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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3681-3687
Copyright © 1998 by The Endocrine Society

Original Studies

Change of Peripheral Levels of Pituitary Hormones and Cytokines after Injection of Interferon (IFN)-ß in Patients with Chronic Hepatitis C

Yasuhiro Ohno, Mika Fujimoto, Akiyoshi Nishimura and Norihiko Aoki

Second Department of Medicine, Kinki University School of Medicine, Osaka 589, Japan

Address correspondence and requests for reprints to: Norihiko Aoki, MD, Ph.D., Professor of Medicine, Kinki University School of Medicine, 377-2, Ohno-Higashi, Osaka-Sayama, Osaka 589, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Interferons (IFNs) are now in use worldwide for the treatment of chronic viral hepatitis. Unfortunately, various side effects of IFNs have been reported. Because cytokines, which include IFNs, can affect endocrine function, endocrinological abnormalities are sometimes observed in patients treated with IFNs. We examined the effects of IFN-ß on peripheral levels of pituitary and adrenal hormones and cytokines. Six million international units of IFN-ß dissolved in glucose solution was injected for 30 min.

As a control study, glucose solution without IFN-ß was injected. Pituitary hormones (ACTH, GH, TSH, prolactin (PRL), LH, FSH, and arginine-vasopressin (AVP)), cortisol, and cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-{alpha} (TNF), and interleukin-1 receptor antagonist (IL-1ra) were measured before and after IFN-ß injection. The study was carried out on 14 patients with chronic hepatitis type C who were under treatment with IFN-ß. All studies were performed when the patients were afebrile. None of the patients had any endocrine or autoimmune diseases.

Plasma ACTH levels increased significantly at 60–120 min after IFN-ß injection compared with the levels before IFN-ß injection and in the control study using glucose injection. Plasma cortisol levels increased after IFN-ß injection, in parallel with plasma ACTH elevation. Serum GH levels increased significantly at 120 min after IFN-ß injection. All the increased hormones including ACTH, cortisol, and GH, were decreased at the end of the study—180 min after IFN-ß injection. Serum levels of TSH, PRL, LH, FSH, and AVP were not changed significantly by IFN-ß injection. Plasma IL-1 and TNF levels did not change after IFN-ß injection, while IL-6 and IL-1ra were elevated significantly. The increases in IL-6 and IL-1ra were gradual, reaching their peak levels at 180 min after IFN-ß injection. However there were no correlations between the hormones measured in this study and the levels of IL-6 or IL-1ra. It would seem that IFN-ß has direct or indirect stimulatory effects for ACTH and GH without mediation of the cytokines. These in vivo results are important for investigating the relationship between endocrine and cytokine systems in humans.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CYTOKINES products of immune response, are considered as not only localized hormones, but also systemic hormones (1, 2, 3). There are many reports demonstrating the effects of cytokines on endocrine function. Most investigators have focused on interleukin (IL)-1, IL-6, and tumor necrosis factor-{alpha}, all of which are potent modulators of endocrine function (4, 5, 6, 7). However, there are few reports that demonstrate that type I interferons (IFN) (IFN-{alpha} and IFN-ß) also have effects on endocrine function, despite their wide use in the treatment of patients with chronic hepatitis or malignant tumors (8, 9, 10). Although the mechanisms remain obscure, it is well known that administration of IFNs induces a variety of side effects, including suppression of hematopoiesis in the bone marrow, elevation of body temperature, depression (11, 12), autoimmune disease (12, 13, 14), thyroid disease (15, 16), and diabetes mellitus (17, 18). IFNs have modulatory effects on immune and endocrine function as well as antiviral effects (2, 19, 20). Most of the reports demonstrating the effects of IFN on immune and endocrine function have been observed in vitro or in animal studies (21, 22). It is important to know the interactions of cytokine and the endocrine system to understand the mechanisms in the development of endocrinological events in IFN administration as well as in autoimmune endocrinopathies. Herein we have studied the interaction between cytokines and the endocrine system in patients treated with IFN-ß.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects

Fourteen patients (43.5 ± 6.5 yr, mean ± SD) with chronic active hepatitis type C were studied. Both antibodies and RNA of antihepatitis C virus (HCV) were detected in the serum of all the patients. Anti-HCV antibody was measured by a passive hemagglutination kit (Dinabot, Tokyo, Japan). HCV RNA was detected by a branched DNA probe assay (23). HCV RNA genotype was determined by the method of Okamoto et al. (24). The genotype was classified as I, II, III, or IV, based on variations in the nucleotide sequence within restricted regions in the putative core region of HCV. Genotypes I and IV were not determined in the patients. Chronic active hepatitis was confirmed by histological observation of specimens obtained by needle biopsy. Histological grade of chronic hepatitis was determined according to the method described in the previous report (25). None of the patients in the study had endocrine or autoimmune disorders. No antinuclear, antimitochondrial, antithyroglobulin, or antithyroid microsomal autoantibodies (Toray Fuji Bionics, Tokyo, Japan) were detected in the serum of any of the patients. The patient profiles are shown in Table 1Go.


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  		Table 1. Characteristics of 14 patients with chronic hepatitis C

 
Experimental design

All patients approved to be treated with IFN for chronic hepatitis were injected with 6 x 106 IU of IFN-ß. Most patients treated with interferons experience fever for 1–2 weeks after the start of a course of IFN-ß injection, then adapt and become afebrile. All patients received the IFN-ß therapy for 6 weeks. To avoid the effects of fever and pyrogenetic factors due to IFN-ß preparation on the release of hormones and cytokines, the patients in this study were monitored by an IFN-ß loading test carried out between the 15th to 20th day after the start of IFN-ß treatment. None of the patients had fever during the study. Six million IU recombinant IFN-ß (Daiichi Pharmaceutical Inc., Tokyo, Japan) was dissolved in 250 mL 5% glucose solution and drip-infused iv for 30 min. To analyze the levels of hormones and cytokines, venous blood was drawn from the brachial vein at 30, 60, 120, and 180 min after the start of infusion. This IFN-ß loading test was started at 0800 h and finished at 1100 h. Patients did not take any food, drink, or medicine during the study.

The control study was carried out as follows: before the start of IFN-ß therapy, 250 mL 5% glucose solution was injected iv for 30 min on fasting in patients with chronic hepatitis C. The same control study was performed in six normal male volunteers, who were 33.5 ± 3.2 yr (mean ± SD). In normal volunteers, the baseline levels of the hormones were measured three times at intervals of 15 min, from 0730 to 0800 h. To analyze the peripheral levels of the hormones and cytokines, venous blood was obtained at 30, 60, 120, and 180 min after the start of infusion.

To evaluate the baseline hormone levels accurately, venous blood was drawn three times every 15 min, from 0730 to 0800 h, to measure baseline levels of GH, ACTH, and cortisol in 6 of 14 patients; this is called "the baseline study" in this report. The six patients were 2 males and 4 females. This baseline study was performed after the 6-week IFN-ß therapy was finished.

We explained the aim and detail of the study procedure to all patients and normal volunteers. The study protocol was approved by our ethical committee, and informed consent was obtained from all patients and normal volunteers.

Measurement of hormones and cytokines

Serum levels of TSH, LH, FSH, GH, and prolactin (PRL), and plasma levels of ACTH, cortisol, and arginine-vasopressine (AVP) were measured by RIA. The RIA kits had the following measurable ranges; ACTH kit (Nichols Institute Diagnostic, CA), 1–1500 pg/mL; TSH kit (Dinabot, Tokyo, Japan), 0.1–200 µg/mL; PRL kit Daiichi Radioisotpe Institute, Tokyo, Japan), 1–300 ng/mL; LH and FSH kits (Daiichi Radioisotpe Institute), 0.5–200 mIU/mL; GH kit (Daiichi Radioisotpe Institute), 0.1–50 ng/mL; AVP kit (Mitsubishi Chemistry Inc., Tokyo, Japan), 0.15–18.7 pg/mL. Plasma levels of interleukin-1ß (IL-1), IL-6, IL-1 receptor antagonist (IL-1ra), and tumor necrosis factor-{alpha} (TNF) were measured by sensitive enzyme-linked immunosorbent assay (ELISA) kits (R&D System Inc., Minneapolis, MN). The cytokine ELISA kits had sensitivities of 0.125 pg/mL, 0.156 pg/mL, 0.5 pg/mL, and 15.6 pg/mL for IL-1ß, IL6 TNF, and IL-1ra, respectively.

Plasma cytokine levels of the patients were compared with the corresponding levels of 25 normal subjects, consisting of 15 males and 10 females with a mean age of 38±8.2 yr (mean±SD).

Statistical analysis

Results of the cytokines and hormones are expressed as the mean ± standard deviation (SD), and data were analyzed by the Student’s t test for the determination of statistical significance of differences. Analysis of the ordinary least-square regression was used for testing the strength of correlation.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effect of IFN-ß on pituitary and adrenal hormones

There was no significant change in serum PRL levels after IFN-ß injection, compared with those in the control study (5% glucose solution injection) and those before IFN-ß injection. Similarly, serum levels of LH and FSH did not change significantly during the study (data not shown). Plasma AVP levels showed no change at any point after IFN-ß injection. TSH was slightly decreased, but the change was not significant at any point after IFN-ß injection. Serum TSH levels before and after IFN-ß injection in all patients were within normal range (data not shown).

The plasma ACTH level was 23.6 ± 4.6 pg/mL before IFN-ß injection, increased significantly (P < 0.05) at both 60 and 120 min after IFN-ß injection (Fig. 1AGo), and returned to the basal level at 180 min after IFN-ß injection. Serum cortisol levels were increased in parallel with plasma ACTH (Fig. 1BGo), and the elevation was significant at 120 min after IFN-ß injection.



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  		Figure 1. Elevation of plasma ACTH and serum cortisol levels by IFN-ß administration. Plasma ACTH levels (upper panel, A) were increased at 60 and 120 min after IFN-ß injection, as compared with those before IFN-ß injection and those in the control study. Serum cortisol levels (lower panel, B) were increased in parallel with the elevation of plasma ACTH levels after IFN-ß injection. Results are given as mean ± SD. {circ}, ACTH (A) and cortisol (B) levels in the control study; •, ACTH (A) and cortisol (B) levels in IFN-ß administration; *, P < 0.05 compared with the levels before IFN-ß injection and those in the control study.

 
Serum GH levels were significantly increased (P < 0.05) at 60 to 120 min after IFN-ß injection, compared with those before IFN-ß injection and in the control study (Fig 2Go). GH showed a decrease at 180 min after IFN-ß injection.



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  		Figure 2. Elevation of serum GH levels by IFN-ß administration. Serum GH levels (•) were increased at 60 and 120 min after IFN-ß injection, compared with those before IFN-ß injection and those ({circ}) in the control study. Results are given as mean ± SD. *, P < 0.05 compared with the GH levels before IFN-ß injection and those in the control study.

 
ACTH, cortisol, and GH in the baseline study were compared with the hormone levels at zero time (0800 h) in the control study and in the IFN-ß loading test. There was no difference in these hormone levels between different days (Fig. 3AGo, 3BGo). The maximum levels of ACTH, cortisol, and GH were significantly higher than those in the baseline study and in the control study.



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  		Figure 3. Comparison of the baseline levels of ACTH, cortisol, and GH between different days. These baseline data were obtained from 6 of 14 patients. The ACTH (•) and cortisol ({circ}) levels were shown in the upper pannel (A), and the GH levels (•) were shown in the lower pannel (B). The baseline data of a, b and c on a horizontal line obtained at different time on the same days as follows; a: 0730, b: 0745, c: 0800 h, respectively. Data c and d on a horizontal line were obtained from the same patients on the days of the control study (5% glucose injection) and the IFN-ß loading test, respectively. There was no significant difference between the baseline hormone levels of a, b, c, and d. Results are given as mean ± SD.

 
In normal volunteers, three samples as baseline hormone levels were obtained at 0730, 0745, and 0800 h. Thereafter the control study was performed in the samples. No significant changes were observed in the levels of ACTH, cortisol, or GH (Fig. 4Go). We did not carry out the IFN-ß loading test in normal volunteers for ethical reasons.



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  		Figure 4. Changes of ACTH, cortisol, and GH after 5% glucose injection in normal volunteers. Injection of 250 mL of 5% solution was started at zero time (0800 h) (see Materials and Methods). There was no significant change in the levels of ACTH (•), cortisol ({circ}) and GH ({blacksquare}) after the injection of 250 mL of 5% glucose solution. Results are given as mean ± SD.

 
Effect of IFN-ß on plasma cytokine levels

Plasma levels of IL-1, IL-1ra, IL-6, and TNF in the patients with chronic hepatitis C were compared with those in normal subjects (Fig. 5Go). There were no significant differences in the plasma levels of any cytokine between the patients and normal subjects. Plasma IL-1, IL-1ra, IL-6, and TNF were measured in the same plasma samples used for hormone measurement. Plasma IL-1 levels were not changed by IFN administration (Fig. 6AGo). There were no significant changes in plasma TNF levels compared with the basal level or with those in the control study (Fig. 6BGo). On the other hand, plasma IL-6 was increased significantly (P < 0.01) at 120–180 min after IFN-ß injection (Fig. 7Go). Moreover, IL-1ra showed gradual increases, climbing significantly above the levels from before IFN-ß injection and in the control study (Fig. 8Go). The highest level of IL-1ra was observed at 180 min after IFN-ß injection, suggesting that IL-1ra might still have been increasing (Fig. 8Go).



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  		Figure 5. Comparison of plasma IL-1, IL-6, IL-1ra, and TNF levels between patients with chronic hepatitis C and normal subjects. There were no significant differences of IL-1 (A), IL-6 (B), IL-1ra (C), and TNF (D) between patients with chronic hepatitis C and normal subjects. Results are given as mean ± SD.

 


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  		Figure 6. Changes of plasma IL-1ß and TNF-{alpha} levels after IFN-ß administration. Neither the plasma levels of IL-1 (upper panel, A) or TNF-{alpha} (lower panel, B) were changed significantly by IFN-ß injection. Plasma levels of IL-1ß and TNF-{alpha} were measured by the enzyme-linked immunosorbent assay. Results are given as mean ± SD. {circ}: Plasma levels of IL-1ß (A) or TNF-{alpha} (B) in the control study. •: Plasma levels of IL-1ß (A) or TNF-{alpha} (B) in IFN-ß injection.

 


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  		Figure 7. Elevation of plasma IL-6 levels by IFN-ß administration. IL-6 levels (•) were significantly increased at 120 and 180 min after IFN-ß injection, compared with those before IFN-ß injection and those ({circ}) in the control study. Plasma levels of IL-6 were measured by the enzyme-linked immunosorbent assay. Results are given as mean ± SD. *, P < 0.01, compared with the IL-6 levels before IFN-ß injection and those in the control study.

 


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  		Figure 8. Elevation of plasma IL-1ra levels by IFN-ß administration. IL-1ra levels (•) were significantly increased at 120 and 180 min after IFN-ß injection, compared with those before IFN-ß injection and those ({circ}) in the control study. Plasma levels of IL-1ra were measured by enzyme-linked immunosorbent assay. Results are given as mean ± SD. *, P < 0.01, compared with the IL-1ra levels before IFN-ß injection and those in the control study.

 
Relationship between hormones and cytokines after IFN-ß injection

When all data obtained in the present loading test were collectively studied for statistics, plasma levels of IL-1, IL-1ra, IL-6, or TNF were not correlated with any of the hormones measured (data not shown). The only time point at which a significant correlation was found between ACTH and plasma levels of IL-6 and IL-1ra was at 120 min after IFN-ß injection (Fig. 9Go). However, such correlation was lost at 180 min after IFN-ß injection.



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  		Figure 9. Correlation between plasma ACTH and IL-6 or IL-1ra in patients at 120 min after IFN-ß administration. ACTH levels were positively correlated with plasma IL-6 (upper panel, A) and IL-1ra (lower panel, B) at 120 min after IFN-ß injection respectively.

 
Clinical effect of IFN-ß on chronic hepatitis

Clinical effectiveness of IFN-ß on chronic hepatitis C was defined as follows: 1) complete response (CR), 2) partial response (PR), 3) nonresponder (NR). In observation after IFN therapy, the patients were divided into three groups: 4 CR, 5 PR and 5 NR. The therapeutic response by patients to IFN was dependent on the amount of HCV/RNA, HCV genotype, as previously reported (26, 27).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we demonstrated the effects of IFN-ß on peripheral hormone and cytokine levels in patients with chronic hepatitis C. It is known that pituitary hormones including ACTH and GH are secreted episodically (pulsatile secretion). Therefore, to evaluate baseline hormone levels, the baseline study was carried out, and the hormone levels were compared with those in the control study and in the IFN-ß loading test. Also the control study was performed on normal subjects, in whom no changes of ACTH, cortisol, or GH levels were observed. These results support the reliability of this study. Remarkably, IFN-ß increased both ACTH and cortisol significantly. Roosth et al. (22) demonstrated that IFN increased cortisol levels by acting directly on the adrenal gland. If IFN has direct stimulatory effects on the adrenals, ACTH levels should accordingly be decreased. However, in agreement with a report on IFN-{alpha} (21), ACTH levels in the present study were increased, and plasma cortisol levels were increased in parallel with ACTH. It is natural, therefore, that IFN-ß could stimulate directly or indirectly the release of ACTH, causing cortisol secretion.

IL-1, IL-6, and TNF stimulate ACTH secretion directly or via hypothalamic CRH secretion (28, 29, 30, 31, 32), and it is interesting to note that pituitary cells per se secrete IL-6 (33). In contrast to previous reports (31, 34), which showed that in vitro production of IL-1, IL-6, and TNF-{alpha} by peripheral mononuclear cells was significantly higher in patients with chronic hepatitis than in normal subjects, the present study demonstrates that there was no significant difference in the basal levels of plasma IL-1, IL-6, IL-1ra, and TNF-{alpha} between patients with chronic hepatitis and normal subjects. As the previous reports were in vitro studies and ours was an in vivo study, this discrepancy might be attributed to the different experimental design. Plasma IL-6 was increased markedly after IFN-ß administration in this study, although the levels of IL-1 and TNF in the same sample did not show any IFN-ß-induced change. Plasma IL-6 concentration reached a peak at the end of the study (180 min), while the maximum levels of ACTH and cortisol were observed at 120 min, returning to the basal level at 180 min. Although plasma ACTH levels were significantly correlated with plasma levels of IL-6 and IL-1ra at 120 min after IFN-ß injection, overall IL-6 or IL-1ra levels were not correlated with ACTH concentrations for the data obtained before and at 30, 60, 120, 180 min after IFN-ß injection. Therefore, the possibility that IL-6 may be a sole stimulator of ACTH secretion from the pituitary gland is difficult to assume from the present data. The increase in ACTH may be due to the direct effect of IFN-ß or to factors other than IL-6 induced by IFN-ß. For instance, mononuclear cells (MNC) are believed to have the ability to produce proopiomelanocortin (POMC) and to secrete ACTH and endorphins derived from POMC (35, 36). IL-1 and TNF are stimulators of ACTH secretion, although neither was changed after IFN-ß injection in the present study.

In the present study, GH was increased markedly after IFN-ß injection. Interestingly, Spangelo et al. (4) demonstrated that IL-6 had direct stimulatory effects on GH secretion from pituitary cells in vitro. GH is also produced by activated lymphocytes (37, 38), although GH thus produced is very small and negligible in circulation. In patients treated with IFN-{alpha}, insulin like growth factor-1 (IGF-1) was elevated without increment of GH in circulation (39). Honeggar et al. (5) demonstrated that IL-1 could stimulate both GH-releasing hormone (GHRH) and somatostatin secretion from the hypothalamus, although it was unknown whether IL-1 showed direct stimulatory effects on pituitary GH secretion (5). Additional reports have demonstrated a stimulatory effect of IL-1 on GH secretion (40, 41). Taken together, GH elevation in the present study would most probably indicate an increase of IL-6 secretion caused by IFN-ß.

In this study, it was demonstrated that both IL-6 and IL-1ra were increased in patients after injection of IFN-ß. IL-1ra, an intrinsic inhibitor of IL-1, increased greatly, suggesting that the biological activity of IL-1 might be reduced by increased IL-1ra (45) following injection of IFN-ß. Overall, the relative activity of IL-6 was increased after injection of IFN-ß, whereas the activity of IL-1 in circulation showed a relative decline by the increment of IL-1ra. IL-6 is a B lymphocyte differentiation factor, which enhances immunoglobulin production (46). On the other hand, IL-1 and TNF are presumed to be mediators of hepatitis (42, 43, 44, 47, 48), and IFN-ß- induced increase of IL-1ra possibly suppresses the inflammation of the liver through reduction of IL-1 activity. As GH is known to enhance immune function (49, 50, 51), IFN-ß seems to enhance immune functions in vivo in humans in many ways with the release of immunosuppressive hormones such as ACTH and cortisol (52, 53).

Interestingly, although we observed the remarkable changes of ACTH, cortisol, and GH levels in patients treated with IFN-ß, there are few reports demonstrating the symptoms or signs of hypersecretion of ACTH and GH. The clinical significance of the elevation of ACTH, cortisol, and GH during IFN-ß treatment is important. For instance, these hormones cause glucose intolerance, as occasionally found in patients treated with IFN. Also, diabetes mellitus is closely related to the disturbance of cytokine functions as previously reported (54). Furthermore, the present data would supply important clues to elucidate the interplay between cytokines and pituitary hormones.

Further study, covering the mechanism of the cytokine-induced release of hypothalamic hormones will be necessary to elucidate side effects of IFN and to prepare for the development of efficacious IFN treatment in chronic viral hepatitis.


   Acknowledgments
 
We would like to thank Dr. Saika, Dr. Kishitani, and Dr. Maruyama for helpful discussion. The authors are grateful to Miss Kaoru Shiozawa for her secretarial assistance.

Received November 6, 1997.

Revised June 2, 1998.

Accepted July 8, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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