Growth Hormone and Prolactin Responses to ThyrotropinReleasing Hormone in Patients with Severe Liver Disease ALBERTO E, PANERAI, FRANCESCO SALERNO,* MIRKO MANNESCHI,* DANIELA COCCHI, AND EUGENIO E. MULLERf Departments of Pharmacology (1st Chair) and ^Experimental Endocrinology, and *Clinica Medica III, University of Milan, Milan, Italy in controls. Mean baseline GH levels were higher in patients than in controls. An exaggerated and sustained PRL rise was present after TRH in the subjects with liver disease, whose mean baseline plasma PRL levels were within normal range. (J Clin Endocrinol Metab 45: 134, 1977)

ABSTRACT. Thyrotropin-releasing hormone (TRH) was administered iv to 10 patients with severe liver disease and 10 control subjects. Injection of 400 ptg TRH as a bolus induced in 7 out of 10 patients a clear-cut GH rise (s*10 ng/ml) occurring 15-120 min after the injection, and no effect on GH levels

I

N NORMAL human beings, administration of thyrotropin-releasing hormone (TRH) does not evoke growth hormone release (1,2). In several abnormal states, however, e.g., acromegaly (3), renal failure (4), mental depression (5), and anorexia nervosa (6), TRH elicits release of growth hormone. Interestingly, most of these conditions are characterized by high circulating levels of GH and impaired and/or paradoxical GH responses to insulin hypoglycemia or glucose loading (7-9). High fasting concentrations of GH and lack of suppression or paradoxical GH rises after glucose are seen also during chronic hepatitis (10-12). To ascertain if the abnormality in the release of GH of the subjects with liver disease was similarly associated with a positive GH response to TRH, the latter was administered to a group of patients with severe liver disease and the GH response was evaluated. In addition, the prolactin (PRL) response to TRH was studied in the same subjects. Patients and Methods Table 1 gives clinical and laboratory characteristics of the patients investigated (9 men and 1 women in the 1st experiment; 5 men and 1 woman in the 2nd experiment). Severe liver Received September 22, 1976. Request for reprints to: Dr. E. E. Miiller, Department of Experimental Endocrinology, Via Vanvitelli 32, University of Milan, Milan 20129, Italy.

disease was clearly established by biochemical

and histological criteria. No patient was obese or gave a family history of diabetes mellitus. Clinical signs of hyperestrogenism were present in some of patients. In addition, 10 nonobese hospitalized patients (9 men, 1 woman) without endocrine or metabolic disease were selected as controls. The groups were matched as closely as possible and there was no significant difference between age and weight of patients and controls. The experiments were always performed at 0900 and 0930 h, after an overnight fast and at least 1 h of bed rest. An iv catheter was inserted in a forearm vein 30 min prior to TRH administration and kept open by a slow infusion of 0.9% NaCl solution. After baseline blood samples were taken (—30, 0 min) 400 ;ug of synthetic TRH (Hoffmann La Roche, Basel, Switzerland) was given iv over 30 sec and further blood samples were obtained 15, 30, 45, 60, 90 and 120 min later. In a second experiment, 6 patients with severe liver disease, whose laboratory and clinical characteristics were similar to those of the 10 patients given TRH (Table 1), received under identical experimental conditions an iv injection of 10 ml of normal saline at time 0; blood samples were obtained at the same time intervals for GH determinations. No side effects were noted after TRH injection. Plasma GH and PRL were assayed by double antibody radioimmunoassays (13) using reagents kindly supplied by NIAMDD, Bethesda, Md. The GH and PRL standards were NIH-GH-HS 20196G and NIH-PRL-VLS #3, respectively. Doses up to 100 ng/ml of GH and PRL did not cross-react in the reciprocal assay. Normal

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GH AND PRL IN LIVER DISEASE ranges for baseline GH levels are in this laboratory 0-3 ng/ml for both men and women and baseline PRL levels 2-8 ng/ml for men and 4-12 ng/ml for women. Total and free tryptophan were evaluated according to the methods of Denkla and Dewey (14) and Tagliamonte et al. (15), respectively.

Results

Growth hormone Mean baseline GH values were significantly elevated in the 10 patients with chronic liver disease when compared to control subjects (3.8 ±1.0 us. 0.8 ± 0.4 ng/ml, respectively, P < 0.02) (Table 2). Of the 10 patients, 5 (nos. 1, 2, 4, 5, 7) had GH values higher than 5 ng/ml, while the remaining 5 had GH values within the normal range for male subjects in this laboratory (Table 2). A clear-cut GH rise (2=10 ng/ml) was present following TRH in 7 out of 10 patients (nos. 1, 2, 5, 6, 7, 8, 10); a rise of 6 ng/ml was present in patient no. 3 and inconsistent GH rises in patients nos. 4 and 9 (Table 2). The mean (±SE) maximum value of plasma GH following TRH in the 10 patients

was significantly higher than that of control subjects (16.3 ± 2.9 ng/ml vs. 1.9 ± 0.3 ng/ml, P < 0.01). In 4 out of 7 "responders," the GH peaks were present between 60 and 120 min, in the 3 remaining patients between 15 and 30 min. In control subjects, TRH did not induce any GH rise. No significant change in plasma GH was present i n 6 patients with chronic liver disease after the injection of saline (Table 3). Prolactin Mean baseline PRL values were not significantly higher in patients vs. control subjects (12.6 ±2.1 vs. 8.1 ± 1.4 ng/ml, respectively, NS). Of the 10 patients, 3 (nos. 5, 7,10) had PRL values higher than 15 ng/ml, 3 (nos. 1, 2, 4) higher than 10 ng/ml, while the remaining 4 patients had PRL values within the normal range for male subjects in this laboratory. After TRH administration, plasma PRL values rose to levels significantly higher in patients than in control subjects (Pig iv

-TIME (MIN)

magnitude of the GH rises (mean increase ~ 3-fold over baseline values) but also by the observation that no fluctuations in GH levels were detected in patients with liver disease during infusion with saline. Since no stressful conditions were found in these patients, it is also unlikely that the elevated plasma GH levels after TRH resulted from a non-specific stress. Similar to the delayed GH responses found in 4 patients of this study, delayed GH responses to TRH (90-120 min) have been reported by Maeda et al. (5) in 3 out of 8 patients with mental depression. As already reported by other investigators (10, 16, 17), mean baseline GH values were elevated in patients with liver disease. The normal total metabolic clearance rate and hepatic clearance of GH in cirrhotic patients (16) make it unlikely that the elevated peripheral levels of GH may be due to altered metabolic disposal of the hormone, but instead suggest actual GH hypersecretion (17). The release of GH by TRH observed in patients with chronic liver disease expands the list of pathologic conditions in which this event takes place (see Introduction).

In these disease states, as well as in chronic hepatic disease, abnormal GH responses to variations of glucose homeostasis are often encountered; these events have been ascribed to disturbances of the central nervous system (CNS) (18). Interestingly, in hepatic failure a disturbance of brain serotonin (5-HT) turnover, due to an increased passage of tryptophan, the 5-HT amino acid precursor, from plasma into the brain, has been postulated (19). Indeed, very high concentrations of "free" tryptophan and 5-hydroxyindoleacetic acid, the main 5-HT catabolic product, were found in the cerebrospinal fluid of cirrhotic patients (20). In our patients, plasma levels of "free" tryptophan were elevated and a positive correlation was found between peak levels of GH after TRH and plasma "free" tryptophan. It has also been suggested that in hepatic failure, amines {e.g., tyramine) produced by bacterial action in the gut enter the general circulation and may become "false neurotransmitters" in the brain, displacing the normal adrenergic transmitters dopamine and norepinephrine (21). In at least two other pathologic conditions, e.g., mental depression and anorexia nervosa, in which

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both impaired GH responses to usual challenges (22,9) and nonspecific release of GH by TRH (5,6) are present, a disturbance of brain 5-HT (23,24) and/or brain catecholamine (25,26) metabolism has been suspected. On the basis of the foregoing, the nonspecific release of GH by TRH may be a hallmark of conditions in which the normal CNS influences for the control of GH secretion have been temporarily or permanently impaired. In support of this view are the findings that TRH releases GH also in the hypophysectomized rat bearing a pituitary transplant (27) or the intact rat with extensive hypothalamic lesions (28). Obviously other reasons, some of which are noted below, may be invoked to explain the abnormality in the release of GH found in patients with chronic liver disease. Mean baseline plasma PRL levels were not significantly higher in patients with hepatic failure; however, in some of them, PRL levels were elevated and positive and negative correlations, respectively, were found with SGOT and choline esterase, parameters which reflect the degree of the liver disease. Since brain serotonin has been implicated in a positive manner in the control of prolactin secretion (29,30), it is of interest that a positive correlation was found between baseline PRL values and plasma "free" tryptophan, an indicator of brain 5-HT metabolism (15,31). One factor which has to be considered when evaluating plasma GH and PRL concentrations in patients with chronic liver disease is the possible role of estrogens. Plasma growth hormone and prolactin concentrations are elevated by hyperestrogenemia (32,33), and that was the explanation given by Hernandez et al. (11) for the elevated fasting GH concentrations in some of their patients with active cirrhosis. In our study, the presence of hyperestrogenemia may be the reason for the elevated baseline GH and PRL levels found in some patients, even though no positive correla-

tion existed between these latter two parameters. Increased estrogen levels, however, by no means accounted for the rise of GH after TRH administration; no significant GH rise after TRH was in fact observed in male subjects after estrogen administration, although baseline GH levels were elevated following the treatment (33). Instead, a state of hyperestrogenemia in the male cirrhotic patients of this study may account, at least in part, for the female type of the PRL response to TRH. However, in our study, plasma PRL titers were still considerably elevated 120 min after TRH administration, a time at which in normal women PRL is back to baseline values (33,34). Therefore, a decreased degradation of PRL in our patients with liver disease, perhaps due to a reduced number of lactogenic receptors in the liver (35), cannot be excluded as a contributing factor to the persistence of the raised PRL levels. An exaggerated and sustained PRL rise after TRH similar to that reported in our study, has been recently observed in male cirrhotic patients by Zanoboni and Zanoboni-Muciaccia (36). In conclusion, while it is suggested that the rise of GH by TRH may be primarily due to a disturbance of the neuroendocrine control of GH secretion, the exaggerated PRL rise after the tripeptide seems more likely ascribable to peripheral factors (estrogen, metabolic disposal). However, the existence of a common mechanism for the two events cannot be excluded at present; interestingly, a positive correlation was found between the absolute increases of GH and PRL after TRH. Acknowledgments The authors wish to thank Mrs. Fosca De Vita for technical assistance and Miss Delia Deriu for secretarial help. The generous supply of TRH by Prodotti Roche, Milan, Italy, is gratefully acknowledged.

References 1. Anderson, M. S., C. Y. Bowers, A. J. Kastin, D. S. Schalch, A. V. Schally, P. J. Snyder, R. D. Utiger,

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GH AND PRL IN LIVER DISEASE J. F. Wilber, and A. J. Wise, Synthetic thyrotropin releasing hormone, N Engl J Med 285: 1279, 1971. 2. Schalch, D. S., D. Gonzales-Barcena, A. J. Kastin, A. V. Schally, and L. A. Lee, Abnormalities in the release of TSH in response to thyrotropinreleasing hormone (TRH) in patients with disorders of the pituitary, hypothalamus and basal ganglia, 7 Clin Endocrinol Metab 35: 609, 1972. 3. Irie, M., and T. Tsushima, Increase of serum growth hormone concentration following thyrotropinreleasing hormone injection in patients with acromegaly or gigantism, J Clin Endocrinol Metab 35: 97, 1972. 4. Gonzales-Barcena, D., A. J. Kastin, D. S. Schalch, M. Torres-Zamora, E. Perez-Pasten, A. Kato, and A. V. Schally, Responses to thyrotropin-releasing hormone in patients with renal failure and after infusion in normal men,/ Clin Endocrinol Metab 36: 117, 1973. 5. Maeda, K., Y. Kato, S. Ohgo, K. Chihara, Y. Yoshimoto, N. Yamaguchi, S. Kuromaru, and H. Imura, Growth hormone and prolactin release after injection of thyrotropin-releasing hormone in patients with depression,/ Clin Endocrinol Metab 40: 501, 1975. 6. Maeda, K., Y. Kato, N. Yamaguchi, K. Chihara, S. Ohgo, Y. Okanishi, Y. Yoshimoto, K. Moridera, S. Kuromaru, and H. Imura, Growth hormone release following thyrotropin-releasing hormone injection into patients with anorexia nervosa, Ada Endocrinol (Kbh) 81: 1, 1976. 7. Beck, P., M. L. Parker, and W. H. Daughaday, Paradoxical hypersecretion of growth hormone in response to glucose. / Clin Endocrinol Metab 26: 463, 1966. 8. Wright, A. D., C. Lowly, T. Russel Fraser, I. M. Spitz, A. H. Rubinstein, and I. Bersohn, Serum growth hormone and glucose intolerance in renal failure, Lancet 2: 798, 1968. 9. Brauman, H., and F. Gregoire, The growth hormone response to insulin-induced hypoglycemia in anorexia nervosa and control underweight or normal subjects, EurJ Clin Invest 5: 289, 1975. 10. Becker, M. D., G. C. Cook, and A. D. Wright, Paradoxical elevation of growth hormone in active chronic hepatitis, Lancet 2: 1035, 1969. 11. Hernandez, A., E. Zorrilla, and H. Gershberg, Decreased insulin production, elevated growth hormone levels, and glucose intolerance in liver disease,/ Lab Clin Med 73: 25, 1969. 12. Podolsky, S., H. J. Zimmerman, B. A. Burrows, J. A. Cardarelli, and C. G. Pattavina, Potassium depletion in hepatic cirrhosis. A reversible cause of impaired growth hromone and insulin response to stimulation, N EnglJ Med 288: 644, 1973. 13. Utiger, R. D., M. L. Parker, and W. H. Daughaday, Studies on human growth hormone. I. A

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radioimmunoassay for human growth hormone, / Clin Invest 41: 254, 1962. 14. Denkla, W. D., and H. K. Dewey, The determination of tryptophan in plasma, liver and urine, / Lab Clin Med 69: 160, 1967. 15. Tagliamonte, A., G. Biggio, L. Vargiu, and G. L. Gessa, Free tryptophan in serum controls brain tryptophan level and serotonin synthesis, Life Sci 12: 277, 1973. 16. Cameron, D. P., H. G. Burger, K. J. Catt, E. Gordon, and J. Watts, Metabolic clearance of human growth hormone in patients with hepatic and renal failure, and in the isolated perfused pig liver, Metabolism 21: 895, 1972. 17. Pimstone, B. L., D. Le Roith, S. Epstein, and S. Kronheim, Disappearance rates of plasma growth hormone after intravenous somatostatin in renal and liver disease, / Clin Endocrinol Metab 41: 392, 1975. 18. Reichlin, S., Regulation of somatotrophic hormone secretion, In Knobil, E., and W. H. Sawyer (eds.), The Pituitary Gland and its Neuroendocrine Control, part 2, American Physiological Society, Washington, D.C., 1974, p. 405. 19. Munro, H. N., J. D. Femstrom, and R. J. Wurtman, Insulin, plasma amino acid imbalance and hepatic coma, Lancet 1: 722, 1975. 20. Lai, S., S. N. Young, and T. L. Sourkes, 5-hydroxytryptamine and hepatic coma, Lancet 2: 979, 1975. 21. Fischer, J. E., and R. J. Baldessarini, False neurotransmitters and hepatic failure, Lancet 2: 75,1971. 22. Sachar, E. J., G. Mushrush, M. Perlow, E. D. Weitzman, and J. Sassin, Growth hormone response to L-Dopa in depressed patients, Science 178: 1304, 1972. 23. Aschroft, G. W., T. B. B. Crawford, D. Eccleston, D. F. Sharman, E. J. Mac Dougall, J. B. Stauton, and J. K. Binns, 5-hydroxyindole compounds in the cerebrospinal fluid of patients with psychiatric or neurological disease, Lancet 2: 1049, 1966. 24. Shaw, D. M., F. E. Camps, and E. G. Eccleston, 5-hydroxytryptamine in the hind brain of depressive suicides, Br J Psychiatry 113: 1407, 1967. 25. Schildkraut, J. J., Catecholamine metabolism and affective disorders: studies of MHPG excretion, In Usdin, E., and S. Snyder (eds.), Frontiers in Catecholamine Research, Pergamon Press, New York, 1973, p. 1165. 26. Barry, V. C , and H. L. Klawans, On the role of dopamine in the pathophysiology of anorexia nervosa,/ Neural Trans 38: 107, 1976. 27. Udeschini, G., D. Cocchi, A. E. Panerai, I. Gil-Ad, G. L. Rossi, P. G. Chiodini, A. Liuzzi, and E. E. Miiller, Stimulation of growth hormone release by thyrotropin releasing hormone in the hypophysectomized rat bearing an ectopic pituitary, Endocrinology 98: 807, 1976. 28. Miiller, E. E., A. E. Panerai, D. Cocchi, I. Gil-

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mals, In Pasteels, J. L., and C. Robyn (eds.), Excerpta Medica, Amsterdam, 1973, p. 105. Carlson, H. E., L. S. Jacobs, and W. H. Daughaday, Growth hormone, thyrotropin and prolactin responses to thyrotropin-releasing hormone following diethylstilbestrol pretreatment, J Clin Endocrinol Metab 37: 488, 1973. Noel, G. L., H. K. Suh, and A. G. Frantz, LDopa suppression of TRH stimulated prolactin release in man, J Clin Endocrinol Metab 36: 1255, 1973. Friesen, H., G. Tolis, R. Shiu, and P. Hwang, Studies on human prolactin: chemistry, radioreceptor-assay and clinical significance, In Pasteels, J., and C. Robyn (eds.), Human Prolactin, Excerpta Medica Foundation, Amsterdam, 1973, p. 11. Zanoboni, A., and W. Zanoboni-Muciaccia, Gynaecomastia in alcoholic cirrhosis, Lancet 2: 876, 1975.

National Institute of Arthritis, Metabolism, and Digestive Diseases hGH, hFSH and hLH These hormones are available for clinical investigative use within the USA. hGH (12 IU/vial) is available not only for the study of hypopituitarism but also for other human research studies (burns, osteoporosis, liver failure, hypoglycemia, etc.). hFSH (50 IU/vial) and hLH (2200 IU per vial) are available for gonadotropin and gonadal studies. For further information, contact the Director: Doctor S. Raiti, National Pituitary Agency, Suite 503-9, 210 West Fayette Street, Baltimore, Maryland 21201.

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Growth hormone and prolactin responses to thyrotropin-releasing hormone in patients with severe liver disease.

Growth Hormone and Prolactin Responses to ThyrotropinReleasing Hormone in Patients with Severe Liver Disease ALBERTO E, PANERAI, FRANCESCO SALERNO,* M...
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