Short Communication
Effect of sodium valproate on the secretion of prolactin, cortisol and growth hormone in migraine patients
Rachel Hering, Irit Gilad1, Z Laron1, A Kuritzky
Departments of Neurology and Pediatric Endocrinology1, Beilinson Medical Center, and Tel Aviv University Sackler School of Medicine, Israel Cephalalgia
Hering R, Gilad I, Laron Z, Kuritzky A. Effect of sodium valproate on the secretion of prolactin, cortisol and growth hormone in migraine patients. Cephalalgia 1992;12:257-8. Oslo. ISSN 0333-1024 A single oral dose of 500 mg sodium valproate had no effect on prolactin, growth hormone and cortisol secretion in 10 migraine patients when compared with five healthy controls and four migraine patients receiving placebo. Basal values of prolactin (PRL), cortisol and growth hormone (GH) were within the normal range, though PRL basal levels were lower in three patients (21.5%) in the migraine group. • cortisol growth hormone, migraine, prolactin, sodium valproate R Hering, Department of Neurology, Beilinson Medical Center, Petach Tikva 49 100, Israel. Received 27 December 1991, accepted 30 April 1992
Sodium valproate was found to be effective in the prophylactic treatment of migraine (1, 2). Its mechanism of action is not yet known. Sodium valproate, a GABA agonist, easily crosses the blood-brain barrier and significantly increases hypothalamic GABA concentrations (3). Recent evidence suggests that GABA plays an important role in the regulation of anterior pituitary hormone secretion (4, 5). GABA participates in controlling prolactin (PRL) release with both stimulatory and inhibitory effect. Horrobin suggested that PRL might be involved in the mechanism of the migraine attack (7). Thus one possible mechanism of action of sodium valproate in migraine is its effect on PRL. We therefore evaluated the basal PRL, cortisol and growth hormone (GH) levels and the effect of acute administration of sodium valproate on their secretion in migraine patients and healthy volunteers. Patients and methods
Fourteen migraine patients (10F and 4M) aged 23-56 years, suffering from common (migraine without aura) and classic migraine (migraine with aura) (8), drug-free for at least three months, were studied. Ten received one tablet of sodium valproate 500 mg and four placebo. The control group comprised five healthy subjects, (3F and 2M) aged 24-52 years, who received one tablet of sodium valproate 500 mg. The experiments were performed in the morning after an overnight fast. Baseline blood samples were drawn and each subject received the drug or the placebo. Further blood samples were collected at 60, 120 and 1/30 min after sodium valproate or placebo administration. Plasma was separated and kept frozen until assayed for PRL, cortisol and GH. Plasma PRL, cortisol and GH were determined by a standard double antibody radioimmunoassay. Plasma PRL and GH levels were determined with the aid of materials provided by Sorin Biomedica (Italy). The sensitivities of the assays were 0.5 ng/ml and 2 ng/ml, respectively, and the mean intra-assay coefficients of variation were 4.5% and 4.8% respectively (9). Plasma cortisol levels were determined using materials provided by the Diagnostic Product Corporation (Los Angeles, CA). The sensitivity of the assay was I µg/dl and the mean intra-assay coefficient of variation was 4% (10). All the hormonal assays were run in the same batch. Since the data had a non-gaussian distribution we applied the square-root transformation in order to approach a normal distribution. Using these data we applied the BMDP2V-analysis of variance and co-variance with repeated measures testing for differences between the placebo and sodium valproate treated groups and time-related trends. Results
Basal PRL, cortisol and GH levels were within the normal range in all migraine patients. Nevertheless, PRL basal levels were lower in 3/14 migraineurs (2.0, 2.0, 2.7 ng/ml)o Administration of 500 mg sodium valproate did not affect PRL blood levels, and had no effect on the expected diurnal variations in the cortisol and GH secretion. In the migraine group, however, 4/10 patients had an increase in GH secretion after administration of sodium valproate (Fig. 1).
Discussion
Basal values of PRL, cortisol and GH were within the normal range, even though PRL basal levels were lower in three (21.5%) patients in the migraine group. These results are in accord with previous studies that have found normal PRL levels in migraine patients (11, 12). In the present study acute oral administration of 500 mg sodium valproate produced no changes of PRL, cortisol and GH secretion, in migraineurs or controls. These findings do not support an influence of sodium valproate on PRL secretion. Different doses and chronic administration of sodium valproate, however, should be studied to totally discount the relationship between sodium valproate and PRL secretion. References
1.
Sørensen KV. Valproate: a new drug in migraine prophylaxis. Acta Neurol Scand 1988;78:346-8
2.
Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 1992;12:81-4
3.
Bernasconi R. The GABA hypothesis of affective illness: influence of clinically effective antimanic drugs on GABA turnover. In: Emerich HM, Aldenhof JB, Lux HD eds Basic mechanisms of the action of lithium. Amsterdam: Excerpta Medica, 1982;183-92
4.
Vincent SR, Hokfelt T, Wu J. GABA neuron systems in the hypothalamus and the pituitary gland. Neuroendocrinology 1983;34:117-25
5.
Melis GB, Mais V, Paoletti AM, Antinori D, de Ruggiero A, Fioretti P. GABAergic control of anterior pituitary function in humans. In: Racagni G, Alfredo O eds GABA and endocrine function. New York: Raven Press, 1986:219-43
6.
McCann SM, Rettori V. Gamma amino butyric acid (GABA) controls anterior pituitary hormone secretion. In: Racagni G, Alfredo O eds GABA and endocrine function. New York: Raven Press, 1986:173-91
7.
Horrobin DF. Prevention of migraine by reducing prolactin levels? Lancet 1974;i:777
8.
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8:27
9.
Peake GT, Morris J, Buckman MT. Growth hormone in methods of hormone radioimmunoassay. In Jaffe BM, Behrman HR eds New York: Academic Press, 1979:223
10.
Foster L, Dunn R. Clinical chemistry 1974;20:365
11.
Capellan JIL, Dacosta CV, Garcia JMG, Servan PR, Cermeno JCA. Tuberoinfundibular dopaminergic tonus in common migraine. Headache 1990;30:282-4
12.
D'Andrea G, Cananzi AR, Grigoletto F, Meneghini F, Cortesi S, Soffiati G, Joseph R, Nordera G, Ferro-Milone F. The effect of dopamine receptor agonist on prolactin secretion in childhood migraine. Headache 1988;28:354-9
Effect of sodium valproate on the secretion of prolactin, cortisol and growth hormone in migraine patients
Rachel Hering, Irit Gilad1, Z Laron1, A Kuritzky
Departments of Neurology and Pediatric Endocrinology1, Beilinson Medical Center, and Tel Aviv University Sackler School of Medicine, Israel Cephalalgia
Hering R, Gilad I, Laron Z, Kuritzky A. Effect of sodium valproate on the secretion of prolactin, cortisol and growth hormone in migraine patients. Cephalalgia 1992;12:257-8. Oslo. ISSN 0333-1024 A single oral dose of 500 mg sodium valproate had no effect on prolactin, growth hormone and cortisol secretion in 10 migraine patients when compared with five healthy controls and four migraine patients receiving placebo. Basal values of prolactin (PRL), cortisol and growth hormone (GH) were within the normal range, though PRL basal levels were lower in three patients (21.5%) in the migraine group. • cortisol growth hormone, migraine, prolactin, sodium valproate R Hering, Department of Neurology, Beilinson Medical Center, Petach Tikva 49 100, Israel. Received 27 December 1991, accepted 30 April 1992
Sodium valproate was found to be effective in the prophylactic treatment of migraine (1, 2). Its mechanism of action is not yet known. Sodium valproate, a GABA agonist, easily crosses the blood-brain barrier and significantly increases hypothalamic GABA concentrations (3). Recent evidence suggests that GABA plays an important role in the regulation of anterior pituitary hormone secretion (4, 5). GABA participates in controlling prolactin (PRL) release with both stimulatory and inhibitory effect. Horrobin suggested that PRL might be involved in the mechanism of the migraine attack (7). Thus one possible mechanism of action of sodium valproate in migraine is its effect on PRL. We therefore evaluated the basal PRL, cortisol and growth hormone (GH) levels and the effect of acute administration of sodium valproate on their secretion in migraine patients and healthy volunteers. Patients and methods
Fourteen migraine patients (10F and 4M) aged 23-56 years, suffering from common (migraine without aura) and classic migraine (migraine with aura) (8), drug-free for at least three months, were studied. Ten received one tablet of sodium valproate 500 mg and four placebo. The control group comprised five healthy subjects, (3F and 2M) aged 24-52 years, who received one tablet of sodium valproate 500 mg. The experiments were performed in the morning after an overnight fast. Baseline blood samples were drawn and each subject received the drug or the placebo. Further blood samples were collected at 60, 120 and 1/30 min after sodium valproate or placebo administration. Plasma was separated and kept frozen until assayed for PRL, cortisol and GH. Plasma PRL, cortisol and GH were determined by a standard double antibody radioimmunoassay. Plasma PRL and GH levels were determined with the aid of materials provided by Sorin Biomedica (Italy). The sensitivities of the assays were 0.5 ng/ml and 2 ng/ml, respectively, and the mean intra-assay coefficients of variation were 4.5% and 4.8% respectively (9). Plasma cortisol levels were determined using materials provided by the Diagnostic Product Corporation (Los Angeles, CA). The sensitivity of the assay was I µg/dl and the mean intra-assay coefficient of variation was 4% (10). All the hormonal assays were run in the same batch. Since the data had a non-gaussian distribution we applied the square-root transformation in order to approach a normal distribution. Using these data we applied the BMDP2V-analysis of variance and co-variance with repeated measures testing for differences between the placebo and sodium valproate treated groups and time-related trends. Results
Basal PRL, cortisol and GH levels were within the normal range in all migraine patients. Nevertheless, PRL basal levels were lower in 3/14 migraineurs (2.0, 2.0, 2.7 ng/ml)o Administration of 500 mg sodium valproate did not affect PRL blood levels, and had no effect on the expected diurnal variations in the cortisol and GH secretion. In the migraine group, however, 4/10 patients had an increase in GH secretion after administration of sodium valproate (Fig. 1).
Discussion
Basal values of PRL, cortisol and GH were within the normal range, even though PRL basal levels were lower in three (21.5%) patients in the migraine group. These results are in accord with previous studies that have found normal PRL levels in migraine patients (11, 12). In the present study acute oral administration of 500 mg sodium valproate produced no changes of PRL, cortisol and GH secretion, in migraineurs or controls. These findings do not support an influence of sodium valproate on PRL secretion. Different doses and chronic administration of sodium valproate, however, should be studied to totally discount the relationship between sodium valproate and PRL secretion. References
1.
Sørensen KV. Valproate: a new drug in migraine prophylaxis. Acta Neurol Scand 1988;78:346-8
2.
Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 1992;12:81-4
3.
Bernasconi R. The GABA hypothesis of affective illness: influence of clinically effective antimanic drugs on GABA turnover. In: Emerich HM, Aldenhof JB, Lux HD eds Basic mechanisms of the action of lithium. Amsterdam: Excerpta Medica, 1982;183-92
4.
Vincent SR, Hokfelt T, Wu J. GABA neuron systems in the hypothalamus and the pituitary gland. Neuroendocrinology 1983;34:117-25
5.
Melis GB, Mais V, Paoletti AM, Antinori D, de Ruggiero A, Fioretti P. GABAergic control of anterior pituitary function in humans. In: Racagni G, Alfredo O eds GABA and endocrine function. New York: Raven Press, 1986:219-43
6.
McCann SM, Rettori V. Gamma amino butyric acid (GABA) controls anterior pituitary hormone secretion. In: Racagni G, Alfredo O eds GABA and endocrine function. New York: Raven Press, 1986:173-91
7.
Horrobin DF. Prevention of migraine by reducing prolactin levels? Lancet 1974;i:777
8.
Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8:27
9.
Peake GT, Morris J, Buckman MT. Growth hormone in methods of hormone radioimmunoassay. In Jaffe BM, Behrman HR eds New York: Academic Press, 1979:223
10.
Foster L, Dunn R. Clinical chemistry 1974;20:365
11.
Capellan JIL, Dacosta CV, Garcia JMG, Servan PR, Cermeno JCA. Tuberoinfundibular dopaminergic tonus in common migraine. Headache 1990;30:282-4
12.
D'Andrea G, Cananzi AR, Grigoletto F, Meneghini F, Cortesi S, Soffiati G, Joseph R, Nordera G, Ferro-Milone F. The effect of dopamine receptor agonist on prolactin secretion in childhood migraine. Headache 1988;28:354-9
