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MELATONIN: PERSPECTIVES IN LABORATORY MEDICINE AND CLINICAL RESEARCH
| Authors: | Andrew Miles Academic Department of Psychological Medicine |
| University of Wales College of Medicine Heath Park, Cardiff, Wales; and Tenovus Institute for Cancer Research University of Wales College of Medicine Heath Park, Cardiff, Wales | |
| David Philbrick Academic Department of Psychological Medicine | |
| University of Wales College of Medicine Heath Park, Cardiff, Wales | |
| Referee: | Frank J. Liu Department of Laboratory Medicine The University of Texas System Cancer Center M. D. Anderson Hospital and Tumor Institute Houston, Texas |
I. INTRODUCTION
The pineal gland has historically been considered an organ of endocrine potential,1,2 but it was not until the discovery of its principle 5-methoxyindole characterized as N-acetyl, 5- methoxytryptamine or melatonin by Lerner in 1958’ that interest in the physiological status of the gland and the possible importance of its pathophysiology to diagnostic laboratory medicine and clinical research was realized. Even in these modern times, the mysteries surrounding the pineal are still only gradually being solved, and pinealology very much represents an active science that has seen considerable methodological advances really only in recent years. Despite such advances, however, even a simple human physiology for melatonin has not been worked out, although there is some circumstantial data implicating melatonin in the regulation of pubertal onset.4.5 This situation is in contrast to that in animals where a fairly well recognized neuroendocrine role for melatonin in the modulation of hypothalamic-pituitary function is present.4-12 In man, the absence of purely physiological data concerning this hormone can be contrasted to the more abundant information that implicates disturbances and alterations in melatonin secretion in various disease processes involving hypothalamic-pituitary function. Although the pathophysiological importance of such findings is not yet fully understood, an abnormality in any biochemical parameter does not have to possess primary etiological significance to be of clinical utility. In this regard, the observed and well-documented abnormalities in melatonin secretion within specific clinical syndromes and disease processes have been put to use in diagnosis and clinical investigation. The present review outlines the basic biochemical aspects of melatonin and describes the available literature, which implicates a role for melatonin in laboratory medicine and demonstrates the value of melatonin analysis as a biochemical tool in clinical research.
II. MELATONIN: BASIC PERSPECTIVES
A. Basic Biochemistry
The discovery of melatonin1 and its biochemical characterization13 was soon followed by a rapid growth of interest in the metabolism of this compound. By 1960, the basic pathway of synthesis14.15 and catabolismhad been elucidated, and interest in the clinical importance of this pineal factor followed. 16-19,21 Some 28 years later, our knowledge of the circadian characteristics of melatonin secretion is still incomplete, although the accepted range in the daily interindividual variation of secretory levels is now more or less uncontestedly stand- ardized. At the present time, we can define the normal secretory pattern in human subjects as one which shows a 24-hr cycle of marked circadian rhythmicity, with the diurnal variation in output resulting in very low daytime serum concentrations22,23 and maximum levels during the night.23,24 The serum levels and secretory characteristics of melatonin show striking interindividual variation but marked intraindividual stability,24,25 and it has been suggested that excretion of melatonin is genetically determined.24,26 The daytime levels of melatonin are extremely low (10 pg/ml), with nocturnal levels frequently reported as ranging between 25 and 120 pg/ml.24-27 The 24-hr circadian rhythm of melatonin secretion in human plasma and saliva is shown in Figure 1.
The pinealocyte is the locus of melatonin biosynthesis. Initially, this process involves uptake and concentration of circulating tryptophan into the pinealocyte followed by 5- hydroxylation and subsequent decarboxylation such that step one of melatonin synthesis represents the generation of the central compound serotonin or 5-HT. The formation of melatonin involves two distinct enzymatic processes: synthesis of N-acetylserotonin (NAS) by N-acetyltransferase (NAT), 14,28 and generation of melatonin by 5-methylation of NAS, with this step being mediated through the activity of pineal hydroxyindole, O-methyltrans- ferase (HIOMT).15 In this pathway, it is NAT that has been described as rate limiting, with the actual mechanism involving transfer of an acetyl CoA derived acetyl moiety to the N- terminus of 5-HT.28 The biosynthetic pathway is illustrated in Figure 2. Both synthesis and release are subject to modulation by noradrenergic mechanisms29 and, since melatonin is not stored in the conventional sense, release follows production.29 The inhibitory effect of light on melatonin secretion and synthesis is well documented,30-32 and is mediated through what for simplicity may be described as the retinopineal tract.32 Melatonin is secreted into cerebrospinal fluid (CSF) in addition to plasma,33 which might suggest the former process as a physiologically important one.34,35 While this remains an interesting possibility with relation to bioavailability and site of melatonin action, it has become clear that direct secretion of hormone into plasma is the major route for transport of endogenous melatonin to target sites.36 On secretion into plasma, only around 30% of melatonin escapes binding to plasma albumin.37 The active compound has a reported half-life of 20 min, and degradation involves hepatic microsomal 6-hydroxylation to 6-hydroxymelatonin which becomes conjugated, mainly to sulfate, for urinary excretion.38 The brain differs in its catabolic treatment of melatonin, and metabolism within this organ reportedly generates N-acetyl, 5-methoxykynurenamine.39
B. Basic Pharmacology
The availability of radioactive melatonin has resulted in the search for specific receptors for this hormone. The main features of this research have included the quest for points of recognition of hormone, together with the actual locus of hormone transduction or ampli- fication. Concerning melatonin, we know more about the first than the second. The difficulty in establishing the recognition function is that it has been difficult to distinguish between melatonin binding and a functional receptor-mediated activity that is consequent to binding. The presence of melatonin has been demonstrated in numerous areas of brain,40 and sites which show high-affinity binding of melatonin have been located in hippocampus, striatum,
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and, most interestingly, the hypothalamus.41 Glass and Lynch42 have identified a brain site of melatonin action in mouse brain, but no group has yet been able to demonstrate a conventional distant type of receptor in man, with a melatonin-mediated cascade of events such as, for example, that which occurs following interaction of catecholamine with cate- cholamine receptor.
In 1960, Lerner and Case43 demonstrated intravenous injections of melatonin capable of producing sedation in adult men, and later similar studies observed changes in electroen- cephalographic patterns and rhythms in sleep and motor activity following administration of this hormone.36,44 Arendt and colleagues45 have administered small doses of melatonin to healthy volunteer subjects over 4 weeks in a double blind cross-over study. The major observation of this study was the increase in self-rated fatigue in the evening, and the experimental dosage, which was well tolerated, failed to elicit any consistent effects on mood or sleep rating. Earlier studies in normals have generally recorded “feelings of con- tentment” and mild euphoria following melatonin administration,18,19,46 but these studies have differed considerably in construction, timing of hormone administration, and in the dose of hormone given. All of these factors are now known to be of critical importance in the interpretation of the observed response.45,47,48 It is now accepted that melatonin admin- istration orally and, especially, intranasally — a route which avoids first pass hepatic me- tabolism of melatonin49 - has psychopharmacologial effects in humans remarkably similar to those produced by drugs with sedative and hypnotic properties, giving rise to drowsiness and slowed performance.50 Lieberman and associates51 have studied the effects of 240 mg orally administered melatonin (80 mg at 12:00 hr, 80 mg at 13:00 hr, and 14:00 hr) in 14 healthy male volunteers in a double-blind placebo-controlled cross-over study with evaluation of mental performance, visual sensitivity, and use of a battery of standardized self-reported mood analyses. The investigators found melatonin-mediated alterations in mood state com- parable with those produced by benzodiazepines in therapeutic dosage. This had given rise to the suggestion that melatonin may be physiologically involved in the induction and maintenance of normal sleep architecture, and that its use as a hypnotic might be feasible on the grounds of lack of side effects. Indeed, Lieberman and colleagues51 noted that unlike common hypnotics, melatonin did not impair anterograde memory even in doses that pro- duced daytime sedation. Melatonin was observed to produce delayed reaction times that, like its sedative properties, were considerable but brief. This brevity of action is perhaps not surprising when one considers the short half-life of circulating hormone or perhaps a rapid down-regulation of available melatonin receptors as possible explanations.
III. MELATONIN: CLINICAL PERSPECTIVES
A. Melatonin Assays in Laboratory Medicine and Clinical Research
Following the discovery of melatonin, there appeared the first bioassays which were largely time-consuming, insensitive techniques of poor specificity.52 Following these, fluorometric methods appeared, but their lack of specificity and disappointing level of sensitivity led to their replacement by the solvent extraction radioimmunoassay techniques of which at least four were published by 1976.53-56 All of these used relatively specific antisera of high titer and satisfactory sensitivity, but all required extraction of melatonin from plasma or serum into a nonpolar solvent before addition of antiserum and radiolabel. These assays were successfully validated according to definitive technical requirements including low cross- reactivity with structural analogs, good correlation with gas chromatography mass spectro- metric (GC-MS) results, high recovery of melatonin following extraction with solvents together with low inter- and intraassay variability, and were used fairly extensively in the basic and clinical studies of that time. There exist currently some extremely sensitive and specific techniques for melatonin estimation, and a classic example of one of these is seen
in melatonin analysis by gas chromatography negative chemical ionization mass spectrometry described by Lewy and Markey in 1978.27 Such a technique, although ideal from the biochemists’ theoretical standpoint, is not the most easily accessible from the practical point of view, and other assays such as high-performance liquid chromatography (HPLC) of melatonin in solvent-extracted systems have been given attention.57 In terms of specificity and sample capacity, such techniques have their attractions. However, with an HPLC system, samples still require solvent extraction, which is often tedious and adds significantly to assay length, complexity, and cost. Thus, it was with enthusiasm that investigators began to see the development of nonsolvent extraction radioimmunoassay systems in laboratory medicine, and two of these are currently available for the assay of plasma and salivary melatonin. 58,59 The first direct assay for plasma melatonin was described by Frazer and co-workers58 and represented a rapid technique of satisfactory sensitivity and excellent specificity involving no solvent-extraction system and included an efficient charcoal separation technique. Assay of melatonin with enzyme-labeled antibodies has also been described.60 Most radioimmu- noassays currently published for melatonin assay employ tritiated hormone as radiotracer, and at least three different specific activities are presently commercially available.58,59 Io- dinated melatonin has been prepared, studied, and characterized,61.62 but gamma-emitting isotopes have yet to be used extensively in melatonin radioimmunoassays. Their use within a validated system is to be encouraged, since counting of gamma radiation as the final step in analytical technique is considerably easier and certainly less expensive than beta scintil- lation counting, and can add to the “neatness” of current direct melatonin radioimmunoassays.
In addition to serum,22-27 urine, 68-71 and CSF,33-35 melatonin has been described as being present in human saliva.59,63 The general practical importance of salivary assays in laboratory medicine is readily appreciated and has been discussed in a useful review by Riad-Fahmy and co-workers on the applications of such methods in the assessment of endocrine function. 64 In recognizing the great advances in clinical pineal research that have been made possible by the advent of sensitive and specific methods for melatonin estimation, one must also recognize the basic limitations to research in this area. One major limitation has been the practical difficulty associated with critical assessment of melatonin secretion, which occurs maximally at night. Such difficulties are perhaps most readily appreciated in pediatric studies of longitudinal design, and are compounded even in the short term in psychiatric studies by the ethical considerations associated with multiple nocturnal venesection in the acutely or chronically ill patient.63.65,66 Such difficulties led Miles and associates to develop their direct radioimmunoassay for salivary melatonin59 and to apply this technique in preliminary63 and extended studies of the 24-hr salivary melatonin profiles.65,66 In such studies it became apparent that salivary melatonin levels represented a mean 30% of the corresponding plasma level, a result consistent with reports that melatonin is around 70% bound to plasma albumin, and giving rise to the possibility that the salivary concentration represents the free fraction, and thus the fraction of immediate functional relevance. 64 Salivary melatonin assay has been employed in some preliminary investigations of melatonin secretion in psychiatric patients, 67 and it is likely that this technique will become popular in future studies. Urinary melatonin assay, with estimation of the major urinary metabolite 6-hydroxymelatonin, has been de- scribed as a direct radioimmunoassay by Arendt and associates.68 The technique appears sensitive and specific for melatonin, and since assay of urinary metabolite has been proven a reliable index of endogenous secretion,69,70 this technique is likely to become of increasing importance and utility as a more practical and easily accessible technique than, for example, mass spectrometric analysis of urinary metabolites of melatonin.71
Anticoagulants have long been known to interfere with radioimmunological reactions, and along with hemoglobinemia, hyperlipidemia, and the presence of certain drugs must be assessed for possible interference with the efficiency of melatonin radioimmunoassays. 72-74 The presence of significant interference need not always preclude use of a hemolyzed or
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“fatty” sample. Indeed, when large differences outside the established biochemical param- eter are considered diagnostic, then a limited amount of assay noise and interference can be tolerated. However, subtle and minor alterations in circadian organization of hormone se- cretion can be as important as large ones and, since the assessment and monitoring of these changes require assays of reliable performance, there is a need for careful assessment of the nature and extent of any assay interference. In this regard, Johansson and colleagues72 have studied the effects of various commercially available heparin and related preparations on the solvent-extraction radioimmunoassay described by Grota and co-workers,75 and using this assay system, three injectable heparin preparations all showed interference. Lithium and sodium heparin showed markedly less though still significant interference in the system when compared to the injectable preparations, and the difference was thought attributable, at least in part, to the presence of benzyl alcohol as a preservative in the injectable prepa- rations. The degree to which these anticoagulants may interfere with melatonin determi- nations depends to a major extent on the assay and in particular to the antibody in question, and is a parameter which requires full evaluation in operating assay systems.
B. Melatonin and Clinical Disease
1. Introduction
The investigation of the mechanisms involved in the production of pathological lesions has expanded markedly in recent years, and it is well recognized that there exist specific markers associated with specific disease processes. Some of these may represent an integral component of the lesion but others are often indirectly involved. The presence of predisposing factors, usually genetically based, have been demonstrated in many conditions such as in the multiplicity of enzymopathies linked to the development of metabolic disorders, which are prime examples of the application of biological markers. In other cases, serum proteins or particular enzymes have been shown closely though secondarily associated with specific pathological states. Melatonin estimation in the clinical laboratory in such a role is by no means well established and remains experimental, though much current data indicate a potential role for assay of this hormone as a diagnostic marker in laboratory medicine and as a biochemical tool in clinical research.20,59,63,65,66 The potential usefulness of melatonin in this regard was probably first suggested by Wetterberg and colleagues who proposed that measurement of this endocrinological parameter in conjunction with cortisol assay could be a diagnostically selective procedure in the investigation of major depressive disorders. Sub- sequent studies have cast doubt on the clinical utility of melatonin assay in simple form. The fact that disturbed melatonin secretion appears not to be specifically confined to major affective disorders but has been reported in many other syndromes and disease processes requires careful evaluation of any claims for the status of melatonin as a diagnostic and biological marker.
2. General Disease Categories
Birau20 has investigated melatonin secretion in an impressively large number of clinical categories with interesting results. Markedly disturbed melatonin secretion was observed in Klinfelters syndrome (KS), Turners syndrome (TS), psoriasis vulgaris (PV), spina bifida occulta (SBO), and sarcoidosis (SCD). Indeed, serum melatonin profiles over 31 hr in 19 patients with KS showed 24-hr melatonin production to be significantly lower than that seen in control subjects (Figure 3). An essential absence of circadian rhythm was observed with melatonin concentrations in serum recorded as 30 pg/ml at all times studied. In pubertal patients with KS, daily serum concentrations exhibited the same low values with a serum melatonin concentration that was consistently recorded as around 35 pg/ml. In these indi- viduals, a minor peak in secretion was seen at 20:00 hr, and the 08:00 and 14:00 hr value was significantly higher than in control groups. Serum melatonin profiles were also studied
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in 13 patients with TS over 31 hr. A similarly lowered serum level of melatonin was recorded (15 pg/m{) with values never exceeding 35 pg/m{. As in KS, the 08:00 and 14:00 hr value was significantly higher than in normal control women who showed a marked circadian rhythm with a peak level of 100 pg/ml at 02:00 hr (Figure 4). Interesting results were also recorded in a study of 32 patients with SBO who when investigated were undergoing orthopedic, neurological, or drug treatment. In this study, 8 children, 8 patients in early puberty, and 16 adults were investigated over 31 hr. Patients with SBO reach puberty earlier than healthy children, and in this phase exhibited melatonin levels which were 100 pg/ml
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below children with the same disorder, but were fivefold elevated above the controls. The 16 adult subjects with SBO had higher levels than those of patients in puberty. At each time of the day melatonin secretion in adult patients with SBO was significantly higher than the levels in healthy individuals, but with the absence of circadian rhythm (Figure 5). High levels of melatonin were also recorded in patients with SCD. Birau has studied 30 such patients before and after cortisone therapy where the disease was chronic with established lung pathology. Untreated patients with SCD show melatonin levels greater than 400 pg/ me with loss of circadian rhythmicity and levels significantly higher in female than in male patients.
Cortisone therapy was found to elicit an increase in melatonin secretion to levels more than 1 ng/ml with no entrainment of rhythm being seen. In volunteer subjects taking cortisone, melatonin levels increased but were substantially lower than those seen in cor- tisone-treated patients. Furthermore, the melatonin rhythm in these controls was maintained (Figure 6). In contrast to the grossly elevated levels of melatonin in patients with SCD, Birau20 has found lowered melatonin secretion at all times in the 24-hr cycle (15 pg/ml) in 124 untreated adult patients with PV studied over 31 hr, with absence of circadian rhyth- micity. Birau has also measured melatonin levels in 42 other diseases and although a 14:00 hr plasma level is recorded in many of these increased levels, some ranging from 50 to 100 pg/ml at this time, are interesting and the reader is referred to the original publication for their full description.
3. Hypothalamic-Hypophyseal Disorders
Other clinical observations suggest that melatonin may be involved in some hypothalamic- hypophyseal disorders. High melatonin levels have been recorded in boys with delayed
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puberty76 and low levels observed in patients with panhypopituitarism secondary to hypo- physectomy.23 In addition, low or high melatonin levels have been shown in hyperprolac- tinaemic individuals.23 Lissoni and associates77 recently evaluated melatonin secretion and rhythmicity in some idiopathic hypothalamic-hypophyseal diseases including delayed puberty and hypopituitarism. The authors found a functional hyperpinealism in patients with delayed puberty, and markedly elevated melatonin levels were recorded. Furthermore, evaluation of the light-dark secretory profile revealed an anomaly in the circadian organization of melatonin secretion. In their investigations on hypophyseal hormone deficiencies, the authors report low melatonin levels and an absence of circadian rhythm in two of six patients studied. In contrast, Cohen and colleagues76 have reported high melatonin levels in an isolated case of growth-hormone deficiency.
4. Melatonin and Disturbed Carbohydrate Metabolism
Melatonin is reportedly capable of influencing carbohydrate metabolism, which is clini- cally represented by the so-called Mendenhalls syndrome - familial pineal hypertrophy with diabetes mellitus. The first report was made by Rabson and Mendenhall in 1956,78 with subsequent reports by Barnes and colleagues79 in 1974, and West and associates in 1975.80 Patients with this syndrome usually die in childhood (6 to 12 years), and marked hypertrophy of the pineal with an increase in weight from around 100 to 900 mg has been revealed on post-mortem examination. In the series of case reports by West et al.,80 case no. 2 received 200 mg/day melatonin for a 12-day period, but no improvement of diabetic pathology was seen, and drowsiness and slurring of speech were recorded as side effects.
Several hypotheses have been advanced with relation to the pathogenesis of the condition among which defects in pineal hormone biosynthesis have been the most popular. Several other reports have appeared on the effects of melatonin on carbohydrate metabolism. Atkins and colleagues81 have shown depression of glucose-stimulated insulin secretion by melatonin, and Smyth and Lazarus82 have demonstrated an ability of melatonin to inhibit rat growth- hormone secretion and to decrease blood glucose concentrations.
5. Melatonin and Neoplastic Disease
a. Introduction
Several experimental observations point to a relationship between the pineal gland, me- latonin, and neoplastic disease, and many reports have demonstrated the tumor-growth and metastasis-enhancing effects of pinealectomy83-85 and an inhibitory effect of melatonin admin- istration on neoplastic progression.86-88 The mechanism of action of melatonin in this regard has not yet been clarified, although it is known that melatonin has the ability to inhibit mitosis89 and the production of some growth factors.90 In these experiments, the timing of melatonin administration has been shown to be important,91 since effects on cell proliferation depend on the point in the photoperiod at which melatonin is administered. Tumor growth is stimulated by administration in the morning and is inhibited by administration in the afternoon.91 The behavior of the pineal gland itself in malignancy is similarly in need of clarification. Pineal enlargement has been seen in some patients with lymphoma or leuke- mia,92 but atrophic changes of the gland have been recorded in post-mortem pineal tissue from other oncological patients.93 Pineal hypertrophy has been recorded in patients with mammary carcinoma and malignant melanoma, with normal weights seen in patients with sarcoma. 94
Reports of melatonin levels in cancer patients are rare and contradictory. Raikhlin and associates95 have reported elevated serum melatonin levels in oncological patients that were independent of the type and localization of the tumor. Other workers have reported pre- dominantly lowered levels,96,97 and thus either high or low melatonin secretion can be related to oncological status. Lissoni and colleagues98 recently concluded in a study of pineal function in 35 oncological patients that two subpopulations of individuals in relation to altered melatonin secretion appear to exist: one with high secretion and the other with normal secretion. The high melatonin secretion in the former category may be interpreted as a marker of pineal gland hyperfunction in an effort to increase secretion of oncostatic agents, although melatonin production by the tumor itself or altered peripheral metabolism in these patients are important points to consider. However, the findings of Lapin and Frowein99 suggest that there are true alterations in melatonin synthesis and secretion in oncological patients as opposed to alterations in metabolism. These authors observed that the levels of melatonin in the rat pineal gland decreased concomitantly with tumor growth and progression in these animals. Relkin100 has similarly suggested that in the development of cancer the pineal gland becomes hyperactive in an effort to secrete putative oncostatic agents and that it is this continued hyperactivity that results in final degeneration of the gland and, consequently, depressed melatonin secretion. This hypothesis is supported interestingly by the findings of Bartsch and associates101 in their study of melatonin secretion in men with prostate neoplasms. The authors found increased melatonin levels in patients with incidental carcinoma (where malignant cells are present but have not proliferated and are demonstrable on post-mortem examination or biopsy) with essentially normal levels in benign prostatic hypertrophy, but markedly lowered levels in established prostatic carcinoma. There is at least one report that suggests that monitoring of melatonin levels in serum can provide a useful index of the cellular effect of chemotherapeutic agents. Lissoni and colleagues98 have reported a massive decline in elevated melatonin levels of oncological patients following institution of chem- otherapy - in one case from 3.92 ng/ml to 71.5 pg/ml. Melatonin assay in oncological
patients may thus have an important role in diagnosis and investigation, and secretion of this hormone within specific neoplastic disease categories will now be discussed.
b. Prostatic and Mammary Carcinoma
In 1978, Cohen and colleagues102 published a report that postulated pineal hypofunction as a mechanism involved in the development of mammary carcinoma. Indeed, the inhibitory effects of melatonin on tumor growth in experimental animals had been recorded, but in 1969 Hamilton103 had suggested that melatonin could actually induce malignant change of 9, 10-dimethyl, 1, 2-benzanthracene (DMBA)-induced mammary tumors in rats. Interest- ingly, Tapp104 has shown that autopsied pineal weight is greater in breast cancer patients than in controls, and more recently, Tamarkin and colleagues97 have published important work linking abnormalities in melatonin secretion with the estrogen-receptor status of human mammary carcinoma. These workers investigated 24-hr plasma melatonin secretion in 20 women with varying clinical stages of breast cancer. The nocturnal increase in melatonin secretion was significantly lowered in ten of the patients with estrogen-receptor-positive cancer, while women with estrogen-receptor-negative tumors had levels elevated above control values. Bartsch and associates96 found that in 10 postmenopausal Indian women with advanced stages of breast cancer, 24-hr urinary melatonin extretion averaged 31% less than in normal healthy controls. The possible utility of melatonin analysis as an adjunct in the differentiation of estrogen-receptor-positive mammary carcinoma from receptor-negative tissue is an interesting and important one, since both prognosis and therapeutic strategy are determined by delineation of the estrogen-receptor status of biopsied breast carcinoma. 105 Indeed, from an etiological standpoint, the identification of what appears to be a melatonin receptor in human ovary suggests an influence of this hormone on ovarian function, 102 and there remains the link between a possible involvement of melatonin in the regulation of pubertal onset106 and the risk-factor association between early menarche and breast tumor malignancy.100,104 In addition, Danforth and colleagues107 have provided evidence which indicates the capacity of melatonin to increase the estrogen-receptor binding activity of MCF- 7 human breast cancer cells within 40 min of in vitro incubation. This effect could be attenuated by cycloheximide, thus indicating a requirement for continuous protein synthesis.
A similar potential role for melatonin analysis in differentiating tumor types and char- acteristics may be seen in males with prostatic neoplasms. Bartsch and associates101 have recorded the levels and rhythms of melatonin secretion as essentially normal in patients with benign prostatic hypertrophy, but have documented alterations in both these parameters in patients with carcinoma of the gland. Reports on melatonin levels in patients with prostatic carcinoma have, however, differed in their observations. Birau20 has found normal, de- creased, and increased levels of melatonin in patients with prostatic cancer. Further inves- tigation will necessarily involve complete assessment of 24-hr melatonin secretion in such patients and, together with an attendant histological diagnosis, should provide us with useful information about the nature and significance of the altered pineal function in this disease.
c. Melatonin and Pineal Tumors
Pineal tumors are rare and account for only 1% of all intracranial growths. These neoplasms are classifiable into three distinct types, the first of which includes the frequently reported germinomas and teratomas. These tumors account for at least 50% of pineal and pineal- associated tumors, are commonly termed the germ-cell tumors, and have the highest reported incidence in Japan.108 When germinomas occur as posterior third ventricle tumors, major destruction of pineal tissue is often produced.109 In contrast to the germinomas, pineal- associated teratomas are very rare and generally represent partially encapsulated noninvasive tumors capable of considerable growth. As with germinomas, destruction of pineal tissue is a common feature of these neoplasms and the pineal gland can often become replaced by
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the tumor, resulting in obstruction of CSF outflow and consequent symmetrical hydroceph- alus.110 The second category of pineal neoplasms comprise the very rare pineal parenchymal cell neoplasms which are termed the true pinealomas and may be divided into the pineal- ocytomas and pinealoblastomas. The latter division represents a poorly differentiated type of primitive neuroepithelial cell neoplasm of high malignancy. They occur primarily in children, although they can occur also in adolescence, and metastasize widely throughout the CSF pathway with destruction of tissues surrounding the posterior third ventricle. The former division, the pinealocytomas, are considerably more differentiated tumors that are less likely to cause metastatic disease via the CSF pathway though demonstrate a malignant potential that may be compared to that of the pinealoblastomas. Generally, these tumors remain localized in the posterior third ventricle but retain the potential to invade surrounding tissues.109 The third category of pineal neoplasms are the so-called glial tumors and cysts which are pineal-associated growths including the ependymomas, glioblastomas, astrocy- tomas of low grade, and oligodendromas, and tend to be restricted to the posterior third ventricle. 112-114 Pineal tumors present with two major clinical manifestations: neurological and endocrinological. Precocious puberty and delayed sexual maturation have been the principal conditions of interest, but diabetes insipidus and anterior pituitary dysfunction may also commonly be seen. 114-116
The potential use of melatonin as a clinical tool in the initial and differential diagnosis of these histologically heterogenous tumors is unresolved. Barber and colleagues117 have reported markedly high midday melatonin levels in patients with pinealoma. In five patients studied, plasma melatonin analysis revealed levels of 183, 131, 142, 182, and 140 pg/ml with a control reference value of 20 ± 3 pg/ml, and the authors suggested that melatonin assay could be useful in the initial diagnosis of this condition. In contrast, Kennaway and associates118 could demonstrate no such elevation in two patients with pineal tumors, and Tapp119 has recorded a value of 185 pg/ml in a 30-year-old male in whom biopsy revealed a pineal-associated tumor and not a true pinealoma. These disparate results emphasize the caution that should be exercised in the interpretation of melatonin results in patients with pinealoma, since they bring the specificity and utility of melatonin assay in this regard into question.120 The histological heterogeneity of pineal tumors means that they may originate from pineal tissue per se or may be more associated with pineal tissue. Indeed, pineal- associated tumors together with the pinealoblastomas might be expected to reduce melatonin secretion through local destruction of pineal tissue, while pinealocytomas representing pro- liferation of cells genetically equipped for melatonin biosynthesis are more likely to give rise to high nocturnal levels and inappropriate daytime secretion. However, Quay121 has suggested that even in tumors which show great increases in pinealocyte-like cells, the enzymatic capacity for melatonin synthesis may be only 4 to 7% of normal pinealocytes, depending on tumor differentiation characteristics.
However, if a pineal tumor can be demonstrated as melatonin secreting, then melatonin analysis may be useful in the prognostic monitoring of patients treated for such tumors. Surgical or functional pinealectomy produced by irradiation removes the source of endo- genous detectable melatonin, and the appearance of melatonin in plasma or saliva with time following therapy may provide an “early warning” of localized tumor regeneration or metastatic complication.122 That such philosophy may prove useful in the follow-up of such patients has been suggested by Miles and colleagues,122 who have reported the case of a 17-year-old neurosurgical patient who presented with an intracranial growth located within the left cerebral hemisphere. The patient was admitted with right hemiparesis, and over 2 years previously had been treated successfully with irradiation. Melatonin levels at 11.30 hr were 120 pg/ml compared to an age- and sex-matched control value of 14 pg/ml. Irradiation therapy resulted in disappearance of the intracranial tumor and parallel diminuition of melatonin levels to undetectable values. The authors suggested that the high level of
melatonin recorded in the patient derived from the intracranial tumor, giving rise to the possibility that this growth represented a single or closely associated group of metastases from the original pinealoma.
d. Melatonin and Malignant Melanoma
In 1967, Das Gupta and Terz84 observed pinealectomy capable of producing a remarkable enhancement of the growth and metastasis of malignant melanoma, and although in 1973 El-Domeiri and Das Gupta86 reported no influence of melatonin itself on melanoma growth when administered to tumor-bearing hamsters, they did observe that its administration was capable of suppressing the melanoma-growth-promoting effect of pinealectomy. Experiments in this regard have also been performed in man. In 1976, Svet-Moldavsky and associates123 administered a large amount of pineal extract to seven terminal melanoma patients, and one of these was reported as having shown some regression of skin metastasis. Tapp104 has interestingly reported that the pineal gland is enlarged in some cases, but Mori124 has observed essentially normal pineal weights in seven autopsied cases of malignant melanoma. Labunets and colleagues125 have shown a decreased urinary excretion of melatonin in patients with melanoma and documented the disturbance in pineal function through melatonin assay.
6. Melatonin and Psychiatric Disease
a. Introduction
The pineal gland has been the foremost organ of esoteric fascination to man as the point considered to localize the soul and the point from which the soul exercised its somatic functions.2 This philosophy, extended and much popularized by the French philosopher Rene Descartes,3 survived into the early part of the present century where physicians and scientists associated pineal pathology with psychiatric disturbance. Although melatonin itself was not characterized until 1958 by Lerner, clinical interest in the possible therapeutic efficacy of administered pineal extracts can be traced back notably to Becker in 1920,126 whose exper- iments in this regard may be thought to represent the beginning of present clinical interest in the pineal. In psychiatry, a large amount of investigation has been reported from exper- iments in subhuman species with the assessment of the mechanisms involved with and significance of the interactions of the pineal, melatonin, and the antidepressant drugs, with a view to determining the role that melatonin may play as a marker of central noradrenergic beta-receptor function.
b. Melatonin and Antidepressant Drugs
Parfitt and Klein128 were among the first investigators who demonstrated the ability of desmethylimipramine (DMI) to increase rat melatonin synthesis and secretion through in- duction of pineal NAT activity. Subsequent studies by Frazer et al., 129 Moyer et al.,130.131 and Heydorn et al. 132,133 have examined the acute and chronic effects of DMI administration in this regard. They found that acute treatments resulted in elevation of pineal cyclic adenosine monophosphate (cAMP) concentration elicited by either catecholamine or exposure to con- tinuous darkness, whereas chronic treatment was associated with a disappearance of this effect and reduction in both postsynaptic beta-receptor density and responsiveness to en- dogenous and exogenous catecholamine. Results from such studies in humans have produced differing results and some controversy. Thompson and colleagues134 found persistence of elevated melatonin levels in depressed patients even after 3 weeks of treatment with DMI, and such results have been fairly recently supported by the similar study of Sack and Lewy135 and by Golden and associates,136 who showed increased urinary 6-hydroxymelatonin excre- tion following chronic DMI administration. Reports from independent workers have produced contradictory evidence. Cowen and colleagues137 have reported decreases in DMI-elevated melatonin levels in normal subjects to recorded baselines 3 weeks following the commence-
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ment of study. Mendlewicz et al.138 and Brown et al.139 have also failed to demonstrate persistence of enhanced melatonin secretion following chronic DMI administration. Expla- nations for these discrepancies in results are few. Important points of direct relevance in this regard are the considerations of (1) the initial clinical state of the experimental individual, i.e., normal, euthymic or depressed; (2) the specific diagnostic category, i.e., neurotic or melancholic depressive illness; (3) the actual serum level of drug attained and maintained; (4) the time of appearance of an unequivocal therapeutic response; and (5) the time at which drug treatment can be described as chronic.
In the case of assessment of beta-receptor changes through melatonin assay and the relevance of such changes to depressive symptomatology, we must remain aware that pineal beta-receptor changes assessed by this means may represent epiphenomena or only one factor involved in the clinical response to antidepressant drugs. Regardless of the cellular and molecular mechanisms involved, changes in melatonin secretion following antidepressant drug therapy have been set to clinical use by Halbreich and colleagues. 140 These investigators studied the relationship between chronic DMI concentration in plasma, changes in melatonin secretion, and changes in the clinical status of their patients. An inverse correlation between plasma levels of DMI and those of melatonin was recorded in patients showing unequivocal symptomatic response to DMI, but higher levels were observed in nonresponders at a comparable level of drugs. In this study, the clinical response to antidepressant drug and plasma melatonin level are apparently linked.
c. Melatonin, Chronopathological Change, and Phototherapy in Affective Disorders
Many studies have now linked disturbances in circadian rhythm physiology to affective disorder, and the present literature has been recently reviewed by Hallonquist and col- leagues.141 The pineal gland is known to modulate neuroendocrine function in subhuman species,7.114 and many investigators have associated human pineal dysfunction with the chronopathological abnormalities of the manic-depressive individual. 141-143,151 Manic-de- pressive individuals are reportedly supersensitive to the suppressive effect of bright white light on nocturnal melatonin synthesis and secretion.144-146 Exposure of 500 lux between 02.00 and 04.00 hr elicits a 50% reduction in melatonin secretion, whereas secretion in normal individuals is unaffected by this intensity; 1500 lux completely suppressed melatonin output in patients but reduced secretion by only 50% in controls.144 This phenomena appears to be a trait marker since in a study of 11 euthymic manic-depressive individuals, pineal response to light remained supersensitive. 145.146 The therapeutic effects of bright white light recorded in some of these patients, most notably in those with seasonal components to their ill- ness, 143,147 has led to the formulation of a phototherapeutic regime where light may be administered early morning, midday, or early evening. 147-149 Kripke has reviewed the current perspectives of light therapy.150
A variety of observations suggest a relationship between a light-induced alteration in pineal function and affective disorder, although the nature of the interaction remains unclear. The intensity of light required to induce therapeutic response in patients with seasonal affective disorder (SAD) must be of sufficient intensity to suppress melatonin synthesis and secretion. 143,150 Disturbed circadian rhythm physiology in affective disorder has been sug- gested as a possible result of an alteration in the functional pathway conveying information about the photoperiod to the pineal, 151 with alteration in the pineal interpretation of photo- period and production of an inappropriate biochemical information that retains the physio- logical capacity to modify the function of various systems clinically important in affective disorders. If phototherapy has to suppress melatonin secretion to achieve therapeutic success, then whether or not this effect is biologically or coincidentally involved in the process, melatonin assay is of direct significance in determining primarily the presence or absence of suppressive capacity of light, which may identify likelihood of response, and also in
determining the degree of suppression necessary for optimal therapeutic response in a given individual. Phototherapy apart, melatonin assay following nocturnal exposure of a patient to bright white light may mark a response that is specific to manic-depressive illness, and one that is not seen at all or to the same extent in other diagnostic psychiatric categories. The differential diagnostic potential of this response assessed through melatonin assay, especially in combination with the other cardinal features of pineal dysfunction of manic- depressive illness, has not yet been assessed.
d. The Low Melatonin Syndrome and Affective Disorders
Melatonin levels are consistently reported as reduced in major depressive disorder, and Beck-Friis and colleagues152 have formally described a “low-melatonin syndrome”. The first investigations of melatonin secretion in depressed individuals were probably conducted in 1977 by Jimerson and colleagues,153 who were unable to demonstrate differences in the absolute levels between patients and controls. Subsequent methodological advances enabled Lewy and co-workers154 and Wetterberg and associates155 to demonstrate reduced melatonin secretion in major depression. To date, marked changes in maximal level,152.154,155 circadian organization,156 “on-off” secretory characteristics, 151.152.157 and light-induced suppression of nocturnal hormone synthesis and secretion144-146 have been described as the archetypal features of disturbed pineal function in these individuals.
In 1979, Wetterberg and colleagues158 reported a 62% reduction in melatonin secretion in a 48-year-old female with a 10-year history of major depressive disorder, comparing levels to those recorded during the patient’s euthymic phase. The lowered secretion of melatonin in affective disorder was simultaneously described by Mendlewicz et al.,156 who showed marked changes in the circadian organization of melatonin secretion with essential absence of nocturnal secretion and inappropriate daytime output in the patients studied. Wirc- Justice and Arendt159 have recorded lowered 08:00-hr melatonin levels in six patients with unipolar affective disorder, and a marked decrease in nocturnal output has been described by Claustrat and colleagues.160 In addition, Brown and colleagues161 have demonstrated lowered melatonin secretion in patients with major depressive disorder of melancholic sub- type, showing a significant difference between secretion in these individuals and that in patients with major depressive disorder without melancholia. Boyce162 has similarly shown an association between reduced melatonin secretion and melancholic subtype.
Wetterberg and colleagues155.158,163-165 have extensively recorded lowered melatonin se- cretion in major depression and have shown the greatest reductions present in those indi- viduals who fail to suppress cortisol secretion following dexamethasone administration. Steiner and Brown166 have, however, failed to identify this difference in a study of some 25 patients with major depression, all of whom had reduced melatonin levels and 13 of whom had no cortisol response to dexamethasone, thus casting doubt on the possibility that melatonin assay in depressed individuals can identify those likely to give pathological dex- amethasone suppression test. A possible physiological association between melatonin and cortisol secretion in health, and a pathophysiological association between these two hormones in affective disorders has been much discussed. 155.158,163-165 The apparent association has given rise to the suggestion that estimation of cortisol and melatonin secretion as the me- latonin-cortisol or cortisol-melatonin ratio can provide a diagnostically selective marker for major depressive disorder. 158,162 The specificity and clinical utility of this index has been assessed by Ferrier et al. 167,168 and more recently by Steiner and Brown166 with largely negative conclusions.
e. Melatonin and Mania
In contrast to the extensive data on melatonin secretion in major depression, there is a relative sparsity of data on melatonin secretion during mania. Lewy and associates154 have
described elevated melatonin levels in patients with mania with absolute excretion increased twofold above normals. Patients were also studied longitudinally, and the recorded trend demonstrated melatonin secretion as highest during early mania with lowered though still much elevated melatonin secretion present during late mania. When depressed, these patients showed markedly reduced melatonin secretion. High melatonin levels during mania have been infrequently reported by other investigators. Miles and Philbrick (unpublished) have recorded melatonin levels in a 42-year-old female admitted with hypomania; 08:00 hr plasma melatonin was 94 pg/m{ with a control value of 36 pg/ml. Higher melatonin secretion during mania has also been reported by Wirc-Justice and Arendt. 169
f. Melatonin and Schizophrenia
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In addition to the well-documented changes in melatonin secretion in affective disorders, there have been limited observations suggesting a possible modification of pineal function in schizophrenia. McIsaac170 is classically cited as the first investigator to postulate an involvement of melatonin in schizophrenia, with an hypothesis built on the structural sim- ilarity between the hallucinogenic compound harmine and the then newly characterized melatonin. Subsequent thinking, notably by Smythies,171 argued for abnormal metabolism of endogenously synthesized indoleamines by O- or N-methylation reactions to a com- pound(s) etiologically involved in the schizophrenic disease process. Hartley and Smith172 reported the ability of HIOMT to synthesize psychotogens from abnormal substrates, and suggested that abnormal metabolism could conceivably occur if the activity of HIOMT became out of phase with its normal substrate. Earlier studies demonstrated a different metabolic treatment of melatonin by schizophrenic subjects,17 and McIsaac170 himself had suggested that the psychotomimetic agent 10-methoxyharmalan could be endogenously syn- thesized from melatonin with secondary effects on brain serotoninergic function. More recent studies have shown no significant differences in HIOMT activity in post-mortem schizo- phrenic pineals when compared to normal subjects,173 and studies of melatonin secretion in schizophrenic subjects have found the diurnal secretory characteristics essentially normal, although 8:00 hr levels may be lower and 24:00-hr levels higher.174 Fairly recent work by Beckmann and colleagues175 on CSF melatonin concentrations in neuroleptic treated schiz- ophrenics, drug-free paranoid schizophrenics, and normal subjects failed to show significant differences between the groups. Most recently, Steiner and Brown166 have documented essentially normal melatonin secretion in schizophrenia. Ferrier et al. have shown altered secretory characteristics in chronic schizophrenia,168 but the studied group may have con- tained patients with affective pathology, which complicates interpretation of the data. Indeed, there is the possibility that the development of affective symptomatology during the chronic course of the schizophrenic syndrome is accompanied or preceeded by changes in pineal function which cannot be detected in the acute disease. Generally, recent evidence does not support the case for altered pineal function in schizophrenia, and to date no group has been able to demonstrate any clinical utility of melatonin assay in the management and diagnosis of this disease.
IV. SUMMARY
We are presently at a point in human pineal research where we have recognized through melatonin assay the presence of pineal dysfunction in a variety of disease categories. Me- latonin may now be quickly and accurately quantified in a range of body fluids, and our well-developed knowledge of the basic biochemistry and neuroanatomical connections of the pineal enables us to see at least how abnormalities in melatonin secretion occur, if not why. The reported increases in melatonin secretion in early malignancy with a reduction in secretion during the neoplastic process is interesting, as is the great decline in the elevated
melatonin level of oncological patients following institution of chemotherapy. The corre- lations between estrogen receptor status of breast cancer and melatonin level, and between neoplastic status of the prostate and melatonin secretion, points to interesting differential diagnostic utilities of melatonin analysis in these conditions. Furthermore, an etiological involvement of melatonin in neoplasia is suggested by experiments which have demonstrated the capacity of melatonin to induce mitotic arrest, and to increase the affinity of mammary carcinoma estrogen receptors for their substrate. These are important observations among many others of direct relevance to research and treatment in oncology, and warrant much further investigation. Melatonin assay may also prove useful in the prognostic monitoring of patients treated for melatonin-secreting pineal tumors, and in such cases may form a logical part of follow-up investigation in the screening for metastatic complication. In psy- chiatry research, melatonin analysis has functioned as a tool by which alterations in pineal function within specific psychiatric diagnoses have been demonstrated and assessed. Its uses in the assessment of the effects of antidepressant drugs on central beta-receptor function, as a tool in the investigation of light-induced alterations in pineal function in manic-depressive individuals, and as a tool in the investigation of the putative pineal-adrenocortical functional interaction have produced the fundamental building blocks of modern research into the pineal and psychiatry.
The experimental clinical utility of melatonin assay is not localized to oncology and psychiatry, and significant alterations in melatonin secretion have been reported in several other disease categories. Indeed, the demonstration of markedly elevated melatonin secretion in patients with spina bifida occulta might suggest that assay of melatonin in amniotic fluid could be useful as an experimental adjunct in the prenatal diagnosis of this condition. In conclusion, laboratory medicine awaits a final clarification of the role of melatonin in diagnosis and investigation. While awaiting the answer from clinical research, the next step in laboratory medicine must be development of a monoclonal-antibody-based chemilumi- nescent assay for melatonin. Such a technique will provide us with the convenience of the classic radioimmunoassay but a greatly enhanced level of sensitivity for detailed and critical studies of melatonin secretion within the disease categories already known to show elements of pineal dysfunction.
ACKNOWLEDGMENTS
The authors extend their appreciation to Dr. David Shaw for his support and advice, Canon David Williams, Dr. Joseph Grey, and Dr. Alan Wardrop for their interest, and Mrs. Gillian Warren for excellent secretarial assistance.
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