Effect of progesterone on the oxytocic action of estradiol-17β

Effect of progesterone on the oxytocic action of estradiol-17p ROBERTO

MARTIN

ESTEBAN

PINTO,

MONTUORI,

M.D.

M.D.

ULRICO

LERNER,

HECTOR

BALEIRON,

MARCOS

GLAUBERMAN,

M.D.

HECTOR

NEMIROVSKY,

M

Buenos

Aires,

M.D. M.D.

D

Argentina

Ex P ERI al E NT s carried out with myometrial strips in vitro have shown the blocking effect of progesterone upon the oxytocic action of oxytocin.” On the other hand, experiments on the pregnant human uterus in v,ivo with progestational substances administered by intramyometrial, intra-amniotic, intramuscular, or intravenous injection, led to contradictory results.‘, 4, L 7. ‘. 9, I”, I’. Is. I!’ A blocking effect on the oxytocic action of oxytocin was observed in some cases while in some others the results were negative. In the present paper the results of research on the effect of intravenous progesterone upon the oxytocic action of estradiol17p. upon oxytocin-induced contractions, and on the spontaneous uterine activity are described. Material

and

Transabdominal amniocentesis for recording of the intra-amniotic pressure was performed by techniques already described.l A control tracing of the spontaneous uterine activity was recorded for 45 minutes during an administration of a 5 per cent dextrose solution to which polyvinylpyrrolidone (PVP) 1 the diluent of the hormone employed, was later added. A solution of estradiol- 17/I hemisuccinate (200 mg. diluted in 500 ml. of 5 per cent dextrose solution) was then started by intravenous drip and given at a rate of 400 to 1,200 pg per minute while its effects on the uterine activity were recorded. The solution of estradiol hemisuccinate is clear and transparent and therefore different from the suspension of estradiol microcrystals, which gives a turbid milky solution, used in previous investigations. I32 l4 Estradiol-17/3 hemisuccinate in the amount of 136 mg. is equimolecularly equivalent to 100 mg. estradiol-17/.? microcrystals.* As soon as the changes in the uterine activity as a result of the oxytocic action of estradiol were established, a solution was infused in 4 of the cases, consisting of 100

methods

Four patients, multiparas, either near term or slightly overdue, with a ripe cervix, and a fifth patient with a dead fetus and unripe cervix were selected for induction. A sixth case was a patient already in spontaneous labor.

From The Research Obstetriu, University School of Medicine Hospital.

Department

of

of Buenos Aires,

Ramo.~

Mejia

1084

Volume Number

91 8

Effect

EFFECT OF PROGESTERONE

of progesterone

ON THE

OXYTOCIC

Fig. 1. Case 2. Notice how progesterone hibited the oxytocin effect in this case.

mg. progesterone microcrystals diluted in PVP and incorporated to 5,000 ml. of 5 per cent dextrose solution. This mixture forms a colloidal suspension of milky appearance. The rate of infusion was from 400 to 1,200 pg per minute. In the fifth patient the administration of this solution was first carried out after the estradiol soIution had been stopped. Later the estradiol hemisuccinate and progesterone were given simultaneously. In the sixth case, the patient in labor, the recording of the spontaneous uterine activity, which proved very high, was immediately followed by progesterone intravenously. Case reports Case 1. P. 0. M., aged 24; para 5-O-O-5 with an expected date of confinement of NOV. 21, 1963, was admitted on Dec. 3, 1963. Vaginal examination revealed an effaced cervix 3 cm. dilated. There were no contractions. On December 10 induction with estradiol-17p hemisuccinate was started after a recording of the intraamniotic pressure by transabdominal puncture. Once the oxytocic action of the estradiol was established, this infusion was stopped and progesterone at a rate of 700 to 1,400 pg per minute

on estradiol-17/3

ACTlON

1085

OF ESTRADIOL-I7f

almost completely

in-

was started. The frequency and intensity of the contractions decreased. At that moment the estradiol infusion was restarted together with the progesterone; uterine activity increased and reached its peak when progesterone was stopped. Induction was then continued with oxytocirl (1 u. in 500 ml. of 5 per cent dextrose in water, 2 to 4 mu. per minute and a living infant weighing 3,450 grams was delivered spontaneousiy L 1 hours later. Case 2. N. V. L., aged 26; para 2-O-l-3; with an expected date of confinement of Dec. 8, 1963, was admitted on Dec. 12, 1963. Vaginal examination revealed cervix soft, posterior, uneffaced, and 1 cm. dilated. On December 14 induction was started as described; once we got the oxytocic action of the estradiol-17/3 we decreased that uterine activity with 400 to 800 pg per minute of intravenous progesterone given simultaneously. Induction with oxytocin then followed and a living infant weighing 3,200 grams was delivered spontaneously 14 hours later (Fig. 1). Case 3. L. R. M., aged 24, para 3-O-O-3, with an expected date of confinement of Jan. 1, 1964, was admitted to the ward on Dec. 27, 1963. Vaginal examination showed the cervix to be thick, soft, and 1 cm. dilated. Once the oxytocic action of estradiol-17,G was obtained, we added progesterone at a rate of 1,200 to 1,600 pg per

1086

April 15, I!965 Am. J. Obst. & Gym.

Pinto et al.

minute. Uterine activity decreased. Spontaneous delivery was accomplished 4 hours, 45 minutes, after the induction with oxytocin (Table I). Case 4. R. S. G., aged 24, para 4-O-l -3, with an expected date of confinement of Jan. 29,

1964, was admitted to the ward on Jan. 23, 1964. Vaginal examination revealed an uneffaced cervix in the axis of the pelvis, 1 cm. dilated. On February 1 induction was started and recording was carried out as described. Once we recorded

EFFECT Of PROQSTERONE ON THE OXYTOCICACTIONOFESTRADIOL-17P _T

CONTROL ;*

ESTRADIOI 4OOlq'm

ESTRADIOL rlOOjx,,'m PROGESTERONE

A:

ESTRADIOL 400&,m PROGESTERONE 1200~7n

Fig. 2. Case 4. As in Case 3, the moderating upon may

the oxytocic be observed.

effect

of estradiol-17B,

but

action of progesterone not on the oxytocin,

EFFECTOFPROSESTERONE ON THE SPONTANEOUS UTERINE ACTIVITY CONTROL

47 (PROGESTERO~~E 12oo~i~

4’ 17

PROGESTERONE2OOC;rm

m

Fig. 3. Case 6. The modifications of the concentrations of labor progesterone, can be observed.

in type,

the frequency produced by

and intensity the action of

Effect

Table

of

progesterone

on

estrodiol-17/3

1087

I. Case 3* Minutes Control

Hormones (pg) Estradiol-17/3 Progesterone Uterine

I

-

tonus

40

I

800

-

65

I

75

I

9.5

I

11.5

1,200 1,200

1,200 1,200

1,200 1,600

1,600 -

3

12

7

15

20

10

irreg. 4 30

ef/3 30 45

e/2 40 45

e/8 15 35

Contractions Frequency

Intensity Duration

(min.)

(mm. Hg) (sec.) -’

*Notice the effect in frequency; and, estradiol.

of estradiol-178 next, the action

upon of

contractions, progesterone

that which

reach values of 40 in a dose of 1,600

-

mm. Hg in intensity and fig p er minute completely

e/3 30 20 of 2 per minute blocks that of

tEach.

the oxytocic action of the estradiol we added simultaneously progesterone intravenously at a rate of 800 to 1,400 pg per minute which diminished the frequency and intensity of the contractions. Induction was then followed with oxytocin but this failed and was interrupted; it was restarted 48 hours later, this time ending in spontaneous delivery of a living infant of 2,900 grams (Fig. 2). Case 5. E. 0. B., aged 42, para 9-O-O-7, with an expected date of confinement of April 27, 1964, was admitted to the ward on April 22 with a term pregnancy by date and with a diagnosis of intrauterine fetal death. Vaginal examination revealed an uneffaced cervix which was posterior and 1 cm. dilated. Induction with estradiol-17p and recording of uterine activity was carried out after adding 400 to 800 pg per minute of progesterone. The activity first decreased and later disappeared. Induction was then continued with oxytocin and delivery took place 18 hours later with the expulsion of a dead and macerated fetus (Table II). Case 6. M. P. U., aged 27, para O-0-2-0, with an expected date of confinement of April 10, 1964, was admitted to the ward on April 22 with a term pregnancy in labor. Vaginal examination revealed an effacing cervix, 4 cm. dilated. Painful contractions every 5 minutes lasted 35 seconds. Four hours after admission, a recording of intra-amniotic pressure was taken which showed high uterine activity. Progesterone intravenously was then added simultaneously at a rate of 1,200 to 2,000 pg per minute. Uterine activity was markedly reduced. This infusion was followed by intravenous estradioL17P and artificial rupture of the bag of water. Delivery

of a living infant of 3,600 grams took place 5 hours after the infusion of progesterone was stopped (Fig. 3). Comment In previous papers, Pinto and colleagues I37 14* x5 have demonstrated that an infusion drip of estradiol-17/3, at a steady rate of 400 to 800 pg per minute, producing a level of 4 to 12 pg per 100 C.C. of plasma, has a moderate oxytocic action on the pregnant uterus at term, causing painless or slightly painful contractions and, what is very important, ripening of the cervix. The effect of progesterone (microcrystals), prepared in the same way and administered by continuous intravenous drip, in doses of 400 to 2,000 pg per minute, producing levels of 4 to 40 pg per 100 C.C. of plasma, on the contractions elicited by estradiol-17P is clear. This is evident, from Tables I and II and graphs, in which uterine activity is observed slowly to decrease for 20 to 30 minutes after the addition of progesterone and even to disappear in some cases, only to re-appear later with the interruption of progesterone. Other investigatorsr4 have found that the blocking action of progesterone on the spontaneous activity of a uterus in labor takes longer to be effective and sometimes several hours elapse between the infusion of progesterone and such evidence of a blocking action. and Ejarque6 sustain that Bengtsson

1088

et al

Pinto

Table II.

Case

5” I

Minute\ Control

Hormones (pg) Estradiol-178 Progesterone Uterine tonus Contractions Frequency (min.) Intensity (mm. Hg) Duration (sec.) dose

*Notice how of 800 pg

progesterone minute

per

-

..~_ completely ;ntravenously.

blucks

the

30

90

400

1,2UC

180

/

5

7 to 10

400 400 10 to 15

irreg. 30 so

10 to 1’ 30 30

10 to 15 40 30

oxytocic

action

of

u,stBadiol-lib,

30

210

-I

230

81)O 600 8

1 ,..“00 ml 8

et/l:! 35 30

to

60

minutes

after

infusion

in

a

tEach.

progesterone has a moderating action upon the uterine activity of some mammals but not in the human being. He adds that the placental production of progesterone in a term pregnancy is about 260 to 270 mg. per 24 hours. results that Jung,’ 1 however, obtained showed the blocking action of progesterone both in animals and in human beings. He succeeded, in vitro, in inhibiting the contractile activity in myometrial strips of rats as well as of women. With 0.7 mg. progesterone, he inhibited in 5 minutes the electrical conductivity and through tocographical recording of the human uterus in labor he brought about the diminution of contractile activity. He concluded that in a pregnant human uterus at terrn it might not be possible completely to stop uterine activity with progesterone, but it certainly could be diminished. Fuchs, Fuchs, and Shortlo showed that the concentration of progesterone in the uterine blood ranges from 8 to 97 I-cg per 100 ml. plasma, that is, 10 times as high as in a peripheral vein at the same stage of pregnancy. These workers add that progesterone disappears rapidly from the mother’s blood, which may account for failure in the treatment of threatened abortion, since it would be difficult to reach high concentrations of progesterone in the myometrium. Taubert and Haskins,l? giving progesterone in lower doses than those we employed, did not find variations in the uterine contractions of the patients in labor, as ob-

served clinically with the tocodynamometer. We believe that our results, which show a moderating effect of progesterone upon the oxytocic action of estradiol-17P, are due to the high dosage employed (100 to 200 mg. per hour), an amount which is almost as much as the total produced by a term placenta in 24 hours, and also to the intravenous route of administration. This action may not be evident when the time of starting the infusion is too close to the onset of labor. This does not invalidate the cases in which that action has been observed, as is shown in Case 6. In Cases 3 and 4, where progesterone and oxytocin were used simultaneously, no inhibiting action of progesterone upon the uterine contractions elicited by oxytocin was observed (Figs. 1 through 3). These results support the theory that the onset of labor is closely related to local hormonal factors, where estradiol and progesterone play a decisive role. Summary

1. Six patients with term pregnancies were selected for recording of the action of progesterone upon the oxytocic effect of estradiol-17/3, upon the action of oxytocin and upon spontaneous labor. 2. Progesterone

nous minute

drip may

administered

in doses of 400 diminish

or

by

intrave-

to 2,000

inhibit

activity elicited by estradiol-17/?. 3. In 2 cases, the contractions

the

pg per uterine

produced

Volume 91 Numhcr

8

by oxytocin were not inhibited by progesterone. 4. In a single case where the uterine activity of a patient in spontaneous labor was

REFERENCES

1. 2. 3. 4. 5.

6. 7. 8. 9. 10.

Alvarez, H., and Caldeyro-Barcia, R.: Surg. Gynec. & Obst. 1: 91, 1950. Aitken, E. H., Preed, J. R. K., Eton, B., and Short, R. V.: Lancet 2: 1096, 1958. Barnafi, L., and Croxatto, H.: Acta Physiol. Latinoamericana, XIII: 26, 1963. Bengtsson, L., Diczfalusy, E., and Fuchs, F.: Acta Obst. Ginecol. Stand. 61: Suppl. 1, 1962. “Progesterone and the Bengtsson, L.: In Defence Mechanism of Pregnancy,” Ciba Found. Study Group 9, J. and A. Churchill, Ltd., London 1961. Bengtsson, L. Ph., and Ejarque, P. M.: Acta Obst. et Gynecol. Scandinav. 43: 49, 1964. Brenner, W. E., and Hendricks, Ch.: AM. J. OBST. & GYNEC. 83: 1094, 1962. Csapo, A., Mattos, C. R., and Sousa Filho, M.: AM. J. OBST. & GYNEC. 87: 793, 1963. Fuchs, F., and Stakeman, G.: AM. J. OBST. & GYNEC. 79: 172, 1960. Fuchs, F., Fuchs, A., and Short, R. V.: Acta Obst. Gynec. Scandinav. 42: Suppl. 6, 94, 1963.

Effect

of progesterone

on

estradiol-17/3

1089

recorded, 2,000 jig per minute (40 pg per 100 plasma per minute) of progesterone given intravenously also markedly reduced the activity.

11. 12. 13.

14.

15.

16.

17. 18.

19.

Jung, H.: Arch. f. Gynsk. 198: 145, 1963. Kumar, D., Goodno, S. A., and Barnes, A. C.: Nature (Lond.) 195: 1204, 1962. Pinto, R. M., Votta, R. A., Montuori, E., and Baleiron, H.: AM. J. OBST. & GYNEC. 88: 759, 1964. Pinto, R. M., Votta, R. A., Montuori, E., and Baleiron, H.: Rev. Sot. Obst. Ginec. Bs. As. 42: 225, 1963. Pinto, R. M., and Nemirovsky, H.: Actas IV Congreso Chileno de Obst. y Ginec., Tomo II (a publicarse) . Pinto, R. M., Votta, R. A., Montuori, E., and Baleiron, H.: British Med. J. 5: 934, 1963. Taubert, H., and Haskins, A.: Obst. & Gynecol. 22: 405, 1963. Wood, C., Elstein, M., and Pinkerton, J. H. M.: J. Obst. Gynec. Brit. Commonw. 70: 839, 1963. Zander, J.: Arch. f. Gyniik. 198: 113, 1963. Mansilla Buenos

2610 Aires, Argentina