Epinephrine and norepinephrine in pregnancy

Epinephrine and norepinephrine in pregnancy A comparative in different

McC. A.

study

of the

adrenal

gland

and

catechol

output

species of animals and man

GOODALL W.

DIDDLE

Galveston,

Texas,

and

Knoxville,

Tennessee

The purpose of these studies was to determine the adrenal medullary changes produced by pregnancy and evaluate urinary output of epinephrine and norepinephrine during pregnancy, labor, and the postpartum period. The adrenals of 18 goats, 12 sheep, 42 cats, and 4.5 rats were obtained at various times during pregnancy and the postpartum period and bioassayed for epinephrine and norepinephrine. Further, daily 24 hr. urinary outputs of epinephrine and norepinephrine were determined on 20 women during pregnancy, labor, and the postpartum period. The results indicate that pregnancy, labor, and the postpartum period produce no significant alterations in the epinephrine and norepinephrine content of the adrenal gland (Tables I to IV). Urinary output of epinephrine and norepinephrine during the course of pregnancy remains within normal limits until the onset of labor. Concomitant with the onset of labor, there is a marked increase in the output of both eginephrine and norepinephrine, especially the latter (Table VI). Further, after delivery, there is also a gradual increase in both hormones, reaching the highest level at the 6 to 18 hr. postpartum period (Tables V and VII). A patient with hydatidiform mole of the Destrusens type showed a normal urinary output of epinephrine and norepinephrine; small amounts of epinephrine and norepinephrine were demonstrated in the mole.

T H E R E S P 0 N S E 0 F Uterhe KlUSCk t0 epinephrine and norepinephrine varies from one species of animal to another. Generally, epinephrine and norepinephrine produce uterine relaxation in the nonpregnant but contraction in the pregnant cat, guinea pig, and rat.‘. ‘2 ‘, *, I1 The difference in uterine between the pregnant and nonresponse pregnant animal has focused attention on the role of epinephrine and norepinephrine in pregnancy and labor. However, the physiologic results obtained from studies on uteri of animals and strips of human uteri have

not proved meaningful since the results cannot be accurately extrapolated in terms of the pregnant and nonpregnant human uterus in situ. Following the intravenous infusion of epinephrine in the pregnant woman, spontaneous activity of the uterus is significantly decreased, both in terms of intensity and frrquency of contraction.7, X3, “‘, If’. Ii Contrariwise, an infusion of norepinephrine produces an increase in contractility and a pattern which differs from that of spontaneous contractions 1. 7. 16. 17 It is obvious that both the adrenal medullary hormone epinephrinc and the syncpathetic neurohormone norepinephrine, ha1.c an effect upon the pregnant utrrns, but the rolr of the sympathoadrenal medullary system in pregnancy and labor is not clear. Therefore, the purpose of these studies was: ( 1) to determine the adrenal medullar)

From the Department of Pharmacology, University of Texas Medical Branch, and the Department of Obstetrics and Gynecology, University of Tennessee. Supported by United States Public Health Service Grant AM 12805. 896

Volume Number

111 7

changes produced by evaluate the changes of epinephrine and pregnancy, labor, and

Epinephrine

pregnancy, and (2) to in the urinary output norepinephrine during the postpartum period.

Methods

Although less sensitive than most fluorometric methods, the bioassay”, 4, 8s L, measures the biologic activity of the naturally occurring isomers of epinephrine and norepinephrine and therefore has been used in these experiments.

Adrenal gland. General. Because of possible species variation, 4 different species of animals were used, i.e., 18 goats, 12 sheep, 42 cats, and 45 rats. At various times during pregnancy and during the postpartum period, the animals were killed, and their adrenals were removed and bioassayed for epinephrine and norepinephrine. Preparation of adrenal gland extract. The procedure used for preparing the adrenal extract was similar to that described under Urine extract. As a preliminary step, the adrenal gland was homogenized in trichloroacetic acid. The epinephrine and norepinephrine were then selectively adsorbed on aluminum hydroxide and subsequently eluted. Biological assay of adrenal gland extract. This procedure is also described under Biological assay of urine. Because of the large quantities of both epinephrine and norepinephrine in the adrenal gland extract, the extract was diluted before testing. Computation of results. This is similar to that described under Urine extract.

Urine extract. General. Twenty-four hour urine samples were collected from 20 women (18 to 36 years old) during pregnancy, labor, and to 6 weeks post partum. In some patients, the urines were collected during the first trimester of pregnancy and continued at varying intervals throughout labor and the postpartum period. Other patient’s collections were restricted to the last trimester. During

and

norepinephrine

in pregnancy

897

the labor and the immediate postpartum period, the urine was collected at 3 hr. intervals. All specimens were bioassayed for epinephrine and norepinephrine. Preparation of urine extract. The procedure was adopted from von Euler and Hellner.l The urine was hydrolyzed, and the epinephrine and norepinephrine were selectively adsorbed on aluminum hydroxide and filtered. The precipitate was washed and redissolved with 2N H,SO,. The remaining salts were precipitated out by mixing the extract with alcohol and acetone. The filtrate was concentrated in vacua. Biological assay of urine. This procedure has been previously described.3, ‘s ‘J, I2 In brief, the fowl’s rectal cecum, which is sensitive to epinephrine was used in conjunction with the cat’s blood pressure which is sensitive to norepinephrine. The fowl’s rectal cecum was suspended in a water bath containing Tyrode’s solution at 39’ C. Through the Tyrode solution, 6.5 per cent of CO, in oxygen was bubbled. Injections of epinephrine, norepinephrine, and urinary extract were made into the bath, and the degree of cecal relaxation was recorded on a kymograph. The cat’s blood pressure was recorded from the carotid artery, and injections of epinephrine, norepinephrine, and urinary extract were made into the femoral vein. Computation of results. The relative amounts of epinephrine and norepinephrine in the urinary extract were calculated after determining the activity ratio for epinephrine and norepinephrine on the cat’s blood pressure and on the hen’s rectal cecum, and the activity of the unknown urinary extract in terms of Z-norepinephrine.3, 4, 8, D Results

Adrenal glands of pregnant animals. Sheep. Whereas there was a great deal of individual variation in the catecholamine content of the individual adrenal glands, nevertheless, there appeared a mild downward shift in the residual quantity of epinephrine as the pregnancy progressed. This was reflected by a decrease in the percentage of epinephrine. In the early part of preg-

898

Goodall

and Diddle

Table I. Epinephrine sheep” .--.-

at various I

and norepinephrine periods during gestation

No. of days pregnant

Sheep

Control 1 2 3 4 5 6 7 i

I

gestation

period

Table II. Epinephrine goats*

at various

Goat

No.

periods

i

and norepinephrine during gestation

of days pregnant

28 30 40 52 59 60 61 62 82 90 90 116 120 127 130 to 135 140 14.5 4 wk. post partum goat gestation

period

/ ,

-...

_

EpinephrinP ( 7% )

849 1,218 554 437 H3:i 1,174 740

549 941 36.i

60.3 55.6 67.0

is 150 dqs.

Control

“The

..Vorepinephrine (ag/Gm .I

66.9 il..> 711.2 61.8 74.8 84.2 73.9 68.7 59.0 70.4

content of adrenal glands and 4 weeks post partum

Epinephrine

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

of pregnant

2‘30 to 910; ‘4\.. 540 479 340 640 387 361 271 --DDJ 304 234

1,911

150 150 4 wk. post partum sheep

/

Epinephrine (/&Cm.)

750 to 1,500; ;2v. 1,090 1,198 1 ‘?18 1:0X! 1,14::

32 64 74 90 115 128 141 143 141

10 11 12 ‘The

I

content of adrenal glands and 4 weeks post partum

Norepinephrine

(&Gm.) 840 to 3,000; Av. 1,782 1,256 1,461 1,010 866 1,440 1,135 1,506 1,325 1,850 1,842 1,239 2,046 1,787 1,775 2,096 1,902 2,228 1,782

of pregnant

(pg/Gm .) 320 to 1,800; Av. 858 1,071 782 361 764 433 865 488 506 1,180 636 813 660 858 632 958 282 1,029 858 -_

Epinephrine

(%I 67.5 54.0 65.2 73.7 53.2 76.9 56.8 75.6 72.4 61.1 74.4 60.4 75.7 67.6 73.8 68.7 87.1 68.5 67.6

is 151 days.

of epinephrine was nancy, the percentage 65 to 75 per cent, and toward the end of the pregnancy this shift was in the range of 55 to 60 per cent (Table I). The quantity of epinephrine was on the lower limits of normal. Goat. Little could be concluded from the results on the goat because there was too much individual variation. Whereas the percentage of epinephrine fluctuated during the

gestation period, the actual quantity of epinephrine toward the end of the gestation period rose toward the high side of normalcy (Table II). Rats. Throughout the gestation period, the percentage of epinephrine in the adrenal gland remained constant at approximately 80 per cent, range 77 to 85 per cent. The actual quantity of epinephrine and norepinephrine was on the high side of the control

Vohune Number

111 7

Epinephrine

and norepinephrine

in pregnancy

899

Table III. Epinephrine and norepinephrine content of adrenal glands of pregnant rats* at various periods during gestation and 2, 4, and 6 days post partum Rat

No.

of days

Efiinephrine (p&m.)

pregnant

Control

426.4 to 660.8; Av. 546.9

: 3 4 5 6 7 8 9 10 11 12 13 *Each 21 days.

53 7 9 11 13 15 17 19 21 2 days post partum 4 days post partum 6 days post partum figure

represents

the average

63.8 to 197.2; Av. 124.3

639.2 534.9 554.8 701.5 641.7 541.6 635.7 630.0 587.9 535.8 581.6 730.8 617.5

results

obtained

from

Epinephrine (%)

Norepinejhrine (w/Gm.)

81.8

162.0 120.4 151.2 146.7 140.6 165.3 157.8 123.9 153.5 136.0 168.3 192.3 171.1 the adrenal

glands

81.8 79.4 80.0 83.1 82.2 76.8 80.1 83.5 80.6 81.9 77.7 79.8 77.7

of 3 different

rats.

The

rat gestation

period

is

Table IV. Epinephrine and norepinephrine content of adrenal glands of pregnant cats* at various periods during gestation and 2,4, 6, and 9 days and 5 and 7 weeks post partum Cat

No.

of days

Epinephrine (m/Gm.)

pregnant

Control

Norepinephrine (pdGm.1

611.5 to 1,271.0; Av. 983.4

Epinephrine (%)

396.5 to 1,339.0; Av. 836.5

55.3

: 3 4 5 6 7

7-15 o-7 15 - 21 21- 28 28 - 35 35 - 40 40 - 45

1,084.3 827.0 1,084.O 972.0 904.0 928.4 666.4

624.3 830.7 680.5 922.5 730.2 641.5 598.9

56.2 56.4 61.4 51.4 55.2 60.6 53.4

i

55 45 - 55 64 2 days post partum 4 days post partum 6 days post partum 9 days post partum 5 weeks post partum 7 weeks post partum

740.3 758.7 1,472.4 1,049.o 1,286.0 614.0 610.8 1,076.O

583.9 699.5 871.1 329.0 603.0 532.0 737.9 960.0

51.2 56.7 62.8 76.1 68.1 53.5 45.3 52.8

io 11 12 13 14 15

*Each figure represents period is 60 days.

the

average

results

obtained

from

range. On the contrary, the norepinephrine titer was slightly elevated 2 to 6 days post partum (Table III). Cuts. Early post partum, 2 to 6 days, the adrenal glands demonstrated an elevation in the percentage of epinephrine; this was reflected largely by the fact that the adrenal titer was on the high side of the normal range. Other than this, no significant changes were noted (Table IV).

the

adrenal

glands

of

3

different

cats.

The

cat

gestation

General information. The results of these animal studies can be summarized as follows: 1. There is a great species difference in the quantity of epinephrine and norepinephrine in the adrenal glands. The goat and the sheep are the most similar of all the animals tested; they are both ruminants. The percentage of epinephrine is approximately 70 per cent in each of these 2 animals whereas in the cat, a predatory animal, the percen-

Post 1 2 3 4 5 6 7 2 3

partum day days days days days days days wk. wk.

day

trimester mo. mo. mo. + I mo. + 2 mo. + 3 mo. + 3 mo. + 3 mo. + 3 mo. + 3 mo. + 3 mo. + 3 mo. + 3

Delivery

Third 7 8 8 8 8 8 8 8 8 8 8 8

+ + + + + + +

1 2 3 4 5 6 7

day days days days days days days

2 4 16 5 4 4 4 2 2

15 6 8 6

5 6

5

13

7 9 6 8 11 6

11 7 7 7

5

10

9 15 19 8 14 2

7

B.J. 3

8 a 14 5 19 9 10 5

8

8

12 12 17 6 3 3 11 9 8 11

W. C.t 4

6 12 6 9

19 17 25 a

14

9

22 11

P.M. 5

of the woman

21 17 5 7 4 5 2 9 17

9

6

14 7

13

L. K. 6

during

6 6 3 6 6 5 4 3

5

3

5

D. T. 7

9 7

11

14 4 4 8

82

7 7 7

11

2 14 20

labor,

23 16

8

12

10

17

17

10

10

20 10 16

12

B. N. 9 /

Subjects H. G. 1 8

pregnancy,

1 1 3

R.I. 2

of epinephrine

Second trimester 4 mo. 5 ma 6 mo.

W. B. I

output

1

wk. wk. wk. wk. wk. wk. wk. wk. wk. wk.

urinary

First trimester 1 mo. 2 ma 3 mo.

Time

Table V. Daily

per 24 hr.* -

a

8

19 3

16

2

11 6

13

11 16 3

5 5

4 13 16

J.S. 10

11 10

7 5

:

5

3

14

8

4

12

8 7

S. P.f II

and the postpartum

9 11

15

14

8 10

13

4

12

10

9 9

a 10 6

9

M. B.? 12

19 17

;

10 5

10

15

13 4

6

9 28

11 11

7 4

3

3

i 3 5

9

5

9 4 4 7

2 4

3

3

C. H.f 14

expressed

E. A. 13

period

4 8 a

12

6

12 11 10

5

a

4 6

9 a 9

10

J. S. 15

23

22

9

N. c. 16

in micrograms

0 0” i% =

z

Volume Number

Epinephrine

111 7

and norepinephrine

in pregnancy

901

Table VI. Comparison of urinary output of epinephrine and norepinephrine of the woman in the immediate antepartum and postpartum periods of 2 primiparas and 2 multiparas” Norepineghrine

Epinephrins T.P.

Tims

1

J. P.t

(

B. W.t

1

C. G.

T. P.

1

J. P.t

1 B. W.t

1

C. G.

Beforedelivery

2t.o 3.3

15.1 9.0 9.0 11.3 8.1 24.8$ 11.1 8.6 4.4 5.1 7.0

0 - 3 hr. 3 - 6 hr. 6- 9hr. 9-12 hr. 12 - 15 hr. 15-18 hr. 18-24 hr. 24-32 hr. 32 - 48 hr.

26.1 4 45.4 53.8 8.7 9.0 8.2 11.0 11.6

2.4 14.9 22.1 4.2 5.3 40.1 11.1 7.5 15.2

Day Day Day Day Day

11.5

13.0 14.2 11.8 14.2

2 wk. 9 days 6 days 3 days 48 hr. 18-24 hr. 12-18 hr. 9-12 hr. 6- 9 hr. 3 - 6 hr. 0- 3 hr. After

18.6 30.2 14.1 16.5 11.4 21.4$

11.1 8.8 8.3 5.3 8.6 10.83 J 41.3 3.7

20.7 16.0 10.1

23.7

10.5 29.3$ 14.6 20.4 24.6

15.1 24.2$ J 34.6 3.9

22.8 25.8 62.7 40.0 21.0 150.5$ 52.5 44.1 39.1 11.8 12.9

11.6 J 10.1 4 33.1 4 16.4 17.7 55.5

14.7 J 26.8 27.0 14.7 55.0 17.5 7.8 6.8

27.; 50:8 4.3 9.0 91.5 26.0 36.2 44.5

24.9 10.6 21.5

29.6

14.7 7.9

49.0 66.2 36.2 37.1 33.5

33.6 2.3

79.8$ 4 40.3 12.2

ii& 13.0 16.2 24.5

9.4

7.5 J 8.2 J. 119.9

7.2

delivery

3 4 5 7 10

8.3

10.9 1 8.2 I 6.7 7.5 10.2 15.1 8.0 19.3 14.3 13.1

8.4

14.3

*Urine collections were made at 3 hr. intervals for the 24 hr. preceding figures were extrapolated in terms of 24 hr. output. Normal epinephrine epinephrine output is 20 to 45 /.tg per 24 hr.

delivery output

33.0 55.0 41.6 26.3

I 40.5 i 34.6 13.8 20.8 4.7 20.0 9.9 18.6 17.4

and the 48 hr. following is 3 to 25 pg per 24 hr.;

Lo 19:3 23.5 2.8 5.4 18.1 13.2 delivery; normal

all nor-

tPrimiparas. :Onset

of labor.

tage of epinephrine is low, i.e., 50 to 60 per cent. In the rat, the percentage of epinephrine is high, i.e., 80 to 85 per cent. 2. During pregnancy, labor, and the postpartum period, the adrenal gland epinephrine and norepinephrine remained within normal limits, indicating the total capability of the adrenal gland to maintain a normal level of these hormones. To state this differently, pregnancy and labor produced little or no alteration in the titer of epinephrine and norepinephrine in the adrenal gland with the equivocal exceptions noted above under the results of each animal. 3. From these animal results, it is theorized that the human adrenal under normal conditions of pregnancy, labor, and the post-

partum period would show little or no change in it’s content of epinephrine and norepinephrine. Urinary output of epinephrine in the woman during pregnancy. Table V represents daily 24 hr. urinary output of epinephrine during pregnancy, labor, and the postpartum period. These results indicate that the epinephrine output is within normal limits except after the onset of labor and the early postpartum period. In view of these findings, additional studies were undertaken with 4 gravid subjects. These women were followed at 3 hr. intervals for the 24 hr. preceding delivery and at 3 hr. intervals for the first 48 hr. post partum (Table VI). These latter results show that concomitant

mo. mo. mo. mo. mo. mo.

jartum

day days days days

3 wk.

days days 7 days 2 wk.

Past 1 2 3 4 5 6

Delivery

8 8 8 8 8 8

+ + + + + +

day

3 3 3 3 3 3

wk. wk. wk. wk. wk. wk.

+ + + + + +

2 3 4 5 6 7

days days days days days days

wk. wk. wk. 8 mo. + 3 wk. + 1 day

Third trimester 7 mo. 8 mo. 8 mo. + 1 8 mo. + 2 8 mo. + 3

Second trimester 4 mo. 5 mo. 6 mo.

3 mo.

First

Daily urinary per 24 hr.++

Time

trimester 1 mo. 2 mo.

Table VII. micrograms

18 14 23 27 51 33 24 18

21

38 15 19 11 13 29 14 10 12

W. B. I

output

9 25

26 11 7 12

21

14

42 61 53 10 10 11

R. I. 2

18 22

24 29 36 21 11

115

43 32 35

41

17

:“2 11 8 31 32 25 22

35 19

10 7 14 13

8 7 17

22

25

18 9 4 13

P.M. 5

of the rvoman

W. C.f 4

110

14

27 22 12 7 13 14

28

B. J. 3

of norepinephrine

; 6 18

18 6 15 11 2

26

26

16 12

12

L. K. 6

during

26 26 14 12 4 8 8 18 12

27

11

50 20 10 6 13 12 15 16 1

D. T. 7

7 18

12

39 10 7 10

100

14 9 4

21

10 24 22

4 5 5

4

H. G. 8

Subjects

pregnancy,

47 8

8

11

18

26

18

10

25

26 14 33

5

B. N. 9

labor,

30

40

100 218

31

11

41 45

28

53 13 18

10 12

12 17 38

18 12

12 9

6

2

21

18

30

13

88 12

S. P.j I1

12 5

10

21

15 18

10

4

36

12

12 17

9 11 7

13

M.B.f I2

and the postpartum

6 24

9 30 18 4

8

36

11 17

17

24 23

27 18

58 36

E. A. 13

period

23

21

13 2 14 20

14

3

14 17 7 31

9 17

18

27

1 C.H.f 14

expressed

29 40 39

18 50 25 38

40

19

43 51 67

42

36

28 43

15 24 18

7

J.S. 15

in

35

18

1 N.C. j 16

Volume Number

11 I 7

Epinephrine

with the onset of labor there is an immediate and marked increase in the urinary output of epinephrine. This increased output decreased somewhat as the time of delivery approached. But after delivery, the amout of epinephrine again rose. This rise extended for approximately 18 hours into the postpartum period (Table VI) .

Urinary output of norepinephrine woman during pregnarq. Table VII

in the

represents daily 24 hr. norepinephrine output during pregnancy, labor, and the postpartum period. These results indicate that the norepinephrine output remains within normal limits until the onset of labor which is followed by a marked increase in the output of norepinephrine. Therefore, additional studies were done in which 4 subjects were followed at 3 hr. intervals for the 24 hr. preceding delivery and at 3 hr. intervals for the 48 hr. following delivery. The results showed a marked increase in the output of norepinephrine simultaneous with the beginning of labor. This increased output declined somewhat during the 3 hr. period just prior to delivery but increased again during the 3 to 9 hr. post partum and reached high levels by 18 hr. post partum (Patients C. G. and J. P., Table VI). The primipara had an earlier onset of labor than the multipara. Consequently, there was a longer period of increased output of epinephrine and norepinephrine. Further, with the onset of labor, the primipara showed a greater release of norepinephrine than the multipara (Table VI).

Urinary output of epinephrine and norepinepbrine of a patient with hydatidiform mole of the Destrusens type. Four urine samples were obtained from a patient with hydatidiform mole of the Destrusens type and were assayed for epinephrine and norepinephrine. The epinephrine ranged from a low of 11.1 ,ug per 24 hr. to a high of 19.8 pg, and the norepinephrine ranged from 20.6 to 38.1 pg; these results were well within the normal range. In addition, the hydatidiform mole was analyzed and found to contain small amounts of epinephrine and norepinephrine, i.e., 0.18 pg of epinephrine and

0.57 sue.

and norepinephrine

pg of norepinephrine

in pregnancy

per gram

903

of tis-

Comment Epinephrine is the principal hormone of the human adrenal medulla (approximately 90 per cent) while norepinephrine is the neurohormone of the sympathetic nerves.2l 3, lo Both of these hormones are excreted in the urine in quantities which parallel the sympathicoadrenal medullary activity.3 Under normal conditions, the 24 hr. urinary output of epinephrine is 3 to 25 pg and that of norepinephrine is 25 to 45 pg.3! 4, g However, this output varies during periods of rest and activity, being decreased with rest and increased with activity.3j l5 Under stressful situations such as severe muscular exercise, centrifugation, trauma, operation, thermal injury, radiation, emotional stress, etc., there is a marked increase in the urinary output of these hormones reflecting an increase in sympathetic nerve and adrenal medullary activity.3y g, I5 The results of these experiments during pregnancy demonstrate that with the onset of labor there is an increased output of both epinephrine and norepinephrine. However, the increase in norepinephrine is considerably greater than that of epinephrine and reaches, on some occasions, very high levels as is seen in Patient B. W. (Table VI). Further, this increase in norepinephrine was greater in the primiparous than in the mulitparous patients. As the labor progressed, the urinary output of epinephrine and norepinephrine gradually decreased so that at the time of delivery both of these hormones were within normal limits. The fact that increased epinephrine and more especially the increased norepinephrine occurred concomitantly with the onset of labor rather than at any time prior to or after the onset of labor would seem to indicate that the increase of epinephrine and norepinephrine is the result of labor, rather than the cause of labor. Why there is an increase in the output of both epinephrine and norepinephrine immediately following labor can best be explained on the basis of “stress” related to

904

Goodall

and

Diddle

labor and delivery just as severe muscular exercise, operation, and trauma also produce an increase in the output of these hormones.3, go I5 These findings are in good agreement with Zuspan’P analysis of urines in pregnancy. It should also be noted that the epinephrine and norepinephrine content of the fetal adrenal glands of various animals was quite different from that of the maternal adrenal glands and could not be correlated with the maternal urinary output of epinephrine and norepinephrine. This, however, was to be expected since fetal adrenal glands contain principally norepinephrine and very little epinephrine.12 The question naturally rises as to what are the changes in the human adrenal medulla during pregnancy. Obviously, adrenal glands cannot be removed from pregnant women; therefore, it was necessary to remove the adrenal gland from animals at different periods during gestation (Tables I to IV) . Further, since animal adrenals vary greatly in their content of epinephrine and norepinephrine,3’ s it was necessary to use several different species of animals, i.e., sheep, goat, rat, and cat (Tables I to IV). In this way, the animal results could be more reliably extrapolated in terms of the human adrenals.

From these animal adrenal gland exp~iments, it is apparent that pregnancy and labor per se have no significant effect uport the adrenal medulla, even though some slight variation was noted. This simply means that the stress of a normal pregnancy, labor, and the postpartum period is not of the magnitude or duration to produce any change in the adrenal medulla per se such as is seen in severe thermal injury or irradiation where the adrenal medulla can be depleted of epinephrine.Q In brief, these pregnant animal experiments would seem to justify the conclusion that the adrenal medulla in a normal pregnancy is not significantly changed. Albeit, this does not detract from the possibility that a depletion of the adrenal medulla could take place during a difficult pregnancy and labor. It has been postulated that the hypertension associated with hydatidiform moles was possibly related to an increase in catecholamines. This does not seem to be the case since the urinary output of both epinephrine and norepinephrine was within the normal limits. Nevertheless, the hydatidiform mole does contain small amounts of epinephrinr and norepinephrine, i.e., 0.18 and 0.57 !rg per gram, respectively.

REFERENCES

1.

Cibils,

AM.

L.

A.,

T. OBSTET.

Pose,

S. V.,

and

Zuspan,

F. P.:

11.

GYNECOL. 84: 307. 1962.

2. von Euler, 3. 4. 5. 6. 7.

8. 9. 10.

U. S.: Acta Physiol. Scan& 12: 73, 1946. von Euler, U. S.: Noradrenaline, Springfield, Illinois, 1956, Charles C Thomas, Publisher, p. 199. von Euler, U. S., and Hellner, S.: Acta Physiol. Stand. 22: 161, 1951. Gaddum, J. H., Peart,. W. S., and Vogt, M.: T. Phvsiol. 108: 467. 1949. de Jalon, P. G., Bayo Bayo, J., and de Jalon, M. G.: Farmacoter. Actual. 2: 313, 1945. Garret, W. J.: J. Obstet. Gynaecol. Br. Commonw. 61: 586, 1954. Goodall, McC.: Acta Physiol. Stand. 24: 7, 1951. (Suppl. 85.) Goodall, McC., and Haynes, B. W., Jr.: J. Clin. Invest. 39: 1927, 1960. Goodall, McC., and Kirshner, N.: Circulation 17: 366, 1958.

12. 13. 14. 15. 16. 17.

18.

Goodman, L. S., and Gilman, A.: The Pharmacoloaical Basis of Theraueutics. ed. 3. New York, l?365, The Macmillan Company, p. 491. Hijkfelt, B.: Acta Physiol. Stand. 25: 1, 1951. (Suppl 92.) Kaiser, I. H.: Surg. Gynecol. Obstet. 90: 649, 1950. Kaiser, I. H., and Harris, J. S.: AM. J. OBSTET. GYNECOL. 59: 775, 1950. Karki, N. J.: Acta Physiol. Stand. 39: 5, 1957. (Suppl. 132.) Pose, S. V., Cibils, L. A., and Zuspan, F. P.: AM. J. OBSTET. GYNECOL. 81: 297, 1962. Reynolds, S. R. M., Harris, J. S., and Kaiser, I. H., editors: Clinical Measurement of Uterine Forces in Pregnancy and Labor, Springfield, Illinois, 1951, Charles C Thomas, Publisher. Zuspan, F. P.: J. Clin. Endocrinol. Metab. SO: 357, 1970.