J Clin Endocrinol Metab 41: 797, 1975 EFFECTS OF MORPHINE ON SERUM GROWTH HORMONE, CORTISOL, PROLACTIN AND THYROID STIMULATING HORMONE IN MAN G. Tolis, J. Hickey and H. Guyda. Departments of Experimental Medicine and Obstetrics and Gynecology, McGill University, Montreal, Canada. ABSTRACT: Morphine administration in man results in a significant increase in serum prolactin without altering the levels of growth hormone, thyroid stimulating hormone and cortisol. Apomorphine prevented the morphine induced prolactin rise. It is suggested that the effect on prolactin is not mediated via non specific stress or changes in the thyroid stimulating hormone releasing factor, but via suppression of prolactin inhibiting factor or activation of a specific prolactin releasing factor. Increase in serum prolactin follows the administration of chlorpromazine or thyrotropin releasing factor (1-6). The latter directly stimulated the pituitary prolactin cell whereas the former is thought to act indirectly by liberating the pituitary from the inhibitory drive exerted by the prolactin inhibitory factor (PIF)(1,7). In addition to these stimuli, stress states have also been noted to be associated with a rise in serum prolactin (6). Morphine, a narcotic drug with high affinity for the hypothalamus (8), has been shown to block GH and ACTH responses to surgical stress presumably at a suprahypophyseal level (9). We now report a stimulatory effect of morphine on prolactin secretion. PATIENTS AND METHODS Ten women in the reproductive age undergoing elective gynecological surgery were the subjects of the study. After overnight fasting, on the morning of expected surgery and prior to the induction of anesthesia, blood was collected between 7-9 a.m. from an indwelling catheter 15 and 1 minutes prior to and at 15, 30, 45, 60, 90 and 120 minutes following the i.v. bolus injection of 10 mg morphine (N 5) or placebo (N 5 ) . Blood was analyzed for
radioimmunoassayable prolactin (PRL), growth hormone (GH), thyroid stimulating hormone (TSH) and protein bound cortisol (F) as previously described(lO) Two women underwent the morphine test after they had been pre-injected with 0.75 mg apomorphine S.C. RESULTS Basal (mean of -15 and -1) and peak serum levels of serum PRL, GH, TSH and F during the morphine experiment are given in Table 1. Following morphine injection a significant increase in serum PRL was noted from a mean of 13.8 ng/ml to a mean of 45.2 ng/ml, a mean increment of 390% which occurred between 45 to 75 minutes after the I.V. injection. In contrast to the elevation of serum PRL no significant change occurred in GH, TSH or cortisol. Serum levels of PRL, GH, TSH and F were unaltered in the subjects injected with placebo (Table 2 ) . In two subjects tested apomorphine injection effectively prevented morphine induced prolactin rise (Fig. 1). DISCUSSION Morphine induced elevation of serum prolactin may be due to either an enhancement of prolactin releasing factor (PRF) or suppression of PIF. The unaltered serum TSH levels makes it unlikely that TRH is this releasing
submitted April 18th, 1975.
797
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JCE & M • 1975 Vol 41 • No 4
RAPID COMMUNICATIONS
798
TABLE 1 . Response to I..V. Morphine
Subject
Basal ng/ml
PROLACTIN Peak Peak Time ng/ml
GH
TSH
CORTISOL
ng/ml
%
B
P
B
P
B
P
(min) H.A.
18
66
45
48
267
5.0
6.2
2.1
4.2
7.9
13.5
A.N.
24
42
45
18
76
1.5
1.0
3.0
4 . 1 19.8
11.2
A.G.
5
26
45
21
420
0.5
0.5
1.5
1.7 15.6
9.6
J.F.
5
60
75
55
1100
0.5
0.5
0.9
1.5 12.8
11.5
R.N.
17
32
75
15
88
1.2
2.0
4.5
7.4 18.0
15.9
Mean
13.8 5-24
42.5
390
1 .7
2 .0
2. 4
3. 8 14. 8
12 . 3
761100
0 . 5 - 0 . 5 - 0. 95 .0 6 .2 4. 5
1. 5- 7. 97. 4 19 .8
9. 615 .9
Range
57
26-66
45-75
31.4 15-55
Basal - mean of -15 to - 1 minute. - increment between b a s a l and peak v a l u e s . TABLE 2.
Response to I. V. Saline
PRL ng/ml
GH n g / m l
-15
SB 15
LM 11
KN 9.3
AB 7.6
0 15 30 45 60 90 120
15 12 10. 5 9. 6 7. 7 7. 4 8. 8
9.5 7.5 9.1 8.8 7.0 7.2 7.5
9.1 8.8 8.6 6.8 6.2 8.0 7.5 TSH MU/ml
-15 0 15 30 45 60 90 120
_ _
1.2 1.2 0.9 1.2 1.1 2.8 1.5
4.0 4.5 3.8 4.2 4.5 4.3 4.8 4.0
GD
SB
7.0 9.2 5.8 6.9 7.2 5.8 6.0
12.0 12.6 10.0 14.2 10.0 9.5 7.5 8.2
2.2 3.0 2.7 2.0 1.5 2.2 1.3 1.1
2.0 2.0 1.5 1.2 0.9 1.6 2.6 1.2
1.5 1.5 2.2 1.6 1.8 2.0
16.2 22.0 17.5 12.8 12.8 8.6 _
GD KN AB 7.4 9.1 3.2 5.6 8.5 9.1 8.0 4.2 9.0 6.0 4.6 3.5 6.0 7.5 2.5 5.0 4.0 2.0 10.5 8.2 8.0 2.0 CORTISOL Mg/100 ml _ 16 22.0 25 18.2 16.0 9.2 17.4 12.3 9.6 12.0 12.0 9.8 15.1 8.4 13.1 10.0 6.7 10.2 12.5 _ 8.2 9.0 10.2
LM
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RAPID COMMUNICATIONS
799
Serum Prolactin ng/ml 30 20
EM
10
-30' 0 30* 60# 90* 120*
-30* 0U 30'60'90' 120* JU
Morphine lOmg IV T Mi
Morphine lOmg IV.
Apomorphine a75mgSC.
30 20
R.L
10
-30' 0 30'60'90'120'
-30' 0' 3O#6O'90fl2Cr
I Morphine 10 mg IV.
Morphine lOmg IV.
Apomorphine o.75mgS.C. Fig. 1.
Apomorphine blockage of morphine induced prolactin elevation in serum.
factor but the release of a specific PRF is not excluded. The morphine induced prolactin release was selective and resembled a response to chlorpromazine for which experimental evidence indicates that it acts by the suppression of PIF secretion of the hypothalamus (7). The dopamine receptor agonist, apomorphine, effectively prevented the morphine induced prolactin rise, as has similarly been described for chlorpromazine. It is of interest that in
the rat, apomorphine also effectively blocked prolactin rise induced either by dopamine competitors like chlorpromazine and haloperidol or narcotic drugs such as methadone (11). However our experimental design does not allow us to determine whether the morphine response is mediated via PIF or PRF. The clinical significance of the acutely elevated PRL in the immediate pre-operative period following morphine premedication has yet to be studied although it could be anticipated that
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800
RAPID COMMUNICATIONS
the short-lived prolactin changes have no clinical implications. Our studies, however, may provide some insight into the problems of amenorrhea, galactorrhea or impotence in persons addicted to narcotics or maintained on methadone (12) since hyperprolactinaemia of tumorous or functional origin is associated with aberrations in gonadal function (13). ACKNOWLEDGEMENTS We wish to express our gratitude to Mrs. Jean Parodo and Miss B. Cullen for technical assistance. Materials were provided by NIAMD for the radioinununoassay of GH and TSH, and by Dr. Henry Friesen for PRL. The work was supported in part by the Medical Research Council of Canada grant MT-4403 and Quebec MRC grant 750101. REFERENCES 1. Tolis, G. and Friesen, H.G. Recent studies on hypothalamic function, Karger, Basal, p. 134, 1974. 2. Kleinberg, D.L., Noel, G.L. and Frantz, A.G. J. Clin. Endocrinol. Metab. 33: 873, 1971. 3. Tolis, G., Goldstein, M. and
JCE & M • 1975 Vol 41 • No 4
Friesen, H.G. J. Clin. Invest. 53: 783, 1973. 4. Jacobs, L.S., Snyder, P.J., Wilber, J.f., Utiger, R.D. and Daughaday, W.H. J. Clin. Endocrinol. Metab. 33: 996, 1971. 5. Bowers, C.Y., Friesen, H.G., Hwang, P., Guyda, H.J. and Folkers, K. Biochem. Biophys. Res. Comm. 45: 1033, 1971. 6. Friesen, H.G., Hwang, P., Guyda, H.J., Tolis, G., Tyson, J., Myers, R. The 4th Tenovus Workshop on Prolactin and Carcinogenesis. K. Griffiths and A. Boyne, (eds.), 1972. p. 64. 7. Sulman, F.G. Hypothalamic Control of Lactation. Springer-Verlag, 1970. p. 59-141. 8. Snyder, S.H., Pert, C.B. and Pasternack, G.W., Ann. Int. Med. 81: 534, 1974. 9. Raier, C.E., George, J.M. and Kliman, J.W. Anesthesia Analgesia 52: 1003, 1973. 10. Tolis, G., Lewis, W., Verdy, M., Friesen, H.G., Solomon, S., Pagalis, C , Pavlatos, F. , Fessas, Ph., and Rochefort, J.G., J. Clin. Endocrinol. Metab. 39: 1061, 1974. 11. Clemens, J.A. and Sawyer, B.D. Endo. Res. Comm. 1: 373, 1974. 12. Cushman, P. N.Y. State J. Med. 72: 1261, 1971. 13. Tolis, G., Somma, M., Van Campenhout, J. and Friesen, H. Amer. J. Obstet. Gynecol. 118: 91, 1974.
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radioimmunoassayable prolactin (PRL), growth hormone (GH), thyroid stimulating hormone (TSH) and protein bound cortisol (F) as previously described(lO) Two women underwent the morphine test after they had been pre-injected with 0.75 mg apomorphine S.C. RESULTS Basal (mean of -15 and -1) and peak serum levels of serum PRL, GH, TSH and F during the morphine experiment are given in Table 1. Following morphine injection a significant increase in serum PRL was noted from a mean of 13.8 ng/ml to a mean of 45.2 ng/ml, a mean increment of 390% which occurred between 45 to 75 minutes after the I.V. injection. In contrast to the elevation of serum PRL no significant change occurred in GH, TSH or cortisol. Serum levels of PRL, GH, TSH and F were unaltered in the subjects injected with placebo (Table 2 ) . In two subjects tested apomorphine injection effectively prevented morphine induced prolactin rise (Fig. 1). DISCUSSION Morphine induced elevation of serum prolactin may be due to either an enhancement of prolactin releasing factor (PRF) or suppression of PIF. The unaltered serum TSH levels makes it unlikely that TRH is this releasing
submitted April 18th, 1975.
797
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2015. at 23:32 For personal use only. No other uses without permission. . All rights reserved.
JCE & M • 1975 Vol 41 • No 4
RAPID COMMUNICATIONS
798
TABLE 1 . Response to I..V. Morphine
Subject
Basal ng/ml
PROLACTIN Peak Peak Time ng/ml
GH
TSH
CORTISOL
ng/ml
%
B
P
B
P
B
P
(min) H.A.
18
66
45
48
267
5.0
6.2
2.1
4.2
7.9
13.5
A.N.
24
42
45
18
76
1.5
1.0
3.0
4 . 1 19.8
11.2
A.G.
5
26
45
21
420
0.5
0.5
1.5
1.7 15.6
9.6
J.F.
5
60
75
55
1100
0.5
0.5
0.9
1.5 12.8
11.5
R.N.
17
32
75
15
88
1.2
2.0
4.5
7.4 18.0
15.9
Mean
13.8 5-24
42.5
390
1 .7
2 .0
2. 4
3. 8 14. 8
12 . 3
761100
0 . 5 - 0 . 5 - 0. 95 .0 6 .2 4. 5
1. 5- 7. 97. 4 19 .8
9. 615 .9
Range
57
26-66
45-75
31.4 15-55
Basal - mean of -15 to - 1 minute. - increment between b a s a l and peak v a l u e s . TABLE 2.
Response to I. V. Saline
PRL ng/ml
GH n g / m l
-15
SB 15
LM 11
KN 9.3
AB 7.6
0 15 30 45 60 90 120
15 12 10. 5 9. 6 7. 7 7. 4 8. 8
9.5 7.5 9.1 8.8 7.0 7.2 7.5
9.1 8.8 8.6 6.8 6.2 8.0 7.5 TSH MU/ml
-15 0 15 30 45 60 90 120
_ _
1.2 1.2 0.9 1.2 1.1 2.8 1.5
4.0 4.5 3.8 4.2 4.5 4.3 4.8 4.0
GD
SB
7.0 9.2 5.8 6.9 7.2 5.8 6.0
12.0 12.6 10.0 14.2 10.0 9.5 7.5 8.2
2.2 3.0 2.7 2.0 1.5 2.2 1.3 1.1
2.0 2.0 1.5 1.2 0.9 1.6 2.6 1.2
1.5 1.5 2.2 1.6 1.8 2.0
16.2 22.0 17.5 12.8 12.8 8.6 _
GD KN AB 7.4 9.1 3.2 5.6 8.5 9.1 8.0 4.2 9.0 6.0 4.6 3.5 6.0 7.5 2.5 5.0 4.0 2.0 10.5 8.2 8.0 2.0 CORTISOL Mg/100 ml _ 16 22.0 25 18.2 16.0 9.2 17.4 12.3 9.6 12.0 12.0 9.8 15.1 8.4 13.1 10.0 6.7 10.2 12.5 _ 8.2 9.0 10.2
LM
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RAPID COMMUNICATIONS
799
Serum Prolactin ng/ml 30 20
EM
10
-30' 0 30* 60# 90* 120*
-30* 0U 30'60'90' 120* JU
Morphine lOmg IV T Mi
Morphine lOmg IV.
Apomorphine a75mgSC.
30 20
R.L
10
-30' 0 30'60'90'120'
-30' 0' 3O#6O'90fl2Cr
I Morphine 10 mg IV.
Morphine lOmg IV.
Apomorphine o.75mgS.C. Fig. 1.
Apomorphine blockage of morphine induced prolactin elevation in serum.
factor but the release of a specific PRF is not excluded. The morphine induced prolactin release was selective and resembled a response to chlorpromazine for which experimental evidence indicates that it acts by the suppression of PIF secretion of the hypothalamus (7). The dopamine receptor agonist, apomorphine, effectively prevented the morphine induced prolactin rise, as has similarly been described for chlorpromazine. It is of interest that in
the rat, apomorphine also effectively blocked prolactin rise induced either by dopamine competitors like chlorpromazine and haloperidol or narcotic drugs such as methadone (11). However our experimental design does not allow us to determine whether the morphine response is mediated via PIF or PRF. The clinical significance of the acutely elevated PRL in the immediate pre-operative period following morphine premedication has yet to be studied although it could be anticipated that
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800
RAPID COMMUNICATIONS
the short-lived prolactin changes have no clinical implications. Our studies, however, may provide some insight into the problems of amenorrhea, galactorrhea or impotence in persons addicted to narcotics or maintained on methadone (12) since hyperprolactinaemia of tumorous or functional origin is associated with aberrations in gonadal function (13). ACKNOWLEDGEMENTS We wish to express our gratitude to Mrs. Jean Parodo and Miss B. Cullen for technical assistance. Materials were provided by NIAMD for the radioinununoassay of GH and TSH, and by Dr. Henry Friesen for PRL. The work was supported in part by the Medical Research Council of Canada grant MT-4403 and Quebec MRC grant 750101. REFERENCES 1. Tolis, G. and Friesen, H.G. Recent studies on hypothalamic function, Karger, Basal, p. 134, 1974. 2. Kleinberg, D.L., Noel, G.L. and Frantz, A.G. J. Clin. Endocrinol. Metab. 33: 873, 1971. 3. Tolis, G., Goldstein, M. and
JCE & M • 1975 Vol 41 • No 4
Friesen, H.G. J. Clin. Invest. 53: 783, 1973. 4. Jacobs, L.S., Snyder, P.J., Wilber, J.f., Utiger, R.D. and Daughaday, W.H. J. Clin. Endocrinol. Metab. 33: 996, 1971. 5. Bowers, C.Y., Friesen, H.G., Hwang, P., Guyda, H.J. and Folkers, K. Biochem. Biophys. Res. Comm. 45: 1033, 1971. 6. Friesen, H.G., Hwang, P., Guyda, H.J., Tolis, G., Tyson, J., Myers, R. The 4th Tenovus Workshop on Prolactin and Carcinogenesis. K. Griffiths and A. Boyne, (eds.), 1972. p. 64. 7. Sulman, F.G. Hypothalamic Control of Lactation. Springer-Verlag, 1970. p. 59-141. 8. Snyder, S.H., Pert, C.B. and Pasternack, G.W., Ann. Int. Med. 81: 534, 1974. 9. Raier, C.E., George, J.M. and Kliman, J.W. Anesthesia Analgesia 52: 1003, 1973. 10. Tolis, G., Lewis, W., Verdy, M., Friesen, H.G., Solomon, S., Pagalis, C , Pavlatos, F. , Fessas, Ph., and Rochefort, J.G., J. Clin. Endocrinol. Metab. 39: 1061, 1974. 11. Clemens, J.A. and Sawyer, B.D. Endo. Res. Comm. 1: 373, 1974. 12. Cushman, P. N.Y. State J. Med. 72: 1261, 1971. 13. Tolis, G., Somma, M., Van Campenhout, J. and Friesen, H. Amer. J. Obstet. Gynecol. 118: 91, 1974.
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