasma, or variable hypertonicity superimposed on previous physiologic contractility was encountered. Within the plasma OT levels above 60 J.L U. per milliliter essentially three types of uterine responses were noted: (I) continuation of physiologic type of contractility with good relaxations, (2) tetanicity superimposed on previous physiologic labor, and (3)
174 Vasicka et al. Am.
0
~
0
0
0
0
\!! 0
0
0
!
0
~
0
c:
e "'
:r:
0
0
§
E
E
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0
co 0
o during oxytocin Infusion
::;
:!
;: 0
....
· - - • after oxytocin infusion 0
"'
0
N
0
0
20
40
60
80
plasma oxytoc•n concentration
100
120
,uu 1 ml
Fig. 3. Plasma OT and uterine activity. Note linear correlation of plasma OT and uterine activity after OT was discontinued (lower curve). During OT infusion (upper curve) linear correlation is observed only during 20 to 60 ~-tU. per milliliter, but not with higher or lower OT levels.
desultory contractility-failure of the uterus to produce good contractions (tachyphylaxis). The lower curve in Fig. 3 shows the comparison of uterine contractility and plasma OT concentration after OT infusion of 100 m U. per minute had been stopped, and Fig. 4 shows both these parameters in relation to time. Mean uterine contractility (mm. Hg X min.) and plasma OT levels expressed in microunits per milliliter are plotted on vertical lines and time in minutes on horizontal lines. It could be seen that plasma OT concentration exponentially decreased with OT half-life (t\12) of 71!2 minutes, whereas contra<:tility showed a similar curve but distinctly more flat with half-life contractility of 22 minutes.
Comment It has been common clinical experience that oxytocin causes the uterus to contract and, depending on the dose and duration of infusion, it induces labor at term. At the same time it is difficult to conceive that relatively
January 15, 1977 Obstet. GynN·ol.
J.
high concentrations of OT have been found in the blood of pregnant patients 6 without evidence ol proportional uterine a<:tivitv. Quantitative relationship of plasma OT and uterine response is an important clinical issue which had been studied extensively, e~pe <:ially since the introduction of measurements of intrauterine pressures by Caldeyro-Barcia and assmiarcs 7 abroad and bv Hendricks in this country. Conviming evidence has been produced that the induction of labor with the use of OT has to be done in a controlled manner. As far as the mechanism of labor is concerned, the results of these studies led to a belief that uterine
Oxytocin activity in midtrimester pregnancy
Volume 127 Number 2
i " I)
I ' ~
,. ~
l
l ~
0
~
.:.~
~
~
i
v
a
175
'
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..
,. Ttl'flf II¥ Hfl'lf/riS
...
...
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AFTU Ol't7!XIfl/ INFfiSION HAS IIIN t1'fllli*l>
Fig. 4. Plasma OT and uterine contractility decline after the OT infusion was stopped at the end period of the rate of 100 mU. per minute. The curve for plasma OT level is indicated by dotted circles and uterine contractility by plus signs.
ship between plasma OT concentration and uterine response, plus the evidence that immunologically competent OT has been measured, leads us to consider that
individual myometrial sensitivity to OT exists and serves as the determining factor of uterine work, and possibly the labor itself.
REFERENCES I. Glick, S. M., Kumaresan, P., Kagan, A., et a!.: Radioim-
munoassay of oxytocin. Protein and polypeptide hormones, Excerpta Medica International Congress Series 161: 81, 1968. 2. Van Dyke, H. P., Chow, B. F., Greep, R. 0., et a!.: 'T'he isolation of protein from the neurohypophysis of ox pituitary with content of oxytocic, pressor and diuretic inhibiting activity, J. Pharmacal. Exp. Ther. 74: 190, 1942. 3. Ferrier, B. M., Hendrie,]. M., and Branda, L. A.: Plasma oxytocinase: The synthesis and biological properties of the first product of the degradation of oxytocin by this enzyme, Can.]. Biocbem. 52: 60, 1974. 4. Kumaresan, P., Kagan, A., and Glick, S. M.: Oxytocin:
5. 6.
7.
8.
Effects of degradation on radioimmunologic and biologic activity, Science 166: 1160, 1969. Kumaresan, P.: Immunological properties of 1,2-acyclic oxytocin, (Manuscript in Preparation, 1976.) Kumaresan, P .. Anandarangam, P. B., Dianzon, W., et al.: Plasma oxytocin levels during human pregnancy and labor as determined by radioimmunoassay, AM. J. 0BSTET. GYNECOL. 119: 215, 1974. Caldeyro-Barcia, R., Sica-Blanco, Y., Poseiro,]. ]., eta!.: A guantiative study of the action of synthetic oxytocin on the pregnant human uterus, J. Pharmacal. Exp. Ther. 121 (1): 18, 1957. Caldeyro-Barcia. R., and Heller, H., editors: Oxytocin, Oxford, 1961, Pergamon Press, Inc., 137.