Endocrine and neurological adverse effects of the therapeutic interferons

Toxicology 142 (2000) 161 – 172 www.elsevier.com/locate/toxicol

Endocrine and neurological adverse effects of the therapeutic interferons Thierry Vial *, Genevie`ve Choquet-Kastylevsky, Christine Liautard, Jacques Descotes Lyon Poison Centre and Pharmaco6igilance Unit, Hoˆpital Edouard Herriot, 5 place d’Arson6al, 69437 Lyon cedex 03, France

Abstract There is experimental evidence that the nervous central and the neuroendocrine systems can influence the immune system, which can in turn influence the brain activity. Endogenous cytokines are known to play a critical role in the pathophysiology of many diseases. The recently acquired experience on the adverse effects of therapeutic cytokines, particularly neurological and endocrine adverse effects, are further illustrative of these interferences. Interferons-a have been used in thousands of patients, so that the information accumulated with this group of closely related products is essential to delineate the potential and severity for non-immunological, but largely immune-mediated adverse effects to develop in patients treated with immuno-activating agents. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Endocrine adverse effects; Neurological adverse effects; Therapeutic cytokines; Interferons

1. Introduction Data on the relationships between the immune and the neuro-endocrine system has accumulated during the past years. There is ample evidence that the brain can influence the immune system in several ways, e.g. via the hypothalamic pituitary axis, the neuro-endocrine system and the autonomic nervous system. In turn, the immune system can influence the brain activity, and the role of endogenous cytokines is thought to be crucial in several acute or chronic neuropathological pro* Corresponding author. Tel.: +33-4-721-16997; fax: +334-721-16985. E-mail address: [email protected] (T. Vial)

cesses, such as ischemia, multiple sclerosis and Alzheimer’s disease. As regards our clinical experience with the therapeutic use of cytokines, neuropsychiatric and endocrine disorders rapidly came into light and proved to be major adverse effects of most cytokines (Vial and Descotes, 1996). Importantly, our expanding knowledge on this pattern of toxicities gives opportunities for a better understanding of the pathophysiological mechanisms of several diseases. However, it should be remembered that most of the current clinical experience results from the use of interferon-a (IFN-a). This review will therefore focus on the neurological and endocrine adverse effects associated with this cytokine, which is approved worldwide

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for the treatment of several malignancies and viral diseases, in particular chronic viral hepatitis B or C. Considerable experience is available as thousands of patients have been treated for up to 2 years or more. Large surveys or clinical trials in patients treated with IFN-a for chronic hepatitis C confirmed that neuropsychiatric and endocrine manifestations, mostly thyroid disorders, are among the most significant treatment-limiting adverse effects. 2. Neuropsychiatric adverse effects of the interferons

2.1. Interferon-a Neuropsychiatric complications associated with IFN-a treatment have been recognized in the early 1980s (Smedley et al., 1983; Adams et al., 1984). They consist of a large spectrum of symptoms. At the early phase of treatment, neuropsychological disturbances are usually associated with the flu-like syndrome. During this period, subtle impairment of memory and concentration, lack of initiative and generalized slowing are the most frequent findings with low-dose IFN-a, whereas acute and severe neuropsychiatric manifestations (e.g. acute encephalopathy, dementia or delirium) have been nearly exclusively described in patients receiving more than 20 – 50 MU (Smedley et al., 1983). The most disturbing neuropsychiatric manifestations are subacute or chronic. They are typically identified after several weeks of treatment when the flu-like syndrome tends to disappear. They consist of various cognitive, emotional, mood and behavioural changes, which are sometimes difficult to recognize, because their onset may be insidious in patients treated with low-dose IFN-a (Meyers and Valentine, 1995). Unfortunately, the role of the underlying disease, dose and schedule of treatment is rarely taken into account and very few controlled studies specifically addressed this issue. Neuropsychiatric examinations have evidenced significant deterioration during IFN-a treatment as compared to placebo or no treatment in the setting of chronic hepatitis C (McDonald et al., 1987), chronic myelogenous leukemia (Pavol

et al., 1995) or amyotrophic lateral disease (Poutiainen et al., 1994). Renault et al. (1987) proposed to classify these disorders into three main categories. The organic personality syndrome includes irritability and personality changes, which rapidly reverse after dosage reduction or treatment discontinuation. The organic affective syndrome consists of depressive disorders and emotional liability. Finally, psychotic manifestations with agitation, delirium, paranoia and suicidal behaviour are found in a few patients. Electroencephalographic (EEG) examinations have documented reversible cerebral changes with slow-wave a activities and occasional emergence of delta and theta activities. As these changes were mostly found in the frontal lobes, neurotoxicity was suggested to result from a direct effect on fronto-subcortical functions with mild subcortical dementia (Renault et al., 1987; Meyers and Valentine, 1995). The correlation between EEG disorders and neuropsychiatric symptoms was sometimes lacking, and marked EEG abnormalities have been observed in asymptomatic patients (Rohatiner et al., 1983). Although rarely severe enough to require permanent treatment discontinuation, neuropsychological complications may lead to severe psychic distress in long-lasting treatment or in patients otherwise not severely affected. They should be carefully taken into account in management of the patient’s disease. Severe depressive disorders, manic episodes and psychosis are undoubtedly the major clinical neuropsychiatric complications, and the reported incidence of depression ranged from 7 to 35% of patients depending on the duration of treatment (Prasad et al., 1992; Meyers and Valentine, 1995; Strite et al., 1997). This was occasionally associated with suicidal ideation and suicidal attempts, which were found in 1.3–1.4% of patients during or after the termination of treatment (Janssen et al., 1994; Rifflet et al., 1998). Although most patients improved or recovered after IFN-a dosage reduction or withdrawal, the possibility of neurotoxicity persisting for months or years emerged from a retrospective evaluation in 14 cancer patients who had completed a mean of 26 weeks of IFN-a therapy (Meyers et al., 1991a,b).

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Unfortunately, no clear predictive factors for the development of psychiatric adverse effects have yet been identified. Whereas the pattern of neurotoxicity seems to be independent of the dosage, the severity of symptoms might be more pronounced in patients receiving high doses. The duration of treatment was also deemed to play an important role (Valentine et al., 1998). A previous history of psychiatric disorders, exposure to cranial irradiation, organic brain injury, or addictive behaviour, are usually considered as potential risk factors and therefore relative contra-indications for IFN-a treatment. The data is however still limited and IFN-a induced worsening of the psychiatric disease is not the rule in patients with active psychiatric disorders (Van Thiel et al., 1995).

2.2. Interferon-b and interferon-g Other IFNs are rarely associated with neurotoxicity. Although a direct CNS toxicity of natural IFN-b has been regarded as a possible effect of intraventricular and/or intratumoral injection (Matsumura et al., 1988), IFN-b-induced neuropsychiatric complications were thought to be much less frequent than with IFN-a (Liberati et al., 1990). A possible increased incidence of depressive disorders was recently noted after 3 – 5 years of IFN-b-1b treatment (Lublin et al., 1996), and fatigue, depression and the chronic progressive course of multiple sclerosis were found to be significantly associated with IFN-b discontinuation (Neilley et al., 1996). However, this issue is still a matter of debate because severe depressive disorders were spontaneously more frequent in untreated multiple sclerosis patients than in the general population. Finally, neuropsychiatric complications of IFN-b treatment in other diseases were extremely infrequent, and only one case of depression has been so far reported in a patient treated for chronic hepatitis C (Sasaki et al., 1996). Although IFN-g can exert multiple effects on the CNS (Popko et al., 1997), the clinical use of this cytokine has not been clearly associated with neuropsychiatric manifestations. This is consistent with the fact that the blood – brain or the blood –

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spinal cord barriers have low permeability to IFN-g (Pan et al., 1997). However, careful examination found that neurophysiological changes produced by IFN-g were very similar to those observed after IFN-a treatment (Born et al., 1989), and data from the manufacturer also includes rare cases of CNS adverse effects in patients treated with high-dose IFN-g (Todd and Goa, 1992).

3. Other neurological and neurosensorial disorders Various other central neurological disorders have been described in IFN-a treated patients. Seizures were reported to occur in 1.3% of patients (Shakil et al., 1996), and were also found to be a relatively common adverse effect in children aged under 5 years of age, with fever and potential perinatal CNS injury as possible contributing factors (Woynarowski and Socha, 1997). These findings are consistent with experimental data reporting that IFN-a can enhance the excitability of cortical and cerebellar neurons (Calvet and Gresser, 1979). Neurological toxicity of IFN-a also included peripheral and cranial neuropathy, but there is as yet no evidence to support any mechanism by which IFN-a could induce such disorders. Doserelated paresthesias have been reported in a significant number of patients (Vial and Descotes, 1996), but frank peripheral neuropathies were extremely rare. Such reports mostly described patients who received high cumulative doses of IFN-a, but induction or exacerbation of sensory or motor axonal polyneuropathy may also occur after long-term low-dose treatment (La Civita et al., 1997; Rutkove, 1997). Other rare forms of neuropathy included anterior ischemic neuropathy, trigeminal sensory neuropathy and bilateral neuralgic amyotrophy. IFN-a has been involved in the development or the triggering of an underlying silent myasthenia gravis. In these patients the diagnostic criteria for myasthenia gravis were clearly fulfilled. An autoimmune reaction was the most likely mechanism and each patient had serum anti-acetylcholine receptor antibodies and required permanent anti-

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cholinesterase drugs long after the withdrawal of IFN-a (Batocchi et al., 1995; Mase et al., 1996; Rohde et al., 1996). Neurosensorial disturbances mostly consisted of ophthalmic disorders, which were identified in more than one half of patients and included usually asymptomatic retinal abnormalities with mild ischemic lesion, cotton wool exsudate, capillary occlusion or retinal hemorraghe (Hayasaka et al., 1995; Kawano et al., 1996). In these patients, diabetes mellitus and hypertension were both found as significant risk factors. Subclinical, but eventually irreversible abnormally long, visual evoked responses were more recently identified in 24% of patients (Manesis et al., 1998). Other neurosensorial disorders consisted of spontaneously reversible otological impairment with tinnitus and/or mild-to-moderate sensorineural hearing loss after IFN-a or IFN-b administration (Kanda et al., 1994). The clinical relevance and the pathophysiology of neurosensorial damages are unknown, but might involve micro-vascular lesions resulting from vasculitis or vasospasm. Recent experimental data suggested that retinal micro-infarction might be the result of IFN-a induced increase in leukocyte adherence to the vascular endothelium (Nishiwaki et al., 1996).

Although the role of cytokines in the normal physiology of the brain is not clearly established, their involvement in the regulation of CNS functions is supported by the identification of genes encoding various cytokines and cytokine receptors in several areas of the brain. In addition, cytokines may be produced within the CNS resulting in the presence of low brain concentrations (Benavides and Toulmond, 1993; Meyers and Valentine, 1995). For example, IFN-a and receptors for IFNa have been detected in the brain tissue of normal humans and/or in patients with chronic neuropathological processes. However, the mechanism by which the systemic administration of IFN-a or other cytokines produce neurotoxicity is still unknown. It may result from a complex intrication between direct and indirect effects involving the brain vasculature, the neuro-endocrine system, neurotransmitters and, more importantly, the secondary cytokine cascade (Licino et al., 1998; Valentine et al., 1998). It is indeed difficult to determine whether a clinical effect is directly mediated through the action of one given cytokine, or results from a secondary pathway through the induction of other cytokines or second messengers.

4.1. Brain transfer of cytokines 4. Mechanisms of IFNs-induced neurotoxicity The neuropsychiatric complications seen in IFN-a treated patients illustrate some of the effects of this cytokine on brain functions. In respect to the affected anatomic area of the brain, IFN-a might produce various biochemical and functional changes, and related neuropsychiatric or neurovegetative symptoms (Bocci, 1988). Essential functions such as temperature, sleep, appetite, behaviour, sexual function are affected. Interestingly, a wide range of neuropsychiatric adverse effects of IFN-a are in keeping with some of the behavioural changes observed in response to infectious or inflammatory processes (Hickie and Lloyd, 1995). In addition, the pattern of cognitive impairment described in healthy patients receiving single dose IFN-a (Smith et al., 1988) resembled to that observed during influenza infection.

Cytokines are high-molecular-weight and hydrophilic molecules that are not expected to cross the blood brain barrier to any appreciable extent. For example, the CSF concentration of IFN-a in humans is only 0.1% of that in plasma (Bocci, 1988). However, regional differences may exist. For example, the ability of IFNs and TNF-a to cross the blood–brain or blood–spinal cord barrier was demonstrated in several CNS areas of rodents (Pan et al., 1997), and this might also be the case for other cytokines. The transfer was deemed possible by the presence of putative carrier-mediated pathways or cytokine transfer to unprotected areas of the brain, such as circumventricular organs, allowing a direct effect in these areas of the CNS. This hypothesis is supported by the findings of very severe neurotoxic symptoms in patients receiving intraventricular IFN-a for leptomeningeal metastases (Meyers et al.,

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1991a,b). It was also proposed that peripherally administered cytokines stimulate visceral afferentneuronal pathways to produce a neuronal message which, in turn, is translated into the CNS by the intracerebral production of cytokines (Dantzer, 1994). Other putative mechanisms involved the activation of the brain cerebral vasculature and perivascular glial cells with subsequent release of mediators, such as nitric oxide or prostaglandins.

In addition, in vitro naloxone reversed IFN-a induced changes in neuronal activity, whereas IFN-a reversed withdrawal symptoms in morphine-dependent animals (Meyers and Valentine, 1995). Based on these findings, naltrexone has been proposed for improving cognitive dysfunction in IFN-a treated patients (Valentine et al., 1995). An opioid-mediated dopaminergic mechanism was therefore proposed to account for IFNa induced neurotoxicity.

4.2. Neuro-endocrine and neurotransmitters effects

4.3. Secondary cytokines induction

Mood and cognitive changes induced by IFN-a might result from the modulation of neuro-endocrine hormone production, such as the adrenocorticotrophic hormone (ACTH) and cortisol, which are involved in the regulation of emotions and memory (Meyers and Valentine, 1995; Licino et al., 1998). In addition, IFNs share molecular structure similarity with ACTH. Both findings have received considerable attention because perturbations of the hypothalamic – pituitary – adrenal axis (HPA) have also been evidenced in several subtypes of major depression (Meyers and Valentine, 1995). However, the activation of the HPA axis has been essentially reported after acute IFN-a administration. Depressive disorders are associated with abnormalities of various neurotransmitters, such as noradrenaline, dopamine or serotonin. IFN-a reduces brain serotonergic metabolism and a possible decrease in central serotonergic transmission has been found in IFN-g treated patients (Fa¨rkkila¨ et al., 1988). Experimental data suggested that repeated exposures to IFN-a inhibit dopaminergic neural activity (Shuto et al., 1997). However, no correlation between the action of IFNs on these neuronal systems and the occurrence of depressive disorders has yet been demonstrated. Other investigators focused on a possible central dopaminergic activity mediated by the binding of IFN-a to opiate receptors and the resulting excitatory effects (Meyers et al., 1991a,b; Valentine et al., 1998). Intra-ventricular IFN-a produces a catatonic-like reaction close to that described in animals treated with opiate agonists.

The release of several secondary cytokines, e.g. IL-1, IFN-g, IL-2 or TNF-a, which exert effects on the CNS, might represent another mechanism of IFN-a induced neuropsychiatric symptoms (Licino et al., 1998). IL-1 is involved in sleep regulation and in the release of ACTH and corticotrophin-releasing factor (CRF) with subsequent increased peripheral steroid production (Curti and Smith, 1995). In humans, IL-1 very frequently induces a flu-like syndrome, and several patients had clinical features of septic-like syndrome. In animals, septic-like symptoms resulting from the administration of IL-1b were prevented by the concomitant administration of the endogenous receptor antagonist IL-1Ra, whereas IL-1b receptor knockout mice did not develop systemic symptoms in response to peripheral inflammation (Licino et al., 1998). The production of TNF-a is enhanced by IFN-a, and TNF receptors are widely distributed in the human brain. In the brain, TNF-a exerts effects very similar to those of IL-1, with fever, anorexia, cachexia, and secretion of CRF. In the clinic, TNF-a is considered a major neurotoxic agent as most patients receiving large doses, developed CNS symptoms or neurophysiological test disturbances (Vial and Descotes, 1996). IL-2 can also contribute to the CNS adverse effects of IFN-a. Experimental data evidenced a variety of effects of IL-2 on the CNS and neuro-endocine function, as well as myelin damage and increased blood brain barrier permeability (Licino et al., 1998). The neurotoxic effects of IL-2 have been investigated in few human studies which consistently found moderate cognitive impairment and sleep

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disturbances to severe and usually dose-related behavioural changes (Denicoff et al., 1987; Caraceni et al., 1992; Walker et al., 1996). The intra-ventricular administration of IL-2 has also been involved in memory and frontal lobe dysfunction (Meyers and Valentine, 1995). Some of these cognitive deficits were assumed to mimick those observed in dementia, such as Alzheimer’s disease. Whether a direct effect of IL-2 on neuronal tissues, an increased vascular brain permeability with subsequent increased brain water content, or an IL-2-induced release of neuro-endocrine hormones (b-endorphin, ACTH or cortisol), account for these effects, remains unknown.

5. Endocrine disorders The existence of a close relationship between the immune and endocrine systems is well known. Several cytokines are expressed in the HPA, the adrenal, the thyroid and the reproductive target cells. In turn, cytokines exert multiple effects on central and peripheral endocrine cells for the regulation of most endocrine gland functions (Mandrup-Poulsen et al., 1995a,b). Cytokines have been shown to produce a wide range of hormonal responses, but most of the data has been obtained in experimental studies. Among the endocrinological adverse effects of therapeutic cytokines, IFNa induced thyroid disorders, has been the most extensively studied.

5.1. Cytokine-induced thyroid dysfunction Since the initial description of hypothyroidism in IFN-a treated breast cancer patients (Fentiman et al., 1985), numerous investigators have provided careful clinical and biological data on hundreds of patients treated for chronic viral hepatitis (Watanabe et al., 1994; Marazuella et al., 1996), solid tumors (Ro¨nnblom et al., 1991) or hematological malignancies (Gisslinger et al., 1992; Vallisa et al., 1995). Thyroid abnormalities ranged from asymptomatic increases in antithyroid autoantibody titers to moderate or severe thyroid disorders with clinical features of hypothyroidism, hyperthyroidism or biphasic thyroiditis. The dis-

order was usually detected within 3–6 months of treatment, but its occurrence may be delayed after the completion of IFN-a (Preziati et al., 1995; Mekkakia Benhabib et al., 1996). Although usually reversible upon treatment discontinuation (Baudin et al., 1993; Marazuella et al., 1996), severe and sustained hypothyroidism sometimes required long-term substitutive therapy (Watanabe et al., 1994; Marazuella et al., 1996). The long-term consequences on thyroid function awaits further investigations, but preliminary data suggests that patients with a previous history of IFN-a induced thyroid dysfunction might develop further thyroid abnormalities after the administration of pharmacological doses of iodine (Minelli et al., 1997). Overall, the incidence of clinical or subclinical thyroid abnormalities ranged from 5 to 12% (Mekkakia Benhabib et al., 1996; Vial et al., 1996), and up 31% (Preziati et al., 1995). Potential predisposing risk factors are manifold and include female patient, the underlying disease (i.e. cancer or chronic hepatitis C), combination therapy with IL-2 and the pre-treatment positivity or development of thyroid auto-antibodies during treatment. There is no clear evidence to suggest a role for the dose and/or duration of treatment, and the type of the IFN-a (i.e. natural or recombinant IFN-a). The presence of thyroid auto-antibodies seems to be more strongly associated with the occurrence of thyroid dysfunction, a risk factor consistently found by most investigators (Watanabe et al., 1994; Vial et al., 1996). In addition, patients with previous auto-immune thyroid diseases are prone to develop a severe form of hypothyroidism (Chen et al., 1996). The possible mechanisms of thyroid dysfunction have been previously discussed (Vial and Descotes, 1995). Since thyroid auto-antibodies are detected in about 70–80% of IFN-a treated patients with thyroid disorders, the induction of an auto-immune reaction and/or the exacerbation of a pre-existing latent thyroid auto-immunity are the most attractive hypotheses. Other auto-antibodies (e.g. antinuclear and anti-dsDNA antibodies) or clinical signs of auto-immune disorders were significantly more frequent in patients who developed thyroid disorders (Marazuella et al.,

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1996). The clinical course of thyroid disease after IFN-a treatment was also suggested to closely mimic post-partum auto-immune thyroiditis (Chen et al., 1996). In spite of these findings, auto-immunity is probably not a universal or the primary mechanism of IFN-a induced thyroid disorders since 20–30% of negative thyroid antibody patients developed thyroid diseases. Although direct toxicity of IFN-a on thyroid gland or TSH release has been considered unlikely (Jones et al., 1998), the acute systemic administration of IFN-a in volunteers or chronic hepatitis patients decreased TSH levels (Wiedermann et al., 1991; Barreca et al., 1992). IFN-a directly inhibits thyrocyte function in vitro at clinically observable levels (Yamazaki et al., 1993). Reversible defects in the intra-thyroidal organification of iodine were also found in 22% of antithyroid antibody negative patients treated with IFN-a (Roti et al., 1996). In addition, the thyroid auto-antibody pattern in those patients who developed thyroid dysfunction during cytokine treatment was not different from that of patients without thyroid dysfunction, but differed significantly from that of patients suffering from various forms of spontaneous auto-immune thyroid disease (Schuppert et al., 1997). As previously discussed for neuropsychiatric adverse effects, the production of secondary cytokines resulting from IFN-a stimulation might enhance an auto-immune response directed against the thyroid (MandrupPoulsen et al., 1995a,b). These secondary cytokines includes IFN-g, IL-2 or IL-6. Although IFN-g exerts multiple effects on the thyroid, including increased or aberrant expression of major histocompatibility complex (MHC) class II antigens on thyrocytes or a direct effect on thyrocyte metabolism (Jones et al., 1998), data on the adverse clinical consequences of IFN-g on thyroid function is very limited (Kung et al., 1990; Weber et al., 1994). Whereas the development of several new auto-antibodies or an increase in titers of previously positive auto-antibodies were found in most patients, clinical signs of auto-immune disease were not observed and thyroid function remained essentially unchanged. By contrast, IL-2 alone or in combination with LAK cells, IFN-a or g, or TNF-a has been re-

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peatedly associated with reversible thyroid disorders (Vial and Descotes, 1995). Up to 41% of previously euthyroid cancer patients treated with low or high-dose IL-2 developed thyroid dysfunction with hypothyroidism as the most frequent disorder (Krouse et al., 1995). In similitude with IFN-a, an auto-immune phenomenon has been suggested as the primary mechanism. This is supported by the presence of antithyroid antibodies, the increased expression of MHC class II antigens on thyrocytes as well as the presence of mononuclear cell infiltrates on histological examination of the thyroid (Pichert et al., 1990). Again, a direct or other cytokine-mediated effect of immunotherapy on thyroid hormonal function cannot be ruled out in patients who had no detectable thyroid antibodies (Mo¨nig et al., 1994). Finally, although short-term IL-6 treatment decreased TSH release and total serum concentrations of thyroid hormones in humans (Spa¨th-Schwalbe et al., 1996), no studies extensively addressed the clinical relevance of these findings, and no clinical thyroid disorders have so far been reported.

5.2. Diabetes mellitus Clinical data on the occurrence of IFN-a induced diabetes mellitus is actually limited to isolated case reports. In patients treated for chronic hepatitis, this event is probably very rare with only ten of 11 241 patients who developed diabetes. In addition, the relationship between chronic viral hepatitis, IFN-a treatment and the development of glucose metabolism disorders are still unclear, and a higher prevalence of diabetes mellitus has been noted in chronic hepatitis C (Fraser et al., 1996). However, several lines of evidence suggest that the occurrence of diabetes mellitus in IFN-a treated patients is probably not only coincidental. Prompt amelioration or complete recovery was sometimes noted after treatment withdrawal (Guerci et al., 1994; Waguri et al., 1994; Gori et al., 1995). Two successive episodes of severe diabetes following each course of treatment were reported in a patient with a previous history of glucose intolerance (Frankart et al., 1997). Transgenic mice expressing IFN-a in

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pancreatic b-cells developed type 1 diabetes, an effect prevented by IFN-a neutralizing antibodies (Stewart et al., 1993). More recently an increased expression of IFN-a was found in the pancreas of patients with type 1 diabetes (Huang et al., 1995). Possible mechanisms include an auto-immune reaction or a more direct interference with glucose metabolism. Because the appearance of islet cell antibodies in IFN-a treated patients has been documented very rarely (Guerci et al., 1994), IFN-a was proposed to trigger rather than induce, a latent auto-immune reaction in patients with genetic susceptibility to insulin-dependent diabetes mellitus (Fabris et al., 1998). The association between auto-immune disorders and IFN-a treatment could be predicted from the role of cytokines in immune regulation (Miossec, 1997), in particular in the control of the TH1/TH2 balance, with IFN-a favouring the development of TH1 clones and subsequently enhancing T-cell mediated immune diseases with a TH1 and proinflammatory pattern (i.e. thyroiditis or diabetes mellitus). IFN-a was also shown to induce insulin resistance through the impairment of the early phase of insulin response to glucose or a reduced sensitivity of peripheral tissues or liver to insulin (Koivisto et al., 1989; Imano et al., 1998). This might result in a subsequent destruction of stimulated pancreatic b-cells, and this mechanism is in keeping with the induction or exacerbation of non-insulin-dependant (type 2) diabetes mellitus in predisposed patients (Lopes et al., 1994). IL-1, IL-6, TNF-a or IFN-g have also been implicated in the destruction of pancreatic b-islet cells (Jones et al., 1998), but the clinical experience is limited to transient hyperglycemia without overt diabetes mellitus. An increased release in glucagon and other counter-regulatory hormones (cortisol, GH, catecholamines), or the induction of peripheral resistance to insulin were suggested to account for the moderate, but significant dosedependant increase in blood glucose levels after single-dose IL-6 (Tsigos et al., 1997).

5.3. Other hormonal abnormalities In humans, there is ample evidence that the acute administration of IFN-a can stimulate the

HPA axis with markedly increased serum cortisol and ACTH levels, whereas the secretion of others hormones, excepted TSH, are not significantly affected. This effect was supposedly the result of an indirect effect of IFN-a through the production of cytokines known to directly stimulate the HPA axis (e.g. IL-1, IL-2, IL-6, TNF-a) (Shimizu et al., 1995; Jones et al., 1998). In vitro studies also indicated that a direct stimulating effect of IFN-a on the hypothalamus, and/or less likely on the adrenal cells, is possible (Gisslinger et al., 1993). However, no further significant stimulation was observed after several weeks of IFN-a treatment, pointing out on a possible downregulation of the ACTH secretory system (Mu¨ller et al., 1992; Gisslinger et al., 1993). As a result, sub-acute or long-term treatment with IFN-a is not thought to influence pituitary hormones at a clinically observable level. The concentrations of several hormones (e.g. calcitonin, TSH, LH, FSH, prolactin, growth hormone, ACTH, cortisol, testosterone or estradiol) were not changed by prolonged IFN-a treatment (Mu¨ller et al., 1992; Del Monte et al., 1995). No clinical endocrinopathies attributable to disorders in the regulation of these hormones have yet been reported. As a matter of fact, long-term IFN-a treatment has never been associated with features of the Cushing’ syndrome, despite its effects on the hypothalamic-pituitary axis. One single case of hypopituitarism reversible upon IFN-a discontinuation was attributed to a possible auto-immune phenomenon with positive pituitary antibody for GH3 cells (Sakane et al., 1995). Although sexual complaints (decreased libido, impotence or erectile failure) were sometimes reported during IFN-a, data on the effect of IFN-a on sex hormone levels is conflicting. A decrease in serum estradiol and progesterone concentrations without changes in FSH or LH concentrations has been observed in healthy women treated with IFN-a (Kaupilla et al., 1982), but there was no report of libido or fertility impairement in women. Similarly, male patients treated for 2–12 months did not exhibit significant changes in sexual hormone levels and sexual function (Schilsky et al., 1987), and sexual complaints reported in the treatment of chronic hepatitis C were pre-

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sumably related to other mechanisms, namely fatigue, anxiety, psychological disorders (Piazza etal., 1997). As regards to the long-term use of IFN-a in children, there is no evidence of impaired developmental milestones. Growth retardation in children receiving long-term IFN-a treatment for recurrent respiratory papillomatosis was more likely to be a consequence of the underlying disease (Crockett et al., 1987). In addition, the significant decrease in bodyweight loss and nutritional status observed in children treated for chronic viral hepatitis was transient and not associated with growth impairment (Gottrand et al., 1996).

6. Conclusion As illustrated by experimental data and the clinical experience with the interferons, there is growing evidence to suggest that cytokines exerted a large range of effects on the CNS and the endocrine system. As these cytokines are naturally produced in the body, understanding their physiological role in the regulation of neurological and endocrinological functions may be helpful to predict corresponding adverse effects when these agents are developed for therapeutic purpose. Neuropsychological disorders are a well-identified potential consequence of short-term or prolonged systemic administration of IFN-a, IL-1, IL-2 or TNF-a. Among endocrinological adverse effects, only thyroid abnormalities are clearly associated with IFN-a or IL-2 treatment. Other endocrinological effects have been observed only after acute administration, and it remains to be determined whether these changes persist and produce significant clinical consequences during long-term treatment. Finally, the neuroendocrinological adverse effects of therapeutic cytokines indicate that a wide range of systems and organs other than the immune system can be the targets of immuno-activating agents, either directly or indirectly. This should be borne in mind during the development of any new agent with known, possible or even may be unexpected immunoactivating properties.

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