Effect of Clonidine on Growth Hormone, Prolactin, Luteinizing Hormone, Follicle-Stimulating Hormone, and ThyroidStimulating Hormone in the Serum of Normal Men SAMARTHJI LAL, GEORGE TOLIS, JOSEPH B. MARTIN, GREGORY M. BROWN,1 AND HARVEY GUYDA Departments of Psychiatry and Neurology, Montreal General Hospital, and The Department of Medicine, Royal Victoria Hospital, Montreal, Quebec, Canada. The Protein and Polypeptide Hormone Laboratory, McGill University, Montreal, Province of Quebec, Canada. The Clarke Institute of Psychiatry, Toronto, Ontario, Canada selective dopamine receptor agonist, elevated GH in each of these 6 subjects (>10 ng/ml). Clonidine had no effect on serum prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), or thyroid-stimulating hormone (TSH). These data are compatible with a dual dopaminergic and noradrenergic mechanism modulating GH secretion in normal men and with the absence of a noradrenergic mechanism in the regulation of PRL, LH, FSH, or TSH. (J Clin Endocrinol Metab 41: 827, 1975)
ABSTRACT. Clonidine (0.15 mg iv), a selective noradrenergic receptor agonist, increased serum growth hormone (GH) levels (>6 ng/ml) on 8 out of 12 administrations to 6 normal men. This increase was independent of the hypotensive effects of the drug and unrelated to changes in serum cortisol. Clonidine induced a hyperglycemic effect in all subjects which was greatest 15 min after commencing the injection. No changes in blood sugar or GH occurred after placebo injection. Apomorphine, a
T
HERE is evidence that dopamine (DA) and norepinephrine (NE) modulate the secretion of growth hormone (GH) (1), prolactin (PRL) (2-6), luteinizing hormone (LH) (3,7,8), follicle-stimulating hormone (FSH) (2,8,9), and thyroid-stimulating hormone (TSH) (10,11) in the rat. In man, studies with apomorphine (12-16), a selective DA receptor agonist (17-19), point to an inverse dopaminergic system controlling GH and PRL. The role of a noradrenergic mechanism in the modulation of human anterior pituitary secretion is unclear. Results obtained with L-dopa (20-22), the precursor of DA and NE, are compatible with a regulatory role for either or both these monoamines on GH and PRL secretion. Received March 14, 1975. Supported by grants from the Medical Research Council of Canada. Additional support was received from Merck Sharp and Dohme, Canada Ltd., Montreal, Quebec. Clonidine hydrochloride was supplied by Boehringer-Ingelheim (Canada) Ltd. 1 G. M. Brown is an Ontario Mental Health Foundation Research Associate.
Anden et al. (23) have shown that clonidine selectively stimulates central NE receptors without affecting DA or serotonin receptors. In the present study we have investigated the effect of clonidine on serum GH, PRL, LH, FSH, and TSH in normal men as a means of assessing the contribution of a noradrenergic system in the regulation of anterior pituitary hormone secretion. We also provide GH data in these subjects following apomorphine administration. Materials and Methods Six physically healthy non-obese male volunteers aged 21-36 years and on no medication served as subjects. Each volunteer was tested with intravenous clonidine on two separate occasions and also on one occasion with saline placebo injection. At 8:00 AM, after an overnight fast, a 19-gauge scalp vein needle was inserted into an arm vein and kept open with heparinsaline. Baseline samples of blood were drawn at 9:00 and 9:30 AM. Immediately after the 9:30 AM sample was drawn, clonidine HC1 (0.15 mg), diluted in physiological saline, was injected iv over a 10 min period. Further samples of blood were drawn at 15, 30, 45, 60, and 90 min after
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828
LAL ETAL.
commencement of the injection. Samples for hormone detenuinations were kept at 0 - 4 C until centrifuged and the serum then stored at —20 C until assayed. GH, PRL, L H , FSH, and TSH were assayed by a double-antibody radioimmunoassay. T h e GH standard was obtained through the courtesy of the National Pituitary Agency (NPA). F S H and L H were measured with kits obtained from the Medical Research Council of Canada; LER 907 was used as the standard. The latter was obtained from the NPA. Human PRL was assayed by homologous radioimmunoassay using materials our own own laboratorv TSH materials prepared in in our laboratorv. TSH
JCE & M . 1975
During the clonidine studies blood pressure was monitored with an electronic blood pressure recorder pressurometer. GH was also measured in the serum in these same 6 subjects following apomorphine HC1 (0.75 mg SC at time '0' min). Four of the subjects received apomorphine on 2 separate occasions, GH was also measured after placebo injection in 5 of these volunteers, Results I n
t h e
s u b
fen
^
first
^
w i t h lQ_2Q
c l o n i d i n e m{n
fou
all
6
.
, . ,. . . . r . i 1 .1 j.. ' c commencement 01 the clonidine miection was measured by the radioimmunoassay of 1 1 Daud and Odell (24). Cortisol was measured by a n d awakened by 60 mm. In the second a competitive protein-binding assay as de- t n a l > i n w h i c h t h e subjects were asked to scribed by Murphy and Pattee (25). Glucose was keep awake, none fell asleep though all estimated with a Technicon Autoanalyser by the became drowsy. Serum GH increased in 4 ferricyanide reduction method. of the 6 subjects above 6 ng/ml on each 1 TABLE 1. Effect of clonidine and apomorphine on serum GH levels in normal men Time (min) 2 Subject
Treatment
-30
0
15
30
45
60
90
Peak
1
Clonidine Apomorphine
2
2.1
2
4.2 12.8
5.7 20
4.7 12
1.4 2.7
5.7 20
Clonidine Apomorphine
1.2
1.3
29
55
1.2 64
1
1.2
1.2 64
7.3 1.4
14.2 13.5
12.3 15
3.2 7
14.2 15
6.4 3.2
5.2 16.9
4.1 11.4
2.1
6.4 16.9
2.5 15.8
6.5 17
13.8 20
6.8 16.8
13.8 20
4
7.8 5.1
13.4 11.1
8.7 5
8.6
13.4 11.1
2 3
Clonidine Apomorphine
2
4
Clonidine Apomorphine
5
Clonidine Apomorphine
ABSTRACT. Clonidine (0.15 mg iv), a selective noradrenergic receptor agonist, increased serum growth hormone (GH) levels (>6 ng/ml) on 8 out of 12 administrations to 6 normal men. This increase was independent of the hypotensive effects of the drug and unrelated to changes in serum cortisol. Clonidine induced a hyperglycemic effect in all subjects which was greatest 15 min after commencing the injection. No changes in blood sugar or GH occurred after placebo injection. Apomorphine, a
T
HERE is evidence that dopamine (DA) and norepinephrine (NE) modulate the secretion of growth hormone (GH) (1), prolactin (PRL) (2-6), luteinizing hormone (LH) (3,7,8), follicle-stimulating hormone (FSH) (2,8,9), and thyroid-stimulating hormone (TSH) (10,11) in the rat. In man, studies with apomorphine (12-16), a selective DA receptor agonist (17-19), point to an inverse dopaminergic system controlling GH and PRL. The role of a noradrenergic mechanism in the modulation of human anterior pituitary secretion is unclear. Results obtained with L-dopa (20-22), the precursor of DA and NE, are compatible with a regulatory role for either or both these monoamines on GH and PRL secretion. Received March 14, 1975. Supported by grants from the Medical Research Council of Canada. Additional support was received from Merck Sharp and Dohme, Canada Ltd., Montreal, Quebec. Clonidine hydrochloride was supplied by Boehringer-Ingelheim (Canada) Ltd. 1 G. M. Brown is an Ontario Mental Health Foundation Research Associate.
Anden et al. (23) have shown that clonidine selectively stimulates central NE receptors without affecting DA or serotonin receptors. In the present study we have investigated the effect of clonidine on serum GH, PRL, LH, FSH, and TSH in normal men as a means of assessing the contribution of a noradrenergic system in the regulation of anterior pituitary hormone secretion. We also provide GH data in these subjects following apomorphine administration. Materials and Methods Six physically healthy non-obese male volunteers aged 21-36 years and on no medication served as subjects. Each volunteer was tested with intravenous clonidine on two separate occasions and also on one occasion with saline placebo injection. At 8:00 AM, after an overnight fast, a 19-gauge scalp vein needle was inserted into an arm vein and kept open with heparinsaline. Baseline samples of blood were drawn at 9:00 and 9:30 AM. Immediately after the 9:30 AM sample was drawn, clonidine HC1 (0.15 mg), diluted in physiological saline, was injected iv over a 10 min period. Further samples of blood were drawn at 15, 30, 45, 60, and 90 min after
827
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 19 December 2015. at 11:15 For personal use only. No other uses without permission. . All rights reserved.
828
LAL ETAL.
commencement of the injection. Samples for hormone detenuinations were kept at 0 - 4 C until centrifuged and the serum then stored at —20 C until assayed. GH, PRL, L H , FSH, and TSH were assayed by a double-antibody radioimmunoassay. T h e GH standard was obtained through the courtesy of the National Pituitary Agency (NPA). F S H and L H were measured with kits obtained from the Medical Research Council of Canada; LER 907 was used as the standard. The latter was obtained from the NPA. Human PRL was assayed by homologous radioimmunoassay using materials our own own laboratorv TSH materials prepared in in our laboratorv. TSH
JCE & M . 1975
During the clonidine studies blood pressure was monitored with an electronic blood pressure recorder pressurometer. GH was also measured in the serum in these same 6 subjects following apomorphine HC1 (0.75 mg SC at time '0' min). Four of the subjects received apomorphine on 2 separate occasions, GH was also measured after placebo injection in 5 of these volunteers, Results I n
t h e
s u b
fen
^
first
^
w i t h lQ_2Q
c l o n i d i n e m{n
fou
all
6
.
, . ,. . . . r . i 1 .1 j.. ' c commencement 01 the clonidine miection was measured by the radioimmunoassay of 1 1 Daud and Odell (24). Cortisol was measured by a n d awakened by 60 mm. In the second a competitive protein-binding assay as de- t n a l > i n w h i c h t h e subjects were asked to scribed by Murphy and Pattee (25). Glucose was keep awake, none fell asleep though all estimated with a Technicon Autoanalyser by the became drowsy. Serum GH increased in 4 ferricyanide reduction method. of the 6 subjects above 6 ng/ml on each 1 TABLE 1. Effect of clonidine and apomorphine on serum GH levels in normal men Time (min) 2 Subject
Treatment
-30
0
15
30
45
60
90
Peak
1
Clonidine Apomorphine
2
2.1
2
4.2 12.8
5.7 20
4.7 12
1.4 2.7
5.7 20
Clonidine Apomorphine
1.2
1.3
29
55
1.2 64
1
1.2
1.2 64
7.3 1.4
14.2 13.5
12.3 15
3.2 7
14.2 15
6.4 3.2
5.2 16.9
4.1 11.4
2.1
6.4 16.9
2.5 15.8
6.5 17
13.8 20
6.8 16.8
13.8 20
4
7.8 5.1
13.4 11.1
8.7 5
8.6
13.4 11.1
2 3
Clonidine Apomorphine
2
4
Clonidine Apomorphine
5
Clonidine Apomorphine
