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Effects of acute administration of recombinant interferon alpha 2b on pituitary hormone secretion in patients with chronic active hepatitis
CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 5, NOVEMBER 1992
EFFECTS OF ACUTE ADMINISTRATION OF RECOMBINANT I N T E R F E R O N A L P H A 2b ON PITUITARY HORMONE SECRETION IN PATIENTS WITH CHRONIC ACTIVE HEPATITIS T. BARRECA, A. PICCIOTTO, R. FRANCESCHINI, G. VARAGONA, G. CORSINI, F. VALLE, A. CATALDI, S. D'AGOSTINO, AND E. ROLANDI Department of lnternal Medicine, University of Genoa, Genoa, Italy
ABSTRACT The effect of a single i n t r a m u s c u l a r (IM) dose o f 10 x 106 IU o f rec o m b i n a n t i n t e r f e r o n alpha-2b ( a l p h a I F N ) on a d r e n o c o r t i c o t r o p i n (ACTH), b e t a - e n d o r p h i n ( ~ - E P ) , t h y r o t r o p i n (TSH), g r o w t h h o r m o n e (GH), l u t e o t r o p i n (LH), and p r o l a c t i n ( P R L ) was e v a l u a t e d in seven p a t i e n t s s u f f e r i n g f r o m c h r o n i c viral h e p a t i t i s (CVH). A l p h a I F N increased ACTH (from 11.2 -+ 1.1 ng/L to 16.3 - 2.6 ng/L) a n d ~ - E P (from 25.0 -+ 1.9 ng/L to 37.6 --- 1.7 ng/L) p l a s m a c o n c e n t r a t i o n s and lowered p l a s m a TSH c o n c e n t r a t i o n s (from 2.4 -+ 0.4 mIU/L to 1.0 --- 0.2 mIU/L). These effects were recorded between the f o u r t h a n d the 12th hour after alpha IFN administration and occurred without significant v a r i a t i o n s in t h e r e m a i n i n g p l a s m a h o r m o n a l levels. In seven addit i o n a l p a t i e n t s who received a 3 x 10e-IU IM dose o f t h e s a m e I F N , no s i g n i f i c a n t v a r i a t i o n s in ACTH, ~ - E P , or TSH p l a s m a levels were found. D a t a i n d i c a t e t h a t a l p h a I F N m a y influence t h e n e u r a l mecha n i s m s c o n t r o l l i n g a n t e r i o r p i t u i t a r y secretion. However, h i g h a l p h a I F N doses are r e q u i r e d for this effect to occur. INTRODUCTION
Interferon (IFN) is a family of hormone-like peptides produced by the immune system in response to viral infections. IFN has many biological activities, including antiviral, antiproliferative, and immunoregulatory effects. 1 IFN also has a variety of endocrine effects; in particular, IFN inhibits the secretion of sex steroids, 2'3 thyroid hormones, a and insulin, 5 and stimulates that of cortisol 6-s and norepinephrine, s Data regarding the effects of IFN on pituitary hormonal release are at present sparse and not always in agreement; indeed, IFN administration in man has induced adrenocorticotropin (ACTH) release in some studies, 9-11 b u t not in others. 7'12 Furthermore, IFN-induced stimulation of growth hormone (GH) secretion 9'11 and inhibition of thyrotropin (TSH) secretion 13 has been found in some studies, whereas in others the secretion of these hormones Address correspondenceto: Prof. T. Barreca, Department of Internal Medicine, Viale Benedetto XV, 6, 16132 Genova, Italy. Received for publication on July 7, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted. 695
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INTERFERON AND ANTERIOR PITUITARY HORMONES
was not significantly affected by IFN. 3'9 Finally, prolactin (PRL) and luteotropin (LH) secretions do not appear to be influenced by IFN in vivo. 3'11 However, regarding PRL secretion, in vitro studies have shown both stimulatory 14 and inhibitory 15 IFN effects. A recent animal study ~6 showing absence of pituitary effects of IFN when administered systemically but stimulation of ACTH and inhibition of GH and TSH secretion when administered intracerebroventricularly indicates the possibility that IFN may influence the central nervous system (CNS), thereby affecting the hypothalamic centers controlling the pituitary secretory function. Within the IFN family, recombinant IFN alpha 2b has been shown to be the most active on the CNS, as demonstrated in animals by electroencephalographic recording experiments. ~7'~s This IFN, in recent years, has been employed with good results in the treatment of chronic viral hepatitis (CVH). 19'2° In the present study, using recombinant IFN alpha 2b, we evaluated pituitary secretion in a group of CVH patients undergoing IFN treatment for this disease. PATIENTSAND METHODS The study was performed in 14 untreated CVH patients (aged 32 to 55 years). All patients were hospitalized for the study and informed consent was obtained from each one prior to participation. After a preliminary placebo study, seven patients (four men and three postmenopausal women) received a single intramuscular (IM) dose of 10 x 106 IU of recombinant IFN alpha 2b between 8 and 9 AM and seven (five men and two women) received a single IM dose of 3 x 106 IU of the same IFN at the same time in the morning. Blood samples were drawn through an indwelling catheter in an antecubital vein at baseline and every two hours for 12 hours after IFN administration. All patients were in bed resting and did not eat anything during the entire study period. Blood samples were collected in icechilled propylene tubes containing EDTA (1.5 mg/ml) and Aprotinin (500 IU/ml). Plasma obtained by centrifugation was frozen and stored at - 4 0 °C until assayed. Plasma immunoreactive beta-endorphin (~-EP) and ACTH were determined by radioimmunoassay (RIA) after preliminary extraction and concentration by immunoafflnity chromatography; the mean recovery rate for ~-EP and ACTH was 94% and 89%, respectively. The smallest detectable concentrations were 9 ng/L and 3.5 ng/L for ~-EP and ACTH, respectively; the intra- and interassay coefficients of variation were for ~-EP 6.5% and 18.1%, respectively, and for ACTH 8.5% and 19.5%, respectively. Plasma GH and PRL were measured by radioimmunoassay; plasma TSH and LH were determined by immunoradiometric assay methods. Sensitivity and intra- and interassay coefficients of variation for GH were: 0.6 696
T. BARRECAET AL.
mIU/L, 4.4% and 8.8%; for PRL: 30 mIU/L, 6.6% and 7.1%; for TSH: 0.10 mIU/L, 5.9% and 7.6%; and for LH: 0.1 IU/L, 5.7% and 6.4%, respectively. Analysis of variance (ANOVA) followed by multiple range t e s t (Scheffe test) was performed to analyze the kinetics (0 to 12 hours) of hormone levels and to assess the significance of differences between the plasma values recorded at each time point of the study and the pretreatment values. The Mann-Whitney U statistic test was also used to determine statistical differences between the placebo and the treatment groups. RESULTS
Data are expressed as mean ± SEM and are illustrated in the figure. After administration of 10 × 106 IU of IFN a significant (F = 7.220; P < 0.01) plasma ~-EP increase occurred. Plasma ~-EP values (25.0 ± 1.9 ng/L at baseline) were higher at 4 hours (37.6 ± 1.7 ng/L) and remained significantly elevated (P < 0.05 versus baseline and placebo) until 5 hours (36.5 -+ 1.9 ng/L). Plasma ACTH (11.2 ± 1.1 ng/L at baseline) showed a similar pattern: it was significantly increased (P < 0.05) at 5 hours (15.0 ± 1.7 ng/L), 6 hours (16.3 ± 2.5 ng/L), 7 hours (14.2 ± 1.7 ng/L), and 8 hours (12.8 -+ 0.9 ng/L), when compared with placebo values at the corresponding times, b u t not when compared with baseline (F = 1.049; P > 0.05). TSH values showed significant variations (F = 2.090; P < 0.05), undergoing a significant (P < 0.05) decline when compared with both baseline (2.4 + 0.4 mIU/L) and placebo values (2.0 ± 1.3 mIU/L) from 6 hours (1.0 ± 0.2 mIU/L) to 12 hours (1.1 _+ 0.3 mIU/L). Plasma GH values tended to increase, although no significant variations from baseline (F = 1.712; P > 0.05) or placebo values were recorded. Plasma PRL values were not affected by IFN administration (F = 1.758; P > 0.05), nor were plasma LH concentrations (F = 0.919; P > 0.05). IFN administration in a dose of 3 × 106 IU was unable to affect ~-EP, ACTH, or TSH pituitary secretion. In all b u t one patient the administration of both 10 × 106 IU and 3 × 106 IU doses of alpha IFN induced the expected increase in body temperature (from 36.2 °C to 36.6 °C at baseline to 38.5 °C to 39.2 °C between 4 and 6 hours). Two patients experienced mild headache, b u t none suffered serious side effects. DISCUSSION
The results of the present study demonstrate that alpha IFN is able to influence pituitary secretion, as manifested by the increases in ~-EP and ACTH and by the decline in TSH plasma values. However, high IFN doses are needed to elicit this effect. Regarding the alpha I F N effects on ACTH secretion, previous in vitro studies have demonstrated that alpha IFN does not directly affect pitu697
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Figure. Plasma hormonal values (mean + SEM) before and after intramuscular administration of placebo (O), and 3 × l 0 s IU (A) and 10 × 106 IU (*) doses of recombinant IFN alpha 2b in chronic viral hepatitis patients. *P < 0.05 vs placebo; **P < 0.05 vs baseline and placebo. TSH = thyrotropin; ACTH = adrenocorticotropin; LH = luteotropin; GH = growth hormone; PRL = prolactin.
4
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itary ACTH 21 or the adrenocortical steroid secretion.22'23 Thus the possibility that alpha IFN may indirectly influence the mechanisms modulating the hypothalamic-pituitary-adrenocorticotropinaxis (HPA-A) may be proposed. Recent evidence indicates that some cytokines such as interleukin-1 (IL-1) are able to stimulate pituitary ~-EP and ACTH synthesis and secretion via corticotropin-releasing hormone (CRH), 24 or by direct pituitary action. 25 In vitro studies indicate that IFN enhances IL-1 production by human monocytes26'27; furthermore, IL-1 has been identified as a circulating endogenous pyrogen2s and is believed to be the mediator of the fever induced by IFN. 29 The concomitance of fever and the endocrine response to alpha IFN suggests a possible role of this interleukin in activating the hypothalamic-pituitary axis to secrete ~-EP and ACTH in our patients. Alternatively, it may be hypothesized that alpha IFN, when administered in high doses, may cross the blood-brain barrier 3° and activate the stress pathway, thereby inducing HPA-A activation. Regarding the decrease in plasma TSH values, animal studies show that endotoxin-containing IFN inhibits TSH and GH secretion via somatostatin ~1 and that IFN is able to induce release of this inhibiting hormone from the rat median eminence.32 On the basis of our experience, a possible somatostatin role in alpha IFNinduced inhibition of TSH release in man cannot be proposed, since in the study significant alpha IFN-induced plasma GH variations were not found. Thus the possibility that alpha IFN may decrease hypothalamic thyrotropin-releasing hormone (TRH) secretion and/or induce desensitization of pituitary cells to this releasing hormone may be suggested. However, experimental studies concerning this hypothesis are at present unavailable. In conclusion, our data demonstrate that alpha IFN may influence pituitary ~-EP, ACTH, and TSH secretions when administered in high doses. However, they also indicate that when alpha IFN is employed at the 3 × 106-IU dose, as in the treatment of our CVH patients, this effect does not occur and therefore the influence of pituitary hormones on the alpha IFN immunoregulatory therapeutic action may be absent or negligible. References: 1. Dianzani F. Sintesi antivirali. Tabloid 1990; 2:34-39. 2. Orava M, Cantell K. Vihko R. Human leukocyte interferon inhibits human chorionic gonadotropin stimulated testosterone production by porcine Leydig cells in culture. Biochem Biophys Res Commun 1985; 106:1256-1258. 3. Kaullipa A, Cantell K, Janne O, et al. Serum sex steroid and peptide hormone concentrations, and endometrial estrogen and progestin receptor levels during administration of human leucocyte interferon. Int J Cancer 1982; 29:291-294. 4. Fentinan IS, Thomas BS, Balkwill FR, et al. Primary hypothyroidism associated with interferon therapy of breast cancer. Lancet 1983; 1:1166-1168. 699
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5. Shimizu F, Shimizu M, Kamiyama K. Inhibitory effect of interferon on the production of insulin. Endocrinology 1985; 117:2081-2084. 6. Scott GM, Ward RJ, Wright DJ, et al. Effects of cloned interferon alpha two in normal volunteers: Febrile reaction and changes in circulating corticosteroids and trace metal. Antimicrob Agents Chemother 1983; 23:589-592. 7. Holsboer F, Stalla GB, Bardeleben V, et al. Acute adrenocortical stimulation by recombinant gamma interferon in human controls. Life Sci 1988; 42:1-5. 8. Pende A, Musso NR, Vergassola C, et al. Neuroendocrine effects of interferon alpha 2a in healthy human subjects. J Biol Regul Homeostatic Agents 1990; 4:67-72. 9. Goldstein D, Gockerman J, Krishnan R, et al. Effects of gamma-interferon on the endocrine system: Results from a phase I study. Cancer Res 1987; 47:6397-6401. 10. Krishnan R, Ellinwood EH, Laszlo J, et al. Effect of gamma-interferon on the hypothalamic-pituitary-adrenal axis. Biol Psychiatry 1987; 22:1163 - 1166. 11. D'Urso R, Falaschi P, Canfalone G, et al. Neuroendocrine effect of recombinant alpha interferon administration in humans. Prog Neuroendocrinoimmunol 1991; 4:20-25. 12. Spath-Shwalbe E, Porzsolt F, Digel W, et al. Elevated plasma cortisol levels during interferon gamma treatment. Immunopharmacology 1989; 17:141-145. 13. Wiederman CJ, Vogel W, Tilg H, et al. Suppression of thyroid function by interferon , alpha 2 in man. Arch Pharmacol 1991; 343:665-668. 14. Yamaguchi M, Kolke K, Matsuzaki N, et al. The interferon family stimulates the secretion of prolactin and interleukin-6 by the pituitary gland in vitro. J Endocrinol Invest 1991; 14:457-461. 15. Walton PE, Cronin MJ. Tumor necrosis factor alpha and interferon gamma reduce prolactin release in vitro. A m J Physiol 1990; 259:E672-E676. 16. Gonzales MC, Riedel M, Rettori V, et al. Effect of recombinant human gamma IFN on the release of anterior pituitary hormones. Prog Neuroendocrinoimmunol 1990; 3:49-54. 17. Brown JL, Carman NF, Thomas HC. The hepatitis B virus. Bailliere's Clin Gastroenterol 1990; 4:721-747. 18. Sheron N, Alexander GJM. Hepatitis C, D and E virus infection. Bailliere's Clin Gastroenterol 1990; 4:749-774. 19. Dafny N. Interferon modifies EEG and EEG-like activity recorded from sensory, motor, and lymbic system structures in freely behaving rats. Neurotoxicology 1983; 4:235-238. 20. Prieto-Gomez B, Reyes-Vazquez C, Dafny N. Differential effects of interferon on ventromedial hypothalamus and dorsal hippocampus. J Neurosci Res 1983; 10:273-275. 21. Vankalecom H, Carmeliet G, Heremans H, et al. Interferon gamma inhibits stimulated adrenocorticotropin, prolactin and growth hormone secretion in normal rat anterior pituitary cell cultures. Endocrinology 1990; 126:2919-2926. 22. Epstein LB, Rose ME, McManus WH, Choch HL. Absence of functional and structural homology of natural and recombinant human leucocyte interferon (IFN-alpha) with human alpha-ACTH and beta-endorphin. Biochem Biophys Res Commun 1982; 104:341346. 23. Wetzel R, Howard L, Levina J, et al. Human leucocyte interferon has no structural or biological relationship to corticotropin. Biochem Biophys Res Commun 1982; 3:944-949. 700
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24. Ovadia H, Abramsky O, Barak V, et al. Effect ofinterleukin-1 on adrenocortical activity in intact and hypothalamic deafferentated male rats. Exp Brain Res 1990; 76:246-249. 25. Bernton EW, Beach JE, Holoday JW, et al. Release of multiple hormones by direct action of interleukin-1 on pituitary cells. Science 1987; 238:519-521. 26. Newton RC. Effect of interferon on the induction of human monocyte secretion of interleukin-1 activity. Immunology 1985; 56:441-445. 27. Arend WP, D'Anagelo S, Joslin FG. Regulation of interleukin production in human monocytes. Clin Exp Immunol 1988; 74:377-381. 28. Dinarello CA. Interleukin 1 and its biological related cytokines. Adv Immunol 1989; 44:153-205. 29. Quesada JR, Talpaz M, Rios A, et al. Clinical toxicity of interferons in cancer patients. J Clin Oncol 1986; 4:234-243. 30. Dianzani F. Il sistema interferon. Rome: Sedac Edizioni, 1990. 31. Kasting NW, Martin JB. Altered release of growth hormone and thyrotropin induced by endotoxin in the rat. A m J Physiol 1982; 243:E332-E336. 32. Gonzales MC, Aguila MC, McCann SM. In vitro effects of recombinant human gammainterferon on growth hormone release. Prog Neuroimmunoendocrinol 1991; 4:222-227.
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EFFECTS OF ACUTE ADMINISTRATION OF RECOMBINANT I N T E R F E R O N A L P H A 2b ON PITUITARY HORMONE SECRETION IN PATIENTS WITH CHRONIC ACTIVE HEPATITIS T. BARRECA, A. PICCIOTTO, R. FRANCESCHINI, G. VARAGONA, G. CORSINI, F. VALLE, A. CATALDI, S. D'AGOSTINO, AND E. ROLANDI Department of lnternal Medicine, University of Genoa, Genoa, Italy
ABSTRACT The effect of a single i n t r a m u s c u l a r (IM) dose o f 10 x 106 IU o f rec o m b i n a n t i n t e r f e r o n alpha-2b ( a l p h a I F N ) on a d r e n o c o r t i c o t r o p i n (ACTH), b e t a - e n d o r p h i n ( ~ - E P ) , t h y r o t r o p i n (TSH), g r o w t h h o r m o n e (GH), l u t e o t r o p i n (LH), and p r o l a c t i n ( P R L ) was e v a l u a t e d in seven p a t i e n t s s u f f e r i n g f r o m c h r o n i c viral h e p a t i t i s (CVH). A l p h a I F N increased ACTH (from 11.2 -+ 1.1 ng/L to 16.3 - 2.6 ng/L) a n d ~ - E P (from 25.0 -+ 1.9 ng/L to 37.6 --- 1.7 ng/L) p l a s m a c o n c e n t r a t i o n s and lowered p l a s m a TSH c o n c e n t r a t i o n s (from 2.4 -+ 0.4 mIU/L to 1.0 --- 0.2 mIU/L). These effects were recorded between the f o u r t h a n d the 12th hour after alpha IFN administration and occurred without significant v a r i a t i o n s in t h e r e m a i n i n g p l a s m a h o r m o n a l levels. In seven addit i o n a l p a t i e n t s who received a 3 x 10e-IU IM dose o f t h e s a m e I F N , no s i g n i f i c a n t v a r i a t i o n s in ACTH, ~ - E P , or TSH p l a s m a levels were found. D a t a i n d i c a t e t h a t a l p h a I F N m a y influence t h e n e u r a l mecha n i s m s c o n t r o l l i n g a n t e r i o r p i t u i t a r y secretion. However, h i g h a l p h a I F N doses are r e q u i r e d for this effect to occur. INTRODUCTION
Interferon (IFN) is a family of hormone-like peptides produced by the immune system in response to viral infections. IFN has many biological activities, including antiviral, antiproliferative, and immunoregulatory effects. 1 IFN also has a variety of endocrine effects; in particular, IFN inhibits the secretion of sex steroids, 2'3 thyroid hormones, a and insulin, 5 and stimulates that of cortisol 6-s and norepinephrine, s Data regarding the effects of IFN on pituitary hormonal release are at present sparse and not always in agreement; indeed, IFN administration in man has induced adrenocorticotropin (ACTH) release in some studies, 9-11 b u t not in others. 7'12 Furthermore, IFN-induced stimulation of growth hormone (GH) secretion 9'11 and inhibition of thyrotropin (TSH) secretion 13 has been found in some studies, whereas in others the secretion of these hormones Address correspondenceto: Prof. T. Barreca, Department of Internal Medicine, Viale Benedetto XV, 6, 16132 Genova, Italy. Received for publication on July 7, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted. 695
0011-393X/92/$3.50
INTERFERON AND ANTERIOR PITUITARY HORMONES
was not significantly affected by IFN. 3'9 Finally, prolactin (PRL) and luteotropin (LH) secretions do not appear to be influenced by IFN in vivo. 3'11 However, regarding PRL secretion, in vitro studies have shown both stimulatory 14 and inhibitory 15 IFN effects. A recent animal study ~6 showing absence of pituitary effects of IFN when administered systemically but stimulation of ACTH and inhibition of GH and TSH secretion when administered intracerebroventricularly indicates the possibility that IFN may influence the central nervous system (CNS), thereby affecting the hypothalamic centers controlling the pituitary secretory function. Within the IFN family, recombinant IFN alpha 2b has been shown to be the most active on the CNS, as demonstrated in animals by electroencephalographic recording experiments. ~7'~s This IFN, in recent years, has been employed with good results in the treatment of chronic viral hepatitis (CVH). 19'2° In the present study, using recombinant IFN alpha 2b, we evaluated pituitary secretion in a group of CVH patients undergoing IFN treatment for this disease. PATIENTSAND METHODS The study was performed in 14 untreated CVH patients (aged 32 to 55 years). All patients were hospitalized for the study and informed consent was obtained from each one prior to participation. After a preliminary placebo study, seven patients (four men and three postmenopausal women) received a single intramuscular (IM) dose of 10 x 106 IU of recombinant IFN alpha 2b between 8 and 9 AM and seven (five men and two women) received a single IM dose of 3 x 106 IU of the same IFN at the same time in the morning. Blood samples were drawn through an indwelling catheter in an antecubital vein at baseline and every two hours for 12 hours after IFN administration. All patients were in bed resting and did not eat anything during the entire study period. Blood samples were collected in icechilled propylene tubes containing EDTA (1.5 mg/ml) and Aprotinin (500 IU/ml). Plasma obtained by centrifugation was frozen and stored at - 4 0 °C until assayed. Plasma immunoreactive beta-endorphin (~-EP) and ACTH were determined by radioimmunoassay (RIA) after preliminary extraction and concentration by immunoafflnity chromatography; the mean recovery rate for ~-EP and ACTH was 94% and 89%, respectively. The smallest detectable concentrations were 9 ng/L and 3.5 ng/L for ~-EP and ACTH, respectively; the intra- and interassay coefficients of variation were for ~-EP 6.5% and 18.1%, respectively, and for ACTH 8.5% and 19.5%, respectively. Plasma GH and PRL were measured by radioimmunoassay; plasma TSH and LH were determined by immunoradiometric assay methods. Sensitivity and intra- and interassay coefficients of variation for GH were: 0.6 696
T. BARRECAET AL.
mIU/L, 4.4% and 8.8%; for PRL: 30 mIU/L, 6.6% and 7.1%; for TSH: 0.10 mIU/L, 5.9% and 7.6%; and for LH: 0.1 IU/L, 5.7% and 6.4%, respectively. Analysis of variance (ANOVA) followed by multiple range t e s t (Scheffe test) was performed to analyze the kinetics (0 to 12 hours) of hormone levels and to assess the significance of differences between the plasma values recorded at each time point of the study and the pretreatment values. The Mann-Whitney U statistic test was also used to determine statistical differences between the placebo and the treatment groups. RESULTS
Data are expressed as mean ± SEM and are illustrated in the figure. After administration of 10 × 106 IU of IFN a significant (F = 7.220; P < 0.01) plasma ~-EP increase occurred. Plasma ~-EP values (25.0 ± 1.9 ng/L at baseline) were higher at 4 hours (37.6 ± 1.7 ng/L) and remained significantly elevated (P < 0.05 versus baseline and placebo) until 5 hours (36.5 -+ 1.9 ng/L). Plasma ACTH (11.2 ± 1.1 ng/L at baseline) showed a similar pattern: it was significantly increased (P < 0.05) at 5 hours (15.0 ± 1.7 ng/L), 6 hours (16.3 ± 2.5 ng/L), 7 hours (14.2 ± 1.7 ng/L), and 8 hours (12.8 -+ 0.9 ng/L), when compared with placebo values at the corresponding times, b u t not when compared with baseline (F = 1.049; P > 0.05). TSH values showed significant variations (F = 2.090; P < 0.05), undergoing a significant (P < 0.05) decline when compared with both baseline (2.4 + 0.4 mIU/L) and placebo values (2.0 ± 1.3 mIU/L) from 6 hours (1.0 ± 0.2 mIU/L) to 12 hours (1.1 _+ 0.3 mIU/L). Plasma GH values tended to increase, although no significant variations from baseline (F = 1.712; P > 0.05) or placebo values were recorded. Plasma PRL values were not affected by IFN administration (F = 1.758; P > 0.05), nor were plasma LH concentrations (F = 0.919; P > 0.05). IFN administration in a dose of 3 × 106 IU was unable to affect ~-EP, ACTH, or TSH pituitary secretion. In all b u t one patient the administration of both 10 × 106 IU and 3 × 106 IU doses of alpha IFN induced the expected increase in body temperature (from 36.2 °C to 36.6 °C at baseline to 38.5 °C to 39.2 °C between 4 and 6 hours). Two patients experienced mild headache, b u t none suffered serious side effects. DISCUSSION
The results of the present study demonstrate that alpha IFN is able to influence pituitary secretion, as manifested by the increases in ~-EP and ACTH and by the decline in TSH plasma values. However, high IFN doses are needed to elicit this effect. Regarding the alpha I F N effects on ACTH secretion, previous in vitro studies have demonstrated that alpha IFN does not directly affect pitu697
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Figure. Plasma hormonal values (mean + SEM) before and after intramuscular administration of placebo (O), and 3 × l 0 s IU (A) and 10 × 106 IU (*) doses of recombinant IFN alpha 2b in chronic viral hepatitis patients. *P < 0.05 vs placebo; **P < 0.05 vs baseline and placebo. TSH = thyrotropin; ACTH = adrenocorticotropin; LH = luteotropin; GH = growth hormone; PRL = prolactin.
4
T. BARRECAET AL.
itary ACTH 21 or the adrenocortical steroid secretion.22'23 Thus the possibility that alpha IFN may indirectly influence the mechanisms modulating the hypothalamic-pituitary-adrenocorticotropinaxis (HPA-A) may be proposed. Recent evidence indicates that some cytokines such as interleukin-1 (IL-1) are able to stimulate pituitary ~-EP and ACTH synthesis and secretion via corticotropin-releasing hormone (CRH), 24 or by direct pituitary action. 25 In vitro studies indicate that IFN enhances IL-1 production by human monocytes26'27; furthermore, IL-1 has been identified as a circulating endogenous pyrogen2s and is believed to be the mediator of the fever induced by IFN. 29 The concomitance of fever and the endocrine response to alpha IFN suggests a possible role of this interleukin in activating the hypothalamic-pituitary axis to secrete ~-EP and ACTH in our patients. Alternatively, it may be hypothesized that alpha IFN, when administered in high doses, may cross the blood-brain barrier 3° and activate the stress pathway, thereby inducing HPA-A activation. Regarding the decrease in plasma TSH values, animal studies show that endotoxin-containing IFN inhibits TSH and GH secretion via somatostatin ~1 and that IFN is able to induce release of this inhibiting hormone from the rat median eminence.32 On the basis of our experience, a possible somatostatin role in alpha IFNinduced inhibition of TSH release in man cannot be proposed, since in the study significant alpha IFN-induced plasma GH variations were not found. Thus the possibility that alpha IFN may decrease hypothalamic thyrotropin-releasing hormone (TRH) secretion and/or induce desensitization of pituitary cells to this releasing hormone may be suggested. However, experimental studies concerning this hypothesis are at present unavailable. In conclusion, our data demonstrate that alpha IFN may influence pituitary ~-EP, ACTH, and TSH secretions when administered in high doses. However, they also indicate that when alpha IFN is employed at the 3 × 106-IU dose, as in the treatment of our CVH patients, this effect does not occur and therefore the influence of pituitary hormones on the alpha IFN immunoregulatory therapeutic action may be absent or negligible. References: 1. Dianzani F. Sintesi antivirali. Tabloid 1990; 2:34-39. 2. Orava M, Cantell K. Vihko R. Human leukocyte interferon inhibits human chorionic gonadotropin stimulated testosterone production by porcine Leydig cells in culture. Biochem Biophys Res Commun 1985; 106:1256-1258. 3. Kaullipa A, Cantell K, Janne O, et al. Serum sex steroid and peptide hormone concentrations, and endometrial estrogen and progestin receptor levels during administration of human leucocyte interferon. Int J Cancer 1982; 29:291-294. 4. Fentinan IS, Thomas BS, Balkwill FR, et al. Primary hypothyroidism associated with interferon therapy of breast cancer. Lancet 1983; 1:1166-1168. 699
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5. Shimizu F, Shimizu M, Kamiyama K. Inhibitory effect of interferon on the production of insulin. Endocrinology 1985; 117:2081-2084. 6. Scott GM, Ward RJ, Wright DJ, et al. Effects of cloned interferon alpha two in normal volunteers: Febrile reaction and changes in circulating corticosteroids and trace metal. Antimicrob Agents Chemother 1983; 23:589-592. 7. Holsboer F, Stalla GB, Bardeleben V, et al. Acute adrenocortical stimulation by recombinant gamma interferon in human controls. Life Sci 1988; 42:1-5. 8. Pende A, Musso NR, Vergassola C, et al. Neuroendocrine effects of interferon alpha 2a in healthy human subjects. J Biol Regul Homeostatic Agents 1990; 4:67-72. 9. Goldstein D, Gockerman J, Krishnan R, et al. Effects of gamma-interferon on the endocrine system: Results from a phase I study. Cancer Res 1987; 47:6397-6401. 10. Krishnan R, Ellinwood EH, Laszlo J, et al. Effect of gamma-interferon on the hypothalamic-pituitary-adrenal axis. Biol Psychiatry 1987; 22:1163 - 1166. 11. D'Urso R, Falaschi P, Canfalone G, et al. Neuroendocrine effect of recombinant alpha interferon administration in humans. Prog Neuroendocrinoimmunol 1991; 4:20-25. 12. Spath-Shwalbe E, Porzsolt F, Digel W, et al. Elevated plasma cortisol levels during interferon gamma treatment. Immunopharmacology 1989; 17:141-145. 13. Wiederman CJ, Vogel W, Tilg H, et al. Suppression of thyroid function by interferon , alpha 2 in man. Arch Pharmacol 1991; 343:665-668. 14. Yamaguchi M, Kolke K, Matsuzaki N, et al. The interferon family stimulates the secretion of prolactin and interleukin-6 by the pituitary gland in vitro. J Endocrinol Invest 1991; 14:457-461. 15. Walton PE, Cronin MJ. Tumor necrosis factor alpha and interferon gamma reduce prolactin release in vitro. A m J Physiol 1990; 259:E672-E676. 16. Gonzales MC, Riedel M, Rettori V, et al. Effect of recombinant human gamma IFN on the release of anterior pituitary hormones. Prog Neuroendocrinoimmunol 1990; 3:49-54. 17. Brown JL, Carman NF, Thomas HC. The hepatitis B virus. Bailliere's Clin Gastroenterol 1990; 4:721-747. 18. Sheron N, Alexander GJM. Hepatitis C, D and E virus infection. Bailliere's Clin Gastroenterol 1990; 4:749-774. 19. Dafny N. Interferon modifies EEG and EEG-like activity recorded from sensory, motor, and lymbic system structures in freely behaving rats. Neurotoxicology 1983; 4:235-238. 20. Prieto-Gomez B, Reyes-Vazquez C, Dafny N. Differential effects of interferon on ventromedial hypothalamus and dorsal hippocampus. J Neurosci Res 1983; 10:273-275. 21. Vankalecom H, Carmeliet G, Heremans H, et al. Interferon gamma inhibits stimulated adrenocorticotropin, prolactin and growth hormone secretion in normal rat anterior pituitary cell cultures. Endocrinology 1990; 126:2919-2926. 22. Epstein LB, Rose ME, McManus WH, Choch HL. Absence of functional and structural homology of natural and recombinant human leucocyte interferon (IFN-alpha) with human alpha-ACTH and beta-endorphin. Biochem Biophys Res Commun 1982; 104:341346. 23. Wetzel R, Howard L, Levina J, et al. Human leucocyte interferon has no structural or biological relationship to corticotropin. Biochem Biophys Res Commun 1982; 3:944-949. 700
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