Neuropeptides (1992) 22,205-207 0 Longman Group UK Ltd 1992
Impaired PRL Response to Hyperthermia Alcoholic Men
in
P. P. VESCOVI, M. PEDRAZZONI, M. MICHELINI, L. MANINETTI and M. PASSERI Ciinica Medica Genera/e e Terapia Medica, to PPV)
Universita’
di Parma, itaiy (Reprint requests
Abstract -The aim of this study was to evaluate the release of PRL to sauna-induced hyperthermia in 10 chronically alcohol-addicted male subjects after a few weeks of abstinence. In contrast with normal men the alcoholic men showed higher basal levels of PRL and the exposure to hyperthermic stress did not stimulate in PRL secretion. These results indicate that chronic alcohol abuse is associated with functional pituitary alterations similar to other states of addiction. Introduction In previous studies we have shown that saunainduced hyperthermia stimulates the secretion of beta-endorphin and ACTH in normal men (l), but not in chronic alcoholics after a few weeks of abstinence (2). Chronic alcohol abuse has several important effects on pituitary function (3); in particular, some authors have reported a stimulatory effect on PRL secretion (4,5). Since PRL levels also increase after thermal stress in normal men (6, 7), we have examined the response of plasma PRL to heat exposure in a sauna room in a group of alcoholic men after a few weeks of abstinence.
Subjects and Methods We have examined 10 alcohol-addicted male subjects (30-49 years old) who gave informed consent Date received 10 April 1992 Date accepted 13 April 1992
to the study. The subjects were involved in a longterm rehabilitation program and were studied in a clinical research center after 5 weeks of complete alcohol abstinence. The duration of drinking abuse varied from 4-14 years; the subjects consumed on average 178 f 40 g/d of alcohol. Their relative body weight ranged from 83 to 118% of normal. No patient had clinical evidence of psychiatric or organic disease, or took any medication (especially psychotropic drugs) in the 3 weeks before the study. Liver abnormalities were mild: SGOT = 56 f 20 UIK, SGPT = 34 + 16 UIK, gamma-GT = 137 f 49 U/l. The presence of cirrhosis was excluded by ultrasound examination and, in dubious cases, by biopsy. Eight normal men, who usually consumed less than 30 g/d and were requested to totally abstain from alcohol both during the study and in the 2 weeks before it, served as controls. Their age ranged from 23-50 years and their body weight was normal (relative body weight 85- 110%). The subjects were studied at 8.00 a.m., after an overnight fast. After inserting an indwelling Teflon
21)s
206
NEUROPEPTIDES
catheter into an antecubital vein, the subjects were allowed to rest in a sitting position for half an hour. Then they sat for 30 mm in a sauna room where the temperature was 90°C and the relative humidity 10%. After the sauna the subjects remained in a sitting position for an additional 30 min at room temperature. Pulse rate, sublingual temperature and blood pressure were recorded just before and immediately after the sauna and after the 30 minrest period at room temperature. At the same time points venous blood was drawn into vacutainer tubes and immediately centrifuged at 4°C. Plasma was frozen within 10 min of collection and stored at -20°C until assayed for PRL, LH and FSH. PRL, LH and FSH were measured with an immunoradiometric method using commercial kits (Boehringer-Mannheim). The sensitivity of the PRL assay is 1 ngml and the intra- and inter- assay coefficients of variations (CV) are 3% and 7% respectively. The sensitivity of both LH and FSH assay is 0.5 mUI/ml and the intra- and inter-assay CVs are 4% and 7% respectively. The comparisons between the basal levels of the parameters examined in the two groups were made using the Mann-Whitney test. The hormonal variations after sauna were tested by the Wilcoxon matched-pair test. Results are given as mean f SEM. Table 1 Changesin body temperature and cardiovascular parameters (mean f SEM) in alcoholic men and controls
HEARTRATE (beatdmin) Alcoholic men Controls SYSTOLIC BLOOD PRBSSURE (mmHg) Alcoholic men Controls DIASTOLIC BLOOD PRESSURE @mHg) Alcoholic men Controls
Basal
End of sauna
7916 74f6
141 f 5* 137 f 7*
79f7 76k4
125f6 122k4
130 * 5*t 158 f 6*
121 f6 115f4
79 f 3 78 f 3
SUBLINGUAL TEMPERATURE (“0 Alcoholic men ’ ’ 36.4 f 0.3 Controls 36.7 k 0.2
71*3* 66k4
39.4 f 0.4 39.4 f 0.3
30 min afrer sauna
77*4 76f4
36.3 f 0.3 36.6 f 0.4
* Significantly different from basal values (p < 0.05) .~ t SignifIcantIy different from control group @ < 0.05)
Results The changes in sublingual temperature, pulse rate and blood pressure during the experiments are shown in Table 1. At the end of the sauna the sublingual temperature, the heart rate and the systolic blood pressure increased significantly, whereas the diastolic blood pressure fell slightly in both groups. However, the increase in systolic blood pressure was significantly lower in alcoholic men than in controls (p < 0.005). All these parameters returned to the basal levels after the 30 min rest period at room temperature. Hormonal data are given in Table 2; the basal levels of PRL were significantly higher (p < 0.005) in alcoholic subjects than in controls. After the sauna, there were no changes in the alcoholic group, whereas a significant increase was observed in normal subjects. Baseline plasma LH and FSH were similar in the two groups. No change was observed after sauna in either group.
Discussion The alcoholic men examined in this study show higher than normal basal levels of PRL and normal levels of LH and FSH after 5 weeks of abstinence. These results are in agreement with previous findings (5) which demonstrated increased levels of PRL and normal levels of LH and FSH in alcohol addicts. Alcoholic subjects show a disturbed hypothalamic control of PRL release, and a reduction of the Table 2 Basal values, at the end of the sauna and 30 min after sauna, of PlU, LH, FSH (mean f SEM) in alcoholic men and controls Basal
End of sauna
30 min after sauna
Pa WW Alcoholic men Controls
12.3 f 1.6 6.5 f 2.8
12.9 f 2.8 24.3 f 5.3*
11.8 f 2.1 8.3 f 4.8
LH W) Alcoholic men Controls
5.9 k 1.6 6.1 k 1.7
6.0 f 1.9 6.3 f 1.8
5.8 f 1.2 6.5 f 1.6
PSI-I WW Alcoholic men Controls
4.7 f 1.3 4.9 f 1.2
5.3 * 1.3 5.0 It 1.0
5.2 f 1.0 4.8 f 1.2
* Significantly different from basal values (p < 0.005)
IMPAIRED PRL RESPONSE
TO HYPERTHERML4
IN ALCOHOLIC
dopaminergic influence on the pituitary after alcohol withdrawal (8). This may be involved in the genesis of basal hyperprolactinemia. Increased estrogen levels might also play a role, but, given the mild alterations of liver function and the absence of cirrhosis in our subjects, this is in our view unlikely. In normal subjects, heat exposure in a sauna room is capable of inducing an increase in plasma PRL, which might be related to a possible role of the hormone in the regulation of water and electrolyte balance (9); FSH and LH, on the contrary, do not seem to be influenced by thermal stress, as reported also by others (7). In contrast, in alcoholic men PRL levels did not change under hyperthermic stress. Other researchers have found an impaired PRL response to hypoglycemia in chronic alcohol abusers (10). Likewise, a lack of PRL response to thermal stress has also been observed in former heroin addicts after a drug free period (1 1), a finding which was attributed to the impairment of the hypothalamic mechanisms controlling PRL secretion. There is evidence (12) that alcoholism is a condition comparable to a true state of addiction, since alcohol increases the formation of morphine-like alkaloids (or tetrahydropapaveralines), which are capable of interacting with the receptors for endogenous opioids. Alcohol can also act directly on specific brain opioid receptors ( 13). Chronic alcoholism may therefore be associated with functional alterations similar to those observed in chronic abusers of opioid substances (11). The altered PRL responsiveness to sauna might also result from the exhaustion of intracellular stores and refractoriness to exogenous stimuli, such as a reduced sensitivity to TRH (14). The hemodynamic alterations may reflect a direct ethanol-induced disruption of myocardial function, but a role of opioid-like substances such as tetrahydropapaveraline on the heart function and on the anatomic regulation of blood pressure may also be suspected, since specific opiate receptors have been identified in the heart and in the brain nuclei involved in cardiorespiratory control (15, 16).
MEN
207
References 1. Vescovi, P. P., Gerra, G., Pioli, G., Pedrazzoni, M., Maninetti, L. and Passeri, M. (1990). Circulating opioidpeptides during thermal stress. Horm. Met. res. 22: 44-49. 2. Vescovi, P. P., Michelini, M., Maninetti, L., Pedrazzoni, M., Magnani, G., Pezzarossa, A. and Passeri, M. (1991). Secretion ofbeta-endorphin, ACTH and cortisol atter hyperthermic stress in chronic alcoholics. Alcologia 3: 267-270. 3. Gavaler, J. S. and Van Thiel, D.H. Endocrine consequences of alcohol abuse. In: Nemeroff, C. B., Loosen, P. T. (ed) Handbook of Clinical Psychoneuroendocrinology. Wiley & Sons Press, Chapter 8, pp 195-208. 4. VLlimiiki, M., Salaspuro, M., Hiirkiinen, M. and Ylikahri, R. ( 1982). Liver damage and sex hormones in chronic male alcoholics. Clin. Endocrinol. (Oxf) 17: 469-477. 5. vIilim&ki. M., Pelkonen, R., Hiirkiinen, M., Tuomala, P., Koistinen, P., Roine, R. and Ylikahri, R. (1990). Pituitarygonadal hormones and adrenal androgens in noncirrhotic female alcoholics after cessation of alcohol intake. Europ. J. Clin. Invest. 20: 177-181. 6. Vescovi, P. P., Maninetti, L., Pedrazzoni, M.. Pioli. G., Girasole. P. and Passeri. M. (1990). Effects of sauna-induced hyperthe’rmia on pit&& secretion of prolactin and gonadotropin hormones. Neuroendocrinol. Len 12: 143147. I. Leppaluoto, J., Huttunen, P., Jirvonen, J., Vaanonen, A., Tuominen, M. and Vuori, J. (1986). Endocrine effects of repeated sauna bathing. Acta Physiol. Stand. 128: 467-472. 8. Rossetti, S. (199 1). Neurobiologia dell’alcolismo. In: Atti de1 Congresso “Alcool: patologia multimodale, turbe metaboliche, endocrine, nutrizionali ed epatiche. Parma, Italia, 3 1 Maggio 199 1. Abstract in press. 9. Bukmen, M. T. and Peake, G. T. (1973). Osmolar control of prolactin secretion in man. Science 24: 755-759. 10. Chalmers, R. J., Bennie, E. H., Johnson, R. H. and Masterton, G. (1978). Growth hormone, prolactin and corticosteroid __ . responses to insulin hypoglicaemia in alcoholics. Brit. Med. J. 1: 745-748. 11. Vescovi, P. P., Pedrazzoni, M.,Maninetti, L., Pioli, G., Gerra, G. and Passeri, M. (1990). Impaired prolactin response to hyperthermia in heroin addicts. Acta Endocrinol. (Copenh) 123: 619-621. 12. Davis, V. E. and Walsh, M. J. (1970). Alcohol, amines and alkaloids: a possible biochemical basis for alcohol addiction. Science 167: 1005-1007. 13. Tabakoff, B. and Hoffman, P. (1982). Alcohol interactions with brain opiate receptors. Life Sci. 32: 197-204. 14. Rodymark, K. S., Adner, H., Andersson, D. E. H., Austen, J. and Lamminpaa, S. (1984). Prolactin and thyrotropin responses to TRH and metoclopramide in men with chronic alcoholism. J. Clin. Endocrinol. Metab. 59: 595-600. 15. Kmmins, S. A., Faden, A. L. and Fevemstein,G. (1985). Diprenotphine in rat heart: modulation of binding sites in the brain. Biochem. Biophys. Res. Comm. 127: 120-123. 16. Khacttarudien, H., Lewis, M. E., Shafer, M. K. M. and Watson, J. J. (1985). Anatomy of the CMS opioid system. Trends in Neuroscience 8: 11-19.
Impaired PRL Response to Hyperthermia Alcoholic Men
in
P. P. VESCOVI, M. PEDRAZZONI, M. MICHELINI, L. MANINETTI and M. PASSERI Ciinica Medica Genera/e e Terapia Medica, to PPV)
Universita’
di Parma, itaiy (Reprint requests
Abstract -The aim of this study was to evaluate the release of PRL to sauna-induced hyperthermia in 10 chronically alcohol-addicted male subjects after a few weeks of abstinence. In contrast with normal men the alcoholic men showed higher basal levels of PRL and the exposure to hyperthermic stress did not stimulate in PRL secretion. These results indicate that chronic alcohol abuse is associated with functional pituitary alterations similar to other states of addiction. Introduction In previous studies we have shown that saunainduced hyperthermia stimulates the secretion of beta-endorphin and ACTH in normal men (l), but not in chronic alcoholics after a few weeks of abstinence (2). Chronic alcohol abuse has several important effects on pituitary function (3); in particular, some authors have reported a stimulatory effect on PRL secretion (4,5). Since PRL levels also increase after thermal stress in normal men (6, 7), we have examined the response of plasma PRL to heat exposure in a sauna room in a group of alcoholic men after a few weeks of abstinence.
Subjects and Methods We have examined 10 alcohol-addicted male subjects (30-49 years old) who gave informed consent Date received 10 April 1992 Date accepted 13 April 1992
to the study. The subjects were involved in a longterm rehabilitation program and were studied in a clinical research center after 5 weeks of complete alcohol abstinence. The duration of drinking abuse varied from 4-14 years; the subjects consumed on average 178 f 40 g/d of alcohol. Their relative body weight ranged from 83 to 118% of normal. No patient had clinical evidence of psychiatric or organic disease, or took any medication (especially psychotropic drugs) in the 3 weeks before the study. Liver abnormalities were mild: SGOT = 56 f 20 UIK, SGPT = 34 + 16 UIK, gamma-GT = 137 f 49 U/l. The presence of cirrhosis was excluded by ultrasound examination and, in dubious cases, by biopsy. Eight normal men, who usually consumed less than 30 g/d and were requested to totally abstain from alcohol both during the study and in the 2 weeks before it, served as controls. Their age ranged from 23-50 years and their body weight was normal (relative body weight 85- 110%). The subjects were studied at 8.00 a.m., after an overnight fast. After inserting an indwelling Teflon
21)s
206
NEUROPEPTIDES
catheter into an antecubital vein, the subjects were allowed to rest in a sitting position for half an hour. Then they sat for 30 mm in a sauna room where the temperature was 90°C and the relative humidity 10%. After the sauna the subjects remained in a sitting position for an additional 30 min at room temperature. Pulse rate, sublingual temperature and blood pressure were recorded just before and immediately after the sauna and after the 30 minrest period at room temperature. At the same time points venous blood was drawn into vacutainer tubes and immediately centrifuged at 4°C. Plasma was frozen within 10 min of collection and stored at -20°C until assayed for PRL, LH and FSH. PRL, LH and FSH were measured with an immunoradiometric method using commercial kits (Boehringer-Mannheim). The sensitivity of the PRL assay is 1 ngml and the intra- and inter- assay coefficients of variations (CV) are 3% and 7% respectively. The sensitivity of both LH and FSH assay is 0.5 mUI/ml and the intra- and inter-assay CVs are 4% and 7% respectively. The comparisons between the basal levels of the parameters examined in the two groups were made using the Mann-Whitney test. The hormonal variations after sauna were tested by the Wilcoxon matched-pair test. Results are given as mean f SEM. Table 1 Changesin body temperature and cardiovascular parameters (mean f SEM) in alcoholic men and controls
HEARTRATE (beatdmin) Alcoholic men Controls SYSTOLIC BLOOD PRBSSURE (mmHg) Alcoholic men Controls DIASTOLIC BLOOD PRESSURE @mHg) Alcoholic men Controls
Basal
End of sauna
7916 74f6
141 f 5* 137 f 7*
79f7 76k4
125f6 122k4
130 * 5*t 158 f 6*
121 f6 115f4
79 f 3 78 f 3
SUBLINGUAL TEMPERATURE (“0 Alcoholic men ’ ’ 36.4 f 0.3 Controls 36.7 k 0.2
71*3* 66k4
39.4 f 0.4 39.4 f 0.3
30 min afrer sauna
77*4 76f4
36.3 f 0.3 36.6 f 0.4
* Significantly different from basal values (p < 0.05) .~ t SignifIcantIy different from control group @ < 0.05)
Results The changes in sublingual temperature, pulse rate and blood pressure during the experiments are shown in Table 1. At the end of the sauna the sublingual temperature, the heart rate and the systolic blood pressure increased significantly, whereas the diastolic blood pressure fell slightly in both groups. However, the increase in systolic blood pressure was significantly lower in alcoholic men than in controls (p < 0.005). All these parameters returned to the basal levels after the 30 min rest period at room temperature. Hormonal data are given in Table 2; the basal levels of PRL were significantly higher (p < 0.005) in alcoholic subjects than in controls. After the sauna, there were no changes in the alcoholic group, whereas a significant increase was observed in normal subjects. Baseline plasma LH and FSH were similar in the two groups. No change was observed after sauna in either group.
Discussion The alcoholic men examined in this study show higher than normal basal levels of PRL and normal levels of LH and FSH after 5 weeks of abstinence. These results are in agreement with previous findings (5) which demonstrated increased levels of PRL and normal levels of LH and FSH in alcohol addicts. Alcoholic subjects show a disturbed hypothalamic control of PRL release, and a reduction of the Table 2 Basal values, at the end of the sauna and 30 min after sauna, of PlU, LH, FSH (mean f SEM) in alcoholic men and controls Basal
End of sauna
30 min after sauna
Pa WW Alcoholic men Controls
12.3 f 1.6 6.5 f 2.8
12.9 f 2.8 24.3 f 5.3*
11.8 f 2.1 8.3 f 4.8
LH W) Alcoholic men Controls
5.9 k 1.6 6.1 k 1.7
6.0 f 1.9 6.3 f 1.8
5.8 f 1.2 6.5 f 1.6
PSI-I WW Alcoholic men Controls
4.7 f 1.3 4.9 f 1.2
5.3 * 1.3 5.0 It 1.0
5.2 f 1.0 4.8 f 1.2
* Significantly different from basal values (p < 0.005)
IMPAIRED PRL RESPONSE
TO HYPERTHERML4
IN ALCOHOLIC
dopaminergic influence on the pituitary after alcohol withdrawal (8). This may be involved in the genesis of basal hyperprolactinemia. Increased estrogen levels might also play a role, but, given the mild alterations of liver function and the absence of cirrhosis in our subjects, this is in our view unlikely. In normal subjects, heat exposure in a sauna room is capable of inducing an increase in plasma PRL, which might be related to a possible role of the hormone in the regulation of water and electrolyte balance (9); FSH and LH, on the contrary, do not seem to be influenced by thermal stress, as reported also by others (7). In contrast, in alcoholic men PRL levels did not change under hyperthermic stress. Other researchers have found an impaired PRL response to hypoglycemia in chronic alcohol abusers (10). Likewise, a lack of PRL response to thermal stress has also been observed in former heroin addicts after a drug free period (1 1), a finding which was attributed to the impairment of the hypothalamic mechanisms controlling PRL secretion. There is evidence (12) that alcoholism is a condition comparable to a true state of addiction, since alcohol increases the formation of morphine-like alkaloids (or tetrahydropapaveralines), which are capable of interacting with the receptors for endogenous opioids. Alcohol can also act directly on specific brain opioid receptors ( 13). Chronic alcoholism may therefore be associated with functional alterations similar to those observed in chronic abusers of opioid substances (11). The altered PRL responsiveness to sauna might also result from the exhaustion of intracellular stores and refractoriness to exogenous stimuli, such as a reduced sensitivity to TRH (14). The hemodynamic alterations may reflect a direct ethanol-induced disruption of myocardial function, but a role of opioid-like substances such as tetrahydropapaveraline on the heart function and on the anatomic regulation of blood pressure may also be suspected, since specific opiate receptors have been identified in the heart and in the brain nuclei involved in cardiorespiratory control (15, 16).
MEN
207
References 1. Vescovi, P. P., Gerra, G., Pioli, G., Pedrazzoni, M., Maninetti, L. and Passeri, M. (1990). Circulating opioidpeptides during thermal stress. Horm. Met. res. 22: 44-49. 2. Vescovi, P. P., Michelini, M., Maninetti, L., Pedrazzoni, M., Magnani, G., Pezzarossa, A. and Passeri, M. (1991). Secretion ofbeta-endorphin, ACTH and cortisol atter hyperthermic stress in chronic alcoholics. Alcologia 3: 267-270. 3. Gavaler, J. S. and Van Thiel, D.H. Endocrine consequences of alcohol abuse. In: Nemeroff, C. B., Loosen, P. T. (ed) Handbook of Clinical Psychoneuroendocrinology. Wiley & Sons Press, Chapter 8, pp 195-208. 4. VLlimiiki, M., Salaspuro, M., Hiirkiinen, M. and Ylikahri, R. ( 1982). Liver damage and sex hormones in chronic male alcoholics. Clin. Endocrinol. (Oxf) 17: 469-477. 5. vIilim&ki. M., Pelkonen, R., Hiirkiinen, M., Tuomala, P., Koistinen, P., Roine, R. and Ylikahri, R. (1990). Pituitarygonadal hormones and adrenal androgens in noncirrhotic female alcoholics after cessation of alcohol intake. Europ. J. Clin. Invest. 20: 177-181. 6. Vescovi, P. P., Maninetti, L., Pedrazzoni, M.. Pioli. G., Girasole. P. and Passeri. M. (1990). Effects of sauna-induced hyperthe’rmia on pit&& secretion of prolactin and gonadotropin hormones. Neuroendocrinol. Len 12: 143147. I. Leppaluoto, J., Huttunen, P., Jirvonen, J., Vaanonen, A., Tuominen, M. and Vuori, J. (1986). Endocrine effects of repeated sauna bathing. Acta Physiol. Stand. 128: 467-472. 8. Rossetti, S. (199 1). Neurobiologia dell’alcolismo. In: Atti de1 Congresso “Alcool: patologia multimodale, turbe metaboliche, endocrine, nutrizionali ed epatiche. Parma, Italia, 3 1 Maggio 199 1. Abstract in press. 9. Bukmen, M. T. and Peake, G. T. (1973). Osmolar control of prolactin secretion in man. Science 24: 755-759. 10. Chalmers, R. J., Bennie, E. H., Johnson, R. H. and Masterton, G. (1978). Growth hormone, prolactin and corticosteroid __ . responses to insulin hypoglicaemia in alcoholics. Brit. Med. J. 1: 745-748. 11. Vescovi, P. P., Pedrazzoni, M.,Maninetti, L., Pioli, G., Gerra, G. and Passeri, M. (1990). Impaired prolactin response to hyperthermia in heroin addicts. Acta Endocrinol. (Copenh) 123: 619-621. 12. Davis, V. E. and Walsh, M. J. (1970). Alcohol, amines and alkaloids: a possible biochemical basis for alcohol addiction. Science 167: 1005-1007. 13. Tabakoff, B. and Hoffman, P. (1982). Alcohol interactions with brain opiate receptors. Life Sci. 32: 197-204. 14. Rodymark, K. S., Adner, H., Andersson, D. E. H., Austen, J. and Lamminpaa, S. (1984). Prolactin and thyrotropin responses to TRH and metoclopramide in men with chronic alcoholism. J. Clin. Endocrinol. Metab. 59: 595-600. 15. Kmmins, S. A., Faden, A. L. and Fevemstein,G. (1985). Diprenotphine in rat heart: modulation of binding sites in the brain. Biochem. Biophys. Res. Comm. 127: 120-123. 16. Khacttarudien, H., Lewis, M. E., Shafer, M. K. M. and Watson, J. J. (1985). Anatomy of the CMS opioid system. Trends in Neuroscience 8: 11-19.
