Response of peripheral plasma progesterone concentration to intra-amniotic hypertonic saline

Response of peripheral plasma progesterone concentration ROBERT

H.

CLIFFORD

Iowa

City,

OSBORN, P.

MICHAEL

to intra-amniotic

E.

hypertonic saline

M.D.*

GOPLERUD, YANNONE,

M.D. M.D.

Iowa

The recent literature contains conflicting results on the peripheral plasma progesterone concentration in abortions induced by intra-amniotic hypertonic saline. In this study peripheral plasma progesterone levels were determined in 15 patients undergoing therapeutic abortion. Plasma samples were taken before and for variable periods of time after the intra-amniotic instillation of 20 per cent sodium chloride. The majority of patients demonstrated a transient drop in concentration with subsequent return to control levels. A minority showed a transient rise with subsequent return to the @reinduction values. No significant diflerence from the control sample was noted in patients followed through labor. Previous studies are reviewed and the relationship between progesterone and the onset and progress of labor discussed.

T H E H Y P 0 T H E s I S that progesterone exerts a blocking effect upon myometrial activity has stimulated considerable interest and investigation. Progesterone measurements have been carried out to evaluate the “blockade” theory when intra-amniotic saline or glucose was used to terminate pregnancy. Presumably, if progesterone concentration falls, the “block” would be removed and labor and delivery effected. Previous studies of plasma progesterone after intraamniotic hypertonic solutions contain conflicting results. A steady rise in concentration has been noted by some’ while others have found a steady decline.*> 3 Normal values with transient small variations have also been recorded.‘m6

From the Department Gynecology, University of Medicine.

The present study was undertaken to observe the progesterone levels in peripheral blood before and after hypertonic saline was instilled into the intra-amniotic cavity. Materials

and

methods

Fifteen patients ranging in age from 14 to 40 years were therapeutically aborted by means of intra-amniotic saline during 19661967 at the University of Iowa Hospitals. The fetus was alive before the infusion in 8 of the patients and was dead for one to 2 weeks in the remainder. The reasonsfor the abortions were suicide risk, Rh-sensitized fetal deaths, severe maternal cardiac disease, and anencephalic fetus. The duration of the above pregnancies ranged from 13 to 36 weeks. Between 130 and 200 C.C. of 20 per cent sodium chloride was instilled into the amniotic cavity after the removal of 100 to 700 C.C.of fluid. Peripheral blood was drawn in heparinized syringes at one-half hour, one hour, 2 hours, and in some instances every 6 hours until delivery. The pregnancies terminated within 11 to 80 hours. The pIasma was stored at -15’ C. until assayed for

of Obstetrics and of Iowa College

This study was supported by Grant No. AM-01686-10, National Institutes of Health, United States Public Health Service. *This work was done as a Research Trainee under Teaching Grant 5TIHD28, National Institutes of Health, United States Public Health Service.

1073

1074

Osborn,

Goplerud,

and

August 15, 1968 Am. J. Ohs. & Gynec.

Yannone

22

s

16

25 31 37 43 49 ?

C

HOURS POST-SALINE

I 24 38 48

HOURSPOST-SALINE

k 8 5

6

6

$8

4

4

$4

2

2

K

12

C

I

2 6

0 12

HOURS POST-SALINE

C I

2

6 I2 I8

E.S.16 WEEKS

C

HOURSPOST-SALINE

I

2

8 I5 21 39 63 80

HOURS POST-SALINE

,Fig. 1. Five patients whose progesterone levels were determined before saline, before labor, during labor, and in one instance one hour post partum. The darker bars indicate levels before labor, the heavily stippled bars during labor, and the lightly stippled bar one hour post partum. The asterisk indicates those patients in whom a second instillation of saline was required because of failure of the initiation of labor after the first instillation. For L. N. the second instillation was at 69 hours and for E. S. at 48 hours. M. McM. required a cesarean section during labor for placenta previa.

IO GM.30WEEKS 8 20 rS.L.26WEEKS 16

$HO!JAS

POST-SALINE

HOURS POST-SALINE

8

20 rM.H30WEEKS 6

- 12 *20

4

e.4 z D P

i

z 8

I I h,

c 0.5 I

2

c 0.5 I

HOURS

GrCM.16WEEKS

6 rPG.2lWEEKS

2

POST-SALINE 6~1~.

36WEEKS'

56 $4 $2

HOURS POST-SALINE

HOURS POST-SALINE

Fig. 2. Four patients whose progesterone levels were determined before saline and for variable periods before labor began. In one patient, A. H., a one-hour postpartum sample was also determined.

progesterone by a gas-liquid chromatographic method previously described.” Results

The concentration of progesterone in the peripheral plasma in each patient is seen in Figs. 1, 2, and 3. One hour after instillation of the saline, 10 patients had a decrease of 0.2 to 2.6 /*g per cent progesterone, whereas 5 had an increase of between 1.5 and 2.2 pg per cent. At 2 hours 6 had concentra-

P

c 0.5 I

2

HOURS

C 0250.61

c 0.5 2

POST-SALINE

Fig. 3. Six patients whose progesterone levels were determined before and for 2 hours after the instillation of saline, Patient I. W. had an anencephalic fetus.

tions above and 5 had concentrations lower than the control level. Between 2 hours postinstillation and the onset of labor, 6 of 7 patients had progesterone levels above or equal to their control values. One patient (M. McM.) had levels below her control during this period. In the 5 patients studied between the onset of labor and delivery of the fetus there were 3 whose plasma progesterone remained greater than and 2 whose levels were (8 per cent and

Volume Number

101 8

Peripheral

24 per cent) less than the control samples. In 2 cases (A. H. and C. L.) determinations were done one hour post partum. The concentration was found to have fallen 77 and 78 per cent, respectively. In this study the responseswere of two types. In the majority of patients there was an initial drop of peripheral plasma progesterone in the immediate postinstillation period (1 to 2 hours). Between this time and the onset of labor the level rose and remained elevated until delivery. In a minority of patients the progesterone rose within one to 2 hours after the saline was injected and remained over the control values until delivery. Patients L. N. and E. S. required a second saline instillation and progesterone levels remained above the control values until delivery. It was also noted that except for L. N. the plasma concentration of progesterone was within normal limits for the time of gestation* in those whose fetuses were dead. Comment

What mechanism(s) triggers labor? This has been and remains today as one of the intriguing mysteries of obstetrics. Without the use of oxytocins, labor is induced effectively by instilling hypertonic solutions into the amniotic cavity.g Labor ensues within a few hours to several days without further manipuIation in most cases. Why this occurs is also unknown. Removal of the “progesterone blockade” by suppressing the endocrine function of the placenta is the basis of one prominent hypothesis which attempts to explain the onset of labor.2 According to this supposition, high concentrations of progesterone in the myometrium beneath and adjacent to the placenta provide a blocking action to synchronous myometrial activity. Hypertonic solutions introduced into the amniotic sac, by incurring placental damage, reduce the progesterone production and remove the blockade, permitting labor to begin. The increase in uterine volume which follows these

plasma progesterone

after 20%

NaCi 1075

hyperosmotic solutions may also be important.1°‘12 To validate this hypothesis it must be shown that ( 1) placental production of progesterone declines just before labor and (2) the concentration of progesterone in the surrounding myometrium decreases. These two parameters have been studied by indirect means, i.e. ( 1) the effect of exogenous progesterone upon deIaying onset of labor13-‘8. , (2) exogenous progesterone effect upon myometrial activity in vitro’g-93; (3) microscopic evidence of placental hama!++ 24-26; and (4) the measurement of uterine vein and peripheral plasma progesterone in the perilabor period.*+ 27 Conflicting evidence exists in all of the above measurements. The following comments relate to plasma progesterone variations. Csapo” reported in 1961 that Kuukkainen noted a drop of about 50 per cent in the systemic blood and placental progesterone concentrations 24 hours after saline induction. In 1966 he reported that in 8 patients studied there was a drop of 38 per cent between instillation and the onset of clinical progress and a further drop of 6 per cent between onset of abortion and delivery.3 In 1962 Wood and Booth’ determined peripheral plasma progesterone levels on 2 patients before and 3 to 17 hours after intra-amniotic 50 per cent glucose infusion. No significant difference was found. Short and associates5studied peripheral plasma progesterone concentrations before and after saline infusion at midpregnancy and found that in 4 patients the level fell and in the other 4 there was an increase of as much as 122 per cent. In 11 other patients a single sample of plasma taken after saline induction was within the normal range. Studies by the same investigators showed that uterine vein plasma progesterone is 9 to 10 times greater than peripheral plasma concentration.2s They measured midpregnancy uterine vein plasma progesterone after saline induction and compared the values to uterine vein pIasma IeveIs of “normal” patients in midpregnancy and found lower values for the

1076

Osborn,

Goplerud,

and

Yannone Am.

former group. The difference, however, was termed “only marginally significant” (0.0 < p > 0.05). The regression rate of fall was 0.71 ? 0.51 pg per 100 ml. plasma which was not a significant fall. The conclusion was that the introduction of 20 per cent saline has little effect upon production of progesterone by the placenta.5 More recently Kerr and associates1 have reported measuring plasma progesterone content before and after glucose induction of abortion. In each of 4 cases the trend was consistent-a 25 to 50 per cent increase. Lurie, Reid, and Villee4 made similar determinations on 3 patients undergoing saline-induced abortion. In 2 there was a transient fall in peripheral progesterone after which the levels returned to normal values. The third patient failed to show this initial transitory drop. Thirty-six patients are recorded in the literature whose peripheral plasma progesterone has been determined after hypertonic soiutions have been introduced into the amniotic sac. Of these, 24 do not show a significant or sustained drop in progesterone while 12 are reported to demonstrate levels consistent with “true progesterone withdrawal.” Our data support the former findings and show the deviations during the period from induction to delivery. The marked decline after delivery in our cases is similar to the marked drop after the delivery of the placenta in normal patients.8 Originally one to 2 hours had been selected as the duration to follow our patients in the belief that placental damage, if it was to occur, would do so almost instantaneously. Since it has been demonstrated that the half-life of progesterone in the peripheral blood is 3.3 minuteqzQ any changes in pe-

REFERENCES

1.

2. 3. 4. 5.

Kerr, M., Roy, E., Harkness, R., Short, R. V., and Baird, D.: Am J. OBST. & GYNEC. 94: 214, 1966: Csapo, A. I.: Ciba Foundation Study Group No. 9. 1961. DD. 3-31. Wies< W. G:,-Kerenyi, T., and Csapo, A. I.: Obst. & Gynec. 27: 589, 1966. Lurie, A. O., Reid, D., and Villee, C. A.: AM. J. OBST. & GYNEC. 96: 670, 1966. Short, R. V., Wagner, G., Fuchs, A.-R., and

August 15, 1968 J. Obst. & Gynec.

ripheral levels should be evident by one to 2 hours. When no consistent and significant drop was found it was decided to follow the patients over longer periods of time. It is possible that the temporary decrease in progesterone found in most of our patients reflects a myometrial concentration low enough to trigger labor but this seems unlikely in view of the fact that several showed, instead, an increased concentration. The transient decrease may only represent a relative drop in concentration due to the osmotic effect of saline reaching the materna circulation. Gochberg and ReidI and King, Freedman and Stee+ have measured amniotic fluid volume after hypertonic solutions were administered. They found an increase of about 200 C.C. Labor has been induced by adding 250 to 500 C.C. of 5 per cent glucose into the amniotic sac,10 whereas no patients went into labor when 200 to 800 C.C. was removed. Uterine volume increase thus may play a role in the onset of labor. Others have suggested that changes in myometrial ionic concentrations and/or stimulation of release of the exogenous hormones (oxyto~in and ADH) may also be important.30r s1 No matter what the mechanism, there does not appear to be a correlation between a decrease of peripheral plasma progesterone concentration and the onset or progress of labor in saline-induced abortions. This lack of correlation has also been found in normal pregnancy and labor.8 No significant difference in peripheral progesterone response is found in women aborted with hypertonic saline who have fetuses alive in utero or dead for one to 2 weeks.

Fuchs, F.: AM. J. OBST. & GYNEC. 91: 132, 1965. 6. Wood, C., and Booth, R. T.: Brit. M. J. 2: 706, 1962. 7. Yannone, M. E.: AM. J. OBST. & GYNEC. In press. 8. Yannone, M. E., McCurdy, J., and Goldfien, A.: Ara. J. OBST. & GYNEC. In press. 9. Wagner, G., Karker, H., Fuchs, F., and Bengtsson, L.: Danish M. Bull. 9: 137, 1962. 10. Csapo, A. I., Jaffin, H., Kerenyi, T., Lipman,

Vohme Number

101 8

J., 11. 12. 13. 14. 15. 16. 17. 1x. 19. 20.

21.

Peripheral

and Wood, C.: Asr. J, OBST. & GYNEC. 85: 819, 1963. Gochberg, S. H., and Reid, D. E.: Obst. & Gvnec. 27: 648. 1966. Kmg, T. M., Freedman, G., and Steev, C. M.: Bull. Sloane Hosp. Women 10: 14, 1964. Csapo, A. I.: AM. J. OBST. & GYNEC. 85: 359, 1963. Bengtsson, L., and Csapo, A. I.: Ax J. OBST. & GYNEC. 83: 1083, 1962. Bengtsson, L.: Acta obst. et -.gynec. scandinav. 41: i24, 1962. Meller, K. J., Wagner, G., and Fuchs, F.: Ax 1. OBST. & GYNEC. 90: 694. 1964. Kumar, D., Goodno, J., and Barnes, A.: Bull. Johns Hopkins Hosp. 113: 53, 1963. Nilsson, L.: Acta obst. et gynec. scandinav. 42 (suppl. 6): 128, 1963. Pinto, R. M., Lerner, U., and Pontelli, H.: Ax J. OBST. & GYNEC. 98: 547, 1967. Kumar, D., Wagatsuma, T., Sullivan, W., and Barnes, A.: AM. J. OBST. & GYNEC. 90: 1355, 1964: Kumar, D., and Barnes, A.: Bull. Johns Hopkins Hosp. 113: 330, 1963.

plasma

22.

23. 24. 25. 26. 27. 28.

29.

30. 31.

progesterone

after

20%

NaCl

1077

Pinto, R., Montouri, E., Lerner, U., Baleiron, H., Glauberman, M., and Nemirovsky, II.: AM. J. OBST. & GYNEC. 91: 1084, 1965. Marshall, J. M., and Csapo, A. I.: Endocrinology 68: 1026, 1963. Brosset, A.: Acta obst. et gynec. scandinav. 37: 519, 1958. Jaffin, H., Kerenyi, T., and Wood, E. C.: AM. J. OBST. & GYNEC. 84: 602, 1962. Bengtsson, L., and Stormby, N.: Acta ohst. et gynec. scandinav. 41: 115, 1964. Kumar. D.. Ward. E.. and Barnes. ;2.: AM. J. 0~s;. &‘G~~~.c.‘90:‘1360, 1964. Fuchs, F. Fuchs, A.-R., and Short, R. V.: Acta obst. et gynec. scandinav. 42 (Suppl. 6): 94, 1963. Pearlman, W. H.: Progesterone, in Antoniades, H. N., editor: Hormones in Human Plasma, Boston, 1960, Little, Brown & Company. Barnafi, L., and Croxatts, H.: Acta physiol. Lat. 13: 26, 1963. Wiqvist, N. E., and Eriksson, G,: AM. J. OBST. & GYNEC. 88: 75, 1964.