- Email: [email protected]
Effect of ergonovine maleate on puerperal prolactin
CURRENT INVESTIGATION
This section offers prompt first announcement of new obseiVations or discoveries. Articles should be limited to 1,500 words and 6 references. Illustrations or additional references require a proportionate reduction in total words.
Effect of ergonovine maleate* on puerperal prolactin JOHN M. SHANE, M.D. FREDERICK NAFTOLIN, M.D., D.PHIL. Boston, Massachusetts The effect of ergonovine maleate on prolactin levels in women on the third day post partum was studied because of ergonovine's known ability to lower circulating prolactin levels in animals and its apparent success in the treatment of non puerperal galactorrhea. A modest, but significant, lowering of the prolactin level following the administration of a single tablet (0.2 mg.) of ergonovine maleate was found. Repetitive doses, often used as a postpartum uterotonic, might have the effect of inhibiting lactation in women wishing to nurse.
T H E I N H I B I T I 0 N of lactation and depression of pituitary and serum prolactin in rats by 2-Br-a-ergocryptine and other ergot alkaloids have been established. 2 Consensus suggests they directly lower the pituitary's
ability to secrete prolactin. 2 One of these alkaloids, ergonovine maleate, IS given routinely on many obstetric services for the purpose of avoiding puerperal uterine atony and hemorrhage. The inhibitory effect of ergonovine on prolactin secretion has not been investigated in the clinical setting. If active in the amounts routinely administered, these antilactogenic compounds would theoretically be beneficial in nonnursing women and deleterious in those desiring to nurse.
From the Department of Obstetrics and Gynecology, Harvard Medical School, Boston Hospital for Women and Beth Israel Hospital. Supported by a grant from the Rockefeller Foundation. Reprint requests: Dr. John M. Shane, Department of Obstetrics and Gynecology, Harvard Medical School, 45 Shattuck St., Baston, Massachusetts 02115.
Methods and material
The study was conducted with 12 normotensive, normal women on the third day after term delivery; they were not breast-feeding and were receiving no medication other than
*Ergotrate, Eli Lilly & Co., Box 618, Indianapolis, Indiana 46206.
129
S!'pl<'lllher I, 1'!74
Shane and Naftolin
130
\m.
J. Oh;tet. ( ;ynrcol.
Table I. Mean and range of prolactin values i nanograms per milliliter of HPr) before and after ---,-------·-·--·-····--
A
Control HPr
B
142.2 ( 119.4172.6*) 107.3 (78.7158.4)
Treatment HPr
282.4 (238.7329.9) 197.2 ( 170.9224.1)
c
D
2.'>0.5
148.3 ( 12R.6-
(227.1272.1) 208.8 (196.2221.8)
169.:))
121.9 ( 91.61.5.1.3)
140.H (127.1160.1) 149.2
(l::l2.6163.9)
157.0
( 124..5-
211.6) 129.:1 (ll5.1173.9)
*Range.
2.
BASELINE PLACEBO BASELINE
+
PLACEBO
60+90+120 ALL IIIIN SAII!PLES
AFTER ERGOTRA TE
Fig. 1. Mean (± standard error of the mean) expressed in log prolactin values (nanograms per milliliter) .
a:
140
:r 10.1
z
::i
120
10.1
II) <(
m
...
100
0
1-
z
80
10.1
u a:
10.1 Q.
•
•• •
"l-.. •
l
I
I
y
:.
..
••
-..
120
150
•
60
40
15 30
60
90
•
.•
MINUTES AFTER TREATMENT
Fig. 2. Per cent change from base-line values (pretreatment and after placebo).
analgesics and/or cathartics. Only patients B and H had received previous ergonovine. The previous dose preceded the study by at least 39 hours. The third postpartum day was chosen because human prolactin ( HPr) levels have been shown to be fairly stable by that time, thereafter declining to nongravid levels within a few weeks. 4 An indwelling scalp vein needle was placed and kept patent with a slow drip of normal saline. To avoid dilutional factors, a small amount of blood was withdrawn and discarded before the sample for analysis was obtained. The experimental protocol was as follows: Blood samples were taken immediately and 15 minutes after venipuncture for base-line values followed by samples 15, 30, and 60 minutes after an oral lactose placebo; then samples were taken 15, 30, 60, 90, 120, and 150 minutes after 0.2 mg. of ergonovine maleate was given orally. After centrifugation and separation, serum samples were frozen until the time of assay for prolactin. This was done by triplicate determinations with a specific homologous double-antibody radioimmunoassay technique. 3 All samples were assayed in -the same assay and fell along the portion of the curve which had an over-all intra-assay variation of 8.5 per cent, measured as the coefficient of variation. Results Several methods were used to examine our data (Table I). Base-line values were compared to the placebo group by the two-sided t test. The difference between the two groups was found not to be significant (p > 0.50), and the data were combined, which enlarged
Volum<•120 Numb!'f 1
Ergonovine on puerperal prolactin
131
treatment Patient G
180.0 ( 165.4195.4) 13.'i.9 (tlO.O174.2)
H
179.3 ( 166.7196.1) 166.3 (113.4201.6)
I
532.0 (515.2565.5) 495.7 (466.4533.3)
the data base (Fig. 1). The treatment was found to lower serum prolactin levels (Fig. 2). The lowering effect of ergonovine was examined with a one-sided t test. The logs of base-line values in nanograms of HPr per milliliter were compared to the logs of the lowest posttreatment values (p < 0.01) and to the log of all posttreatment values collectively (p ,....._; 0.015). A "sampling window" of 60 through 120 minutes after treatment was found to demonstrate maximum lowering (p .-....- 0.013) (Fig. 1). This decrease in circulating HPr is not thought to represent a spontaneous fall of serum HPr levels; there was an abrupt drop 30 minutes after treatment, and the prolactin levels of four patients had returned to or exceeded base-line values when sampling stopped at 150 minutes (Fig.
2).
1
K
L
218.1 ( 198.2-
133.4 (121.3150.3) 124.7 ( !09.8162.9)
153.4 ( 135.7169.3)
248.6)
179.5 (156.3207.3)
172.2
(161.6200.2)
creased prolactin levels in rats2 as well as apparent cure of 4 women with nonpuerperal galactorrhea1 with ergonovine maleate. Because this drug is commonly used as a postpartum uterotonic, it is frequently administered to parturients regardless of their desire to nurse. While this may reinforce treatment to inhibit lactation in nonnursing mothers, its possible effect of inhibiting lactation in women who wish to nurse should be considered since repetitive doses might have a cumulative effect. Appreciation is extended to Dr. Eddington Lee for his assistance with statistical analyses, to the National Pituitary Agency for their gift of radioimmunoassay reagents, and to Drs. Kenneth J. Ryan, Emanuel A. Friedman, and Louis M. Sherwood for their advice and support.
Comment
This preliminary investigation was stimulated by numerous reports demonstrating de-
REFERENCES
1. Lawrence, A. M., and Hagen, T. C.: N. Engl. J. Med. 287: 150, 1972. 2. Shan·, C. J., and Clemens, J. A.: Endocrinology
90: 285, 1972.
3. Sinha, Y. N., Selby, F. W., Lewis, U. J., and
VanderLaan, W. P.: J. Clin. Endocrinol. Metab. 36: 509, 1973. 4. Tyson, J. E., Hwang, P., Guyda, H., and Friesen, H. G.: AM. J. 0BSTET. GYNEOOL. 113: 14, 1972.
This section offers prompt first announcement of new obseiVations or discoveries. Articles should be limited to 1,500 words and 6 references. Illustrations or additional references require a proportionate reduction in total words.
Effect of ergonovine maleate* on puerperal prolactin JOHN M. SHANE, M.D. FREDERICK NAFTOLIN, M.D., D.PHIL. Boston, Massachusetts The effect of ergonovine maleate on prolactin levels in women on the third day post partum was studied because of ergonovine's known ability to lower circulating prolactin levels in animals and its apparent success in the treatment of non puerperal galactorrhea. A modest, but significant, lowering of the prolactin level following the administration of a single tablet (0.2 mg.) of ergonovine maleate was found. Repetitive doses, often used as a postpartum uterotonic, might have the effect of inhibiting lactation in women wishing to nurse.
T H E I N H I B I T I 0 N of lactation and depression of pituitary and serum prolactin in rats by 2-Br-a-ergocryptine and other ergot alkaloids have been established. 2 Consensus suggests they directly lower the pituitary's
ability to secrete prolactin. 2 One of these alkaloids, ergonovine maleate, IS given routinely on many obstetric services for the purpose of avoiding puerperal uterine atony and hemorrhage. The inhibitory effect of ergonovine on prolactin secretion has not been investigated in the clinical setting. If active in the amounts routinely administered, these antilactogenic compounds would theoretically be beneficial in nonnursing women and deleterious in those desiring to nurse.
From the Department of Obstetrics and Gynecology, Harvard Medical School, Boston Hospital for Women and Beth Israel Hospital. Supported by a grant from the Rockefeller Foundation. Reprint requests: Dr. John M. Shane, Department of Obstetrics and Gynecology, Harvard Medical School, 45 Shattuck St., Baston, Massachusetts 02115.
Methods and material
The study was conducted with 12 normotensive, normal women on the third day after term delivery; they were not breast-feeding and were receiving no medication other than
*Ergotrate, Eli Lilly & Co., Box 618, Indianapolis, Indiana 46206.
129
S!'pl<'lllher I, 1'!74
Shane and Naftolin
130
\m.
J. Oh;tet. ( ;ynrcol.
Table I. Mean and range of prolactin values i nanograms per milliliter of HPr) before and after ---,-------·-·--·-····--
A
Control HPr
B
142.2 ( 119.4172.6*) 107.3 (78.7158.4)
Treatment HPr
282.4 (238.7329.9) 197.2 ( 170.9224.1)
c
D
2.'>0.5
148.3 ( 12R.6-
(227.1272.1) 208.8 (196.2221.8)
169.:))
121.9 ( 91.61.5.1.3)
140.H (127.1160.1) 149.2
(l::l2.6163.9)
157.0
( 124..5-
211.6) 129.:1 (ll5.1173.9)
*Range.
2.
BASELINE PLACEBO BASELINE
+
PLACEBO
60+90+120 ALL IIIIN SAII!PLES
AFTER ERGOTRA TE
Fig. 1. Mean (± standard error of the mean) expressed in log prolactin values (nanograms per milliliter) .
a:
140
:r 10.1
z
::i
120
10.1
II) <(
m
...
100
0
1-
z
80
10.1
u a:
10.1 Q.
•
•• •
"l-.. •
l
I
I
y
:.
..
••
-..
120
150
•
60
40
15 30
60
90
•
.•
MINUTES AFTER TREATMENT
Fig. 2. Per cent change from base-line values (pretreatment and after placebo).
analgesics and/or cathartics. Only patients B and H had received previous ergonovine. The previous dose preceded the study by at least 39 hours. The third postpartum day was chosen because human prolactin ( HPr) levels have been shown to be fairly stable by that time, thereafter declining to nongravid levels within a few weeks. 4 An indwelling scalp vein needle was placed and kept patent with a slow drip of normal saline. To avoid dilutional factors, a small amount of blood was withdrawn and discarded before the sample for analysis was obtained. The experimental protocol was as follows: Blood samples were taken immediately and 15 minutes after venipuncture for base-line values followed by samples 15, 30, and 60 minutes after an oral lactose placebo; then samples were taken 15, 30, 60, 90, 120, and 150 minutes after 0.2 mg. of ergonovine maleate was given orally. After centrifugation and separation, serum samples were frozen until the time of assay for prolactin. This was done by triplicate determinations with a specific homologous double-antibody radioimmunoassay technique. 3 All samples were assayed in -the same assay and fell along the portion of the curve which had an over-all intra-assay variation of 8.5 per cent, measured as the coefficient of variation. Results Several methods were used to examine our data (Table I). Base-line values were compared to the placebo group by the two-sided t test. The difference between the two groups was found not to be significant (p > 0.50), and the data were combined, which enlarged
Volum<•120 Numb!'f 1
Ergonovine on puerperal prolactin
131
treatment Patient G
180.0 ( 165.4195.4) 13.'i.9 (tlO.O174.2)
H
179.3 ( 166.7196.1) 166.3 (113.4201.6)
I
532.0 (515.2565.5) 495.7 (466.4533.3)
the data base (Fig. 1). The treatment was found to lower serum prolactin levels (Fig. 2). The lowering effect of ergonovine was examined with a one-sided t test. The logs of base-line values in nanograms of HPr per milliliter were compared to the logs of the lowest posttreatment values (p < 0.01) and to the log of all posttreatment values collectively (p ,....._; 0.015). A "sampling window" of 60 through 120 minutes after treatment was found to demonstrate maximum lowering (p .-....- 0.013) (Fig. 1). This decrease in circulating HPr is not thought to represent a spontaneous fall of serum HPr levels; there was an abrupt drop 30 minutes after treatment, and the prolactin levels of four patients had returned to or exceeded base-line values when sampling stopped at 150 minutes (Fig.
2).
1
K
L
218.1 ( 198.2-
133.4 (121.3150.3) 124.7 ( !09.8162.9)
153.4 ( 135.7169.3)
248.6)
179.5 (156.3207.3)
172.2
(161.6200.2)
creased prolactin levels in rats2 as well as apparent cure of 4 women with nonpuerperal galactorrhea1 with ergonovine maleate. Because this drug is commonly used as a postpartum uterotonic, it is frequently administered to parturients regardless of their desire to nurse. While this may reinforce treatment to inhibit lactation in nonnursing mothers, its possible effect of inhibiting lactation in women who wish to nurse should be considered since repetitive doses might have a cumulative effect. Appreciation is extended to Dr. Eddington Lee for his assistance with statistical analyses, to the National Pituitary Agency for their gift of radioimmunoassay reagents, and to Drs. Kenneth J. Ryan, Emanuel A. Friedman, and Louis M. Sherwood for their advice and support.
Comment
This preliminary investigation was stimulated by numerous reports demonstrating de-
REFERENCES
1. Lawrence, A. M., and Hagen, T. C.: N. Engl. J. Med. 287: 150, 1972. 2. Shan·, C. J., and Clemens, J. A.: Endocrinology
90: 285, 1972.
3. Sinha, Y. N., Selby, F. W., Lewis, U. J., and
VanderLaan, W. P.: J. Clin. Endocrinol. Metab. 36: 509, 1973. 4. Tyson, J. E., Hwang, P., Guyda, H., and Friesen, H. G.: AM. J. 0BSTET. GYNEOOL. 113: 14, 1972.