0021-972X/91/7301-0075$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 73, No. 1 Printed in U.S.A.
Sexual Dimorphism of Pyridostigmine Potentiation of Growth Hormone (GH)-Releasing Hormone-Induced GH Release in Humans ANTONINO BARBARINO, SALVATORE M. CORSELLO, ANNA TOFANI, ROSA SCIUTO, SILVIA DELLA CASA, CARLO ANTONIO ROTA, AND ANGELA BARINI Institutes of Endocrinology and Biochemistry (A3.), Catholic University School of Medicine, 1-00168 Rome, Italy
to GHRH, as assessed by both the maximal GH peak and the area under GH curve. In women, on the contrary, the GH response to GHRH was not potentiated by pretreatment with pyridostigmine at any given dose. Only five female subjects were tested with 120 mg pyridostigmine because of the severe sideeffects of the drug at this dosage. Our present data strongly suggest that in humans there is a sex-related difference in the neuroregulation of GH secretion, and this is probably expressed through a different cholinergic tone. (J Clin Endocrinol Metab 73: 75-78,1991)
ABSTRACT. Sex differences in the neuroregulation of GH secretion are not now known in humans. To investigate whether activation of cholinergic tone by pyridostigmine could cause a sex-related difference in the pituitary responsiveness to GHreleasing hormone (GHRH), we have studied the GH response to GHRH in 16 normal subjects (8 men and 8 women) tested after oral placebo or different doses of pyridostigmine (30, 60, and 120 mg). Each subject presented a normal response after iv administration of 50 ng GHRH and placebo. In men each dose of pyridostigmine induced a significant increase in the GH response
T
GH response to GHRH in normal men and women treated after either placebo or different doses of PD.
HE PATTERN of GH secretion of several mammalian species is pulsatile in nature and sexually differentiated. Both the different ultradian pattern of GH secretion and the GH-releasing hormone (GHRH)induced GH release encountered in male and female animals could arise from gender-related differences in the secretion of GHRH and somatostatin. Recently, several studies have shown that in normal men activation of cholinergic pathways with pyridostigmine (PD) enhances the GH response to GHRH (1-3). Although all of these studies were performed in male subjects, the conclusions have been also applied to female subjects, presuming that no sex-related differences in the cholinergic regulation of GH secretion are present in man. We have recently shown a sex difference in CRH inhibition of GHRH-induced GH release, suggesting a gender-related difference in the neuroregulation of GH secretion in humans (4). To investigate whether activation of the cholinergic tone by PD could cause a sex-related difference in the pituitary responsiveness to GHRH, we have studied the
Materials and Methods Eight normal men, aged 19-24 yr, and 8 normal women, aged 20-25 yr, were studied after they had given informed consent. All subjects were nonstressed. All were within 10% of ideal body weight (weight range, 59-72 kg for men and 52-67 kg for women) and were eating their customary diet before and during the interval between the tests. None had clinical evidence of endocrine or other disease, and all were free of any medication. All women had regular menstrual cycles. After an overnight fast, in recumbent subjects, an indwelling cannula was inserted into an antecubital vein at 0730 h, 30 min before starting the tests. It was used for blood sampling and GHRH injection. Four separate GHRH stimulation tests were performed. A 50-/ng bolus dose of GHRH was iv injected at time zero (0900 h) 1 h after oral administration of placebo or three different doses of PD (30, 60, or 120 mg, respectively). Blood was obtained 60, 30, and 0 min before and 15, 30, 60, 90, and 120 min after GHRH administration. In individual subjects the tests were performed at least at 72-h intervals, and in women during the luteal phase of the same or a different cycle. The time of the cycle was established by measuring estradiol and progesterone levels. Only five female subjects were tested with 120 mg PD because of the severe side-effects of the drug at this
Received August 16,1990. Address all correspondence and requests for reprints to: Antonino Barbarino M.D., via Diano Marina 9/11,1-00168 Rome, Italy.
75
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BARBARINO ET AL.
76
Vol 73 • No 1
dosage. With this exception, all tests were performed in all the subjects. GHRH-(1-44) was provided by Bachem (Bubendorf, Switzerland). Plasma GH, estradiol, and progesterone levels were measured by RIA, as previously described (4, 5). The intra- and interassay coefficients of variation for GH ranged from 2.94.7% and from 6.2-8.9% respectively. All samples from a given study were measured in the same assay. The area under the curve was calculated by the trapezoidal method. Analysis of variance and Newman-Keuls test were used for statistical evaluation. The results are given as the mean ± SE. The significance level was established at P < 0.05.
Results In our subjects, 50 ng GHRH administration after placebo pretreatment induced a clear-cut increase in plasma GH levels without significant differences between sexes. The mean peak plasma GH levels were 21.9 ± 5.6 ixg/L in men and 26.9 ± 6.4 /ig/L in women, while the areas under the curve were 1320 ± 270 /ig/L/min in men and 1921 ± 548 yug/L-min in women (Figs. 1 and 2).
Placebo or PD 30 mq
O
N=8
0
N=8
or"
GHRH 50uq
60. Placebo or 50.
N =8
In men, PD pretreatment induced a significant enhancement {vs. placebo) of the GH response to GHRH at all of the dosages employed in terms of both peak response and area under the curve. In fact, the mean peak plasma GH levels were 37.1 ± 5.5 ng/L after 50 ng GHRH plus 30 mg PD (P < 0.05), 46.2 ± 10.2 Mg/L after 50 fig GHRH plus 60 mg PD (P < 0.05), and 59 ± 6.8 Aig/L after 50 ng GHRH plus 120 mg PD (P < 0.001). The areas under the curve were 3122 ± 459 jug/L-min (P < 0.005), 4048 ± 861 /ug/L-min (P < 0.005), and 4944 ± 551 Mg/L-min (P < 0.005) after 30, 60, and 120 mg PD pretreatment, respectively (Figs. 1 and 2). On the contrary, in women, PD pretreatment was not able to significantly enhance, at any dose, the GH response to GHRH. The mean peak plasma GH levels and the areas under the curve were, respectively, 24.3 ± 2.9 Mg/L and 1575 ± 236 ^g/L-min after 50 ng GHRH plus 30 mg PD, 35.3 ± 3.3 ng/L and 2255 ± 263 /ig/L-min after 50 Mg GHRH plus 60 mg PD, and 28.3 ± 2.8 fig/L and 1860 ± 249 ^g/L-min after 50 ng GHRH plus 120 mg PD, with no significant differences us. values after
PD 30 mq
GHRH 50 M 9
1
1
40
30
!
.1
T
7
20.
10
*
•
«O
-
-
•
*
•
30
-
1
4 0
IS 30
minutes
80
(0
120
-60
30
0
15 30
minutes
tO
90
120
60
30
0
15 30
60
90
120
minutes
FIG. 1. Mean (± SE) GH responses to GHRH plus placebo (O- -O) and GHRH plus PD (30,60, and 120 mg; • — • ) in normal men (upper panel) and women (lower panel). *,P< 0.05; **, P < 0.005 (comparing values after GHRH plus PD with those after GHRH plus placebo at the reported time).
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77
SEXUAL DIMORPHISM IN GH SECRETION
P< O.OO5
5000
4OOO
FIG. 2. Mean (±SE) areas under GH curve after GHRH plus placebo and GHRH plus PD (30, 60, and 120 mg) in normal men (left panel) and women {right panel).
p< 0,005
1
p< 0,005
1
5000.
40OO.
3OOO.
3OOO.
2OOO.
2OOO-
1OOO.
1OOO.
GHRH SO MO
50pg
GHRH SOug
GHRH BOpg
PD 30mg
PD 60 mg
PD 120mg
OHRH
50 ng GHRH plus placebo (Figs. 1 and 2). Furthermore, the areas under the curve after GHRH plus PD at the various doses employed (30, 60, and 120 mg) were significantly higher in men than in women. Different side-effects were observed starting 2 h after the administration of increasing doses of PD in men and women. Women presented more severe and prolonged symptoms than men, especially after the 120-mg dose, experiencing severe abdominal cramps, nausea, vomiting, asthenia, and muscle cramps. Three subjects, after this dose, had an impairment of visual accomodation lasting 4 h; three had fasciculation of the tongue with dysarthria of 2-h duration. Discussion Our present data clearly indicate that the modulation of cholinergic neurotransmission of the pituitary response to GHRH is sex related. In keeping with previous data by Massara et al. (1), the administration of PD potentiated the GH response to GHRH in male subjects. As did other workers (1-3), we found that in male subjects, administration of 120 mg PD potentiated the plasma GH response to GHRH, as assessed by the maximal GH peak and the area under GH curve. Interestingly, administration of 30 or 60 mg PD was also capable of inducing a significant enhancement of the GH response to GHRH. On the contrary, in women, the plasma GH response to GHRH was not potentiated by the administration of 30, 60, and 120 mg PD. Interestingly, women taking 120 mg PD had more severe side-effects than men. The pattern of GH response to GHRH was different
1 GHRH
50 tig
GHRH 50 p 9 PD
30 mg
GHRH 50pfl
GHRH 50 Mg
PD
PD
60 mg
120 r
in men and women after each dose of PD. In men, the plasma GH concentrations reached peak levels at 60 min and then slowly decreased, but remained high until 120 min after the administration of GHRH. In women, plasma GH concentrations peaked at 30 min and returned to basal levels after 90 min. These variations in the GH response to GHRH after the administration of graded doses of PD could be due to gender differences in the cholinergic control of GH secretion. A number of sex differences in the GH secretory pattern have been described in several mammalian species, such as rat, dog, sheep, guinea pig, and monkey (6-11), and are known to be related to the perinatal action of steroid hormones (12, 13). At present, sex differences in the neuroregulation of GH secretion are not known in the human. It is unclear whether sex steroids influence the GH response to GHRH in man, and most workers have failed to observe any consistent differences between male and female responses in normal subjects (14), although it was recently reported that males have a greater response than females (15). In addition, no major differences in the GH response to GHRH at different phases of the menstrual cycle have been reported (16). The precise mechanism underlying the sex-related pattern of responses shown in our studies is open to speculation. Recently, data suggesting that the potentiating effect of PD on the GHRH-induced GH rise results from an inhibition of somatostatin release from the hypothalamus, which allows GH release unopposed by inhibitory hypothalamic influences, have been presented (17,18). Taking into account these findings, our data suggest that men can have a high somatostatinergic tone due to
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 17 November 2015. at 23:27 For personal use only. No other uses without permission. . All rights reserved.
BARBARINO ET AL.
78
a low cholinergic control of GH secretion. PD is capable in these circumstances of potentiating the GHRH-induced GH release. Women, on the contrary, can have a higher cholinergic GH control, which induces a lower somatostatinergic tone; in this situation the secretory capacity of GH cells is maximally stimulated by exogenous GHRH and cannot be further potentiated by PD. The existence of a different cholinergic tone in men and women is also supported by a different genderrelated sensitivity to PD, which induces more severe and frequent side-effects in women than in men. It could be hypothesized that women have lower acetylcholinesterase activity and a higher sensitivity to PD than men. Finally, submaximal doses of PD (60 mg) should be used for testing in view of the serious side-effects encountered after a 120-mg dose.
References 1. Massara F, Ghigo E, Molinatti P, et al. Potentiation of cholinergic tone by pyridostigmine bromide re-instates and potentiates the growth hormone responsiveness to intermittent administration of growth hormone-releasing factor in man. Acta Endocrinol (Copenh). 1986;113:12-6. 2. Massara F, Ghigo E, Demislis K, et al. Cholinergic involvement in the growth hormone releasing hormone-induced growth hormone release: studies in normal and acromegalic subjects. Neuroendocrinology. 1986;43:670-5. 3. Ross RJM, Tsagarakis S, Grossman A, et al. GH feedback occurs through modulation of hypothalamic somatostatin under cholinergic control: studies with pyridostigmine and GHRH. Clin Endocrinol (Oxf). 1987;27:727-33. 4. Barbarino A, Corsello SM, Delia Casa S, et al. Corticotropinreleasing hormone inhibition of growth hormone-releasing hormone-induced growth hormone release in man. J Clin Endocrinol Metab. 1990;71:1368-74. 5. Barbarino A, De Marinis L, Anile C, Menini E, Merlini G, Maira G. Dopaminergic mechanisms regulating prolactin secretion in patients with prolactin secreting pituitary adenoma. Long term studies after selective transsphenoidal surgery. Metabolism. 1982;31:1100-4. 6. Saunders A, Terry LC, Audet J, Brazeau P, Martin JB. Dynamic studies of growth hormone and prolactin secretion in the female
JCE & M • 1991 Vol73«Nol
rat. Neuroendocrinology. 1976;21:193-203. 7. Plotsky PM, Vale W. Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science. 1985;230:461-3. 8. Ferland L, Labrie F, Jobin M, Arimura A, Schally AV. Physiological role of somatostatin in the control of growth hormone and thyrotropin secretion. Biochem Biophys Res Commun. 1976;68:149-54. 9. Terry LC, Martin JB. The effects of lateral hypothalamic-medial forebrain stimulation and somatostatin antiserum on pulsatile growth hormone secretion in freely behaving rats: evidence for a dual regulatory mechanism. Endocrinology. 1981;109:622-7. 10. Clark RG, Robinson ICA. Growth hormone responses to multiple injections of a fragment of human growth hormone-releasing factor in conscious male and female rats. J Endocrinol. 1985;106:281-6. 11. Maiter DM, Gabriel SM, Koenig JI, Russel WE, Martin JB. Sexual differentiation of growth hormone feedback effects on hypothalamic growth hormone-releasing hormone and somatostatin. Neuroendocrinology. 1990;51:174-80. 12. Jansson J-O, Frohman LA. Differential effects of neonatal and adult androgen exposure on the growth hormone secretory pattern in male rats. Endocrinology. 1987;120:1551-7. 13. Gorsky RA. Effects of androgen exposure on the perinatal animal brain. Ann Intern Med. 1982;96:488-92. 14. Gelato MC, Pescovitz OH, Cassorla F, Loriaux DL, Merriam GR. Dose-response relationship for the effects of growth hormonereleasing factor-(l-44)-NH2 in young adult men and women. J Clin Endocrinol Metab. 1984;59:197-202. 15. Smals AEM, Pieters GFFM, Smals AGH, Benraad TJ, Van Laarhoven J, Kloppenborg PWC. Sex difference in human growth hormone (GH) response to intravenous human pancreatic GHreleasing hormone administration in young adults. J Clin Endocrinol Metab. 1986;62:336-40. 16. Evans WS, Borges JCC, Vance ML, et al. Effects of human pancreatic growth hormone-releasing factor-40 on serum growth hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, and somatomedin-C concentrations in normal women throughout the menstrual cycle. J Clin Endocrinol Metab. 1984;59:1006-ll. 17. Locatelli V, Torsello A, Radaelli M, Ghigo E, Massara F, Muller EE. Cholinergic agonist and antagonist drugs modulate the growth hormone response to growth hormone-releasing hormone in the rat: evidence for mediation by somatostatin. J Endocrinol. 1986;lll:271-8. 18. Torsello A, Panzeri G, Cermenati P, et al. Involvement of the somatostatin and cholinergic systems in the mechanism of growth hormone autofeedback regulation in the rat. J Endocrinol. 1988;117:273-81.
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Vol. 73, No. 1 Printed in U.S.A.
Sexual Dimorphism of Pyridostigmine Potentiation of Growth Hormone (GH)-Releasing Hormone-Induced GH Release in Humans ANTONINO BARBARINO, SALVATORE M. CORSELLO, ANNA TOFANI, ROSA SCIUTO, SILVIA DELLA CASA, CARLO ANTONIO ROTA, AND ANGELA BARINI Institutes of Endocrinology and Biochemistry (A3.), Catholic University School of Medicine, 1-00168 Rome, Italy
to GHRH, as assessed by both the maximal GH peak and the area under GH curve. In women, on the contrary, the GH response to GHRH was not potentiated by pretreatment with pyridostigmine at any given dose. Only five female subjects were tested with 120 mg pyridostigmine because of the severe sideeffects of the drug at this dosage. Our present data strongly suggest that in humans there is a sex-related difference in the neuroregulation of GH secretion, and this is probably expressed through a different cholinergic tone. (J Clin Endocrinol Metab 73: 75-78,1991)
ABSTRACT. Sex differences in the neuroregulation of GH secretion are not now known in humans. To investigate whether activation of cholinergic tone by pyridostigmine could cause a sex-related difference in the pituitary responsiveness to GHreleasing hormone (GHRH), we have studied the GH response to GHRH in 16 normal subjects (8 men and 8 women) tested after oral placebo or different doses of pyridostigmine (30, 60, and 120 mg). Each subject presented a normal response after iv administration of 50 ng GHRH and placebo. In men each dose of pyridostigmine induced a significant increase in the GH response
T
GH response to GHRH in normal men and women treated after either placebo or different doses of PD.
HE PATTERN of GH secretion of several mammalian species is pulsatile in nature and sexually differentiated. Both the different ultradian pattern of GH secretion and the GH-releasing hormone (GHRH)induced GH release encountered in male and female animals could arise from gender-related differences in the secretion of GHRH and somatostatin. Recently, several studies have shown that in normal men activation of cholinergic pathways with pyridostigmine (PD) enhances the GH response to GHRH (1-3). Although all of these studies were performed in male subjects, the conclusions have been also applied to female subjects, presuming that no sex-related differences in the cholinergic regulation of GH secretion are present in man. We have recently shown a sex difference in CRH inhibition of GHRH-induced GH release, suggesting a gender-related difference in the neuroregulation of GH secretion in humans (4). To investigate whether activation of the cholinergic tone by PD could cause a sex-related difference in the pituitary responsiveness to GHRH, we have studied the
Materials and Methods Eight normal men, aged 19-24 yr, and 8 normal women, aged 20-25 yr, were studied after they had given informed consent. All subjects were nonstressed. All were within 10% of ideal body weight (weight range, 59-72 kg for men and 52-67 kg for women) and were eating their customary diet before and during the interval between the tests. None had clinical evidence of endocrine or other disease, and all were free of any medication. All women had regular menstrual cycles. After an overnight fast, in recumbent subjects, an indwelling cannula was inserted into an antecubital vein at 0730 h, 30 min before starting the tests. It was used for blood sampling and GHRH injection. Four separate GHRH stimulation tests were performed. A 50-/ng bolus dose of GHRH was iv injected at time zero (0900 h) 1 h after oral administration of placebo or three different doses of PD (30, 60, or 120 mg, respectively). Blood was obtained 60, 30, and 0 min before and 15, 30, 60, 90, and 120 min after GHRH administration. In individual subjects the tests were performed at least at 72-h intervals, and in women during the luteal phase of the same or a different cycle. The time of the cycle was established by measuring estradiol and progesterone levels. Only five female subjects were tested with 120 mg PD because of the severe side-effects of the drug at this
Received August 16,1990. Address all correspondence and requests for reprints to: Antonino Barbarino M.D., via Diano Marina 9/11,1-00168 Rome, Italy.
75
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BARBARINO ET AL.
76
Vol 73 • No 1
dosage. With this exception, all tests were performed in all the subjects. GHRH-(1-44) was provided by Bachem (Bubendorf, Switzerland). Plasma GH, estradiol, and progesterone levels were measured by RIA, as previously described (4, 5). The intra- and interassay coefficients of variation for GH ranged from 2.94.7% and from 6.2-8.9% respectively. All samples from a given study were measured in the same assay. The area under the curve was calculated by the trapezoidal method. Analysis of variance and Newman-Keuls test were used for statistical evaluation. The results are given as the mean ± SE. The significance level was established at P < 0.05.
Results In our subjects, 50 ng GHRH administration after placebo pretreatment induced a clear-cut increase in plasma GH levels without significant differences between sexes. The mean peak plasma GH levels were 21.9 ± 5.6 ixg/L in men and 26.9 ± 6.4 /ig/L in women, while the areas under the curve were 1320 ± 270 /ig/L/min in men and 1921 ± 548 yug/L-min in women (Figs. 1 and 2).
Placebo or PD 30 mq
O
N=8
0
N=8
or"
GHRH 50uq
60. Placebo or 50.
N =8
In men, PD pretreatment induced a significant enhancement {vs. placebo) of the GH response to GHRH at all of the dosages employed in terms of both peak response and area under the curve. In fact, the mean peak plasma GH levels were 37.1 ± 5.5 ng/L after 50 ng GHRH plus 30 mg PD (P < 0.05), 46.2 ± 10.2 Mg/L after 50 fig GHRH plus 60 mg PD (P < 0.05), and 59 ± 6.8 Aig/L after 50 ng GHRH plus 120 mg PD (P < 0.001). The areas under the curve were 3122 ± 459 jug/L-min (P < 0.005), 4048 ± 861 /ug/L-min (P < 0.005), and 4944 ± 551 Mg/L-min (P < 0.005) after 30, 60, and 120 mg PD pretreatment, respectively (Figs. 1 and 2). On the contrary, in women, PD pretreatment was not able to significantly enhance, at any dose, the GH response to GHRH. The mean peak plasma GH levels and the areas under the curve were, respectively, 24.3 ± 2.9 Mg/L and 1575 ± 236 ^g/L-min after 50 ng GHRH plus 30 mg PD, 35.3 ± 3.3 ng/L and 2255 ± 263 /ig/L-min after 50 Mg GHRH plus 60 mg PD, and 28.3 ± 2.8 fig/L and 1860 ± 249 ^g/L-min after 50 ng GHRH plus 120 mg PD, with no significant differences us. values after
PD 30 mq
GHRH 50 M 9
1
1
40
30
!
.1
T
7
20.
10
*
•
«O
-
-
•
*
•
30
-
1
4 0
IS 30
minutes
80
(0
120
-60
30
0
15 30
minutes
tO
90
120
60
30
0
15 30
60
90
120
minutes
FIG. 1. Mean (± SE) GH responses to GHRH plus placebo (O- -O) and GHRH plus PD (30,60, and 120 mg; • — • ) in normal men (upper panel) and women (lower panel). *,P< 0.05; **, P < 0.005 (comparing values after GHRH plus PD with those after GHRH plus placebo at the reported time).
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77
SEXUAL DIMORPHISM IN GH SECRETION
P< O.OO5
5000
4OOO
FIG. 2. Mean (±SE) areas under GH curve after GHRH plus placebo and GHRH plus PD (30, 60, and 120 mg) in normal men (left panel) and women {right panel).
p< 0,005
1
p< 0,005
1
5000.
40OO.
3OOO.
3OOO.
2OOO.
2OOO-
1OOO.
1OOO.
GHRH SO MO
50pg
GHRH SOug
GHRH BOpg
PD 30mg
PD 60 mg
PD 120mg
OHRH
50 ng GHRH plus placebo (Figs. 1 and 2). Furthermore, the areas under the curve after GHRH plus PD at the various doses employed (30, 60, and 120 mg) were significantly higher in men than in women. Different side-effects were observed starting 2 h after the administration of increasing doses of PD in men and women. Women presented more severe and prolonged symptoms than men, especially after the 120-mg dose, experiencing severe abdominal cramps, nausea, vomiting, asthenia, and muscle cramps. Three subjects, after this dose, had an impairment of visual accomodation lasting 4 h; three had fasciculation of the tongue with dysarthria of 2-h duration. Discussion Our present data clearly indicate that the modulation of cholinergic neurotransmission of the pituitary response to GHRH is sex related. In keeping with previous data by Massara et al. (1), the administration of PD potentiated the GH response to GHRH in male subjects. As did other workers (1-3), we found that in male subjects, administration of 120 mg PD potentiated the plasma GH response to GHRH, as assessed by the maximal GH peak and the area under GH curve. Interestingly, administration of 30 or 60 mg PD was also capable of inducing a significant enhancement of the GH response to GHRH. On the contrary, in women, the plasma GH response to GHRH was not potentiated by the administration of 30, 60, and 120 mg PD. Interestingly, women taking 120 mg PD had more severe side-effects than men. The pattern of GH response to GHRH was different
1 GHRH
50 tig
GHRH 50 p 9 PD
30 mg
GHRH 50pfl
GHRH 50 Mg
PD
PD
60 mg
120 r
in men and women after each dose of PD. In men, the plasma GH concentrations reached peak levels at 60 min and then slowly decreased, but remained high until 120 min after the administration of GHRH. In women, plasma GH concentrations peaked at 30 min and returned to basal levels after 90 min. These variations in the GH response to GHRH after the administration of graded doses of PD could be due to gender differences in the cholinergic control of GH secretion. A number of sex differences in the GH secretory pattern have been described in several mammalian species, such as rat, dog, sheep, guinea pig, and monkey (6-11), and are known to be related to the perinatal action of steroid hormones (12, 13). At present, sex differences in the neuroregulation of GH secretion are not known in the human. It is unclear whether sex steroids influence the GH response to GHRH in man, and most workers have failed to observe any consistent differences between male and female responses in normal subjects (14), although it was recently reported that males have a greater response than females (15). In addition, no major differences in the GH response to GHRH at different phases of the menstrual cycle have been reported (16). The precise mechanism underlying the sex-related pattern of responses shown in our studies is open to speculation. Recently, data suggesting that the potentiating effect of PD on the GHRH-induced GH rise results from an inhibition of somatostatin release from the hypothalamus, which allows GH release unopposed by inhibitory hypothalamic influences, have been presented (17,18). Taking into account these findings, our data suggest that men can have a high somatostatinergic tone due to
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 17 November 2015. at 23:27 For personal use only. No other uses without permission. . All rights reserved.
BARBARINO ET AL.
78
a low cholinergic control of GH secretion. PD is capable in these circumstances of potentiating the GHRH-induced GH release. Women, on the contrary, can have a higher cholinergic GH control, which induces a lower somatostatinergic tone; in this situation the secretory capacity of GH cells is maximally stimulated by exogenous GHRH and cannot be further potentiated by PD. The existence of a different cholinergic tone in men and women is also supported by a different genderrelated sensitivity to PD, which induces more severe and frequent side-effects in women than in men. It could be hypothesized that women have lower acetylcholinesterase activity and a higher sensitivity to PD than men. Finally, submaximal doses of PD (60 mg) should be used for testing in view of the serious side-effects encountered after a 120-mg dose.
References 1. Massara F, Ghigo E, Molinatti P, et al. Potentiation of cholinergic tone by pyridostigmine bromide re-instates and potentiates the growth hormone responsiveness to intermittent administration of growth hormone-releasing factor in man. Acta Endocrinol (Copenh). 1986;113:12-6. 2. Massara F, Ghigo E, Demislis K, et al. Cholinergic involvement in the growth hormone releasing hormone-induced growth hormone release: studies in normal and acromegalic subjects. Neuroendocrinology. 1986;43:670-5. 3. Ross RJM, Tsagarakis S, Grossman A, et al. GH feedback occurs through modulation of hypothalamic somatostatin under cholinergic control: studies with pyridostigmine and GHRH. Clin Endocrinol (Oxf). 1987;27:727-33. 4. Barbarino A, Corsello SM, Delia Casa S, et al. Corticotropinreleasing hormone inhibition of growth hormone-releasing hormone-induced growth hormone release in man. J Clin Endocrinol Metab. 1990;71:1368-74. 5. Barbarino A, De Marinis L, Anile C, Menini E, Merlini G, Maira G. Dopaminergic mechanisms regulating prolactin secretion in patients with prolactin secreting pituitary adenoma. Long term studies after selective transsphenoidal surgery. Metabolism. 1982;31:1100-4. 6. Saunders A, Terry LC, Audet J, Brazeau P, Martin JB. Dynamic studies of growth hormone and prolactin secretion in the female
JCE & M • 1991 Vol73«Nol
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