The increasing number of studies in which the endocrine and immune systems were related led Ader to coin a new term "Psychoneuroendocrinoimmunology" to describe a new discipline combining psychological, neurological, endocrine and immunological aspects. More recent studies, moreover, have highlighted the possible role of the pineal gland and that of its best-known hormone product, N-acetyl-5-methoxy-tryptamine, in relation with the immune system, generally as an immune-enhancing hormone, although some studies have suggested controversial actions such as an inhibitory effect on T lymphocytes [1,2]. Significant and substantial documentation on this topic has been published in recent years, highlighting aspects such as: a) Increased antibody response, Thelper lymphocyte activity and interleukin-2 production after the prolonged administration of melatonin [3]; b) An increase in the T-H/NK[4] ratio; c) An increase in antibody-dependent cell cytotoxicity[5]; d) Earlier maturing of lymphocytes5, increased levels of interleukin-2 [3] and of (- interferon [6], increased presence of antigens and production of cytokines [7]; e) In human monocytes, greater cytotoxic activity and increased production of interleukin-1m-RNA; f) A greater number of granulocytes-macrophages forming colony units in the medulla [9].

These interesting results encouraged us to examine and describe their most significant aspects. The present paper consists of three main sections: in the first, we summarise experimental and clinical data, and discuss the relation between the pineal gland and stress. Secondly, we examine the immuneenhancing role of melatonin, and finally we provide a brief review of the relation between the pineal gland and cancer.

The laboratory experiments carried out can be summarized in the following terms: "When rats are sensitized by appropriate adaptation of their conditions to induce a situation of acute stress, the response observed in the animal is of a significant increase in the synthesis and secretion of aMT. It is suggested that these hormonal changes result from certain changes in pineal sensitivity to catecholamines, which are characteristic of the sympathetic innervation of the pineal gland, or to circulating levels of catecholamines".

The above comments refer to animal experimentation; with respect to children, and the results obtained by Molina [10], Rodríguez [11], Martín [12] and Jaldo [13], and without taking into consideration the type of stimulus or its intensity, the pineal gland is said to be sensitive to various stress-related stimuli. The characteristics of the response obtained (i.e. the greater or lesser production of hormones) depend on the class of stimulus it is exposed to. Therefore, and in agreement with the conclusions of studies regarding the potential of melatonin to regulate or modify internal imbalances, and thus to a certain degree combat the effects of stress, it can be said that the existence of situations of acute fetal distress, febrile convulsions, epileptic seizures, surgical intervention or intense traumatism can induce an increase in melatonin production. Another aspect of interest, resulting from mechanisms that to date remain unexplained, is that the rate of secretion described by the above authors, referring to normal children, is clearly different among epileptic children and disappears completely among patients suffering febrile convulsions [14] (Fig. 1). In principle, we cannot say whether these variations are particular to the pathogenic mechanisms involved in the phenomenon or are the expression of the onset of a compensatory endogenous mechanism [15]. In any case, these facts are interpreted as an immediate pineal response to bring the convulsion to an end, and so in addition to its function as a "regulator of internal regulators", melatonin can be said to have a direct effect on neural excitability as a neurotransmitter inhibitor, and therefore to form part of the mechanisms involved at the start of the refractory postseizure period [16,17].

The differences observed between patients with FTS (taken as an example of chronic stress) and the other groups comprising the study (in all of which severe stress was present) suggest that the pineal gland, like other neuroendocrine organs and responses, undergoes reduced functioning and thus the hormonal response is lower [18]. Interpretation of these results is difficult but, following the logic of a response organised in three well-differentiated phases (increase, plateau and decrease), the results obtained for the chronic stress model could represent a declining or an exhausted pineal response and thus a greater susceptibility to multiple factors or extrinsic aggression.

As described in the literature, the variations in response between groups subjected to an identical or to a different stimulus (slight or severe traumatism, fever and convulsions, degree of surgical stress and institutionalisation) comprise valid arguments to corroborate the hypothesis of qualitative/quantitative specificity in the binomial "stimulus-pineal response".

Moreover, and taking into account the above, it seems obvious that the variable "time" (to distinguish a particular moment), in the study of certain endogenously-produced substances following a circadian pattern of secretion, should be considered so that reliable conclusions may be drawn regarding the latter question and its biological effects.

With regard to newborns, and as discussed elsewhere, the mean rate of aMT in the umbilical vein is clearly greater than that found in the artery, a fact which, in principle, might be explained by taking into account the special characteristics of feto-placentary circulation and the capability of N-acetyl-5-methoxy-tryptamine to be diffused through all the organic fluids. In any case, and taking into consideration that the average lifetime is around 20 minutes, it seems incontrovertible that newborns present adequate pineal functioning [19-21].

In the light of current knowledge, it is difficult to explain these variations in terms of biochemistry or of physio-pathological mechanisms. Nevertheless, the literature concerning this question includes respected opinions such as that of Reiter [22], who considers the effects of certain adverse environmental conditions to be more complex than were originally supposed, and that it is not valid to make the simple assumption that high levels of adrenal or other catecholamines may stimulate aMT production in stress-inducing situations.

Similarly, Reiter, Parfitt et al. [23] claim that an excess of catecholamines, rather than stimulating the pineal sympathetic nerve-endings, blocks them, thus inhibiting any stimulant effect on the pinealocyte. This theory was originally substantiated by the following observation: "When a group of laboratory animals were subjected to physical stress (immersion in water), it was found that NAT activity only increased if a catecholamine inhibitor was previously applied". This argument is in line with the study by Craft [24], who also showed pineal response to catecholamine stimuli to be adequate when a group of rats were subjected to conditions of constant light; in consequence, the density of the E-receptors in the pinealocyte membrane increased. Other stress-inducing stimuli, such as the induction of hypoglucemia by insulin injection or by immobilisation, induce intense increases in pineal NAT activity and, presumably, in the synthesis of aMT. On the contrary, this response is not observed when hyperinsulism results from high levels of carbohydrate intake or when the adrenal glands are removed, thus suggesting that a factor of adrenal origin, presumably catecholamine, responsible for the process in question.

Champney et al. [25] showed that immobilisation, daytime hypoglucemia, immersion in cold water, noises, changes in environmental conditions, cold, etc., applied to rats during the day, produce a significant increase, sometimes exceeding 50%, in pineal NAT activity and thus in the pineal production of aMT. On the contrary, in the Syrian hamster, these stimuli have been found to be associated with an increase in catecholamines in plasma and a decrease in the pineal activity of HIOMT and in aMT content. The above studies suggest that the pineal response of rats and hamsters to circulating catecholamines is very different. Consequently, the exogenous administration of isoproternol or NE during the day would be expected to produce a pineal stimulus in the rat but not in the Syrian hamster [26,27].

Another aspect to be considered is the analysis of the intensity of the pineal response to a stimulus. We have found, using different models (neurological, surgical, etc.), that higher degrees of stress lead to a greater intensity of glandular response (Fig. 3).

Different studies have obtained varying results for nocturnal pineal function when a severe stressinducing stimulus is applied. Joshy et al. [28] observed that the injection of saline serum during the night (the period of maximum pineal activity) produced a sharp fall in NAT and, consequently, in aMT, with both parameters returning to normal values after 15-20 minutes. These changes are evidently mediated by the adrenal glands, as the effects described are prevented when the adrenal glands are previously removed from the experimental animal. More recently, it has been found that the immersion of a group of rats in water during the night produces a sharp fall in pineal levels of aMT, these parameters returning to their original levels after 15-20 minutes, while NAT activity remains consistently increased. Unlike the first-described experiment, these variations are not avoided by previous adrenalectomy.

As occurs with animal experimentation, the studies carried out to date with humans are, to a certain degree, contradictory, or at least non-comparable. Vaughan[29] has reviewed various experiments in which after the application of various intensities of electroshock to patients with depressive disorders, levels of aMT in plasma remained unaltered. It should be remembered, however, that according to indoleamine theory on the depression experienced by such patients, we should take into account not just the electric variable but also the typical alterations occurring in the metabolism of serotonin at the central level [30]. It has also been observed that the hypoglucemia induced by insulin and the pneumoencephalography that develop during daylight hours do not produce any measurable pineal response, while there has been shown to be a clear rise in the levels of cortisol, prolactin and growth hormone.

Another experiment has proved that after intense exercise, subjects lacking preparation for this present a significant increase in levels of cortisol and growth hormone, but not in those of aMT. Finally, Akerstdt et al. [31], after provoking a stress-inducing psychic stimulus at different moments of the day (morning, afternoon and night) among various healthy subjects, found no alterations in the urinary elimination of aMT, but did record variations in the above-mentioned biochemical indicators.

We see, thus, that the results presented are hardly comparable, due to the diversity of stimuli and the heterogeneity of samples studied. Moreover, it should be remembered that the concept of psychic trauma was defined by Freud, as long ago as 1893, as an overload of excitation produced by an experience resulting in alterations of the distribution of psychic energy. The relation of psychic trauma with stress is obvious, and we may consider as traumatic any stimulus that requires an unaccustomed effort by the individual’s defence mechanisms, i.e. one that provokes a psychological reaction.

Evidently, the organism is in a continual process of adaptation to the demands of the environment and of its own development. In the case of children, it seems that a certain degree of stress is even necessary for such development to proceed normally, although when the child’s behaviour becomes problematic, he/she may be reacting to environmental circumstances that surpass the child’s capability of adaptation [32]. A child may confront considerable psychological stress when affective support is provided by the parents or other adults performing this role, but if this type of affective relationship is absent then the slightest altercation may constitute a situation of intense stress. In the case of children with FTS, this type of affective relationship is greatly reduced, and many authors have considered maternal separation to be a cause of emotional and affective perturbations [33].

Within this context, Jiménez Tallón [32] studied a group of institutionalised children, evaluating the intensity of the stress to which they were and had been subjected. A comparative analysis was made of the different groups, and the conclusion reached was that greater degrees of stress quickly produce a fall in intellectual performance. There was also found to be an evident relation between emotional and behavioural disorders and situations of psychosocial stress such as inadaptation, the presence of siblings in the institution or an unfavourable family environment. From our review of the literature on this question, in situations of FTS it is necessary to include as a cause of the disorders described both maternal deprivation and institutionalisation, with their circumstances and consequences. These two aspects should be considered independent, but simultaneously present in the group of humans referred to [34-37].

As remarked above, the results obtained with regard to aMT levels among children subjected to continual (chronic) stress are difficult to explain in terms of the arguments described above, although there exist differential aspects which make these experiments non-comparable with others reported in the literature. Such factors include the following: a) Firstly, this infant population was subjected to chronic psychic stress; b) Secondly, if we take into consideration the indoleamine theory of depression, it is possible that the state of isolation and depression experienced by such patients in some way contributes to the impaired adjustment and synchronisation of pineal functioning.

The first contribution of note was made by Maestroni, who observed that when laboratory animals were pinealectomized, the thymus gland became considerably diminished. This finding opened up an interesting area of study which in later years produced important results. Subsequently, Maestroni’s research group [38] performed an experiment that was even more definitive and as far-reaching as the earlier one, using an experimental model with laboratory animals. The encephalomyocarditis virus was injected into two groups of mice, the second of which received a prior injection of melatonin. Both groups were subsequently subjected to a controlled type of stress, with exactly the same quantity of the microbial agent (a sublethal dose) and the same stress (in qualitative and quantitative terms). The results of the experiment were surprising. It was found that: a) The majority of the mice treated with melatonin survived (only 6% died); b) On the contrary, over 80% of the untreated animals died, and of these a significant number died during the first week of the experiment.

In 1992, Caroleo et al. described a laboratory study that revealed the so-called "booster" effect of melatonin, consisting of its capability to raise the antibody response. Antigens derived from horse erythrocytes were administered to two groups of mice, one of which was previously given melatonin. In both groups, as was to be expected, antibodies were produced that were specific to the antigens administered, but among the animals given melatonin, the level of antibodies was more than twice that of the other group.

In a clinical trial carried out by Neri et al. [39], melatonin was administered (10 mg/day for a month) to 33 patients with solid tumors. These patients were also treated with the protocols specific to each case (radiotherapy, chemotherapy, surgery), and which are known to bear important connotations of stress and depression of the immune system. It was found that: 1) Levels of interleukin- 2 increased by over 50%; 2) The factor of tumoral necrosis rose by almost 30%; 3) Levels of (-interferon rose by over 40%. All these mediators are of great importance for the normal functioning of the immune system.

Among the elderly, the possibilities of suffering cancer or an infectious disease are noticeably higher than among a younger population, among the factors intervening in this process being the phenomenon of ageing, the reduced response to stress and, of course, the declining efficiency of the immune system. Today, a further factor should be added, namely the role of melatonin. As observed in several chapters in this book, levels of melatonin decline with age and are closely related to the above- cited parameters. Ben-Nathan et al. [40] showed that among laboratory animals the immunereinforcing role of melatonin is more efficient in older animals. Their experiment also revealed that the appearance of a viral encephalitis (normally lethal) can be prevented in 56% of old mice treated with melatonin, but among only 39% of untreated, younger animals. Among other aspects of interest, it was reported that melatonin is capable of raising levels of secretory IgA. Many of its effects are derived from its relation to the T-helper lymphocytes [41], concerning which Maestroni and Conti demonstrated the existence of receptors for melatonin. From this initial mechanism, important consequences are derived, including: a) An increase in the production of interleukin-4, which in turn stimulates another group of immune factors. A basic outline of these relations is illustrated in Fig. 4; b) As shown in the figure, the natural killer lymphocytes (NK) are directly related with interleukin-4 and with the T-helper lymphocytes. This observation has been corroborated by experiments with humans which show that after a group of young people had taken 2 mg of melatonin per day for two months, the cellular elements of NK increased by up to 240%; c) Morray et al. [42] observed "in vitro" that when human monocytes are treated with aMT their fagocytic capability against certain types of carcinogenic cells increases by up to 73%; d) Maestroni and Conti [41] showed, in an interesting study published in Journal of Pineal Research, that melatonin is capable of reinforcing cell growth in bone marrow; e) Other studies have shown that melatonin directly or indirectly contributes to enabling an increased presence of granulocyte/ macrophage stimulating factors.

The mechanisms by which melatonin is capable of modulating the immune system are still incompletely understood, but various studies have suggested the following [43]:

a) By means of the relation between the pineal gland, the immune system and the endogenous opioid system. It has been reported that certain opioid peptides may act as mediators of the action of melatonin on the immune system [44- 46]. In fact, the immune-stimulant and antistress effects of aMT are eliminated by the administration of naltrexone, a specific opioid antagonist [47,48]. Moreover, dynorphin 1-13 and Eendorphins reproduce the immunological effects of melatonin [49,50]. Melatonin also stimulates the release of opioid peptides by activated T-helper lymphocytes [51].

b) Lymphokines as mediators of the action of melatonin on the immune system. The proof that the production of both interleukin-2 and of (-interferon is stimulated by melatonin, together with the fact that both products, in turn, stimulate the activity of NK cells and other elements of the immune system [52], has led to speculation that these lymphokines might be mediators of the observed effects of melatonin on the immune system [53].

c) Indirect actions of melatonin via other endocrine systems. It has been suggested that the hypothalamus- hypophysis-gonadal axis could be related to the action of melatonin on the immune system [54], on the basis of experiments showing that the photoperiod and treatment with melatonin have a joint effect on reproductive capability, the production of sex hormones and certain immune functions [55,56]. Moreover, melatonin is known to be capable of antagonizing the suppressor effect of corticosteroids on the immune system [57,58]. It has also been suggested that the thymus could be a crucial element in the immune modulation interaction between melatonin and corticosteroids [59]. Additionally, melatonin is capable of stimulating the release of TRH, which has evident effects on antiviral activity and other functional aspects of the immune system; therefore, TRH might comprise another intermediary between melatonin and the immune system [60].

d) The direct action of melatonin on lymphoid tissue. Various studies with [125]-iodomelatonin have shown binding sites in homogenates of lymphoid organs of birds and mammals [61], rat splenocytes [62], human lymphocytes [63], neutrophils [64] and T-helper cells [41]. This evidence, together with the known liposolubility of melatonin (which makes it especially easy for it to enter the lymphatic system), leads us to accept the direct effect of melatonin on the lymphoid tissue.

e) Neutralizing action of free radicals [65]. The high reactivity of free radicals makes them very dangerous, with the capability to damage both macromolecules and cellular components. As has been stressed throughout this book, melatonin is a powerful neutralizer of free radicals.

The first suggestion that the pineal gland might be related to tumor growth[66] was made in 1929, but substantial interest and progress in the subject has only occurred during the last two decades. Most studies have recorded an oncostatic action by the pineal gland, and especially by its principal hormone, melatonin. Apart from the above reference, the authors probably arousing most interest within the scientific community with respect to this question were Tamarkin et al. [67]. Among other studies, the latter described the results obtained with rats after provoking mammary tumors with DMBA, and their possible prevention with melatonin. Subsequently, in 1986, Blask [68] studied the effect of aMT on the growth of a highly malignant cell line (MCF-7) in women. In recent years, a considerable number of studies, both experimental and clinical, have been made, attempting to define the role of melatonin in tumor pathology. However, we have not found any paediatric references in this respect.

There exists experimental evidence that both pinealectomy and the administration of melatonin are related to the growth of malign tumors [68-69]; the most significant references are given below.

a) Effects of pinealectomy. Concerning tumor growth, the following have been studied: sarcomas[ 70], Walker carcinoma[71], MMI melanoma [72], dimethylbenzanthracene-induced melanoma [73], ovarian carcinoma [74], Ehrlich tumor [75], Yoshida tumor [76], NMU-induced mammary carcinoma [77], MCA-induced fibrosarcoma [78], Guerin epithelioma [79] and diethylaminobenzene-induced hepatocarcinoma [80].

b) In vivo administration of melatonin. The administration of melatonin has been shown to be effective against the following types of tumors: LSTRA-induced leukemia [81], R3290AC mammary tumor [82], DMBA-induced mammary carcinoma [83], B16 melanoma [84], DESinduced prolactinoma [85], R3327H prostatic adenocarcinoma [86], NMU-induced mammary carcinoma [87], Kirkman-Robbins hepatoma [88], Guerin epithelioma [80],C3F1 spontaneous mammary carcinoma[89], and C3H/Jax spontaneous mammary carcinoma[90]. There are other types of tumor on which melatonin has no influence and others, still, on which the inhibitory effect is developed when a given dose is administered or even when it is administered at a certain time of day [91,92].

c) In vitro effects of melatonin. Melatonin is capable of inhibiting the following tumors: B7 melanoma [93], MCF-7 lung cancer [94], DES-induced prolactinoma [95], SK-OV-3 ovarian carcinoma [96], the JA-1 line of ovarian carcinoma [96], the Jurkak T-cell lymphoma [97], 180 cervical cancer [98], S180 sarcoma, JAR choriocarcinoma [99], C-19 mammary carcinoma [100], HEP-2 carcinoma of laryngeal cells [101], and M2R melanoma [102].

Despite these interesting contributions, the current situation is such that in the short term melatonin is unlikely to form part of cancer-treatment protocols. On the other hand, it is apparent from the above evidence that it does play an important role and that further study is required to determine precisely what function it could adopt in the treatment of cancer.

The oncostatic role of melatonin can be explained by various mechanisms, the following being of particular interest [103]: a) A direct cellular effect, including the modulation of the estrogenic pathway, direct effects on cell cycles, influence on certain growth factors, interaction with calmodulin and tubulin, and enlargement of the zones of intercellular communication; b) An indirect action as an antioxidant. The book contains several references to explain this action and its protective potential; c) An indirect action by immunostimulation, a mechanism which has been referred to previously. Together with these aspects of interest, studies have been made of various disorders of melatonin production in cancer patients, concerning both its nocturnal secretion and its rhythm.

The differences in the results obtained by different authors are probably due to factors such as the different animal species used, the tumor models, whether in vivo or in vitro studies were made, differences in the mode and moment of administering the melatonin, different methods of measuring the tumor and the diversity of photoperiods used in the experiments.

Various clinical trials are currently being performed using melatonin with cancer patients . In principle, although we remain sceptical, the conclusions of available evidence are to continue work in this line until a more precise definition is obtained of the role of this methoxyindole in tumor pathology. Finally, we again mention that despite the considerable body of documentation published in recent years, we have found no studies referring to paediatric patients.

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